Heterocyclic GLP-1 agonists

Abstract

The present disclosure provides GLP-1 agonists, pharmaceutical compositions comprising GLP-1 agonists and methods for treating GLP-1 associated diseases, disorders or conditions.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to International Application No. PCT / CN2022 / 075603, filed February 9, 2022, which is incorporated herein by reference in its entirety.

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

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

[0004] Diabetes mellitus refers to a group of metabolic disorders characterized by persistently high blood sugar. Type 2 diabetes mellitus (T2DM), the most common form, is an acquired disease that accounts for more than 90% of diabetes cases. It typically develops in obese or sedentary adults and begins with insulin resistance. While lifestyle modifications are helpful in managing the disease, patients with T2DM may require antidiabetic medications, such as 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) simultaneously regulate the insulin secretory response to glucose ingestion. In T2DM, this incretin action is significantly reduced (if present at all), but GLP-1 maintains its insulinotropic action even when the endocrine pancreatic response to GIP is effectively shut down. Therefore, incretin mimetics and other GLP-1-based therapeutics are useful for stimulating insulin production in patients with T2DM. Summary of the Invention

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

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

[0008] The disclosure also provides pharmaceutical compositions comprising one or more compounds of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0009] Also provided herein is a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0010] 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.

[0011] Also provided herein is a method for treating type 2 diabetes in a patient, comprising administering a therapeutically effective amount of a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, to a patient identified or diagnosed as having type 2 diabetes.

[0012] Also provided herein is a method for treating diabetes in a patient, the method comprising: determining that the patient has type 2 diabetes; and administering to the patient a therapeutically effective amount of a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In some embodiments, determining that the patient has type 2 diabetes comprises performing an assay to determine the level of an analyte in a sample from the patient, wherein the analyte is selected from the group consisting of hemoglobin A1c (HbA1c), fasting plasma glucose, postprandial plasma glucose, or any combination thereof. In some embodiments, the HbA1c level is greater than or about 6.5%. In some embodiments, the fasting glucose level is greater than or about 126 mg / dL. In some embodiments, the postprandial plasma glucose level is greater than or about 200 mg / dL.

[0013] In some embodiments, the method further comprises obtaining a sample from the patient. In some embodiments, the sample is a body fluid sample. In some embodiments, the patient is about 40 to about 70 years old and is overweight or obese. In some embodiments, the patient has a body mass index (BMI) of 22 kg / m or less. 2 or more or approximately 22 kg / m 2 In one embodiment, the patient has a BMI of 30 kg / m 2 More than or about 30 kg / m 2 It has.

[0014] In certain embodiments, the method of treating type 2 diabetes comprises reducing fasting plasma glucose levels. In certain embodiments, fasting plasma glucose levels are reduced to about 100 mg / dL or below 100 mg / dL.

[0015] In certain embodiments, the method of treating type 2 diabetes comprises reducing HbA1c levels, hi certain embodiments, the HbA1c level is reduced to about 5.7% or below 5.7%.

[0016] In certain embodiments, the method of treating type 2 diabetes comprises reducing glucagon levels.

[0017] In certain embodiments, the method of treating type 2 diabetes involves increasing insulin levels.

[0018] In certain embodiments, the method of treating type 2 diabetes includes lowering BMI. In certain embodiments, BMI is about 25 kg / m 2 or 25 kg / m 2 It decreases to the following:

[0019] In certain embodiments, a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or pharmaceutical composition thereof, is administered orally.

[0020] In some embodiments, the method for treating type 2 diabetes further comprises administering to the patient another therapy or therapeutic agent. In some embodiments, the other therapy or therapeutic agent is selected from the group consisting of an antidiabetic agent, an antiobesity agent, a GLP-1 receptor agonist, a nonalcoholic steatohepatitis (NASH) therapeutic agent, an antiemetic agent, gastric electrical stimulation, dietary monitoring, physical activity, or any combination thereof. In some embodiments, the antidiabetic agent is selected from the group consisting of a biguanide, a sulfonylurea, a glitazar, a thiazolidinedione, a dipeptidyl peptidase 4 (DPP-4) inhibitor, a meglitinide, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, a glitazone, a GRP40 agonist, a glucose-dependent insulinotropic polypeptide (GIP), insulin or an insulin analog, an alpha-glucosidase inhibitor, a sodium-glucose cotransporter 1 (SGLT1) inhibitor, or any combination thereof. In some embodiments, the biguanide is metformin. In certain embodiments, the anti-obesity agent is selected from the group consisting of a neuropeptide Y receptor type 2 (NPYR2) agonist, an NPYR1 or NPYR5 antagonist, a human islet peptide precursor (HIP), a cannabinoid receptor type 1 (CB1R) antagonist, a lipase inhibitor, a melanocortin receptor 4 agonist, a farnesoid X receptor (FXR) agonist, phentermine, zonisamide, a norepinephrine / dopamine reuptake inhibitor, a GDF-15 analog, an opioid receptor antagonist, a cholecystokinin agonist, a serotonergic agent, a methionine aminopeptidase 2 (MetAP2) inhibitor, diethylpropion, phendimetrazine, benzphetamine, a fibroblast growth factor receptor (FGFR) modulator, an AMP-activated protein kinase (AMPK) activator, or any combination thereof. In certain embodiments, the GLP-1 receptor agonist is selected from the group consisting of liraglutide, exenatide, dulaglutide, albiglutide, taspoglutide, lixisenatide, semaglutide, or any combination thereof.In some embodiments, the NASH therapeutic agent is selected from the group consisting of FXR agonists, PF-05221304, synthetic fatty acid bile conjugates, anti-lysyl oxidase homolog 2 (LOXL2) monoclonal antibodies, caspase inhibitors, MAPK5 inhibitors, galectin 3 inhibitors, fibroblast growth factor 21 (FGF21) agonists, niacin analogs, leukotriene D4 (LTD4) receptor antagonists, acetyl-CoA carboxylase (ACC) inhibitors, ketohexokinase (KHK) inhibitors, ileal bile acid transporter (IBAT) inhibitors, apoptosis signal-regulating kinase 1 (ASK1) inhibitors, or any combination thereof. In some embodiments, the compound in Table 1 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, and another therapeutic agent are administered sequentially in any order as separate formulations.

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

[0022] Also provided herein is a method for modulating glucose levels in a patient in need thereof, comprising administering to the patient an effective amount of a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In certain embodiments, the modulation results in a decrease in glucose levels.

[0023] 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 certain embodiments, the disease, disorder, or condition is selected from the group consisting of type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of adults (LADA), obesity, weight gain due to the use of other medications, gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, lipid Adipocyte dysfunction, sleep apnea syndrome, visceral fat accumulation, 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 hyperlipidemia In some embodiments, the inflammatory bowel disease (IGD) is selected from the group consisting of: diabetes, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, treatment of addiction, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, psychogenic polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof.In certain embodiments, the disease, disorder, or condition is selected from the group consisting of type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat accumulation, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, and the like. In some embodiments, the present invention relates to a condition characterized by a metabolic disorder, a metabolic disorder, anemia, a metabolic disorder, a metabolic disorder characterized by ... In certain embodiments, the disease, disorder, or condition includes, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat accumulation, myocardial infarction, peripheral arterial disease, stroke, transient ischemic attack, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, chronic renal failure, Syndrome X, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, skin and connective tissue disorders, foot ulcers, or any combination thereof.

[0024] All publications, patents, and patent applications mentioned in this specification are herein incorporated 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 the publications, patents, and patent applications incorporated by reference conflict with the disclosure contained herein, the present specification shall take precedence and / or supersede any such conflicting documents. Detailed Description of the Invention

[0025] Before the present compounds and methods are described, it is to be understood that this disclosure is not limited to the methodology, protocols, cell lines, assays, and reagents described, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing embodiments of the present disclosure, and is not intended to limit the scope of the disclosure, which is set forth in the appended claims.

[0026] (definition) It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise.

[0027] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, exemplary methods, devices, and materials are described herein. All publications cited herein are for the purpose of describing and disclosing the methodologies, reagents, and tools reported in the publications that can be used in connection with this disclosure, and are incorporated herein by reference in their entirety.

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

[0029] Where numerical values ​​are stated as ranges, the disclosure will be understood to include disclosure of not only the specific numerical values ​​falling within such ranges, but also all possible subranges within such ranges, whether or not a specific numerical value or specific subrange is explicitly stated.

[0030] As used herein, the term "halo" or "halogen" means -F (also referred to herein as "fluoro"), -Cl (also referred to herein as "chloro"), -Br (also referred to herein as "bromo"), and -I (also referred to herein as "iodo").

[0031] As used herein, the term "alkyl" means a saturated linear or branched monovalent hydrocarbon radical containing the specified number of carbon atoms. For example, "C 1-6 "Alkyl" refers to a saturated straight or branched chain monovalent hydrocarbon of 1 to 6 carbon atoms. Non-limiting examples of alkyl include methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, 2-methyl-2-propyl, pentyl, neopentyl, and hexyl.

[0032] As used herein, the term "alkenyl" refers to a straight or branched monovalent unsaturated hydrocarbon chain containing the specified number of carbon atoms. For example, "(C 2-6 ")Alkenyl" means a straight or branched monovalent unsaturated hydrocarbon chain of 2 to 6 carbon atoms. Non-limiting examples of alkenyl include ethenyl, propenyl, butenyl, or pentenyl.

[0033] As used herein, the term "alkynyl" refers to a straight or branched divalent unsaturated hydrocarbon chain containing the specified number of carbon atoms. For example, "(C 2-6 ")Alkynyl" means a straight or branched divalent unsaturated hydrocarbon chain containing 2 to 6 carbon atoms. Non-limiting examples of alkynyl include ethynyl, propynyl, butynyl, or pentynyl.

[0034] As used herein, the term "cycloalkyl" means a saturated or partially unsaturated cyclic hydrocarbon containing the specified number of carbon atoms. For example, "(C 3-6 ") Cycloalkyl" means a saturated or partially unsaturated cyclic hydrocarbon having 3 to 6 ring carbon atoms. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyls may also be partially unsaturated. Non-limiting examples of partially unsaturated cycloalkyls include cyclohexenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl, and the like. Cycloalkyls may contain multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyls include bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, etc. Cycloalkyl also includes spirocycles (e.g., spirocyclic bicycles in which the two rings are joined by only one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like.

[0035] As used herein, the term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic non-aromatic ring group containing the specified number of ring atoms (e.g., a 3- to 8-membered monocyclic, an 8- to 12-membered bicyclic, or an 11- to 14-membered tricyclic ring group) having 1 to 3 heteroatoms (in the case of a monocyclic ring), 1 to 6 heteroatoms (in the case of a bicyclic ring), or 1 to 9 heteroatoms (in the case of a tricyclic or polycyclic ring), wherein the heteroatoms are O, N, S, or S(O). 1-2 (e.g., in the case of monocyclic, bicyclic, or tricyclic rings, each of which contains carbon atoms and 1 to 3, 1 to 6, or 1 to 9 heteroatoms N, O, S, or S(O) 1-2), and 0, 1, 2, or 3 atoms of each ring may be substituted by substituents. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Heterocyclyl groups may be partially unsaturated. Non-limiting examples of partially unsaturated heterocyclyls include dihydropyrrolyl, dihydropyridinyl, tetrahydropyridinyl, dihydrofuranyl, dihydropyranyl, and the like. Heterocyclyls may include multiple fused and bridged rings. Non-limiting examples of fused / bridged heterocyclyls include 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[4.1.0]hexane, 5-azabicyclo[2.1.1]hexane ...4.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[4.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[4.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[4.1.0]hexane, 5-azabicyclo[2. Examples include bicyclo[3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, etc. Heterocyclyl also includes spirocycles (e.g., spirocyclic bicycles in which the two rings are joined by only one atom).Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[2.2] ]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.

[0036] As used herein, the term "aryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic hydrocarbon group containing the specified number of carbon atoms, in which at least one ring is aromatic (e.g., C6 monocyclic, C 10 Bicyclic or C 14 Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

[0037] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group having a specified number of ring atoms (e.g., 5 to 6 ring atoms; e.g., 5, 6, 9, 10, or 14 ring atoms), in which at least one ring is aromatic (but not necessarily a heteroatom-containing ring; e.g., tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl), and at least one ring in the group contains one or more heteroatoms independently selected from the group consisting of N, O, and S. Heteroaryl groups can be unsubstituted or substituted with one or more substituents. Examples of heteroaryls include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and thiazolyl. Benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl Examples include pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chroman, 2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]oxathiin, and isoindoline.

[0038] As used herein, the term "haloalkyl" refers to an alkyl group, as defined herein, substituted with one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms, one or more (e.g., 1 to 5 or 1 to 3) 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.

[0039] As used herein, the term "alkoxy" refers to an -O-alkyl group, which means that the group is on an oxygen atom. For example, "C 1-6 "Alkoxy" is -O-(C 1-6 "Alkoxy" refers to an -O-haloalkyl group, wherein the group is attached to an oxygen atom. Examples of alkoxy 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 attached to an oxygen atom.

[0040] As used herein, the term “amino” refers to a group of the formula —N(R N1 ) 2 amines, and each R N1 is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which can be optionally substituted, for example, by one or more (e.g., 1 to 5 or 1 to 3) substituents (e.g., halo, cyano, hydroxy, —NH, —NH(alkyl), —N(alkyl), alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, or haloalkoxy).

[0041] As used herein, the term "compound" includes all stereoisomers, geometric isomers, tautomers, and isotopes of a given structure. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0042] As used herein, when a ring is described as "aromatic," it means that the ring has a contiguous, delocalized π-electron system. Typically, the number of out-of-plane π-electrons corresponds to Hückel's rule (4n+2). Examples of such rings include benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thiazole, isoxazole, isothiazole, and the like. When a ring system containing at least two rings is described as "aromatic," it means that the ring system contains one or more aromatic rings. Therefore, when a ring system containing at least two rings is described as "non-aromatic," it means that none of the constituent rings of the ring system are aromatic.

[0043] As used herein, when a ring is described as "partially unsaturated," it is meant that the ring has one or more additional degrees of unsaturation (e.g., one or more double bonds between constituent ring atoms in addition to the degree of unsaturation due to the ring itself), provided that the ring is not aromatic. Examples of such rings include cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like. When a ring system containing at least two rings is described as "partially unsaturated," it is meant that the ring system contains one or more partially unsaturated rings, provided that none of the constituent rings of the ring system are aromatic.

[0044] As used herein, the term "tautomer" means a compound whose structure differs significantly in the arrangement of atoms, but which readily and rapidly exists in equilibrium; the compounds provided herein may be represented as different tautomers; it is understood that when a compound has tautomeric forms, all tautomeric forms are intended to be within the scope of the present invention, and the name of the compound does not exclude tautomers.

[0045] 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 strands, complementary sequences, peptides, polypeptides, proteins, homologous and / or orthologous GLP-1R molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.

[0046] As used herein, the term "GLP-1-related disease" is intended to include, but is not limited to, any disease, disorder, or condition in which modulation of glucagon-like peptide 1 (GLP-1) receptor signaling can alter the pathology and / or symptoms and / or progression of the disease, disorder, or condition.

[0047] 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 fasting and postprandial states; and delays gastric emptying (Karla et al., Glucagon-like peptide-1 receptor agonists in the treatment of type 2 diabetes: Past, present and future, Indian J Endocrinol Metab. 2016 Mar-Apr;20(2):254-267. GLP-1RAs have been shown to treat type 2 diabetes). Examples of GLP-1 RAs include, but are not limited to, albiglutide (TANZEUM®), dulaglutide (LY2189265, TRULICITY®), efpeglenatide, exenatide (BYETTA®, BYDUREON®, exendin-4), liraglutide (VICTOZA®, NN2211), lixisenatide (LYXUMIA®), semaglutide (OZEMPIC®), tirzepatide, ZP2929, NNC0113-0987, BPI-3016, and TT401. See also, for example, additional GLP-1 receptor agonists described in U.S. 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.

[0048] As used herein, the term "pharmaceutically acceptable" indicates that a compound or a salt thereof or composition thereof is chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the patient being treated.

[0049] 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 harmful. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and organic acids. Furthermore, when a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional methods for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, for example, acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example, sodium salts, potassium salts, lithium salts, aluminum salts, ammonium salts, calcium salts, magnesium salts, and the like. Salts derived from organic bases include salts of NH3, or primary, secondary, and tertiary amines, e.g., N-containing heterocycles, N-containing heteroaryls, or salts of the formula N(R N ) 3, salts obtained from amines (e.g., HN + (RN)3 or (alkyl)N + (RN)3), where each R Nis independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally substituted with one or more (e.g., 1 to 5, alternatively 1 to 3) substituents (e.g., halo, cyano, hydroxy, amino, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, or haloalkoxy). Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0050] The term "administration" or "administering" refers to a method for providing a dose of a compound or pharmaceutical composition to a vertebrate or invertebrate, including a mammal, bird, fish, or amphibian. The method of administration can vary depending on various factors, such as the components of the pharmaceutical composition, the site of the disease, and the severity of the disease.

[0051] As used herein, the terms "effective amount," "effective dose," "pharmaceutically effective amount," or "therapeutically effective amount" refer to a sufficient quantity of an administered chemical entity (e.g., a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof) to relieve to some extent one or more symptoms of the disease or condition being treated, and may include curing the disease. "Cure" means that the symptoms of active disease are eliminated. Such results include reduction and / or alleviation of the signs, symptoms, or pathogenesis of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound 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 certain embodiments, a "therapeutically effective amount" of a compound provided herein refers to an amount of the compound that is effective as a monotherapy or combination therapy.

[0052] The term "excipient" or "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In certain embodiments, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and 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, 21 st 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.

[0053] The term "pharmaceutical composition" refers to a mixture of a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, described herein with other chemical components (collectively referred to herein as "excipients"), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or fillers. A pharmaceutical composition facilitates administration of a compound to an organism. Many techniques exist for administering a compound, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0054] The term "pharmaceutical composition" refers to a mixture of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, with other chemical components (collectively referred to herein as "excipients"), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or fillers. A pharmaceutical composition facilitates administration of a compound to an organism. Many techniques exist for administering a compound, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0055] The terms "treat," "treating," and "treatment," in the context of treating a disease, disorder, or condition, include alleviating or arresting the disorder, disease, or condition or one or more symptoms associated with the disorder, disease, or condition; or mean slowing the progression, spread, or worsening of the disease, disorder, or condition or one or more symptoms thereof.

[0056] As used herein, the term "preventing" refers to the prevention of the onset, recurrence or spread, in whole or in part, of a disease or condition described herein or its symptoms.

[0057] 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, cows, sheep, horses, primates, and humans. In some embodiments, the terms refer to a subject, particularly a mammalian subject, for whom diagnosis, prognosis, or treatment is desired or required. In some embodiments, the patient is a human. In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of a disease, disorder, or condition to be treated and / or prevented.

[0058] 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 of the present invention.

[0059] As used herein, the term "pharmaceutical combination" means a pharmaceutical treatment in which more than one active ingredient is mixed or combined, and includes both defined and open-ended combinations of active ingredients.

[0060] As used herein, the term "combination therapy" means a dosing regimen of two different therapeutically active agents (i.e., components of a combination or combination partners), which therapeutically active agents, as defined herein, are administered together or separately in a manner desired by a medical practitioner or in accordance with a regulatory agency.

[0061] As used herein, the term "modulation" means regulation or modulation (e.g., increase or decrease) and can include, for example, agonism, partial agonism, or antagonism.

[0062] It is understood that the substituents defined herein are not intended to include impermissible substitution patterns (e.g., methyl substituted with five fluoro groups, or a hydroxy group attached to an ethenyl or acetylene carbon atom). Such impermissible substitution patterns are well known to those of ordinary skill in the art.

[0063] (compound) Provided herein is a compound selected from Table 1, or a pharmaceutically acceptable salt or solvate thereof: [Table 1] [Table 2] [Table 3] [Table 4]

Table 5

Table 6

Table 7

Table 8

Table 9

Table 10

Table 11

Table 12

Table 13

Table 14

Table 15

[0064] In certain embodiments, provided herein is a compound selected from Table 2, or an acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. [Table 19] [Table 20] [Table 21] [Table 22] [Table 23] [Table 24] [Table 25] [Table 26] [Table 27] [Table 28] [Table 29] [Table 30] [Table 31] [Table 32]

[0065] The compounds of Table 1 include pharmaceutically acceptable salts thereof. Additionally, the compounds of Table 1 or 2 also include other salts of said compounds, which are not necessarily pharmaceutically acceptable salts and which may be useful as intermediate compounds for making and / or purifying the compounds of Table 1 or 2 and / or separating the enantiomers of the compounds of Table 1 or 2. Non-limiting examples of pharmaceutically acceptable salts of the compounds of Table 1 or 2 include trifluoroacetate salts.

[0066] Furthermore, the compounds of Table 1 or 2 or their salts may be isolated in the form of a solvate, and therefore it is understood that any solvate is included within the scope of the present invention. A "solvate" refers to an association or complex of one or more solvent molecules with a compound of the present disclosure. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine. For example, the compounds of Table 1 or 2 and their salts can exist in unsolvated and solvated forms with pharmaceutically acceptable solvents (e.g., water, ethanol, etc.).

[0067] Pharmaceutical Compositions and Administration When used as a pharmaceutical composition, the compounds described herein (e.g., compounds in Table 1 or pharmaceutically acceptable salts or solvates thereof) can be administered in the form of a pharmaceutical composition. These compositions can be prepared by methods well known in the pharmaceutical arts and can be administered by various routes depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (including transdermal, epidermal, ocular, and mucosal delivery, including intranasal, vaginal, and rectal), pulmonary (e.g., inhalation or insufflation of powders or aerosols (including nebulizers); intratracheal or intranasal), oral, or parenteral. Oral administration can include preparations formulated for once-daily or twice-daily (BID) administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracerebral, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose or, for example, via a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder, or oily bases, fillers, and the like may be necessary or desirable.

[0068] Also provided herein are pharmaceutical compositions comprising a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof as an active ingredient in combination with one or more pharmaceutically acceptable excipients (carriers). For example, a pharmaceutical composition prepared using a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the composition is suitable for topical administration. When preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by the excipient, or enclosed within the carrier, for example, in the form of a capsule, sachet, paper, or other container. When an excipient serves as a diluent, it can be a solid, semi-solid, or liquid substance that acts as a vehicle, carrier, or medium for the active ingredient. Thus, composition can be in the form of tablets, pills, powder, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments (e.g., containing 10% by weight of active compound), soft and hard gelatin capsules, suppositories, sterile injection solutions and sterile packaged powders.In some embodiments, composition is formulated for oral administration.In some embodiments, composition is a solid oral formulation.In some embodiments, composition is formulated as tablets or capsules.

[0069] Further provided herein is a pharmaceutical composition comprising a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof together with a pharmaceutically acceptable excipient. Pharmaceutical compositions comprising a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof as an active ingredient can be prepared by thoroughly 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 be in a wide variety of forms depending on the desired route of administration (e.g., oral, parenteral). In some embodiments, the composition is a solid oral composition.

[0070] Suitable pharmaceutically acceptable carriers are well known in the art, and a description of some of these pharmaceutically acceptable carriers is provided in The Handbook of Pharmaceutical Excipients (published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain).

[0071] Methods for formulating pharmaceutical compositions are described in many publications, such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al.; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al.; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al.; published by Marcel Dekker, Inc.

[0072] In some embodiments, compound or pharmaceutical compositions 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 system (SEDDS), such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical preparations, such as Tweens, 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, saturated vegetable fatty acid partial glyceride mixture, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene polyoxypropylene block polymer and wool fat. Cyclodextrins, such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives, such as hydroxyalkylcyclodextrins (including 2- and 3-hydroxypropyl-β-cyclodextrin) or other solubilized derivatives, can be used to enhance delivery of the compounds described herein. Dosage forms or compositions containing the chemical entities described herein in the range of 0.005% to 100%, with the balance composed of non-toxic excipients, can be prepared. The desired compositions may contain the compounds provided herein in the range of 0.001% to 100%, in one embodiment, 0.1 to 95%, in another embodiment, 75 to 85%, and in a further embodiment, 20 to 80%. Actual methods for preparing such formulations are known or apparent to those skilled in the art, and are described, for example, in Remington: The Science and Practice of Pharmacy, 22 nd Edition (Pharmaceutical Press, London, UK. 2012).

[0073] In certain embodiments, the compounds and pharmaceutical compositions described herein or pharmaceutical compositions thereof can be administered to a patient in need thereof by any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, intracervical, endosinusial, intratracheal, intraintestinal, epidural, intrainterstitial, intraabdominal, intraarterial, intrabronchial, intracystic, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrarespiratory, intrathecal, intrasynovial, intratesticular, intrathecal, intraductal, intratumoral, intrauterine, intravascular, intravenous, intranasal (e.g., intranasal), nasogastric, oral, parenteral, transdermal, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and vaginal. In certain embodiments, the route of administration is parenteral (eg, intratumoral).

[0074] In some embodiments, the compound of Table 1 described herein or its pharmaceutically acceptable salt or solvate, or pharmaceutical compositions thereof, can be formulated for parenteral administration, for example, can be formulated for injection by intraarterial, intrasternal, intracerebral, intravenous, intramuscular, subcutaneous or intraperitoneal route.For example, such compositions can be prepared as injectable liquid solutions or suspensions; solid forms suitable for preparing solutions or suspensions by adding liquid before injection can also be prepared; and this formulation can also be emulsified.The preparation of such formulations is known to those skilled in the art from the present disclosure.In some embodiments, a device is used for parenteral administration.For example, such a device can include needle injectors, microneedle injectors, needle-free injectors and injection techniques.

[0075] In some embodiments, the pharmaceutical forms suitable for injection include sterile aqueous solution or dispersion; formulations containing sesame oil, peanut oil or propylene glycol solution; and sterile powders for the immediate preparation of sterile injectable solution or dispersion.In some embodiments, the form must be sterilized and fluid enough to be easily squirted.In some embodiments, the form must be stable under the conditions of manufacture and storage, and must be prevented from the contamination of microorganisms, such as bacteria and fungi.

[0076] In some embodiments, the carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. In some embodiments, proper fluidity can be maintained, for example, by using a coating such as lecithin, maintaining the required particle size during dispersion, and using surfactants. In some embodiments, the action of microorganisms can be prevented by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In some embodiments, isotonic agents (e.g., sugars or sodium chloride) are included. In some embodiments, prolonged absorption of the injectable composition can be achieved by using agents that delay absorption, such as aluminum monostearate and gelatin, in the composition.

[0077] In some embodiments, sterile injectable solution is prepared by incorporating the required amount of the compound of Table 1 or its pharmaceutically acceptable salt or solvate in a suitable solvent with various other ingredients as listed above, and then optionally sterile filtered.In some embodiments, dispersion is prepared by incorporating various sterilized active ingredients into a sterile medium containing a basic dispersion medium and the other ingredients required from those listed above.In some embodiments, sterile powder is used to prepare sterile injectable solution.In some embodiments, the preparation method is vacuum drying and freeze-drying technology to obtain powder of active ingredient and additional desired ingredients from the solution previously sterile filtered.

[0078] In some embodiments, pharmaceutically acceptable excipients that can be used in rectal compositions as gels, creams, enemas, or rectal suppositories include, but are not limited to, cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (e.g., PEG ointment), glycerin, glycerinated gelatin, hydrogenated vegetable oils, poloxamer, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxide SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxobenzoate, sodium propyl p-hydroxybenzoate, diethylamine, carbomer, carbopol, methyl hydroxybenzoate, macrogol cetostearyl ether, cocoyl Any one or more of caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins such as vitamins A and E, and potassium acetate.

[0079] In certain embodiments, suppositories can be prepared by mixing a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein, with a suitable non-irritating excipient or carrier (e.g., cocoa butter, polyethylene glycol, or a suppository wax) that is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum and releases the active compound. In certain embodiments, compositions for rectal administration are in the form of enemas.

[0080] In certain embodiments, a compound of Table 1 described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, is formulated for local delivery to the gastrointestinal or GI tract by oral administration (e.g., a solid or liquid formulation).

[0081] In some embodiments, solid formulations for oral administration include capsules, tablets, pills, powders, and granules. In some embodiments, the compound of Table 1 or its pharmaceutically acceptable salt or solvate is mixed with one or more pharmaceutically acceptable excipients (e.g., 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 carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicic acid, and sodium carbonate; e) solution retarders. In some embodiments, the formulation may contain additives such as sorbitol, PEG, PEG-100, PEG-120, PEG-140, PEG-150 PEG-160, PEG-170 PEG-180, PEG-190, PEG-200 PEG-210, PEG-220, PEG-230, PEG-240, PEG-250 PEG-260, PEG-270, PEG-280, PEG-290, PEG-300 PEG-310, PEG-320, PEG-330, PEG-340, PEG-350, PEG-360, PEG-370, PEG-380, PEG-390, PEG-400, PEG-410, PEG-420, PEG-430, PEG-440, PEG-450, PEG-460, PEG-470, PEG-480, PEG-49 ...

[0082] In some embodiments, the pharmaceutical composition is in the form of a unit dosage form such as a pill or tablet, and thus the composition may contain a diluent, such as lactose, sucrose, dicalcium phosphate, etc.; a lubricant, such as magnesium stearate; and a binder, such as starch, gum arabic, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, etc., together with the compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a separate solid formulation, powder, marume solution, or suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglyceride) is encapsulated in a capsule (gelatin or cellulose-based capsule). In some embodiments, unit dosage forms in which one or more compounds of the present application and the pharmaceutical composition or additional active agent are physically separated, such as a granule capsule and each agent in a granule (or tablet in a capsule); a bilayer tablet; a two-compartment gel capsule, etc. In some embodiments, enteric-coated or sustained-release oral formulations are also included.

[0083] In certain embodiments, other physiologically acceptable compounds may be included as wetting agents, emulsifying agents, dispersing agents, or preservatives, which are particularly useful for preventing the growth or action of microorganisms. For example, various preservatives are well known and include, for example, phenol and ascorbic acid.

[0084] In some embodiments, the excipients are sterile and generally free of undesirable substances. For example, these compositions can be sterilized by conventional, well-known sterilization techniques. In some embodiments, for various oral formulation additives such as tablets and capsules, sterilization is not required. For example, United States Pharmacopeia / National Formulary (USP / NF) standards may be sufficient.

[0085] In some embodiments, the compound of Table 1 described herein, or its pharmaceutically acceptable salt or solvate, or its pharmaceutical composition, is formulated for ophthalmic administration. In some embodiments, the ophthalmic composition may include, but is not limited to, one or more of the following: viscogen (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizer (e.g., Pluronic (triblock copolymer), cyclodextrin); preservative (e.g., benzalkonium chloride, EDTA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloroisothiazolinone complex; Allergan, Inc.)).

[0086] In some embodiments, the compound in Table 1 described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, is formulated for topical administration to the skin or mucosa (e.g., dermal or transdermal). In some embodiments, topical compositions can include ointments and creams. In some embodiments, ointments are typically semi-solid preparations based on petrolatum or other petroleum derivatives. In some embodiments, creams containing selected active agents are typically viscous liquid or semi-solid emulsions, often either oil-in-water or water-in-oil. For example, cream bases are typically water-washable and contain an oil phase, an emulsifier, and an aqueous phase. For example, the oil phase, also referred to as the "internal" phase, is generally composed of petrolatum and a fatty alcohol, such as cetyl or stearyl alcohol, and the aqueous phase usually, although not necessarily, exceeds the volume of the oil phase and generally contains a humectant. In some embodiments, the emulsifier in a cream formulation is generally a nonionic, anionic, cationic, or amphoteric surfactant. In certain embodiments, the ointment base, as well as other carriers or vehicles, should be inert, stable, non-irritating, and non-sensitizing.

[0087] In any of the above embodiments, the pharmaceutical compositions described herein may comprise one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[0088] The amount of the compound in a pharmaceutical composition or formulation can vary within the range used by those skilled in the art. Typically, the formulation contains, on a weight percent (wt%) basis, about 0.01 to 99.99 wt% of the compound of the present disclosure based on the total formulation, with the remainder being one or more suitable pharmaceutical excipients. In one embodiment, the compound is present at a level of about 1 to 80 wt%. Representative pharmaceutical formulations are described below.

[0089] Formulation Example 1 - Tablets The following ingredients were first mixed and pressed into a single scored tablet: [Table 33]

[0090] Formulation example 2 - Capsule formulation The following ingredients were first mixed and filled into hard-shell gelatin capsules: [Table 34]

[0091] Formulation Example 3 - Suspension Formulation The following ingredients were mixed to form a suspension for oral administration: [Table 35]

[0092] Formulation Example 4 - Injectable formulation The following ingredients were mixed to form an injectable formulation: [Table 36]

[0093] Formulation Example 5 - Suppositories Suppositories with a total weight of 2.5 g were prepared by mixing the claimed compounds with Witepsol® H-15 (triglycerides of saturated vegetable fatty acids; Riches-Nelson, Inc., New York) to have the following composition: [Table 37]

[0094] In some embodiments, the dosage of the compound of Table 1 or its pharmaceutically acceptable salt or solvate is determined based on many factors, including but not limited to, patient type, age, weight, sex, medical condition, severity of patient's medical condition, route of administration and the activity of the compound or its pharmaceutically acceptable salt or solvate.In some embodiments, the appropriate dose for a specific situation can be determined by those skilled in the medical field.In some embodiments, the total daily dose can be divided and administered in portions throughout the day or administered by a method that provides sustained delivery.

[0095] In some embodiments, a compound in Table 1 or a pharmaceutically acceptable salt or solvate thereof is administered at a dose of about 0.01 to about 1000 mg. For example, about 0.1 to about 30 mg, about 10 to about 80 mg, about 0.5 to about 15 mg, about 50 mg to about 200 mg, about 100 mg to about 300 mg, about 200 to about 400 mg, about 300 mg to about 500 mg, about 400 mg to about 600 mg, about 500 mg to about 800 mg, about 600 mg to about 900 mg, or about 700 mg to about 1000 mg. In some embodiments, the dose is a therapeutically effective amount.

[0096] In certain embodiments, a compound of Table 1 described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered in a dose range of about 0.0002 mg / Kg to about 100 mg / Kg (e.g., about 0.0002 mg / Kg to about 50 mg / Kg; about 0.0002 mg / Kg to about 25 mg / Kg; about 0.0002 mg / Kg to about 10 mg / Kg; about 0.0002 mg / Kg to about 5 mg / Kg; about 0.0002 mg / Kg to about 1 mg / Kg; about 0.0002 mg / Kg to about 0.5 mg / Kg; about 0.0002 mg / Kg to about 0.1 mg / Kg; about 0.001 mg / Kg to about 50 mg / Kg; about 0.001 mg / Kg to about 25 mg / Kg; about 0.001 mg / Kg to about 10 mg / Kg; about 0.001 mg / Kg to about 5 mg / Kg; about 0.001 mg / Kg to about 1 mg / Kg; about 0.001 mg / Kg to about 0.5 mg / Kg; about 0.001 mg / Kg to about 0.1 mg / Kg; about 0.01 mg / Kg to about 50 mg / Kg; about 0.01 mg / Kg to about 25 mg / Kg; about 0.01 mg / Kg to about 10 mg / Kg; about 0.01 mg / Kg to about 5 mg / Kg; about 0.01 mg / Kg to about 1 mg / Kg; about 0.01 mg / Kg to about 0.5 mg / Kg; about 0.01 mg / Kg to about 0.1 mg / Kg; about 0.1 mg / Kg to about 50 mg / Kg; about 0.1 mg / Kg ~ approx. 25 mg / Kg; approx. 0.1 In certain embodiments, a compound of Table 1 described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of about 100 mg / Kg.

[0097] In certain embodiments, the dosage of a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, can be administered on a daily basis (e.g., as a single dose or two or more divided doses) or off-daily (e.g., every day, every other day, every third day, once a week, twice a week, once every two weeks, once a month).

[0098] In certain embodiments, the administration period of a compound of Table 1 described herein, or a pharmaceutically acceptable salt or solvate thereof, is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more. In some embodiments, the period of time during which administration is 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 more. In some embodiments, a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, is administered to a patient for a period of time, followed by a dissociation period during which administration of the compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, is discontinued. In some embodiments, a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, is administered for a first period of time, followed by a second period of time after the first period, during which administration is discontinued, followed by a third period of time during which administration of a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, is initiated, followed by a fourth period of time after the third period during which administration is discontinued. For example, the period of administration of a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, followed by a period during which administration is discontinued, is repeated for a predetermined or indefinite 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 more.In some embodiments, the period of time for 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 more.

[0099] In certain embodiments, a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, is administered orally to a patient one or more times per day (e.g., a once-daily, twice-daily, three times-daily, four times-daily or once-daily dose).

[0100] In certain embodiments, a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, is parenterally administered to a patient one or more times per day (e.g., 1 to 4 times per day, 2 times per day, 3 times per day, 4 times per day, or a once daily dose).

[0101] In certain embodiments, a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, is parenterally administered to a patient once a week.

[0102] Treatment method In certain embodiments, the disclosure features methods of treating a patient (e.g., a human) having a disease, disorder, or condition in which modulation of GLP-1R (e.g., inhibition or impairment, and / or increase or attenuation of GLP-1R) is beneficial in treating the underlying pathology and / or symptoms and / or progression of the disease, disorder, or condition. In certain embodiments, the methods described herein can include, or can further include, one or more conditions associated with, or resulting in sequelae of, any one or more of the conditions described herein.

[0103] 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 as disclosed herein.

[0104] In certain embodiments, the disease, disorder, or condition includes, but is not limited to, type 1 diabetes, type 2 diabetes, juvenile-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 (e.g., hypothalamic obesity and monogenic obesity), weight gain due to the use of other medications, idiopathic intracerebral hypertension, Wolfram syndrome, gout, Excessive sugar intake, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, renal disease, adipocyte dysfunction, sleep apnea, visceral fat accumulation, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, vascular restenosis, Thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis , osteoporosis, treatment of addiction, 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, and polycystic ovarian syndrome (PCOS).

[0105] In certain embodiments, the disease, disorder, or condition includes, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, gestational diabetes, renal disease (e.g., acute kidney injury, renal tubular dysfunction, inflammatory changes in the proximal tubule), adipocyte dysfunction, sleep apnea, visceral fat accumulation, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, hyperglycemia, postprandial lipemia, metabolic syndrome, and the like. Includes acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, 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), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS) or any combination thereof.

[0106] In certain embodiments, the disease, disorder, or condition includes, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, idiopathic intracerebral hypertension, Wolfram syndrome, weight gain due to the use of other medications, gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat accumulation, myocardial infarction, peripheral arterial disease, stroke, transient ischemic attack, hyperglycemia, postprandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, dysglycemia, 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.

[0107] In some embodiments, the compounds and pharmaceutical compositions and patient treatment methods described herein induce one or more of the following: blood glucose level reduction (e.g., lowering blood glucose level), blood hemoglobin A1c (HbA1c) level reduction, insulin synthesis promotion, insulin secretion stimulation, beta cell mass increase, gastric acid secretion regulation, gastric emptying regulation, body mass index (BMI) reduction, and / or glucagon production (e.g., level reduction).In some embodiments, the compounds and pharmaceutical compositions and patient treatment methods described herein include lowering blood glucose concentration, lowering blood hemoglobin A1c (HbA1c) concentration, promoting insulin synthesis, stimulating insulin secretion, increasing beta cell mass, regulating gastric acid secretion, regulating gastric emptying, reducing body mass index (BMI), reducing glucagon production (e.g., level reduction), or combinations thereof.In some embodiments, the compounds and pharmaceutical compositions and patient treatment methods described herein stabilize serum glucose and serum insulin levels (e.g., serum glucose concentration and serum insulin concentration). Also provided herein are methods for regulating glucose or insulin levels in a patient in need thereof, comprising administering to the patient an effective amount of a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein.

[0108] In certain embodiments, provided herein are methods for reducing the risk of major adverse cardiovascular events (MACE) in a patient in need thereof (e.g., by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%), comprising administering to the patient an effective amount of a compound in Table 1, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein. In any 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 with type 2 diabetes (T2D). In certain embodiments, the patient is an adult with heart disease. In certain embodiments, the patient has type 2 diabetes (T2D) and heart disease.

[0109] Indications Obesity In some embodiments, the condition, disease or disorder is obesity, and conditions, diseases or disorders associated with or related to obesity.Non-limiting examples of obesity and obesity-related conditions include symptomatic obesity, simple obesity, childhood obesity, morbid obesity and abdominal obesity (central obesity characterized by abdominal fat accumulation).Non-limiting examples of symptomatic obesity include endocrine obesity (e.g., Cushing's syndrome, hypothyroidism, insulinoma, obesity-related type 2 diabetes, pseudohypoparathyroidism, hypogonadism), hypothalamic obesity, genetic obesity (e.g., Prader-Willi syndrome, Laurence-Moon-Biedl syndrome) and drug-induced obesity (e.g., steroid-, phenothiazine-, insulin-, sulfonylurea-, or beta-blocker-induced obesity).

[0110] In some embodiments, the condition, disease or disorder is related to obesity.Examples of such condition, disease or disorder include, but are not limited to, impaired glucose tolerance, diabetes (for example, type 2 diabetes, obesity diabetes), dyslipidemia, hyperlipidemia, hypertension, heart failure, hyperuricemia, gout, fatty liver (including non-alcoholic steatohepatitis (NASH)), coronary heart disease (for example, myocardial infarction, angina pectoris), cerebral infarction (for example, cerebral thrombosis, transient ischemic attack), bone or joint disease (for example, knee osteoarthritis, hip osteoarthritis, spondylitis osteoarthritis, lower back pain), sleep apnea syndrome, obesity hypoventilation syndrome (Pickwickian syndrome), menstrual disorders (for example, abnormal menstrual cycle, menstrual bleeding and cycle abnormalities, amenorrhea, abnormal menstrual symptoms), visceral obesity syndrome and metabolic syndrome.In some embodiments, the compounds and pharmaceutical compositions described herein can be used to treat patients who show both symptoms of obesity and insulin deficiency.

[0111] diabetes In some embodiments, the condition, disease or disorder is diabetes.Non-limiting examples of diabetes include type 1 diabetes, type 2 diabetes (for example, diet-treated type 2 diabetes, sulfonylurea-treated type 2 diabetes, extreme type 2 diabetes, long-term insulin-treated type 2 diabetes), diabetes (for example, non-insulin-dependent diabetes, insulin-dependent diabetes), gestational diabetes, obesity-related diabetes, autoimmune diabetes and borderline diabetes.In some embodiments, the condition, disease or disorder is type 2 diabetes (for example, diet-treated type 2 diabetes, sulfonylurea-treated type 2 diabetes, extreme type 2 diabetes, long-term insulin-treated type 2 diabetes).

[0112] Provided herein is a method for treating diabetes in a patient, the method comprising: (a) determining that the patient has type 2 diabetes; and (b) administering to the patient a therapeutically effective amount of a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein.

[0113] Provided herein is a method for treating type 2 diabetes in a patient, the method comprising administering a therapeutically effective amount of a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein, to a patient identified or diagnosed as having type 2 diabetes.

[0114] 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 disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein.

[0115] In certain embodiments, the compounds, pharmaceutical compositions, and methods for treating patients with conditions, diseases, or disorders (e.g., type 2 diabetes) described herein reduce fasting plasma glucose levels. In certain embodiments, the compounds, pharmaceutical compositions, and methods for treating patients with conditions, diseases, or disorders (e.g., type 2 diabetes) described herein reduce non-fasting plasma glucose levels. In certain embodiments, the compounds, pharmaceutical compositions, and methods for treating patients with conditions, diseases, or disorders (e.g., type 2 diabetes) described herein reduce HbA1c levels. In certain embodiments, the compounds, pharmaceutical compositions, and methods for treating patients with conditions, diseases, or disorders (e.g., type 2 diabetes) described herein reduce glucagon levels. In certain embodiments, the compounds, pharmaceutical compositions, and methods for treating patients with conditions, diseases, or disorders (e.g., type 2 diabetes) described herein increase insulin levels. In certain embodiments, the compounds, pharmaceutical compositions, and methods for treating patients with conditions, diseases, or disorders (e.g., type 2 diabetes) described herein reduce BMI.

[0116] In certain embodiments, a reduction in fasting plasma glucose levels of about 5% to about 95% is shown with treatment of type 2 diabetes. A reduction in fasting plasma glucose levels of about 15% to about 80% is shown with treatment of type 2 diabetes. A reduction in fasting plasma glucose levels of about 25% to about 60% is shown with treatment of type 2 diabetes. In certain embodiments, a reduction in fasting plasma glucose levels to 126 mg / dL or less, to about 110 mg / dL or less, or to about 90 mg / dL or less is shown with treatment of type 2 diabetes.

[0117] In certain embodiments, a reduction in non-fasting plasma glucose levels of about 5% to about 95% is demonstrated with treatment of type 2 diabetes. A reduction in non-fasting plasma glucose levels of about 15% to about 80% is demonstrated with treatment of type 2 diabetes. A reduction in non-fasting plasma glucose levels of about 25% to about 60% is demonstrated with treatment of type 2 diabetes. In certain embodiments, a reduction in non-fasting plasma glucose levels to about 200 mg / dL or less, about 150 mg / dL or less, or about 130 mg / dL or less is demonstrated with treatment of type 2 diabetes.

[0118] In certain embodiments, treatment of type 2 diabetes mellitus results in a reduction in HbA1c levels of about 5% to about 95%. Treatment of type 2 diabetes mellitus results in a reduction in HbA1c levels of about 15% to about 80%. Treatment of type 2 diabetes mellitus results in a reduction in HbA1c levels of about 25% to about 60%. In certain embodiments, treatment of type 2 diabetes mellitus results in a reduction in HbA1c levels of about 6.5% or less, about 6.0% or less, or about 5.0% or less.

[0119] In certain embodiments, a reduction in glucagon levels of about 5% to about 95% is shown with treatment of type 2 diabetes. A reduction in glucagon levels of about 15% to about 80% is shown with treatment of type 2 diabetes. A reduction in glucagon levels of about 25% to about 60% is shown with treatment of type 2 diabetes. An increase in insulin levels of about 5% to about 95% is shown with treatment of type 2 diabetes. An increase in insulin levels of about 15% to about 80% is shown with treatment of type 2 diabetes. An increase in insulin levels of about 25% to about 60% is shown with treatment of type 2 diabetes.

[0120] In certain embodiments, a reduction in BMI of about 5% to about 95% is demonstrated with treatment of type 2 diabetes. A reduction in BMI of about 15% to about 80% is demonstrated with treatment of type 2 diabetes. A reduction in BMI of about 25% to about 60% is demonstrated with treatment of type 2 diabetes. In certain embodiments, a reduction in BMI of about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% is demonstrated with treatment of type 2 diabetes. In certain embodiments, a reduction in BMI of about 40 or less, about 30 or less, or about 20 or less is demonstrated with treatment of type 2 diabetes.

[0121] In some embodiments, the condition, disease or disorder is related to diabetes (for example, diabetic complications).Non-limiting examples of the disorder related to diabetes include obesity, obesity-related disorder, metabolic syndrome, neuropathy, nephropathy (for example, diabetic nephropathy), retinopathy, diabetic cardiomyopathy, cataract, macroangiopathy, osteopenia, hyperosmolar diabetic coma, infectious diseases (for example, respiratory infection, urinary tract infection, gastrointestinal infection, skin and soft tissue infection, lower limb infection), diabetic gangrene, xerostomia, hearing impairment, cerebrovascular disease, diabetic cachexia, delayed wound healing, diabetic dyslipidemia, peripheral blood circulation disorder, cardiovascular risk factors (for example, coronary artery disease, peripheral artery disease, cerebrovascular disease, hypertension and risk factors related to uncontrolled cholesterol and / or lipid level and / or inflammation), NASH, fracture and cognitive dysfunction.

[0122] Other non-limiting examples of disorders related to diabetes include prediabetes, hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, hyper-LDL cholesterolemia, hypo-LDL cholesterolemia, postprandial dyslipidemia), 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.

[0123] In certain embodiments, the condition, disease, or disorder is diabetes and obesity (diabetic obesity). In certain embodiments, the compounds described herein are useful for improving the therapeutic effectiveness of metformin.

[0124] Diseases of metabolically important tissues In certain embodiments, the condition, disease, or disorder is a disease of a metabolically important tissue. Non-limiting examples of metabolically important tissues are the liver, adipose tissue, pancreas, kidney, and digestive tract.

[0125] In some embodiments, the condition, disease or disorder is fatty liver disease.Fatty liver disease includes, but is not limited to, non-alcoholic fatty liver disease (NAFLD), steatohepatitis, non-alcoholic steatohepatitis (NASH), fatty liver disease resulting from hepatitis, fatty liver disease resulting from obesity, fatty liver disease resulting from diabetes, fatty liver disease resulting from insulin resistance, fatty liver disease resulting from hypertriglyceridemia, abetalipoproteinemia, hyperlipoproteinemia, glycogen storage disease, Weber-Christian disease, Wolman disease, acute fatty liver of pregnancy and lipodystrophy.

[0126] Nonalcoholic fatty liver disease (NAFLD) refers to a group of diseases that occur in the absence of alcohol abuse and is typically characterized by the presence of fatty liver (fat in the liver). NAFLD is thought to be associated with various conditions, such as metabolic syndrome (including obesity, diabetes, and hypertriglyceridemia) and insulin resistance. This can cause liver disease in adults and children, eventually leading to cirrhosis (Skelly et al., J Hepatol 2001; 35: 195-9; Chitturi et al., Hepatology 2002; 35(2):373-9). The severity of NAFLD ranges from relatively benign, mainly isolated macrovesicular fatty liver (i.e., nonalcoholic fatty liver or NAFL) to nonalcoholic steatohepatitis (NASH) (Angulo et al., J Gastroenterol Hepatol 2002; 17 Suppl:S186-90).

[0127] Other non-limiting examples of disorders of metabolically important tissues include arthropathy (e.g., osteoarthritis, secondary osteoarthritis), fatty liver (e.g., intrahepatic), fibrosis (e.g., intrahepatic), cirrhosis (e.g., intrahepatic), gallstones, gallbladder disease, gastroesophageal reflux, sleep apnea, hepatitis, fatty liver, bone disorders characterized by altered bone metabolism, e.g., osteoporosis (including postmenopausal osteoporosis), decreased bone strength, osteopenia, Paget's disease, osteolytic metastases in cancer patients, and osteodystrophy in liver disease. and bone metabolism changes caused by renal failure or hemodialysis, fractures, bone surgery, aging, pregnancy, protection from fractures, and malnutrition, polycystic ovary syndrome, renal disease (e.g., chronic renal failure, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease), muscular dystrophy, angina pectoris, acute or chronic diarrhea, testicular dysfunction, respiratory dysfunction, frailty, sexual dysfunction (e.g., erectile dysfunction), and geriatric syndrome. In some embodiments, the compounds and pharmaceutical compositions described herein can be used to treat surgical trauma by improving post-surgical recovery and / or preventing catabolic reactions that may be caused by surgical trauma.

[0128] Cardiovascular and vascular diseases In some embodiments, the condition, disease or disorder is cardiovascular disease.Non-limiting examples of cardiovascular disease include congestive heart failure, atherosclerosis, arteriosclerosis, coronary heart disease, coronary artery disease, congestive heart failure, coronary heart disease, hypertension, heart failure, cerebrovascular disease (e.g., cerebral infarction), vascular insufficiency, myocardial infarction, elevated blood pressure (e.g., 130 / 85 mm Hg or higher) and prothrombotic conditions (e.g., elevated blood fibrinogen or plasminogen activator inhibitor).

[0129] In some embodiments, the condition, disease or disorder is related to vascular disease.Non-limiting examples of vascular disease include peripheral vascular disease, macrovascular complications (e.g., stroke), vascular insufficiency, peripheral arterial disease, abdominal aortic aneurysm, carotid artery disease, cerebrovascular disease (e.g., cerebral infarction), pulmonary embolism, chronic venous insufficiency, critical limb ischemia, retinopathy, nephropathy and neuropathy.

[0130] Neurological disorders In certain embodiments, the condition, disease, or disorder is a neurological disorder (e.g., a neurodegenerative disorder) or a psychiatric disorder. Non-limiting examples of neurological disorders include idiopathic intracranial hypertension (IIH), brain insulin resistance, mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), anxiety disorders, dementia (e.g., senile dementia), traumatic brain injury, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, Morbus Parkinson's disease, Steele-Richard syndrome, Down's syndrome, myasthenia gravis, neurotrauma, brain trauma, vascular amyloidosis, cerebral hemorrhage with amyloidosis, encephalitis, Friedreich's ataxia, acute confusional disorder, amyotrophic lateral sclerosis (ALS), glaucoma, and apoptosis-mediated degenerative diseases of the central nervous system (e.g., Creutzfeldt-Jakob disease, bovine spongiform encephalopathy (mad cow disease), and chronic wasting syndrome). See, for example, US Publication 20060275288A1 A1.

[0131] In some embodiments, the condition, disease, or disorder is idiopathic intracranial hypertension. Idiopathic intracranial hypertension is characterized by elevated intracranial pressure and papilledema. See, for example, Virdee et al., Ophthalmol Ther. 2020;9(4):767-781. In some embodiments, the compounds, pharmaceutical compositions, and methods described herein reduce cerebrospinal fluid secretion in patients with idiopathic intracranial hypertension. In some embodiments, the compounds, pharmaceutical compositions, and methods described herein reduce intracranial pressure in patients with idiopathic intracranial hypertension. In some embodiments, the compounds, pharmaceutical compositions, and methods described herein alleviate one or more symptoms in 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 female. In certain embodiments, the patient with idiopathic intracranial hypertension is about 20 to about 30 years old. In certain embodiments, the patient with idiopathic intracranial hypertension is obese.

[0132] In some embodiments, the condition, disease, or disorder is Wolfram syndrome. Wolfram syndrome is caused by a digenic mutation in the wolframin ER transmembrane glycoprotein (Wfs1) gene. See, for example, Seppa et al. Sci Rep 9, 15742 (2019). Wolfram syndrome initially manifests as diabetes, followed by symptoms of optic atrophy, hearing loss, and neurodegeneration. Patients with Wolfram syndrome may experience symptoms of ataxia, sleep apnea, dysphagia, hearing loss, and loss of taste due to brainstem atrophy. In some embodiments, the compounds, pharmaceutical compositions, and methods described herein reduce neuroinflammation in patients with Wolfram syndrome. In some embodiments, neuroinflammation is reduced in the inferior olivary nucleus of the patient. The compounds, pharmaceutical compositions, and methods described herein reduce retinal ganglion cell death in patients with Wolfram syndrome. In some embodiments, the compounds, pharmaceutical compositions, and methods described herein reduce axonal degeneration in patients with Wolfram syndrome. In certain embodiments, the compounds and pharmaceutical compositions and methods described herein alleviate one or more symptoms (eg, any of the symptoms described herein) in patients with Wolfram Syndrome.

[0133] Non-limiting examples of psychiatric disorders include drug addiction / addiction (narcotics and amphetamines) and attention deficit hyperactivity disorder (ADHD).The compounds and pharmaceutical compositions described herein can be useful for improving behavioral responses to addictive drugs, reducing drug dependence, preventing relapse of drug abuse, and alleviating the anxiety caused by the absence of a given addictive substance.See, for example, US Publication 20120021979A1.

[0134] In certain embodiments, the compounds and pharmaceutical compositions described herein are useful for improving learning and memory by enhancing neuroplasticity and promoting cell differentiation, as well as preserving dopamine neuron and motor function in Morbus Parkinson's disease.

[0135] Insulin-Related Conditions and Diseases In certain embodiments, the condition, disease or disorder is impaired fasting glucose (IFG), fasting hyperglycemia (IFG), hyperglycemia, insulin resistance (impaired glucose homeostasis), hyperinsulinemia, increased blood levels of fatty acids or glycerol, hypoglycemic conditions, insulin resistance syndrome, abnormal paresthesia caused by hyperinsulinemia, hyperlipidemia, hypercholesterolemia, poor wound healing, leptin resistance, glucose intolerance, elevated fasting glucose, dyslipidemia (e.g., atherogenic dyslipidemia characterized by hyperlipidemia, high triglycerides and low HDL cholesterol), glucagonoma, hyperprolactinemia, hypoglycemia (e.g., nocturnal hypoglycemia), and insulin-related concomitant comatose endpoint.

[0136] In certain embodiments, the compounds and pharmaceutical compositions described herein can reduce or delay the progression of borderline impaired fasting glucose or impaired fasting glucose to diabetes.

[0137] autoimmune disease In some embodiments, condition, disease or disorder is autoimmune disease.Non-limiting examples of autoimmune disease include multiple sclerosis, experimental autoimmune encephalomyelitis, autoimmune disease associated with immune rejection, graft-versus-host disease, uveitis, optic neuropathy, optic neuritis, transverse myelitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, myasthenia gravis and Graves' disease.See, for example, US Publication 20120148586A1.

[0138] Gastrointestinal disorders In some embodiments, the condition, disease, or disorder is a stomach or intestinal disorder. Non-limiting examples of these disorders include ulcers of any etiology (e.g., gastric ulcer, Zollinger-Ellison syndrome, drug-induced ulcer, ulcer associated with infection or other pathogens), gastrointestinal diseases, malabsorption, short bowel syndrome, blind-tube syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), celiac disease, hypogammaglobulinemia, chemotherapy- and / or radiotherapy-induced mucositis and diarrhea, gastroenteritis, short bowel syndrome, ulcerative colitis, gastric mucosal injury (e.g., aspirin-induced gastric mucosal injury), small intestinal mucosal injury, and cachexia (e.g., cancer cachexia, tuberculosis cachexia, cachexia associated with blood disorders, cachexia associated with endocrine disorders, cachexia associated with infectious diseases, and cachexia caused by acquired immune deficiency syndrome).

[0139] body weight In some embodiments, the compounds and pharmaceutical compositions described herein can be used to reduce weight (e.g., excess weight), prevent weight gain, induce weight loss, reduce body fat, or reduce food intake in a patient (e.g., a patient in need thereof). In some embodiments, the patient's weight gain may be due to excessive or poor food intake, or may be due to concomitant use of a drug (e.g., an insulin sensitizer with PPARγ agonist-like activity, such as troglitazone, rosiglitazone, englitazone, ciglitazone, pioglitazone, etc.). In some embodiments, the weight gain may be pre-obese or may be in an obese patient. In some embodiments, the weight gain may be drug-induced weight gain or weight gain after smoking cessation. In some embodiments, the weight gain may be induced by the use of a steroid or an antipsychotic drug.

[0140] In certain embodiments, the condition, disease, or disorder is an eating disorder (e.g., overeating, binge eating, bulimia, or compulsive overeating) or syndromic obesity (e.g., Prader-Willi syndrome and Bardet-Biedl syndrome).

[0141] Inflammatory diseases In some embodiments, the condition, disease or disorder is inflammatory disease.Non-limiting examples of inflammatory disease include rheumatoid arthritis, spondylitis deformans, osteoarthritis, lower back pain, gout, post-operative or post-traumatic inflammation, abdominal distension, neuralgia, pharyngitis, cystitis, pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory bowel disease), and the inflammation and pro-inflammatory state (for example, the level of inflammatory markers such as pro-inflammatory cytokine C or reactive protein in blood) of metabolically important tissues (including liver, fat, pancreas, kidney and intestine) is increased.

[0142] cancer In some embodiments, the condition, disease, or disorder is cancer. Suitable examples of cancer include breast cancer (e.g., invasive ductal carcinoma, ductal carcinoma in situ, inflammatory breast cancer), prostate cancer (e.g., hormone-dependent prostate cancer, hormone-independent prostate cancer), pancreatic cancer (e.g., pancreatic ductal carcinoma), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), lung cancer (e.g., non-small cell lung cancer, small cell lung carcinoma, malignant mesothelioma), colon cancer (e.g., gastrointestinal stromal tumor), rectal cancer (e.g., gastrointestinal stromal tumor), and rectal cancer (e.g., gastrointestinal stromal tumor). gastrointestinal stromal tumor), colon cancer (e.g., familial colorectal cancer, hereditary non-polyposis colorectal cancer, gastrointestinal stromal tumor), small intestine cancer (e.g., non-Hodgkin's lymphoma, gastrointestinal stromal tumor), 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, uterine cancer, cervical cancer, ovarian cancer (e.g., ovarian epithelial cancer, extragonadal germ cell tumor, ovarian germ cell tumor, low-grade ovarian tumor), bladder cancer, urethral cancer, skin cancer (e.g., intraocular (ocular) melanoma, Merkel cell carcinoma), hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer (e.g., medullary thyroid carcinoma), These include thyroid cancer, nasal cancer, sinus cancer, bone tumors (e.g., osteosarcoma, Ewing's tumor, uterine sarcoma, soft tissue sarcoma), angiofibroma, retinal sarcoma, penile cancer, testicular tumor, childhood solid tumors (e.g., Wilms' tumor, childhood kidney tumor), Kaposi's sarcoma, Kaposi's sarcoma caused by AIDS, maxillary sinus tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia).

[0143] Hypothalamic-pituitary disorders In some embodiments, the condition, disease or disorder is related to the hypothalamic pituitary gonadal axis. For example, the condition, disease or disorder is related to the hypothalamic-pituitary ovarian axis. In another example, the condition, disease or disorder is related to the hypothalamic pituitary testis axis. Diseases of the hypothalamic pituitary gonadal axis include, but are not limited to, hypogonadism, polycystic ovarian syndrome, hypothyroidism, hypopituitarism, sexual dysfunction and Cushing's disease.

[0144] In certain embodiments, the diabetes-related condition, disease or disorder is related to the hypothalamic pituitary gonadal axis.

[0145] Pulmonary disease In certain embodiments, the condition, disease, or disorder is associated with a pulmonary disease, including, but not limited to, asthma, idiopathic pulmonary fibrosis, pulmonary hypertension, obstructive sleep apnea, and chronic obstructive pulmonary disease (COPD) (e.g., emphysema, chronic bronchitis, and refractory (irreversible) asthma).

[0146] In certain embodiments, the diabetes-related condition, disease or disorder is a pulmonary disease.

[0147] Combination therapy In certain embodiments, the present invention is intended to include both monotherapy and combination therapy regimens.

[0148] In certain embodiments, the methods described herein can further include administering one or more additional therapies (e.g., one or more additional therapeutic agents and / or one or more treatment regimens) in combination with the administration of the compound of the present application.

[0149] In some embodiments, the methods described herein include administering a compound of the present application in combination with one or more of dietary therapy (e.g., dietary monitoring for diabetes, dietary therapy), exercise therapy (e.g., physical activity), blood glucose monitoring, gastric electrical stimulation (e.g., TANTALUS®), and dietary modification.

[0150] In certain embodiments, the compounds of Table 1 described herein, or pharmaceutically acceptable salts or solvates thereof, can be administered in combination with one or more additional therapeutic agents.

[0151] Representative additional therapeutic agents include, but are not limited to, anti-obesity agents, therapeutic agents for diabetes, therapeutic agents for diabetic complications, therapeutic agents for hyperlipidemia, antihypertensive agents, diuretics, chemotherapeutic agents, immunotherapeutic agents, anti-inflammatory agents, antithrombotic agents, antioxidants, therapeutic agents for osteoporosis, vitamins, therapeutic agents for dementia, therapeutic agents for erectile dysfunction, therapeutic agents for urinary frequency or urinary incontinence, therapeutic agents for NAFLD, therapeutic agents for NASH, therapeutic agents for dysuria, and antiemetics.

[0152] In certain embodiments, the one or more additional therapeutic agents include, for example, those useful as anti-obesity agents. Non-limiting examples include monoamine reuptake inhibitors (e.g., tramadol, phentermine, sibutramine, mazindol, fluoxetine, tesofensine), serotonin 2C receptor agonists (e.g., lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptor modulators, GABA modulators (e.g., topiramate), GABA receptor agonists (e.g., gabapentin, pregabalin), neuropeptide Y antagonists (e.g., velneperit), peptide YY or analogs thereof, cannabinoid receptor antagonists (e.g., rimonabant, taranabant), and the like. ant), ghrelin antagonists, ghrelin receptor antagonists, ghrelin acylation enzyme inhibitors, opioid receptor antagonists (e.g., GSK-1521498, naltrexone), orexin receptor antagonists, melanocortin 4 receptor agonists, 11β-hydroxysteroid dehydrogenase inhibitors (e.g., AZD-4017, BVT-3498, INCB-13739), pancreatic lipase inhibitors (e.g., orlistat, 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 compounds described in U.S. Patent No. 8,859,577), stearate-CoA desaturase inhibitors, microsomal triglyceride transfer protein inhibitors (e.g., R-256918), sodium glucose 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, or ertugliflozin), SGLT-1 inhibitors, MCR-4 agonists, monoamine reuptake inhibitors, melanocyte-stimulating hormone analogs, 5HT2cagonists, galanin antagonists, eating disorder agents (e.g., bombesin agonists), thyroid hormone mimetics, dehydroepiandrosterone or analogs thereof, human agouti-related protein (AGRP) inhibitors, neuromedin U agonists, NFK inhibitors (e.g., HE-3286), PPAR agonists (e.g., GFT-505, DRF-11605, gemfibrozil, fenofibrate, balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone, CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767, and SB-21 9994), phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate, trodascumine), 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., pyragliatin, AZD-1656, AZD6370, TTP-355, TTP-399, TTP547, ARRY403, MK-0599, TAK-329, AZD5658 or GKM-001, compounds described in 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 WO2008 / 156757), leptin, leptin derivatives (e.g., metreleptin), leptin resistance improving agents, CNTF (ciliary neurotrophic factor), BDNF (brain-derived neurotrophic factor), cholecystokinin agonists, amylin preparations (e.g., pramlintide, AC-2307), neuropeptide Y agonists (e.g., PYY3-36, PYY3-36 derivatives, obinineptide, TM-30339, TM-30335), oxyntomodulin (OXM) preparations, appetite suppressants (e.g., ephedrine), FGF21 preparations (e.g., animal FGF21 preparations extracted from bovine or porcine spleens, preparations; human FGF21 preparations genetically synthesized using E. coli or yeast; fragments or derivatives of FGF21), appetite suppressants (e.g., P-57), human proislet peptide (HIP), melanocortin receptor 4 agonists (e.g., cetamelanoides), melanin-concentrating hormone receptor 1 antagonists, serotonin drugs (e.g., sibutramine, lorcaserin), farnesoid X receptor (FXR) agonists (e.g., obeticholic acid, tropifexor, cilofexor, LY2562175, Met409, TERN-101, EDP305, International Publication No. WO 2020 / 234726 and U.S. Patent No. 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.

[0153] In some embodiments, one or more additional therapeutic agents include, for example, the agent useful as an antidiabetic agent.Non-limiting examples include insulin and insulin preparations (for example, animal insulin preparations extracted from bovine or porcine pancreas; human insulin preparations genetically synthesized using E. coli or yeast; zinc insulin; protamine zinc insulin; insulin fragments or derivatives (for example, INS-1), oral insulin preparations, synthetic human insulin), insulin sensitizers (for example, pioglitazone or its salt), biguanides (for example, metformin, buformin or its salts (for example, hydrochloride, fumarate, succinate)), glucagon analogs (for example, WO 2010 / 011439), drugs that antagonize the action of glucagon or decrease the secretion of glucagon, sulfonylurea drugs (e.g., chlorpropamide, tolazamide, glimepiride, tolbutamide, glibenclamide, gliclazide, acetohexamide, glyclopyramide, glybuzole, glyburide, glipizide), thiazolidinediones (e.g., rosiglitazone, lobeglitazone, troglitazone, balaglitazone, lobeglitazone, or pioglitazone), glitazars ( for example, aleglitazar, tiglitazar, saroglitazar, muraglitazar, tesaglitazar), SGLT2 inhibitors (for example, JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, THR1474, TS-071, ISIS388626, LX4211, remogliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, cerigliflozin etabonate, remogliflozin etabonate, ertugliflozin, WO2010 / 023594), GPR40 agonists (e.g., FFAR1 / FFA1 agonists, e.g., fasiglifam), α-glucosidase inhibitors (e.g., adiposine, camiglibose, pradimicin-Q, salbostatin, voglibose, acarbose, miglitol, emiglitate), insulin secretagogues, e.g., prandial glucose regulators (sometimes referred to as "short-acting secretagogues"), e.g., meglitinides (e.g., repaglinide and nateglinide), cholinesterase inhibitors (e.g., donepezil, galantamine, rivastigmine, tacrine), NMDA receptor antagonists, dual GLP-1 / GIP receptor agonists (e.g., LBT-2000, ZPD1-70), GLP-1R These include agonists (e.g., exenatide, liraglutide, albiglutide, taspoglutide, lixisenatide, semaglutide, AVE-0010, S4P, and Boc5) and dipeptidyl peptidase IV (DPP-4) inhibitors (e.g., vildagliptin, dutogliptin, gemigliptin, alogliptin, saxagliptin, sitagliptin, linagliptin, berberine, adogliptin, anagliptin (SK-0403), teneligliptin, omarigliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, ALS2-0426, TA-6666, TS-021, KRP-104, trelagliptin).

[0154] In certain embodiments, the one or more additional therapeutic agents include, for example, agents useful 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., aranchol), 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., tipekast), 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), ketohexokinase (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), diacylglyceryl acyltransferase 2 (DGAT2) inhibitors (e.g., WO No. 2020 / 234726 and U.S. Publication No. 20180051012), CB1 receptor antagonists, anti-CB1R antibodies, glycyrrhizin, scilla extract, ascorbic acid, glutathione, silymarin, lipoic acid and d-alpha-tocopherol, ascorbic acid, glutathione, vitamin B complex, glitazones / thiazolidinediones (e.g., troglitazone, rosiglitazone, pioglitazone, balaglitazone, rivoglitazone, lobeglitazone), metformin, cysteamine, sulfonylureas, alpha-glucosidase inhibitors, meglitinides, vitamin E, tetrahydrolipstatin, milk thistle proteins, antivirals, and antioxidants.

[0155] In some embodiments, the one or more additional therapeutic agents include, for example, agents useful for treating diabetic complications. Non-limiting examples include aldose reductase inhibitors (e.g., tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat, lidrestat), neurotrophic factors and growth factors (e.g., NGF, NT-3, BDNF, neurotrophic production / secretion promoting agents described in WO2001 / 14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxyl)propyl]oxazole, a compound described in WO2004 / 039365), PKC inhibitors (e.g., ruthenium, erythrocyte sedimentation inhibitors ... Examples of such anti-inflammatory drugs include benzodiazepines (e.g., benzodiazepine mesylate), AGE inhibitors (e.g., ALT946, N-phenacylthiazolium bromide (ALT766), EXO-226, pyridoline, pyridoxamine), serotonin and noradrenaline reuptake inhibitors (e.g., duloxetine), sodium channel inhibitors (e.g., lacosamide), reactive oxygen scavengers (e.g., thioctic acid), cerebral vasodilators (e.g., tiapride, mexiletine), somatostatin receptor agonists (e.g., BIM23190), and apoptosis signal-regulating kinase 1 (ASK-1) inhibitors.

[0156] In some embodiments, the one or more additional therapeutic agents include, for example, agents useful for treating hyperlipidemia. Non-limiting examples include HMG-COA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin, or salts thereof (e.g., sodium salts, calcium salts)), squalene synthase inhibitors (e.g., compounds described in WO97 / 10224, 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]acetate, and the like. [1-methyl]piperidine-4-acetic acid), fibrates (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate), anion exchange resins (e.g., cholestyramine), nicotinic acid drugs (e.g., nicomol, niceritrol, niaspan), phytosterols (e.g., soy sterol, gamma oryzanol (γ-oryzanol)), cholesterol absorption inhibitors (e.g., zetia), CETP inhibitors (e.g., dalcetrapib, anacetrapib), and omega-3 fatty acid preparations (e.g., omega-3 fatty acid ethyl ester 90).

[0157] In certain embodiments, the one or more additional therapeutic agents include, for example, agents useful as antihypertensive agents. Non-limiting examples include angiotensin-converting enzyme inhibitors (e.g., captopril, zofenopril, fusinopril, enalapril, ceranopril, cirazopril, delapril, pentopril, quinapril, ramipril, lisinopril), angiotensin II antagonists (e.g., candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, telmisartan, irbesartan, val ... Non-limiting examples of antihypertensive agents include diuretics (e.g., acetaminophen, benzodiazepine, benzocaine ... (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methychlorothiazide, trichloromethiazide, polythiazide, benzthiazide, triclinafen ethacrynate, chlorthalidone, torsemide, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone), alpha adrenergic blockers, beta adrenergic blockers, calcium channel blockers, channel blockers (e.g., diltiazem, verapamil, nifedipine, and amlodipine), vasodilators (e.g., hydrazine), renin inhibitors, AT-1 receptor antagonists (e.g., losartan, irbesartan, and valsartan), ET receptor antagonists (e.g., sitaxsentan, atorsentan, and compounds described in U.S. Patent Nos. 5,612,359 and 6,043,265), dual ET / AII antagonists (e.g., compounds described in WO 2000 / 01389), neutral endopeptidase (NEP) inhibitors, and when the channel blocker is ivabradine, vasopeptidase inhibitors (dual NEP-ACE inhibitors) (e.g., gemopatrilat and nitrate) are included.

[0158] In some embodiments, one or more additional therapeutic agents include, for example, the agent useful as a diuretic.Non-limiting examples include xanthine derivatives (for example, theobromine sodium salicylate, theobromine calcium salicylate), thiazides (for example, ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penfluthiazide, polythiazide, methyclothiazide), antialdosterone agents (for example, spironolactone, triamterene), carbonic anhydrase inhibitors (for example, acetazolamide) and chlorobenzenesulfonamides (for example, chlorthalidone, mefruside, indapamide).

[0159] In some embodiments, the one or more additional therapeutic agents include, for example, agents useful as immunotherapeutics.Non-limiting examples include microbial or bacterial compounds (e.g., muramyl dipeptide derivatives, picibanil), polysaccharides with immune-enhancing activity (e.g., lentinan, sizofiran, krestin), cytokines obtained by genetic engineering (e.g., interferon, interleukin (IL), e.g., IL-1, IL-2, IL-12) and colony-stimulating factors (e.g., granulocyte colony-stimulating factor, erythropoietin).

[0160] In some embodiments, the one or more additional therapeutic agents include, for example, an agent useful as an antithrombotic agent.Non-limiting examples include heparin (e.g., heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarin (e.g., warfarin potassium), antithrombin agents (e.g., argatroban, dabigatran, boroarginine derivatives, boropeptides, heparin, hirudin, and melagatran), FXa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, betrixaban, YM150, compounds described in WO02 / 06234, WO2004 / 048363, WO2005 / 030740, WO2005 / 058823, and WO2005 / 113504), Thrombolytic agents (e.g., anistreplase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), urokinase, tisokinase, alteplase, nateplase, monteplase, pamiteplase, factor VIIa inhibitors, PAI-1 inhibitors, α2-antiplasmin inhibitors, and anisoylated plasminogen streptokinase activator complex) and platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cilostazol, ethyl icosapentate, beraprost sodium, and sarpogrelate hydrochloride) are included.

[0161] In some embodiments, one or more additional therapeutic agents include, for example, drugs useful for treating osteoporosis.Non-limiting examples include alpha calcidol, calcitriol, elcatonin, salmon calcitonin, 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 therapeutic agents include apomorphine and sildenafil citrate.Suitable examples of frequent urination or urinary incontinence therapeutic agents include flavoxate hydrochloride, oxybutynin hydrochloride and propiverine hydrochloride.Suitable examples of therapeutic agents for urination disorders include acetylcholinesterase inhibitors (e.g., distigmine).Suitable examples of anti-inflammatory agents include nonsteroidal anti-inflammatory agents, such as aspirin, acetaminophen, and indomethacin.

[0162] Other exemplary additional therapeutic agents include agents that regulate hepatic glucose balance (e.g., fructose 1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glycogen synthase kinase inhibitors, glucokinase activators), agents designed to treat complications of persistent hyperglycemia, such as aldose reductase inhibitors (e.g., epalrestat and ranirestat), agents used to treat complications associated with microangiopathy, anti-dyslipidemic agents, such as HMG-CoA reductase inhibitors (statins, e.g., rosuvastatin), pravastatin, pitavastatin, lovastatin, atorvastatin , simvastatin, fluvastatin, itavastatin, ZD-4522), HMG-CoA synthesis inhibitors, cholesterol-lowering agents, bile acid sequestrants (e.g., cholestyramine, questran, colestipol, and colesveram), cholesterol absorption inhibitors (e.g., plant sterols such as phytosterols), cholesteryl ester transfer protein (CETP) inhibitors, inhibitors of the ileal bile acid transport system (IBAT inhibitors), diacylglyceryl acyltransferase 1 (DGAT1) inhibitors (e.g., AZD7687, LCQ908, compounds described in WO2009 / 016462, WO2010 / 086820), monoacylglycerol O-acyltransferase inhibitors, α-amylase inhibitors (e.g., tendamistat, trestatin, AL-3688), α-glucoside hydrolase inhibitors, SIRT-1 activators, c-Jun N-terminal kinase (JNK) inhibitors, VPAC2 receptor agonists, TGR5 receptor modulators (e.g., the described compounds), 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., diliotapide, mitratapide, and impitapide), lipoxygenase inhibitors, PCSK9 modulators (e.g., alirocumab and evolocumab), RXRα modulators, cysteamine, RNA antisense constructs inhibiting protein tyrosine phosphatase PTPRU, vitamin B complex, pentraxin proteins, protein tyrosine phosphatase-1 B (PTP-1 B) inhibitors (e.g., trodasquemine, hiruthiosal extract, and Zhang, et. al. (Drug Discovery Today. 2007, 12(9-10): 373-381), editinbe, betaine, pentoxifylline, αδ-9 desaturase, BCKDK inhibitors, branched-chain α-keto acid 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, e.g., beta-blockers (e.g., atenolol), α-blockers (e.g., doxazosin) and mixed α / β-blockers (e.g., labetalol), adrenergic receptor agonists including α2 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 benzothiazepines (e.g., diltiazem), angiotensin II receptor antagonists (e.g., candesartan), aldosterone receptor antagonists (e.g., eplerenone, spironolactone), centrally acting adrenergic agents, for example, central alpha agonists (e.g., clonidine), diuretics (e.g., furosemide), torsemide, bemethanide, ethacrynic acid, thiazide diuretics (e.g., chlorothiazide, hydrochlorothiazide, benzthiazide, hydroflumethiazide, bendroflumethiazide, methychlorthiazide, polythiazide, trichlormethiazide, indapamide),Phthalimidine diuretics (e.g., chlorthalidone, metolazone), quinazoline diuretics (e.g., quinethazone), potassium-sparing diuretics (e.g., triamterene and amiloride), thyroid receptor agonists (e.g., compounds described in WO2020 / 117987), hemostasis modulating agents including antithrombotic agents (e.g., activators of fibrinolysis), thrombin antagonists, factor VIIa inhibitors, anticoagulants (e.g., vitamin K antagonists such as warfarin), heparin and and their 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 P2Y 12), adenosine diphosphate (ADP) receptor inhibitors (e.g., clopidogrel), phosphodiesterase inhibitors (e.g., cilostazol), glycoprotein IIB / IIA inhibitors (e.g., tirofiban, eptifibatide, and abciximab), adenosine reuptake inhibitors (e.g., dipyridamole), noradrenergic agonists (e.g., phentermine), serotonergic agents (e.g., sibutramine, lorcaserin), diacylglycerol acyltransferases ferase (DGAT) inhibitors, feeding behavior regulators, pyruvate dehydrogenase kinase (PDK) regulators, serotonin receptor modulators, monoamine transmission modulators such as selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine), noradrenaline reuptake inhibitors (NARIs), noradrenaline serotonin reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs) (e.g., toloxatone and amifluramine), WO 2007 / 013694, WO 2007 / 018314, WO 2008 / 093639 and WO 2008 / 099794, GPR40 agonists (e.g., fasiglifam or a hydrate thereof, WO 2004 / 041266, WO 2004 / 106276, WO 2005 / 063729, WO 2005 / 063725, WO 2005 / 087710,compounds described in WO 2005 / 095338, WO 2007 / 013689 and WO 2008 / 001931), SGLT1 inhibitors, adiponectin or its agonists, IKK inhibitors (e.g., AS-2868), somatostatin receptor agonists, ACC2 inhibitors, anti-cachexia agents, for example, cyclooxygenase inhibitors (e.g., indomethacin), progesterone derivatives (e.g., megestrol acetate), glucocorticoids (e.g., dexamethasone), metoclopramide agents, tetrahydrocannabinol agents, fat substitutes metabolic improvers (e.g., eicosapentaenoic acid), growth hormone, IGF-1, antibodies against cachexia-inducing factors TNF-α, LIF, IL-6, and oncostatin M, metabolic improvers 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, glycation inhibitors (e.g., ALT-711), neuroregeneration promoters (e.g., Y-128, VX853, prosaptide), antidepressants (e.g., desipramine, amitriptyline, imipramine), antiepileptics (e.g., lamotrigine, trileptal, keppra, zonegran, pregabalin, halcoceride, carbamazepine), antiarrhythmics (e.g., K, +channel openers, mexiletine, propafenone, metoprolol, atenolol, carbaziol, propranolol, sotalol, dofetilide, amiodarone, azimilide, ibutilide, ditiazem, and verapamil), acetylcholine receptor ligands (e.g., ABT-594), endothelin receptor antagonists (e.g., ABT-627), narcotic analgesics (e.g., morphine), α2 receptor agonists (e.g., clonidine), topical analgesics (e.g., capsaicin), anxiolytics (e.g., benzothiazepines), phosphodiesterase inhibitors (e.g., sildenafil), dopamine receptor agonists (e.g., apomorphine), cytotoxic antibodies (e.g., T cell receptor-specific antibodies, IL-2 receptor-specific antibodies), B cell depletion therapies (e.g., anti-CD20 antibodies such as Rituxan, i-BLyS antibodies), agents affecting T cell migration (e.g., anti-integrin α4 / β1 antibodies (e.g., Tysabri), ), drugs acting on immunophilins (e.g., cyclosporine, tacrolimus, sirolimus, rapamycin), interferons (e.g., IFN-β), immunomodulators (e.g., glatiramer), TNF-binding proteins (e.g., circulating receptors), immunosuppressants (e.g., mycophenolate), metaglidazen, AMG-131, balaglitazone, MBX-2044, rivoglitazone, aleglitazar, tiglitazar, saroglitazar, muraglitazone Examples of such agents include tetracycline, tesaglitazar, lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, exenatide, exendin-4, memantine, midazolam, ketoconazole, ethyl icosapentate, clonidine, azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, etoposide, piroxicam, NO donors (e.g., organic nitrates), and NO promoters (e.g., phosphodiesterase inhibitors).

[0163] In certain embodiments, the one or more additional therapeutic agents include, for example, those useful as antiemetic agents. As used herein, an "antiemetic" agent refers to any agent that neutralizes (e.g., reduces or eliminates) nausea or emesis (vomiting). Without being bound by theory, it is believed that administering one or more antiemetic agents in combination with the compounds of Table 1 described herein may result in a more rapid response to treatment, for example, by allowing the patient to consume a normal diet, thereby allowing for higher doses of the compounds of Table 1.

[0164] Non-limiting examples of antiemetic agents include 5HT3-receptor antagonists (serotonin receptor antagonists), neuroleptics / antipsychotics, antihistamines, anticholinergics, steroids (e.g., corticosteroids), NK1 receptor antagonists (e.g., neurokinin 1 substance P receptor antagonists), antidopaminergics / dopamine receptor antagonists, benzodiazepines, and cannabinoids.

[0165] For example, the antiemetic agent is selected from the group consisting of neuroleptics, antihistamines, anticholinergics, steroids, 5HT-3-receptor antagonists, NK1-receptor antagonists, antidopaminergics / dopamine receptor antagonists, benzodiazepines and non-psychoactive cannabinoids.

[0166] In some embodiments, the antiemetic agent is a 5HT3-receptor antagonist (serotonin receptor antagonist). Non-limiting examples of 5HT3-receptor antagonists (serotonin receptor antagonists) include granisetron (Kytril), dolasetron, ondansetron (Zofran), tropisetron, ramosetron, palonosetron, alosetron, azasetron, bemesetron, zatisetron, batanopride, MDL-73147EF; metoclopramide, N-3389 (endo-3,9-dimethyl-3,9-diazabicyclo[3,3,1]non-7-yl-1H-indazole-3-carboxamide dihydrochloride), Y-25130 hydrochloride, MDL 72222, tropanyl-3,5-dimethylbenzoate, 3-(4-allylpiperazin-1-yl)-2-quinoxalinecarbonitrile maleate, zacopride hydrochloride, and mitrazepine. Other non-limiting examples of 5HT3-receptor antagonists (serotonin receptor antagonists) include cilansetron, clozapine, cyproheptadine, dazopride, hydroxyzine, lerisetron, metoclopramide, mianserin, olanzapine, palonosetron (plus netupitant), quetiapine, camosetron, ramosetron, licasetron, risperidone, ziprasidone, and zatosterone.

[0167] In certain embodiments, the 5HT-3-receptor antagonist is granisetron, dolasetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemesetron, zatisetron, batanopride, MDL-73147EF, metoclopramide, N-3389, Y-25130 hydrochloride, MDL 72222, tropanyl-3,5-dimethylbenzoate 3-(4-allyl-piperazin-1-yl)-2-quinoxalinecarbonitrile maleate, zacopride hydrochloride, and mirtazepine.

[0168] In certain embodiments, the 5HT-3-receptor antagonist is granisetron, dolasetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemesetron, and zatisetron.

[0169] In certain embodiments, the 5HT-3-receptor antagonist is granisetron, dolasetron, or ondansetron.

[0170] In certain embodiments, the 5HT-3-receptor antagonist is granisetron.

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

[0172] In some embodiments, the antiemetic agent is an antihistamine. Non-limiting examples of antihistamines include piperazine derivatives (e.g., cyclizine, meclizine, and cinnarizine); promethazine; dimenhydrinate (Dramamine, Gravol); diphenhydramine; hydroxyzine; buclizine; and meclizine hydrochloride (Bonine, Antivert), doxylamine, and mitrazepine.

[0173] In some embodiments, the antiemetic agent is an anticholinergic (an inhibitor of acetylcholine receptors). Non-limiting examples of anticholinergic agents include atropine, scopolamine, glycopyrone, hyoscine, Artane (trihexy-5-trihexyphenidyl hydrochloride), Contin (benztropine mesylate), Akineton (biperiden hydrochloride), Dizipar (Norflex: orphenadrine citrate), diphenhydramine, hydroxyzine, hyoscyamine, and Chemadrin (procyclidine hydrochloride).

[0174] In some embodiments, the antiemetic agent comprises a steroid (e.g., a corticosteroid). Non-limiting examples of steroids include betamethasone, dexamethasone, methylprednisolone, Prednisone®, and trimethobenzamide (Tigan).

[0175] In certain embodiments, the antiemetic agent is an NK1-receptor antagonist (e.g., a neurokinin 1 substance P receptor antagonist). Non-limiting examples of NK1-receptor antagonists include aprepitant, casopitant, ezlopitant, fosaprepitant, maropitant, netupitant, rolapitant, and vestipitant.

[0176] Other non-limiting examples of NK1-receptor antagonists include: MPC-4505, GW597599, MPC-4505, GR205171, L-759274, SR 140333, CP-96,345, BIIF 1149, NKP 608C, NKP 608A, CGP 60829, SR 140333 (norpitantium besylate / chloride), LY 303870 (lanepitant), MDL-105172A, MDL-103896, MEN-11149, MEN-11467, DNK 333A, YM-49244, YM-44778, ZM-274773, MEN-10930, S-19752, Neuronorm, YM-35375, DA-5018, MK-869, L-754030, CJ-11974, L-758298, DNK-33A, 6b-l, CJ-11974, benserazide and carbidopa, TAK-637 [(aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazotino[2,1-g][1,7]naphthyridine-6,13-dione], PD 154075, ([(2-benzofuran)-CHOCO]-(R)-α-MeTrp-(S)-NHCH(CH)Ph), FK888, and (D-Pro, D-Trp, Phe)SP.

[0177] In some embodiments, the antiemetic agent is an antidopaminergic / dopamine receptor antagonist (e.g., a dopamine receptor antagonist, e.g., a D2 or D3 antagonist). Non-limiting examples include phenothiazines (e.g., promethazine, chlorpromazine, prochlorperazine, perphenazine, hydroxyzine, thiethylperazine, metopimazine); benzamides (e.g., metoclopramide, domperidone), butyrophenones (e.g., haloperidol, droperidol); alizapride, bromopride, clebopride, domperidone, itopride, metoclopramide, trimethobenzamide, and amisulpride.

[0178] In some embodiments, antiemetic agents include non-psychoactive cannabinoids (e.g., cannabidiol (CBD), cannabidiol dimethylheptyl (CBD-DMH), tetra-hydro-cannabinol (THC), cannabinoid agonists such as WIN 55-212 (CB1 and CB2 receptor agonist), dronabinol (Marinol®), and nabilone (Cesamet)).

[0179] Other examples of antiemetics include: c-9280 (Merck); benzodiazepines (diazepam, midazolam, lorazepam); neuroleptic / antipsychotics (e.g., dixyrazine, haloperidol, and prochlorperazine (Compazine®)); cerium oxalate; propofol; sodium citrate; dextrose; fructose (Nauzene); orthophosphate; fructose; glucose (Emetrol); bismuth subsalicylate (Pepto Bismol); ephedrine; vitamin B6; peppermint, lavender, and lemon essential oils; and ginger.

[0180] Further examples of antiemetic agents include those described in US 20120101089A1; US ​​10,071,088 B2; US 6,673,792 B1; US ​​6,197,329 B1; US ​​10,828,297 B2; US 10,322,106 B2; US 10,525,033 B2; WO 2009080351 A1; WO 2019203753 A2; WO 2002020001 A2; US 8,119,697 B2; US 5,039,528; US20090305964A1; and WO 2006 / 111169, each of which is incorporated herein by reference in its entirety.

[0181] In certain embodiments, the additional therapeutic agent or regimen is administered to the patient prior to contact or administration of the compound and pharmaceutical composition (e.g., about 1 hour, about 6 hours, about 12 hours, about 24 hours, about 48 hours, about 1 week, or about 1 month).

[0182] In some embodiments, the additional therapeutic agent or regimen is administered to the patient at approximately the same time as the contact or administration of the compound and the pharmaceutical composition.In one example, the additional therapeutic agent or regimen and the compound and the pharmaceutical composition are simultaneously provided to the patient in the same formulation.In another example, the additional therapeutic agent or regimen and the compound and the pharmaceutical composition are simultaneously provided to the patient in separate formulations.

[0183] Patient selection In certain embodiments, the methods described herein further include identifying a patient (e.g., subject) in need of said treatment (e.g., by blood assay, body mass index, or other conventional methods known in the art).

[0184] In certain embodiments, the methods described herein further include a step of identifying a patient (e.g., a subject) having a disease, disorder, or condition provided herein (e.g., a GLP-1-related disease, disorder, or condition).

[0185] In certain embodiments, the methods described herein further include identifying a patient (e.g., a patient) with type 2 diabetes. In certain embodiments, determining whether a patient has type 2 diabetes includes performing an assay to determine hemoglobin A1c (HbA1c) levels, fasting plasma glucose levels, non-fasting plasma glucose levels, or any combination thereof. In certain embodiments, the HbA1c level is about 6.5% to about 24.0%. In certain embodiments, the HbA1c level is about 6.5% or higher. In certain embodiments, the HbA1c level is about 8.0% or higher. In certain embodiments, the HbA1c level is about 10.0% or higher. In certain embodiments, the HbA1c level is about 12.0% or higher. In certain embodiments, the HbA1c level is about 14.0% or higher. In certain embodiments, the HbA1c level is about 16.0% or higher. In some embodiments, the HbA1c level is about 18.0% or higher. In some embodiments, the HbA1c level is about 20.0% or higher. In some embodiments, the HbA1c level is about 22.0% or higher. In some embodiments, the HbA1c level is about 24.0% or higher.

[0186] In some embodiments, fasting plasma glucose levels are from about 120 mg / dL or greater to about 750 mg / dL or greater. In some embodiments, fasting plasma glucose levels are from about 200 mg / dL or greater to about 500 mg / dL or greater. In some embodiments, fasting plasma glucose levels are from about 300 mg / dL or greater to about 700 mg / dL or greater.

[0187] In some embodiments, non-fasting plasma glucose levels are from about 190 mg / dL or greater to about 750 mg / dL or greater. In some embodiments, non-fasting plasma glucose levels are from about 250 mg / dL or greater to about 450 mg / dL or greater. In some embodiments, non-fasting plasma glucose levels are from about 400 mg / dL or greater to about 700 mg / dL or greater.

[0188] In some embodiments, determining whether a patient has type 2 diabetes further includes determining the patient's BMI. In some embodiments, the patient's BMI is about 22 kg / m 2 or greater to about 100 mg / dL or greater. In some embodiments, the patient's BMI is about 30 kg / m 2 or greater to about 90 mg / dL or greater. In some embodiments, the patient's BMI is about 40 kg / m 2 or greater to about 80 mg / dL or greater. In some embodiments, the patient's BMI is about 50 kg / m 2 or higher to about 70 mg / dL or higher.

[0189] In some embodiments, additional factors (e.g., risk factors) used to determine whether a patient has type 2 diabetes further include the patient's age and ethnicity. In some embodiments, the patient is about 10 years old or older. In some embodiments, the patient is about 15 years old or older. In some embodiments, the patient is about 20 years old or older. In some embodiments, the patient is about 25 years old or older. In some embodiments, the patient is about 30 years old or older. In some embodiments, the patient is about 35 years old or older. In some embodiments, the patient is about 40 years old or older. In some embodiments, the patient is about 42 years old or older. In some embodiments, the patient is about 44 years old or older. In some embodiments, the patient is about 46 years old or older. In some embodiments, the patient is about 48 years old or older. In some embodiments, the patient is about 50 years old or older. In some embodiments, the patient is about 52 years old or older. In some embodiments, the patient is about 54 years old or older. In some embodiments, the patient is about 56 years old or older. In some embodiments, the patient is about 58 years old or older. In some embodiments, the patient is about 60 years old or older. In some embodiments, the patient is about 62 years old or older. In some embodiments, the patient is about 64 years old or older. In some embodiments, the patient is about 66 years old or older. In some embodiments, the patient is about 68 years old or older. In some embodiments, the patient is about 70 years old or older. In some embodiments, the patient is about 72 years old or older. In some embodiments, the patient is about 74 years old or older. In some embodiments, the patient is about 76 years old or older. In some embodiments, the patient is about 78 years old or older. In some embodiments, the patient is about 80 years old or older.In some embodiments, the patient is about 85 years old or older. In some embodiments, the patient is about 90 years old or older. In some embodiments, the patient is about 95 years old or older. In some embodiments, the patient's ethnicity can be African American, American Indian or Alaska Native, Asian American, Hispanic or Latino American, or Native Hawaiian or Pacific Islander.

[0190] In some embodiments, the patient is a pediatric patient.The term "pediatric patient" used herein refers to patients who are under 21 years old at the time of diagnosis or treatment.The term "child" can be further divided into various subgroups, including neonates (from birth to 1 month); infants (from 1 month to 2 years); children (from 2 to 12 years); and adolescents (from 12 to 21 years (up to but not including their 22nd birthday)).Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. In certain embodiments, the pediatric patient is between birth and 28 days of age, between 29 days of age and less than 2 years of age, between 2 and less than 12 years of age, or between 12 and 21 years of age (up to but not including the 22nd birthday). In certain embodiments, the pediatric patient is between birth and 28 days of age, between 29 days of age and less than 1 year of age, between 1 month and less than 4 months of age, between 3 months and less than 7 months of age, between 6 months and less than 1 year of age, between 1 year and less than 2 years of age, between 2 years and less than 3 years of age, between 2 years and less than 7 years of age, between 3 years and less than 5 years of age, between 5 years and less than 10 years of age, between 6 years and less than 13 years of age, between 10 years and less than 15 years of age, or between 15 years and less than 22 years of age. In certain embodiments, the patient is an adult patient. [Example]

[0191] General information: All evaporations were performed in vacuo using a rotary evaporator. Thin-layer chromatography (TLC) was performed on silica gel plates, and spots were visualized with UV light (214 and 254 nm). Column and flash chromatographic purifications were performed using silica gel (100-200 mesh). Solvent systems are listed as volumetric mixtures. NMR spectra were recorded on a Bruker 400 or Varian (400 MHz) spectrometer. 1H chemical shifts are reported in δ values ​​in ppm using deuterated solvents as internal standards. Data are as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constant (Hz), and integration. LCMS spectra were obtained on a SHIMADZU LC20-MS2020 or Agilent 1260 series 6125B mass spectrometer, Agilent 1200 series 6110 or 6120 mass spectrometer equipped with an electrospray ionizer unless otherwise stated.

[0192] The present disclosure will be further understood by reference to the following examples, which are intended to be purely exemplary of the present disclosure. The present disclosure is not limited in scope by the exemplified embodiments, which are intended only as illustrations of one aspect of the present disclosure. Any methods that are functionally equivalent are within the scope of the present disclosure. Various modifications of the present disclosure, in addition to those described herein, will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to be encompassed by the appended claims.

[0193] Example 1: 1-{[2-({4-[2-(2,4-dichlorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (1) [ka] Step A: 4-bromo-2-(2,4-dichlorophenyl)-2-methylbenzo[d][1,3]dioxole A mixture of 3-bromobenzene-1,2-diol (15.0 g, 79.8 mmol), 1-(2,4-dichlorophenyl)ethan-1-one (18.6 g, 95.9 mmol), and TsOH·HO (3.0 g, 15.8 mmol) in toluene (120 mL) was stirred at 148 °C for 48 h under argon. The mixture was filtered, and the residue was purified by silica gel column chromatography to give 4-bromo-2-(2,4-dichlorophenyl)-2-methylbenzo[d][1,3]dioxole (11.2 g, 39.3% yield).

[0194] Step B: tert-Butyl 4-(2-(2,4-dichlorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate A mixture of 4-bromo-2-(2,4-dichlorophenyl)-2-methylbenzo[d][1,3]dioxole (5.0 g, 14.0 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (4.3 g, 14.0 mmol), Pd(dppf)Cl (2.0 g, 2.9 mmol), and KCO (7.7 g, 55.9 mmol) in 1,4-dioxane / HO (100 mL / 10 mL) was stirred at 90 °C for 16 h under argon. The mixture was filtered, and the residue was purified by silica gel column chromatography to give tert-butyl 4-(2-(2,4-dichlorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (4.6 g, yield: 71.3%).

[0195] Step C: tert-Butyl 4-(2-(2,4-dichlorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-carboxylate A mixture of tert-butyl 4-(2-(2,4-dichlorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.0 g, 2.2 mmol) and Pd / C (10% w / w, 100 mg) in EtOAc (100 mL) was stirred under H at room temperature for 16 h. The mixture was filtered and the filtrate was concentrated to give tert-butyl 4-(2-(2,4-dichlorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-carboxylate (1.0 g). MS calculated: 463.1; MS found: 408.2 [M+H-56]. + .

[0196] Step D: 4-(2-(2,4-dichlorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine A mixture of tert-butyl 4-(2-(2,4-dichlorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-carboxylate (75 mg, 0.16 mmol) and TFA (0.5 mL) in DCM (3 mL) was stirred at room temperature for 1 hour. The mixture was concentrated to give 4-(2-(2,4-dichlorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine (56 mg, yield: 96.8%). MS calculated: 363.1; MS found: 364.1 [M+H] + .

[0197] Step E: 1-((2-((4-(2-(2,4-dichlorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile A mixture of 4-(2-(2,4-dichlorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine (56 mg, 0.155 mmol) and TEA (78 mg, 0.78 mmol) in DCM (5 mL) was stirred at room temperature for 0.5 h. 3-((methylsulfonyl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)picolinaldehyde (50 mg, 0.15 mmol) was added, and the mixture was stirred for 2 h. NaBH(OAc)3 (132 mg, 0.62 mmol) was added, and the mixture was stirred at room temperature for 16 h. 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 filtrate was concentrated. The residue was purified by TLC gel to give 1-((2-((4-(2-(2,4-dichlorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (70 mg, yield: 67.9%). MS calculated: 669.2; MS found: 670.3 [M+H] + .

[0198] Step F: 1-{[2-({4-[2-(2,4-dichlorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (1) A mixture of 1-((2-((4-(2-(2,4-dichlorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (70 mg, 0.10 mmol) and NH2NH2·H2O (0.5 mL) in EtOH (2 mL) was stirred at 70 °C for 1 h. The mixture was purified by prep-HPLC to give 1-{[2-({4-[2-(2,4-dichlorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (1) (25.3 mg, yield: 35.7%). MS calculated: 668.2; MS found: 669.3 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 9.21 (s, 1 H), 8.54 (s, 1 H), 7.77 (d, J = 8 Hz, 1 H), 7.55 (s, 1 H), 7.36 (dd, J = 14.4 Hz, 6 Hz, 1 H), 6.85 - 6.75 (m, 3 H), 4.60 - 4.40 (m, 2 H), 3.65 - 3.47 (m, 2 H), 3.13 - 2.95 (m, 5 H), 2.40 - 2.17 (m, 2 H), 2.11 (s, 3 H), 2.10 - 1.98 (m, 2H), 1.44 - 1.40 (m, 2H), 1.32 - 1.25 (m, 2 H). 19 F NMR(377 MHz, CD3OD):δ -65.31.

[0199] Examples 2 and 3: 1-{[2-({4-[2-(2,4-dichlorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (2) (Enantiomer 1) and 1-{[2-({4-[2-(2,4-dichlorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (3) (Enantiomer 2) [ka]

[0200] Step A: (4-(2-(2,4-dichlorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-1,2,3,6-tetrahydropyridine (Enantiomer A and Enantiomer B) (4-(2-(2,4-dichlorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-1,2,3,6-tetrahydropyridine was subjected to chiral separation to give two enantiomers (DAICEL CHIRALCEL® AD, Supercritical CO2 / IPA (+0.1% 7.0 mol / L ammonia in IPA) = 85 / 15). Enantiomer A: MS calculated: 361.1; MS found: 362.2 [M+H] + SFC retention time: 3.40 min. Enantiomer B: MS calculated: 361.1; MS found: 362.1 [M+H] + . SFC retention time: 3.89 min.

[0201] Step B: 1-{[2-({4-[2-(2,4-dichlorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (Enantiomer 1 and Enantiomer 2) 1-{[2-({4-[2-(2,4-dichlorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (2, Enantiomer 1) (2.2 mg) was obtained using a method similar to that described in Example 1. MS calculated: 668.2; MS found: 669.2 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 9.24 (s, 1 H), 8.54 (s, 1 H), 7.76(d, J = 8.4 Hz, 1 H), 7.56 (s, 1 H), 7.36 (dd, J1 = 8.4 Hz / J2 = 6.4 Hz, 1 H), 6.86 - 6.75 (m, 3 H), 4.63 (s, 2 H), 3.70 - 3.60 (m, 2 H), 3.30 - 3.00 (m, 5 H), 2.39 - 2.18 (m, 2 H), 2.18 - 2.03 (m, 5 H), 1.47 - 1.41 (m, 2 H), 1.30 - 1.25 (m, 2 H). 19 F NMR (377 MHz, CD3OD):δ -65.79, -79.63.

[0202] 1-{[2-({4-[2-(2,4-dichlorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (3, enantiomer 2) was prepared using an analogous method. MS calculated: 668.2; MS found: 669.2 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 9.23 (s, 1 H), 8.53 (s, 1 H), 7.76 (d, J = 8.8 Hz, 1 H), 7.56 (s, 1 H), 7.36 (dd, J1 = 8.8 Hz / J2 = 6.4 Hz, 1 H), 6.86 - 6.74 (m, 3 H), 4.57 (s, 2 H), 3.66 - 3.58 (m, 2 H), 3.21 - 3.10 (m, 2 H), 3.08 (s, 2 H), 3.08 - 2.98 (m, 1 H), 2.35 - 2.18 (m, 2 H), 2.18 - 2.00 (m, 5 H), 1.45 - 1.40 (m, 2 H), 1.29 - 1.22 (m, 2 H). 19 F NMR (377 MHz, CD3OD):δ -65.45.

[0203] Example 4: 1-{[2-({4-[2-(2-chloro-4-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (4) [ka] 1-{[2-({4-[2-(2-chloro-4-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (4) (15.5 mg) was obtained using a method similar to that described in Example 1. MS calculated: 652.2; MS found: 653.4 [M+H] + . 1 H NMR(400 MHz, CD3OD):δ 9.20 (s, 1 H), 8.52 (s, 1 H), 7.81 (dd, J = 6.0 Hz / J = 8.8 Hz, 1 H), 7.31 (dd, J = 2.4 Hz / J = 8.8 Hz, 1 H), 7.13 - 7.07 (m, 1 H), 6.85 - 6.73 (m, 3 H), 4.46 (s, 2 H), 3.59 - 3.46 (m, 2 H), 3.15 - 2.90 (m, 5 H), 2.31 - 2.15 (m, 2 H), 2.11 (s, 3 H), 2.09 - 1.94 (m, 2 H), 1.47 - 1.40 (m, 2 H), 1.32 - 1.26 (m, 2 H). 19 F NMR(377 MHz, CD3OD):δ -65.17, -113.07.

[0204] Example 5: 1-{[2-({4-[2-(2,4-difluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (5) [ka]

[0205] 1-{[2-({4-[2-(2,4-difluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (5) (31.2 mg) was obtained using a method similar to that described in Example 1. MS calculated: 636.2; MS found: 637.4 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 9.22 (s, 1 H), 8.52 (s, 1 H), 7.70 - 7.62 (m, 1 H), 7.05 (t, J = 11.2 Hz, 1 H), 6.97 (t, J = 8.4 Hz, 1 H), 6.88 - 6.72 (m, 3 H), 4.54 (s, 2 H), 3.59 (d, J = 12.0 Hz, 2 H), 3.20 - 2.96 (m, 5 H), 2.30 - 2.05 (m, 7 H), 1.46 - 1.40 (m, 2 H), 1.30 - 1.25 (m, 2 H). 19 F NMR(377 MHz, CD3OD):δ -65.37, -110.63.

[0206] Example 6: 1-((2-((4-(2-(2-chloro-4-methylphenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (6) [ka] Step A: ((2-chloro-4-methylphenyl)ethynyl)trimethylsilane A mixture of 2-chloro-1-iodo-4-methylbenzene (5.0 g, 19.8 mmol), ethynyltrimethylsilane (1.9 g, 19.4 mmol), CuI (189 mg, 0.99 mmol), Pd(PPh)Cl (1393 mg, 1.98 mmol), and TEA (3.5 mL) in DMSO (30 mL) was stirred at room temperature for 2 hours under argon. The mixture was poured into water (300 mL) and extracted with EtOAc (2 x 300 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the residue was concentrated. The residue was purified by column chromatography on silica gel (PE) to give ((2-chloro-4-methylphenyl)ethynyl)trimethylsilane (4.1 g, 92.7% yield). 1 H NMR (400 MHz, CDCl3): δ 7.18 (d, J = 8.0 Hz, 1 H), 7.01 (s, 1 H), 6.80 (d, J = 7.6 Hz, 1 H), 2.13 (s, 3 H), 0.08 (s, 9 H).

[0207] Step B: 2-chloro-1-ethynyl-4-methylbenzene A mixture of ((2-chloro-4-methylphenyl)ethynyl)trimethylsilane (4.1 g, 18.47 mmol) and KCO (12.7 g, 92.03 mmol) in MeOH (10 mL) and DCM (10 mL) was stirred at room temperature for 2 h. The mixture was filtered and the residue was concentrated to give 2-chloro-1-ethynyl-4-methylbenzene (2.6 g, yield: 93.9%). 1 H NMR (400 MHz, CDCl3):δ 7.41 (d, J = 8.0 Hz, 1 H), 7.22 (s, 1 H), 7.02 (dd, J1 = 0.8 Hz / J2 = 0.8 Hz, 1 H), 3.32 (s, 1 H), 2.34 (s, 3 H).

[0208] Step C: 4-bromo-2-(2-chloro-4-methylphenyl)-2-methylbenzo[d][1,3]dioxole 3-Bromobenzene-1,2-diol (1.5 g, 8.0 mmol), 2-chloro-1-ethynyl-4-methylbenzene (1.2 g, 8.0 mmol), and Ru(CO) in toluene (15 mL) 12 A mixture of (1.0 g, 1.6 mmol) was stirred in a sealed tube at 110 °C for 16 h under Ar. The mixture was poured into water (200 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the residue was concentrated. The residue was purified by column chromatography on silica gel (PE) to give 4-bromo-2-(2-chloro-4-methylphenyl)-2-methylbenzo[d][1,3]dioxole (360 mg, yield: 13.3%).

[0209] Step D: 1-((2-((4-(2-(2-chloro-4-methylphenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile 1-((2-((4-(2-(2-chloro-4-methylphenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (10.2 mg) was obtained using a method similar to that described in Example 1. MS calculated: 648.2; MS found: 649.5 [M+H] + . 1H NMR (400 MHz, CD3OD):δ 9.09 (d, J = 2.0 Hz, 1 H), 8.51 (d, J = 2.0 Hz, 1 H), 7.60 (d, J = 8.0 Hz, 1 H), 7.28 (s, 1 H), 7.10 (d, J = 8.0 Hz, 1 H), 6.76 - 6.64 (m, 3 H), 3.87 (s, 2 H), 3.26 (s, 2 H), 3.08 - 2.98 (m, 2 H), 2.76 - 2.66 (m, 1 H), 2.39 - 2.27 (m, 5 H), 2.07 (s, 3 H), 2.02 - 1.83 (m, 2 H), 1.79 (d, J = 11.6 Hz, 2 H), 1.41 (dd, J1 = 7.2 Hz / J2 = 4.8 Hz, 2 H), 1.25 (dd, J1 = 10.8 Hz / J2 = 4.8 Hz, 2 H). 19 F NMR (377 MHz, CD3OD):δ -64.58.

[0210] Example 7: 1-((2-((4-(2-(4-chloro-2-methylphenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (7) [ka] Step A: ((4-chloro-2-methylphenyl)ethynyl)trimethylsilane A mixture of 4-chloro-1-iodo-2-methylbenzene (5.0 g, 19.8 mmol), ethynyltrimethylsilane (3.4 mL, 23.6 mmol), CuI (75 mg, 0.40 mmol), Pd(PPh)Cl (556 mg, 0.79 mmol), and TEA (2.5 mL) in toluene (20 mL) was stirred at room temperature under Ar for 2 h. The mixture was poured into water (300 mL) and extracted with EtOAc (2 x 300 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the residue was concentrated. The residue was purified by column chromatography on silica gel (PE) to give ((4-chloro-2-methylphenyl)ethynyl)trimethylsilane (4.2 g, yield: 95.4%). 1 H NMR (400 MHz, CDCl3):7.15 (d, J = 8.4 Hz, 1 H), 6.99 (d, J = 2.0 Hz, 1 H), 6.90 (m, 1 H), 2.21 (s, 3 H), 0.06 (s, 9 H).

[0211] Step B: Synthesis of 4-chloro-1-ethynyl-2-methylbenzene A mixture of ((4-chloro-2-methylphenyl)ethynyl)trimethylsilane (4.2 g, 18.8 mmol) and K2CO3 (13.0 g, 94.17 mmol) in MeOH (10 mL) and DCM (10 mL) was stirred at room temperature for 2 hours. The mixture was filtered and the residue was concentrated to give 4-chloro-1-ethynyl-2-methylbenzene (2.8 g), which was used directly in the next reaction. 1 H NMR (400 MHz, CDCl3):7.37 (d, J = 8.4 Hz, 1 H), 7.22 - 7.20 (m, 1 H), 7.12 (dd, J1= 2.0 Hz / J2= 8.0 Hz, 1 H), 3.30 (s, 1 H), 2.42 (s, 3 H).

[0212] Step C: Synthesis of 4-bromo-2-(4-chloro-2-methylphenyl)-2-methylbenzo[d][1,3]dioxole 3-Bromobenzene-1,2-diol (1.5 g, 7.94 mmol), 4-chloro-1-ethynyl-2-methylbenzene (1.2 g, 7.94 mmol) and Ru(CO) in toluene (8 mL) 12 A mixture of (254 mg, 0.4 mmol) was stirred in a sealed tube at 110 °C for 16 h under Ar. The mixture was poured into water (200 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the residue was concentrated. The residue was purified by column chromatography on silica gel (PE) to give 4-bromo-2-(4-chloro-2-methylphenyl)-2-methylbenzo[d][1,3]dioxole (820 mg, yield: 30.6%). 1 H NMR (400 MHz, CDCl3):7.59 (d, J = 8.4 Hz, 1 H), 7.19 - 7.14 (m, 2 H), 6.92 (dd, J1= 1.2 Hz / J2= 8.4 Hz, 1 H), 6.74 - 6.66 (m, 2 H), 2.56 (s, 3 H), 2.02 (s, 3 H).

[0213] Step D: 1-((2-((4-(2-(4-chloro-2-methylphenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile 1-((2-((4-(2-(4-chloro-2-methylphenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (13.3 mg) was obtained using a method similar to that described in Example 1. MS calculated: 648.2; MS found: 649.3 [M+H] + . 1 H NMR (400 MHz, CD3OD-d4):δ 9.19 (d, J = 2.0 Hz, 1 H), 8.51 (d, J = 2.0 Hz, 1 H), 7.64 (d, J = 8.4 Hz, 1 H), 7.26 (d, J = 2.0 Hz, 1 H), 7.20 (dd, J1= 2.0 Hz / J2= 8.8 Hz, 1 H), 6.83 - 6.73 (m, 3 H), 4.42 (brs, 2 H), 3.56 - 3.47 (m, 2 H), 3.11 (s, 2 H), 3.06 - 2.93 (m, 3 H), 2.57 (s, 3 H), 2.25 - 2.14 (m, 2 H), 2.08 - 2.01 (m, 2 H), 1.98 (s, 3 H), 1.44 - 1.41 (m, 2 H), 1.28 - 1.25 (m, 2 H). 19 F NMR (377 MHz, CD3OD-d4):δ (-65.16).

[0214] Example 8: 1-((2-((4-(2-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (8) [ka] Step A: 4-bromo-2-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxole A mixture of 3-bromobenzene-1,2-diol (2.0 g, 10.6 mmol), 1-(2-fluoro-4-(trifluoromethyl)phenyl)ethan-1-one (2.6 g, 12.6 mmol), and TsOH·HO (1.0 g, 5.62 mmol) in toluene (50 mL) was stirred at 148 °C for 48 h in a water knockout drum under argon. The mixture was poured into aqueous NaHCO (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the residue was concentrated. The residue was purified by column chromatography on silica gel (PE) to give 4-bromo-2-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxole (1.4 g, 35.0% yield). 1 H NMR (400 MHz, CD3OD):δ 7.75 (t, J = 7.8 Hz, 1 H), 7.41 (t, J = 9.6 Hz, 2 H), 6.97 (dd, J1= 1.2 Hz / J2= 8.0 Hz, 1 H), 6.84 (d, J = 2.8 Hz, 1 H), 6.78 - 6.69 (m, 1 H), 2.14 (s, 3 H).

[0215] Step B: 1-((2-((4-(2-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile 1-((2-((4-(2-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (14.1 mg) was obtained using a method similar to that described in Example 1. MS calculated: 686.2; MS found: 687.2 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 9.22 (d, J = 0.8 Hz, 1 H), 8.53 (s, 1 H), 8.19 (t, J = 18 Hz, 1 H), 7.87 - 7.82 (m, 1 H), 7.60 - 7.49 (s, 1 H), 6.87 - 6.77 (m, 3 H), 4.59 - 4.53 (m, 2 H), 3.66 - 3.59 (m, 2 H), 3.16 - 3.12 (m, 2 H), 3.09 (s, 2 H), 2.95 - 2.87 (m, 1 H), 2.26 - 2.19 (m, 2 H), 2.10 - 2.03 (m, 5 H), 1.47 - 1.41 (m, 2 H), 1.30 - 1.25 (m, 2 H). 19 F NMR (377 MHz, CD3OD): δ (-64.46), (-65.51 ), (-112.30).

[0216] Example 9: 1-((2-((4-(2-(2-chloro-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (9) [ka] Step A: 4-bromo-2-(2-chloro-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxole A mixture of 3-bromobenzene-1,2-diol (2.0 g, 10.6 mmol), 1-(2-chloro-4-(trifluoromethyl)phenyl)ethan-1-one (2.8 g, 12.6 mmol), and TsOH·HO (1.0 g, 5.3 mmol) in toluene (50 mL) was stirred at 148 °C for 48 h in a water knockout drum under argon. The mixture was poured into aqueous NaHCO (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the residue was concentrated. The residue was purified by silica gel column chromatography (PE) to give 4-bromo-2-(2-chloro-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxole (1.5 g, 36.0% yield). 1 H NMR (400 MHz, CD3OD):δ 7.89 (d, J = 8.4 Hz, 1 H), 7.69 (s, 1H), 7.53 (d, J = 8.0 H, 1 H), 6.96 (d, J = 8.0 Hz, 1 H), 6.77 (d, J = 8.0 Hz, 1 H), 6.71 (d, J = 8.0 Hz, 1 H), 2.20 (s, 3 H).

[0217] Step B: 1-((2-((4-(2-(2-chloro-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile 1-((2-((4-(2-(2-chloro-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (28.0 mg) was obtained using a method similar to that described in Example 1. MS calculated: 702.2; MS found: 703.2 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 9.28 (d, J = 1. Hz, 1 H), 8.58 (d, J = 2.0 Hz, 1 H), 8.00 (d, J = 8.0 Hz, 1 H), 7.81 (s, 1 H), 7.67 (d, J = 8.0 Hz, 1 H), 6.90 - 6.78 (m, 3 H), 3.83 (s, 2 H), 3.48 - 3.35 (m, 2 H), 3.20 - 3.10 (m, 3 H), 3.08 (s, 2 H), 2.45 - 2.28 (m, 2 H), 2.17 (s, 5 H), 1.51 - 1.44 (m, 2 H), 1.32 - 1.26 (m, 2 H). 19 F NMR (377 MHz, CD3OD):δ (-64.57), (-66.64 ), (-76.87).

[0218] Example 10: 1-{[2-({4-[2-(4-chloro-3-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (10) [ka] 1-{[2-({4-[2-(4-chloro-3-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (10) (6.9 mg) was obtained using a method similar to that described in Example 1. MS calculated: 652.2; MS found: 653.3 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 9.21 (d, J =0.4 Hz, 1 H), 8.51 (d, J = 1.6 Hz, 1 H), 7.54 - 7.42 (m, 3 H), 6.85 - 6.72 (m, 3H), 4.58- 4.44 (m, 2 H), 3.62 - 3.52 (m, 2 H), 3.20 - 2.90 (m, 5 H), 2.32 - 2.17 (m, 2 H), 2.08 - 1.98 (m, 5 H), 1.46 - 1.40 (m, 2 H), 1.30 - 1.22 (m, 2 H). 19 F NMR(377 MHz, CD3OD):δ -65.30, -65.34, -116.79.

[0219] Example 11: 1-{[2-({4-[2-methyl-2-(6-methylpyridin-3-yl)-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (11) [ka]

[0220] Step A: 2-methyl-5-((trimethylsilyl)ethynyl)pyridine A mixture of 5-bromo-2-methylpyridine (30.0 g, 174 mmol), ethynyltrimethylsilane (18.8 g, 192 mmol), CuI (663 mg, 3.5 mmol), and Pd(PPh)Cl (4.9 g, 7.0 mmol) in DMSO (300 mL) and TEA (24 mL) was stirred at 50 °C for 16 h. After the reaction was complete, the mixture was washed with H2O (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 silica gel column chromatography (PE / EA = 10 / 1) to give 2-methyl-5-((trimethylsilyl)ethynyl)pyridine (29.5 g, 90% yield). MS calculated: 189.1; MS found: 190.1 [M+H]. + .

[0221] Step B: 5-ethynyl-2-methylpyridine A mixture of 2-methyl-5-((trimethylsilyl)ethynyl)pyridine (29.5 g, 156 mmol) and K2CO3 (107.7 g, 780 mmol) in MeOH (300 mL) was stirred at room temperature overnight. After the reaction was completed, the mixture was filtered, the filtrate was evaporated to dryness, and the residue was purified by silica gel column chromatography (PE / EA=15 / 1) to give 5-ethynyl-2-methylpyridine (4.1 g, 22.6% yield). MS calculated: 117.1; MS found: 118.2 [M+H] + .

[0222] Step C: 5-(4-bromo-2-methylbenzo[d][1,3]dioxol-2-yl)-2-methylpyridine 3-Bromobenzene-1,2-diol (5.4 g, 28.5 mmol), 5-ethynyl-2-methylpyridine (4.0 g, 34.2 mmol), and Ru(CO) in toluene (40 mL) 12A mixture of (910 mg, 1.425 mmol) was stirred under N at 110 °C 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 silica gel column chromatography (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%). MS calculated: 305.0; MS found: 305.9 [M+H] + .

[0223] Step D: 1-{[2-({4-[2-methyl-2-(6-methylpyridin-3-yl)-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (11) 1-{[2-({4-[2-methyl-2-(6-methylpyridin-3-yl)-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (11) (12.8 mg) was obtained using a method similar to that described in Example 1. MS calculated: 615.3; MS found: 616.4 [M+H] + . 1H NMR (400 MHz, CD3OD):δ 9.22 (d, J = 1.6 Hz, 1 H), 8.64 (d, J = 2.0 Hz, 1 H), 8.52 (d, J = 2.0 Hz, 1 H), 7.96 (dd, J1 = 8.0 Hz / J2 = 2.4 Hz, 1 H), 7.35 (d, J = 4.0 Hz, 1 H), 6.86 - 6.73 (m, 3 H), 4.53 (s, 2 H), 3.60 (d, J = 10.0 Hz, 2 H), 3.24 - 2.95 (m, 5 H), 2.54 (s, 3 H), 2.32-2.16 (m, 2 H), 2.10 - 1.99 (m, 5 H), 1.46 - 1.38 (m, 2 H), 1.33 - 1.25 (m, 2 H). 19 F NMR (377 MHz, CD3OD):δ -65.35.

[0224] Example 12: 1-{[2-({4-[2-(4-chloro-2-fluorophenyl)-7-fluoro-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (12) [ka] Step A: 3-Bromo-6-fluoro-2-hydroxybenzaldehyde To a solution of MgCl (7.9 g, 83.8 mmol) and paraformaldehyde (3.8 g, 125.6 mmol) in THF (100 mL) was added TEA (12.7 g, 125.6 mmol) at room temperature. The reaction was stirred at room temperature for 1 hour. 2-Bromo-5-fluorophenol (8.0 g, 41.9 mmol) was added, and the reaction mixture was stirred at 70 °C for 4 hours. After completion of the reaction, the reaction was quenched with HCl (1 M, 30 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine (50 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (PE:EA = 10:1) to give 3-bromo-6-fluoro-2-hydroxybenzaldehyde (4.8 g, 49% yield). 1 H NMR (400 MHz, DMSO-d6):δ 10.74 (s, 1H), 7.50 (dd, J=8.8, 6.4 Hz, 1 H), 6.75 (dd, J=10.5, 2.9 Hz, 1 H), 6.62 (td, J=8.6, 2.9 Hz, 1 H).

[0225] Step B: 3-Bromo-6-fluorobenzene-1,2-diol To a solution of 3-bromo-6-fluoro-2-hydroxybenzaldehyde (4.8 g, 22.0 mmol) in THF (50 mL) was added HO (30% aqueous solution, 2 mL) and NaOH (2 M, 2 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction mixture was quenched with saturated NaHSO (30 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE) to give 3-bromo-6-fluorobenzene-1,2-diol (2.0 g, 44% yield). 1H NMR (400 MHz, DMSO-d6):δ 9.81 (s, 1 H), 9.65 (s, 1 H), 6.94 (dd, J=9.0, 5.6 Hz, 1 H), 6.64 (dd, J=10.2, 9.0 Hz, 1 H).

[0226] Step C: 4-bromo-2-(4-chloro-2-fluorophenyl)-7-fluoro-2-methylbenzo[d][1,3]dioxole 3-Bromo-6-fluorobenzene-1,2-diol (1.0 g, 4.85 mmol) and 4-chloro-1-ethynyl-2-fluorobenzene (822 mg, 5.34 mmol) and Ru(CO) in toluene (20 mL) 12 A mixture of (155 mg, 0.243 mmol) was degassed and filled with Ar. The reaction mixture was stirred in a sealed tube at 100° C. for 16 hours. After the reaction was completed, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (PE) to give 4-bromo-2-(4-chloro-2-fluorophenyl)-7-fluoro-2-methylbenzo[d][1,3]dioxole (350 mg, 20.0% yield).

[0227] Step D: 1-{[2-({4-[2-(4-chloro-2-fluorophenyl)-7-fluoro-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile 1-{[2-({4-[2-(4-chloro-2-fluorophenyl)-7-fluoro-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (12) (6.9 mg) was obtained using a method similar to that described in Example 1. MS calculated: 670.2; MS found: 671.3 [M+H] + . 1H NMR (400 MHz, CD3OD):δ 9.20 (d, J = 1.6 Hz, 1 H), 8.52 (d, J = 1.6 Hz, 1 H), 7.62 (t, J = 8.4 Hz, 1 H), 7.33 (dd, J = 10.8 Hz, 1.6 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 6.80 - 6.66 (m, 2 H), 4.49 (s, 2 H), 3.55 (d, J = 10.8 Hz, 2 H), 3.09 (s, 2 H), 3.15 - 2.90 (m, 3 H), 2.25 - 2.10 (m, 2 H), 2.11 (s, 3 H), 2.09 - 1.96 (m, 2H), 1.48 - 1.40 (m, 2H), 1.32 - 1.22 (m, 2H). 19 F NMR(377 MHz, CD3OD):δ -65.42, -112.09, -142.88.

[0228] Examples 13 and 14: 1-{[2-({4-[2-(4-chloro-2-fluorophenyl)-6-fluoro-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (Enantiomer 1 (13) and Enantiomer 2 (14)) [ka] Step A: 4-(2-(4-chloro-2-fluorophenyl)-6-fluoro-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine (Enantiomer A and Enantiomer B) 4-(2-(4-chloro-2-fluorophenyl)-6-fluoro-2-methylbenzo[d][1,3]dioxol-4-yl)piperidinyl was subjected to chiral separation (DAICELCHIRALCEL® AD, Supercritical CO2 / MeOH (+0.1% 7.0 mol / l ammonia in MeOH) = 60 / 40) to give 4-(2-(4-chloro-2-fluorophenyl)-6-fluoro-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine Enantiomer A and Enantiomer B. Enantiomer A: MS calculated: 365.1; MS found: 366.2 [M+H] + SFC retention time: 2.68 min. Enantiomer B: MS calculated: 365.1; MS found: 366.2 [M+H] + . SFC retention time: 3.01 min.

[0229] Step B: 1-{[2-({4-[2-(4-chloro-2-fluorophenyl)-6-fluoro-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (Enantiomer 1, 13) 1-{[2-({4-[2-(4-chloro-2-fluorophenyl)-6-fluoro-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (13) (Enantiomer 1) (25.1 mg). MS calculated: 670.2; MS found: 671.2 [M+H] + . 1H NMR (400 MHz, CD3OD-d4):9.17 (d, J = 1.6 Hz, 1 H), 8.51 (d, J = 2.0 Hz, 1 H), 7.60 (t, J = 8.4 Hz, 1 H), 7.30 (dd, J1 = 2.0 Hz / J2 = 11.2 Hz, 1 H), 7.23 (dd, J1 = 2.0 Hz / J2 = 8.8 Hz, 1 H), 6.58 (dd, J1 = 2.4 Hz / J2 = 8.0 Hz, 1 H), 6.51 (dd, J1 = 2.4 Hz / J2 = 10.8 Hz, 1 H), 4.30 (s, 2 H), 3.45 - 3.35 (m, 2H), 3.13 (s, 2 H), 2.97 - 2.79 (m, 3 H), 2.15 - 2.02 (m, 5 H), 2.02 - 1.90 (m, 2 H), 1.44 - 1.40 (m, 2 H), 1.30 - 1.25 (m, 2 H). 19 F NMR (377 MHz, CD3OD):δ -65.15, -112.22, -121.81. 1-{[2-({4-[2-(4-chloro-2-fluorophenyl)-6-fluoro-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (enantiomer 2, 14) was prepared using a similar method using 4-(2-(4-chloro-2-fluorophenyl)-6-fluoro-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine (enantiomer B) as the starting material. MS calculated: 670.2; MS found: 671.2 [M+H] + . 1H NMR (400 MHz, CD3OD-d4):δ 9.16 (d, J = 2.0 Hz, 1 H), 8.51 (d, J = 2.0 Hz, 1 H), 7.60 (t, J = 8.4 Hz, 1 H), 7.30 (dd, J1 = 2.0 Hz / J2 = 10.8 Hz, 1 H), 7.23 (dd, J1 = 2.0 Hz / J2 = 8.4 Hz, 1 H), 6.58 (dd, J1 = 2.8 Hz / J2 = 8.4 Hz, 1 H), 6.51 (dd, J1 = 2.8 Hz / J2 = 10.8 Hz, 1 H), 4.27 (s, 2 H), 3.43 - 3.32 (m, 2H), 3.14 (s, 2 H), 2.94 - 2.75 (m, 3 H), 2.15 - 2.00 (m, 5 H), 2.00 - 1.90 (m, 2 H), 1.44 - 1.40 (m, 2 H), 1.30 - 1.25 (m, 2 H). 19 F NMR (377 MHz, CD3OD):δ -65.11, -112.23, -121.84.

[0230] Example 15: 1-{[2-({4-[2-(4-chloro-2-fluorophenyl)-5-fluoro-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (15) [ka]

[0231] Step A: 2-Bromo-1-fluoro-3,4-dimethoxybenzene To a solution of 4-fluoro-1,2-dimethoxybenzene (2.0 g, 12.8 mmol) and TMEDA (1.5 g, 12.8 mmol) in THF (20 mL) was added n-BuLi (12 mL, 1.6 mol / L, 19.2 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 1.5 hours. Then, 1,2-dibromo-1,1,2,2-tetrachloroethane (5.43 g, 16.7 mmol) was added, and the reaction mixture was stirred at −78° C. for 2 hours. After the reaction was completed, the reaction mixture was quenched with NH4Cl solution (50 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel (PE:EA=10:1) column chromatography to give 2-bromo-1-fluoro-3,4-dimethoxybenzene (2.5 g, crude product).

[0232] Step B: 3-Bromo-4-fluorobenzene-1,2-diol To a solution of 2-bromo-1-fluoro-3,4-dimethoxybenzene (2.5 g, 10.7 mmol) in DCM (25 mL) was added BBr3 (5.3 g, 21.4 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was quenched with MeOH (100 mL) and concentrated in vacuo. The residue was purified by column chromatography (PE:EA=3:1) to give 3-bromo-4-fluorobenzene-1,2-diol (1.4 g, 52.8% yield in two steps).

[0233] Step C: 1-{[2-({4-[2-(4-chloro-2-fluorophenyl)-5-fluoro-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (15) 1-{[2-({4-[2-(4-chloro-2-fluorophenyl)-5-fluoro-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (15) (4.2 mg) was obtained using a method similar to that described in Example 1. MS calculated: 670.2; MS found: 671.3 [M+H] + . 1 H NMR(400 MHz, CDCl3): δ 9.20 (s, 1 H), 8.52 (s, 1 H), 7.62 (t, J = 8.6 Hz, 1 H), 7.32 (dd, J1 = 2.0 Hz / J2 = 10.8 Hz, 1 H), 7.25 (dd, J1 = 1.6 Hz / J2 = 8.8 Hz, 1 H), 6.75 - 6.68 (m, 1 H), 6.61 - 6.52 (m, 1 H), 4.44 (s, 2 H), 3.57 - 3.45 (m, 2 H), 3.25 - 3.15 (m, 1 H), 3.12 (s, 2 H), 3.08 - 2.92 (m, 2 H), 2.53 - 2.38 (m, 2 H), 2.10 - 2.03 (m, 3 H), 2.00 - 1.87 (m, 2 H), 1.47 - 1.40 (m, 2 H), 1.31 - 1.24 (m, 2 H). 19 F NMR(377 MHz, CDCl3): δ -65.38, -112.17, -128.37.

[0234] Example 16: 1-{[2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(difluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (16) [ka]

[0235] Step A: 1-((2-methyl-5-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile A mixture of 1-((5-bromo-2-methylpyridin-3-yl)methyl)cyclopropane-1-carbonitrile (140 mg, 0.56 mmol), 3-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole (358 mg, 1.68 mmol), Pd(OAc) (13 mg, 0.06 mmol), pivalic acid (38 mg, 0.37 mmol), KCO (464 mg, 3.36 mmol), and PCy HBF (41 mg, 0.11 mmol) in toluene (10 mL) was stirred at 140 °C for 16 h under argon. The mixture was filtered, and the filtrate was concentrated. The residue was purified by prep-TLC (DCM:MeOH = 20:1) to give 1-((2-methyl-5-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (20 mg, yield: 9.3%). MS calculated: 383.2; MS found: 384.5 [M+H] + .

[0236] Step B: 1-((2-formyl-5-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile A mixture of 1-((2-methyl-5-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (20 mg, 0.05 mmol) and SeO (58 mg, 0.52 mmol) in 1,4-dioxane (3 mL) was stirred at 80 °C for 16 h. The mixture was filtered, and the filtrate was concentrated to give 1-((2-formyl-5-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (18 mg, yield: 90.68%). MS calculated: 397.2; MS found: 398.3 [M+H] + .

[0237] Step C: (S)-1-((2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile A mixture of (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine (26 mg, 0.05 mmol) and TEA (23 mg, 0.23 mmol) in DCM (5 mL) was stirred at room temperature for 0.5 h. To the mixture was added 1-((2-formyl-5-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (18 mg, 0.05 mmol), and the mixture was stirred for 2 h. To the mixture was added NaBH(OAc)3 (38 mg, 0.18 mmol), and the mixture was stirred at room temperature for 16 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 filtrate was concentrated to give (S)-1-((2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (50 mg). MS calculated: 728.3; MS found: 729.4 [M+H] + .

[0238] Step D: 1-{[2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(difluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (16) A mixture of (S)-1-((2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (50 mg, 0.07 mmol) and TABF (1 M in THF, 2 mL) in THF (1 mL) was stirred at 60° C. for 8 hours. The mixture was purified by prep-HPLC to give 1-{[2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(difluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (16) (6.0 mg, yield: 14.5%). MS calculated: 598.2; MS found: 599.4 [M+H] + . 1 HNMR(400 MHz, CD3OD):δ 9.08 (s, 1 H), 8.53 (s, 1 H), 7.59 (t, J = 8.2 Hz, 1 H), 7.27 (dd, J = 1.6 Hz / J = 10.8 Hz, 1 H), 7.20 (d, J = 8.8 Hz, 1H), 6.80 - 6.65 (m, 3 H), 4.10 - 3.90 (br.s, 2 H), 3.25 - 3.08 (m, 6 H), 2.85 - 2.70 (m, 1 H), 2.53 (s, 3 H), 2.03 (s, 3 H), 2.05 - 1.79 (m, 4 H), 1.47 - 1.40 (m, 2 H), 1.27 - 1.21 (m, 2 H). 19 F NMR(377 MHz, CD3OD):δ -112.28.

[0239] Example 17: 1-{[2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(difluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (17) [ka]

[0240] Step A: (S)-6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-((1-cyanocyclopropyl)methyl)nicotinonitrile A mixture of (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine 4-methylbenzenesulfonate (99 mg, 0.19 mmol) and TEA (96 mg, 0.95 mmol) in DCM (5 mL) was stirred at room temperature for 0.5 h. 5-((1-cyanocyclopropyl)methyl)-6-formylnicotinonitrile (40 mg, 0.76 mmol) was added, and the mixture was stirred for 2 h. NaBH(OAc)3 (161 mg, 0.57 mmol) was added, and the mixture was stirred at room temperature for 16 h. 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 filtrate was concentrated. The residue was purified by silica gel column chromatography to give (S)-6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-((1-cyanocyclopropyl)methyl)nicotinonitrile (44 mg, yield: 42.8%).

[0241] Step B: (S)-6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-((1-cyanocyclopropyl)methyl)-N'-hydroxynicotinimidamide A mixture of (S)-6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-((1-cyanocyclopropyl)methyl)nicotinonitrile (44 mg, 0.081 mmol) and aqueous NHOH (50%) (11 mg, 0.16 mmol) in EtOH (5 mL) was stirred at 90 °C for 1 h. The mixture was concentrated to give (S)-6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-((1-cyanocyclopropyl)methyl)-N'-hydroxynicotinimidamide (47 mg, crude). MS calculated: 575.2; MS found: 576.2 [M+H] + .

[0242] Step C: (S)-1-((2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile To a solution of (S)-6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-((1-cyanocyclopropyl)methyl)-N'-hydroxynicotinimidamide (47 mg, 0.082 mmol) in THF (3 mL) was added 2,2-difluoroacetic anhydride (71 mg, 0.41 mmol) in THF (0.5 mL) dropwise at 0°C. The mixture was stirred at room temperature for 16 hours. The mixture was poured into aqueous sodium bicarbonate (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by prep-TLC to give (S)-1-((2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (52 mg, crude). MS calculated: 635.2; MS found: 636.4 [M+H] + .

[0243] Step D: 1-{[2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(difluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (17) A mixture of (S)-1-((2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (52 mg, 0.082 mmol) and NH2NH2·H2O (0.3 mL) in EtOH (2 mL) was stirred at 70 °C for 4 h. The mixture was purified by prep-HPLC to give 1-{[2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(difluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (17) (17.6 mg, yield: 34.1%). MS calculated: 634.2; MS found: 635.4 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 9.14 (d, J = 1.2 Hz, 1 H), 8.54 (s, 1 H), 7.60 (t, J = 8.4 Hz, 1 H), 7.28 (d, J = 10.8 Hz, 1 H), 7.21 (dd, J = 1.2 Hz / J = 8.4 Hz, 1 H), 7.07 - 6.82 (m, 1 H), 6.82 - 6.70 (m, 3 H), 4.21 (s, 2 H), 3.39 - 3.31 (m, 2 H), 3.18 (s, 2 H), 2.91 - 2.80 (m, 1 H), 2.80 - 2.68 (m, 2H), 2.16 - 2.02 (m, 2 H), 2.04 (s, 3 H), 1.98 - 1.87 (m, 2 H), 1.47 - 1.40 (m, 2 H), 1.30 - 1.22 (m, 2 H). 19 F NMR(377 MHz, CD3OD):δ -112.27, -117.61.

[0244] Example 18: (S)-5-(6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-((1-cyanocyclopropyl)methyl)pyridin-3-yl)-4H-1,2,4-triazole-3-carbonitrile (18) [ka] MS calculated: 609.2; MS found: 610.2 [M+H] + . 1 H NMR (400 MHz, MeOD-d4):δ 9.24 (s, 1 H), 8.51 (s, 1 H), 7.63 (t, J = 4.8 Hz, 1 H), 7.30 (d, J = 11.2 Hz, 1 H), 7.23 (d, J = 8.4 Hz, 1 H), 6.88 - 6.78 (m, 3 H), 4.72 (s, 2 H), 3.81 - 3.71 (m, 2 H), 3.40 - 3.37 (m, 2 H), 3.15 - 3.03 (m, 3 H), 2.38 - 2.07 (m, 7 H), 1.47 - 1.42 (m, 2 H), 1.32 - 1.26 (m, 2 H). 19 F NMR (377 MHz, MeOD-d4):δ (-112.23).

[0245] Example 19: (S)-6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-((1-cyanocyclopropyl)methyl)nicotinic acid (19) [ka] A mixture of (S)-6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-((1-cyanocyclopropyl)methyl)nicotinonitrile (20 mg, 0.037 mmol) and NaOH (6 mg, 0.15 mmol) in EtOH (2 mL) was stirred at 70° C. for 6 h. The mixture was filtered and the residue was purified by prep-HPLC to give compound 19 (5.0 mg, yield: 21.2%). MS calculated: 561.2; MS found: 562.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6):δ 8.73 (s, 1 H), 8.19 (s, 1 H), 7.58 - 7.54 (m, 2 H), 7.34 (dd, J = 2.0 Hz / J = 8.8 Hz, 1 H), 6.78 (d, J = 4.4 Hz, 2 H), 6.74 - 6.71 (m, 1 H), 3.64 (s, 2 H), 3.11 (s, 2 H), 2.88 - 2.83 (m, 2 H), 2.66 - 2.61 (m, 1 H), 2.15 - 2.08 (m, 2 H), 2.02 (s, 3 H), 1.74 - 1.69 (m, 4H), 1.33 - 1.30 (m, 2 H), 1.16 - 1.13 (m, 2 H). 19 F NMR (377 MHz, CD3OD):δ (-110.78).

[0246] Example 20: (S,E)-3-(6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-((1-cyanocyclopropyl)methyl)pyridin-3-yl)acrylic acid (20) [ka] Step A: Ethyl (E)-3-(5-((1-cyanocyclopropyl)methyl)-6-formylpyridin-3-yl)acrylate A mixture of ethyl (E)-3-(5-((1-cyanocyclopropyl)methyl)-6-methylpyridin-3-yl)acrylate (50 mg, 0.185 mmol) and SeO2 (205 mg, 1.85 mmol) in 1,4-dioxane (5 mL) was stirred at 80 °C for 16 h. The mixture was filtered and the residue was concentrated to give ethyl (E)-3-(5-((1-cyanocyclopropyl)methyl)-6-formylpyridin-3-yl)acrylate (30 mg, yield: 39%). MS calculated: 284.2; MS found: 285.0 [M+H] + .

[0247] Step B: Ethyl (S,E)-3-(6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-((1-cyanocyclopropyl)methyl)pyridin-3-yl)acrylate A mixture of (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine 4-methylbenzenesulfonate (107 mg, 0.21 mmol) and TEA (98 mg, 0.97 mmol) in DCM (5 mL) was stirred at room temperature for 0.5 h. To the mixture, ethyl (E)-3-(5-((1-cyanocyclopropyl)methyl)-6-formylpyridin-3-yl)acrylate (55 mg, 0.19 mmol) was added, and the mixture was stirred for 2 h. To the mixture, NaBH(OAC) (165 mg, 0.78 mmol) was added, and the mixture was stirred at room temperature for 16 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 to give ethyl (S,E)-3-(6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-((1-cyanocyclopropyl)methyl)pyridin-3-yl)acrylate (30 mg, yield: 40.0%). MS calculated: 615.3; MS found: 616.2 [M+H] + .

[0248] Step C: (S,E)-3-(6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-((1-cyanocyclopropyl)methyl)pyridin-3-yl)acrylic acid A mixture of ethyl (S,E)-3-(6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-((1-cyanocyclopropyl)methyl)pyridin-3-yl)acrylate (15 mg, 0.024 mmol) and aqueous NaOH (3M, 0.1 mL) in THF (2 mL) was stirred at room temperature for 2 hours. The mixture was purified by prep-HPLC to give (S,E)-3-(6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-((1-cyanocyclopropyl)methyl)pyridin-3-yl)acrylic acid (2.6 mg, yield: 18.5%). MS calculated: 587.2; MS found: 588.4 [M + H] + . 1 H NMR (400 MHz, CD3OD-d4):δ 8.60 (s, 1 H), 8.48 (s, 1 H), 8.11 (s, 1 H), 7.59 (t, J = 8.4 Hz, 1 H), 7.47 - 7.43 (m, 1 H), 7.29 (dd, J1= 2.0 Hz / J2= 10.8 Hz , 1 H), 7.21 (dd, J1= 7.2 Hz / J2= 8.8 Hz , 1 H), 6.83 - 6.63 (m, 4 H), 4.10 - 4.03 (m, 2 H), 3.24 - 3.11 (m, 4 H), 2.86 - 2.74 (m, 1 H), 2.67 - 2.48 (m, 2 H), 2.09 - 1.94 (m, 5 H), 1.90 - 1.80 (m, 2 H), 1.42 - 1.19 (m, 4 H). 19 F NMR (377 MHz, CD3OD-d4):δ (-112.28).

[0249] Example 21: (S)-3-(6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-((1-cyanocyclopropyl)methyl)pyridin-3-yl)propanoic acid (21) [ka]

[0250] Step A: Ethyl (S)-3-(6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-((1-cyanocyclopropyl)methyl)pyridin-3-yl)propanoate A mixture of ethyl (S,E)-3-(6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-((1-cyanocyclopropyl)methyl)pyridin-3-yl)acrylate (15 mg, 0.024 mmol) and Pd / C (0.3 mg, 0.096 mmol) in EtOAc (2 ml) / MeOH (2 ml) and H was stirred at room temperature for 2 h. The mixture was filtered and the residue was concentrated to give ethyl (S)-3-(6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-((1-cyanocyclopropyl)methyl)pyridin-3-yl)propanoate (15 mg, yield: >99%). MS calculated: 617.3; MS found: 618.4 [M+H] + .

[0251] Step B: (S)-3-(6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-((1-cyanocyclopropyl)methyl)pyridin-3-yl)propanoic acid A mixture of ethyl (S)-3-(6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-((1-cyanocyclopropyl)methyl)pyridin-3-yl)propanoate (15 mg, 0.024 mmol) and aqueous NaOH (3 M, 0.1 mL) in THF (2 mL) was stirred at room temperature for 2 hours. The mixture was purified by prep-HPLC to give (S)-3-(6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-((1-cyanocyclopropyl)methyl)pyridin-3-yl)propanoic acid (3.8 mg, yield: 26.9%). MS calculated: 589.2; MS found: 590.4 [M + H] + . 1 H NMR (400 MHz, CD3OD):δ 8.39 (s,1 H),7.84 (s,1 H), 7.59 (t, J = 8 Hz, 1 H), 7.28 (dd, J = 8.8 Hz / J = 10.8 Hz, 1 H), 7.20 (dd, J = 4.0 Hz / J = 8.0 Hz, 1 H), 6.79 (t, J = 8.4 Hz, 1 H), 6.72 (d, J = 7.2 Hz, 2 H), 4.05 (s, 1 H), 3.24 - 3.18 (m, 2 H), 3.13 (s, 2 H), 2.98 (t, J = 6.8 Hz, 2 H), 2.65 - 2.49 (m, 4H), 2.03 (s, 5 H), 1.86 (t, J = 11.2 Hz, 2 H), 1.41 - 1.32 (m, 2 H), 1.24 - 1.14 (m, 2 H). 19 F NMR (377 MHz, CD3OD):δ (-112.26).

[0252] Example 22: 1-{[2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]-3,3-difluoropiperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (22) [ka] Step A: tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-hydroxypiperidine-1-carboxylate To a mixture of tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.0 g, 2.25 mmol) in THF (20 mL) was added BH. THF (1 M in THF, 4.5 mL, 4.5 mmol) was stirred at room temperature for 2 hours. Aqueous NaOH (2 M, 3.4 mL, 6.75 mmol) was added, and the mixture was stirred for 10 minutes. HO (30%, 3.4 mL) was added, and the mixture was stirred at 50° C. for 1.5 hours. MeOH (10 mL) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was poured into water (100 mL) and extracted with EA (2 x 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated to give tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-hydroxypiperidine-1-carboxylate (0.70 g, yield: 67.3%). MS calculated: 463.2; MS found: 486.3 [M+23] + .

[0253] Step B: tert-butyl tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-oxopiperidine-1-carboxylate A mixture of tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-hydroxypiperidine-1-carboxylate (200 mg, 0.43 mmol) and IBX (242 mg, 0.86 mmol) in ACN (5 mL) was stirred at 90° C. for 1 h. The mixture was filtered, and the filtrate was concentrated to give tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-oxopiperidine-1-carboxylate (160 mg, 80.3% yield). MS calculated: 461.1; MS found: 484.2 [M+23]. + .

[0254] Step C: tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3,3-difluoropiperidine-1-carboxylate To a mixture of tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-oxopiperidine-1-carboxylate (140 mg, 0.30 mmol) in DAST (5 mL) was added EtOH (7 drops), and the mixture was stirred at room temperature under Ar for 16 h. The mixture was poured into aqueous NaHCO (70 mL) at 0 °C and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (PE:EA=6:1) to give tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3,3-difluoropiperidine-1-carboxylate (95 mg, yield: 64.8%). MS calculated: 483.1; MS found: 428.3 [M+H-56] + .

[0255] Step D: 4-[2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]-3,3-difluoropiperidine A mixture of tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3,3-difluoropiperidine-1-carboxylate (45 mg, 0.09 mmol) and 2,2,2-trifluoroacetic acid (2 mL) in DCM (2 mL) was stirred at room temperature for 1 hour. The mixture was concentrated to give 4-[2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]-3,3-difluoropiperidine, TFA salt (60 mg). MS calculated: 383.1; MS found: 384.1 [M+H] + .

[0256] Step E: 1-((2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3,3-difluoropiperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile A mixture of 4-[2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]-3,3-difluoropiperidine, TFA salt (45 mg) and TEA (46 mg, 0.46 mmol) in DCM (5 mL) was stirred at room temperature for 0.5 hours. 1-((2-formyl-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (29 mg, 0.09 mmol) was added, and the mixture was stirred for 2 hours. NaBH(OAc)3 (77 mg, 0.36 mmol) was added, and the mixture was stirred at room temperature for 16 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 filtrate was concentrated to give 1-((2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3,3-difluoropiperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (60 mg). MS calculated: 689.2; MS found: 690.3 [M+H] + .

[0257] Step F: 1-{[2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]-3,3-difluoropiperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (22) A mixture of 1-((2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3,3-difluoropiperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (60 mg, 0.09 mmol) and NH2NH2·H2O (0.2 mL) in EtOH (2 mL) was stirred at 70 °C for 1 h. The mixture was purified by prep-HPLC to give 1-{[2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]-3,3-difluoropiperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (22) (4.2 mg, yield: 6.9%). MS calculated: 688.2; MS found: 689.3 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 9.06 (s, 1 H), 8.58 (s, 1 H), 7.60(dd, J1 = 18.8 Hz / J2 = 8.4 Hz, 1 H), 7.29 -7.13 (m, 2 H), 6.83 - 6.70 (m, 3 H), 3.95 (s, 2 H), 3.50 - 3.10 (m, 4 H), 3.02 - 2.92 (m, 1 H), 2.69 - 2.53 (m, 1 H), 2.48 - 2.21 (m, 2 H), 2.05 - 2.20 (m, 3 H), 1.85 - 1.74 (m, 1 H), 1.50 - 1.40 (m, 2 H), 1.27 - 1.21 (m, 2 H). 19 F-NMR (377 MHz, CD3OD):δ -66.42, -102.36, -102.66, -103.00, -103.30, -112.20, -112.32,-112.66, -112.92, -113.30, -113.56.

[0258] Examples 23 and 24: 1-[(2-{[(3,4-trans)-4-[2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]-3-hydroxypiperidin-1-yl]methyl}-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl)methyl]cyclopropane-1-carbonitrile (diastereomer 1) (23) and 1-[(2-{[(3,4-trans)-4-[2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]-3-hydroxypiperidin-1-yl]methyl}-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl)methyl]cyclopropane-1-carbonitrile (diastereomer 2) (24) [ka] Step A: tert-butyl (3,4-trans)-4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-hydroxypiperidine-1-carboxylate (diastereomer A) and tert-butyl (3,4-trans)-4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-hydroxypiperidine-1-carboxylate (diastereomer B) The product tert-butyl (3,4-trans)-4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-hydroxypiperidine-1-carboxylate was subjected to chiral separation (DAICELCHIRALPAK® IG, Supercritical CO2 / IPA (+0.1% 7.0 mol / L ammonia in IPA) = 50 / 50) to give two single diastereomers. Diastereomer A: MS calculated: 463.2; MS found: 486.3 [M+23]. +SFC retention time: 4.17 min. Diastereomer B: MS calculated: 463.2; MS found: 486.3 [M+23] + . SFC retention time: 6.15 min.

[0259] Step B: 1-[(2-{[(3,4-trans)-4-[2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]-3-hydroxypiperidin-1-yl]methyl}-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl)methyl]cyclopropane-1-carbonitrile (diastereomer 1) (23)

[0260] Starting from diastereomer A, 1-[(2-{[(3,4-trans)-4-[2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]-3-hydroxypiperidin-1-yl]methyl}-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl)methyl]cyclopropane-1-carbonitrile (diastereomer 1, 23) (14.3 mg, yield: 28.6%) was obtained using a method similar to that described in Example 1. MS calculated: 668.2; MS found: 669.2 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 9.28 (s, 1 H), 8.58 (d, J = 1.2 Hz, 1 H), 7.75 - 7.63 (m, 1 H), 7.33 - 7.17 (m, 2 H), 6.90 - 6.75 (m, 3 H), 4.48 - 4.30 (m, 1 H), 3.90 - 3.68 (m, 2 H), 3.30 - 3.28 (m, 3 H), 3.19 - 3.11 (m, 1 H), 3.09 (s, 2 H), 3.07 - 2.92 (m, 1 H), 2.44 - 2.05 (m, 5 H), 1.50 - 1.44 (m, 2 H), 1.31 - 1.24 (m, 2 H). 19F NMR(377 MHz, CD3OD):δ -66.68, -76.96, -112.13.

[0261] Step C: 1-[(2-{[(3,4-trans)-4-[2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]-3-hydroxypiperidin-1-yl]methyl}-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl)methyl]cyclopropane-1-carbonitrile (diastereomer 2) (24). MS calculated: 668.2; MS found: 669.2 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 9.28 (s, 1 H), 8.58 (s, 1 H), 7.75 - 7.62 (m, 1 H), 7.33 - 7.17 (m, 2 H), 6.90 - 6.74 (m, 3 H), 4.45 - 4.29 (m, 1 H), 3.88 - 3.68 (m, 2 H), 3.30 - 3.26 (m, 3 H), 3.19 - 3.08 (m, 1 H), 3.07 (s, 2 H), 3.06 - 2.91 (m, 1 H), 2.43 - 2.05 (m, 5 H), 1.51 - 1.44 (m, 2H), 1.32 - 1.24 (m, 2H). 19 F NMR(377 MHz, CD3OD):δ -66.68, -77.03, -112.12.

[0262] Examples 25 and 26: 1-[(2-{[(3,4-trans)-4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-2H-1,3-benzodioxol-4-yl]-3-fluoropiperidin-1-yl]methyl}-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl)methyl]cyclopropane-1-carbonitrile (diastereomers 1) (25) and 1-[(2-{[(3,4-trans)-4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-2H-1,3-benzodioxol-4-yl]-3-fluoropiperidin-1-yl]methyl}-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl)methyl]cyclopropane-1-carbonitrile (diastereomer 2) (26) [ka]

[0263] Step A: (S)-2-(4-bromo-2-methylbenzo[d][1,3]dioxol-2-yl)-5-chloropyridine 2-(4-Bromo-2-methylbenzo[d][1,3]dioxol-2-yl)-5-chloropyridine (4.4 g, 13.5 mmol) was separated by SFC (DAICELCHIRALCEL® AD, Supercritical CO2 / MEOH (+0.1% 7.0 mol / l ammonia / MEOH) = 65 / 35) to give (S)-2-(4-bromo-2-methylbenzo[d][1,3]dioxol-2-yl)-5-chloropyridine (2.2 g, yield: 50%) [MS calculated: 325.0; MS found: 325.9 [M+H]]. + SFC retention time: 0.82 min] and (R)-2-(4-bromo-2-methylbenzo[d][1,3]dioxol-2-yl)-5-chloropyridine (2.2 g, yield: 50%) [MS calculated: 325.0; MS found: 326.1 [M+H] + . SFC retention time: 0.91 min.] was obtained.

[0264] Step B: tert-butyl (S)-4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate A mixture of (S)-2-(4-bromo-2-methylbenzo[d][1,3]dioxol-2-yl)-5-chloropyridine (2.2 g, 6.8 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.1 g, 6.8 mmol), Pd(dppf)Cl (495 mg, 0.68 mmol), and KCO (2.8 g, 20.4 mmol) in dioxane / HO (20.0 mL / 2.0 mL) was stirred at 90 °C for 3 h. After the reaction was complete, the mixture was diluted with HO (100 mL) and extracted with EA (50 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography (PE / EA=20 / 1) to give tert-butyl (S)-4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.1 g, yield: 73%). MS calculated: 428.2; MS found: 373.0 [M-56+H] + .

[0265] Step C: tert-butyl (3,4-trans)-4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-2H-1,3-benzodioxol-4-yl]-3-hydroxypiperidine-1-carboxylate To a solution of tert-butyl (S)-4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.0 g, 4.7 mmol) in THF (40 mL) was added BH THF (9.35 mL, 9.4 mmol) slowly at 0 °C. The mixture was stirred at 0 °C for 2 h. Then, aqueous NaOH (7 mL, 2 M in water) was added, followed by H O (7 mL, 30% in water). The reaction mixture was stirred at 50 °C for 1 h. After the reaction was complete, the mixture was diluted with EA (100 mL) and washed with water (30 mL × 2). The organic layer was dried over Na SO , filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography (PE:EA=2:1) ​​to give tert-butyl (3,4-trans)-4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-2H-1,3-benzodioxol-4-yl]-3-hydroxypiperidine-1-carboxylate (1.5 g, yield: 75%). MS calculated: 446.2; MS found: 469.1 [M+Na] + .

[0266] Step D: tert-butyl (3,4-trans)-4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-2H-1,3-benzodioxol-4-yl]-3-fluoropiperidine-1-carboxylate To a mixture of tert-butyl (3,4-trans)-4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-2H-1,3-benzodioxol-4-yl]-3-hydroxypiperidine-1-carboxylate (1.35 g, 3.03 mmol) in DCM (20 mL) was added DAST (975 mg, 6.05 mmol) slowly at 0 °C. The mixture was stirred at 0 °C for 2 min. After the reaction was complete, the mixture was diluted with EA (100 mL) and washed with water (30 mL x 2). The organic layer was dried over NaSO, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography (PE:EA=10:1) to give tert-butyl (3,4-trans)-4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-2H-1,3-benzodioxol-4-yl]-3-fluoropiperidine-1-carboxylate (1.2 g, yield: 88.9%). MS calculated: 448.2; MS found: 449.2 [M+H] + .

[0267] Step E: tert-butyl 4-(3,4-trans)-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluoropiperidine-1-carboxylate single diastereomers P1 and P2 tert-Butyl (3,4-trans)-4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-2H-1,3-benzodioxol-4-yl]-3-fluoropiperidine-1-carboxylate (1.2 g, 2.68 mmol) was purified by SFC (DAICELCHIRALCEL® AD, Supercritical CO2 / MEOH (+0.1% 7.0 mol / l ammonia in MEOH) = 60 / 40) to give diastereomer P1 (670 mg, yield: 55.8%) and diastereomer P2 (430 mg, yield: 35.8%).

[0268] Diastereomer P1 (670 mg, yield: 55.8%). MS calculated: 448.2; MS found: 449.1 [M+H] + . SFC retention time: 1.02 min. 19 F NMR:(377 MHz, DMSO-d6):δ-182.46.

[0269] Diastereomer P2 (430 mg, 35.8% yield). MS calculated: 448.16; MS found: 449.1 [M+H] + . SFC retention time: 1.37 min. 1 H NMR:δ 8.72 (d, J=0.2 Hz, 1 H), 8.02 (dd, J=2.4 Hz, 8.4 Hz, 1 H), 7.59 (d, J=8.4 Hz, 1 H), 6.80-6.90 (m, 3 H), 4.56-4.81 (m, 1 H), 4.21-4.34 (m, 1 H), 3.87-4.03 (m, 1 H), 2.96-3.07 (m, 1 H), 2.80-2.95 (m, 2 H), 2.02 (s, 3 H), 1.65-1.85 (m, 2 H), 1.42 (s, 9 H). 19 F NMR:(377 MHz, DMSO-d6):δ:-182.27.

[0270] Step F: 5-chloro-2-((S)-4-((3,4-trans)-3-fluoropiperidin-4-yl)-2-methylbenzo[d][1,3]dioxol-2-yl)pyridine TFA salt (from diastereomer P1) To a solution of tert-butyl (3,4-trans)-4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluoropiperidine-1-carboxylate (isomer P1) (100 mg, 0.22 mmol) in DCM (4 mL) was added TFA (1.0 mL). The solution was stirred at room temperature for 1 hour. The reaction mixture was evaporated in vacuo to give 5-chloro-2-((S)-4-((3,4-trans)-3-fluoropiperidin-4-yl)-2-methylbenzo[d][1,3]dioxol-2-yl)pyridine TFA salt (from diastereomer P1) (120 mg, crude). MS calculated: 348.1; MS found: 349.1 [M+H] + .

[0271] Step G: 1-((2-(((3,4-trans)-4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluoropiperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (from diastereomer P1) A mixture of 5-chloro-2-((S)-4-((3,4-trans)-3-fluoropiperidin-4-yl)-2-methylbenzo[d][1,3]dioxol-2-yl)pyridine (from isomer P1) (64 mg, 0.184 mmol) and TEA (93 mg, 0.919 mmol) in DCM (5 mL) was stirred at room temperature for 0.5 h. 3-((methylsulfonyl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)picolinaldehyde (59 mg, 0.184 mmol) was added and the mixture was stirred for 2 h. NaBH(OAc) (156 mg, 0.736 mmol) was added and the mixture was stirred at room temperature for 16 h. 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 filtrate was concentrated. The residue was purified by TLC gel to give 1-((2-(((3,4-trans)-4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluoropiperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (from diastereomer P1) (100 mg, yield: 83.33%). MS calculated: 654.2; MS found: 655.3 [M+H] + .

[0272] Step H: 1-[(2-{[(3,4-trans)-4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-2H-1,3-benzodioxol-4-yl]-3-fluoropiperidin-1-yl]methyl}-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl)methyl]cyclopropane-1-carbonitrile (Diastereomer 1) (25) A mixture of 1-((2-(((3,4-trans)-4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluoropiperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (from diastereomer P1) (100 mg, 0.15 mmol) and NH2NH2·H2O (2.0 mL) in EtOH (2 mL) was stirred at 70 °C for 1 h. The mixture was purified by prep-HPLC to give 1-[(2-{[(3,4-trans)-4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-2H-1,3-benzodioxol-4-yl]-3-fluoropiperidin-1-yl]methyl}-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl)methyl]cyclopropane-1-carbonitrile (diastereomer 1) (6.0 mg, yield: 6.0%). MS calculated: 653.2; MS found: 654.3 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 9.07 (s, 1 H), 8.59 (s, 1 H), 8.54 (s, 1 H), 7.86 (dd, J1 = 8.4 Hz / J2 = 6.0 Hz, 1 H), 7.65 (d, J = 8.4 Hz, 1 H), 6.84 - 6.69 (m, 3 H), 4.99 - 4.90 (m, 1 H), 3.99 - 3.82 (m, 2 H), 3.32 - 3.21 (m, 3 H), 2.95 - 2.80 (m, 2 H), 2.36 - 2.24 (m, 2 H), 2.05 (s, 3 H), 2.06 - 1.90 (m, 1 H), 1.88 - 1.77 (m, 1 H), 1.47 - 1.40 (m, 2 H), 1.38- 1.20 (m, 2 H). 19 F NMR(377 MHz, CD3OD):δ -66.40, -184.98.

[0273] 1-[(2-{[(3,4-trans)-4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-2H-1,3-benzodioxol-4-yl]-3-fluoropiperidin-1-yl]methyl}-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl)methyl]cyclopropane-1-carbonitrile (diastereomer 2) (26) was obtained in a similar manner to that described in Example 25 using tert-butyl (3,4-trans)-4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluoropiperidine-1-carboxylate (diastereomer P2) as the starting material. MS calculated: 653.2; MS found: 654.3 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 9.07 (s, 1 H), 8.60 (d, J = 2.0 Hz, 1 H), 8.54 (s, 1 H), 7.84 (dd, J = 2.4 Hz / J = 8.8 Hz, 1 H), 7.66 (d, J = 8.4 Hz, 1 H), 6.81 - 6.73 (m, 2 H), 6.71 (d, J = 7.2 Hz, 1 H), 4.82 - 4.73 (m, 1 H), 3.98 - 3.85 (m, 2 H), 3.24 (s, 2 H), 3.15 - 3.10 (m, 1 H), 2.95 - 2.80 (m, 2H), 2.35 - 2.25 (t, J = 10.6 Hz, 2 H), 2.03 (s, 3 H), 2.05 - 1.90 (m, 1 H), 1.88 - 1.78 (m, 1 H), 1.47 - 1.42 (m, 2 H), 1.28 - 1.21 (m, 2 H). 19 F NMR(377 MHz, CD3OD):δ -66.18, -184.67.

[0274] Examples 27 and 28: 1-((2-(((3,4-trans)-4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluoropiperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (27) (diastereoisopropyl ether) Diastereomer 1) and 1-((2-(((3,4-trans)-4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluoropiperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (28) (diastereomer 2). [ka]

[0275] MS calculated: 670.2; MS found: 671.2 [M+H] + . 1 H NMR (400 MHz, CD3OD-d4):δ 9.07 (s, 1 H), 8.56 (s, 1 H), 7.63 - 7.54 (m, 1 H), 7.30 - 7.23 (m, 1 H), 7.23 - 7.15 (m, 1 H), 6.82 - 6.69 (m, 3 H), 4.95 - 4.93 (m, 1 H), 4.00-3.86 (m, 2 H), 3.27 - 3.20 (m, 2 H), 2.96 - 2.78 (m, 3 H), 2.35 - 2.25 (m, 2 H), 2.10 - 1.75 (m, 5H), 1.48 - 1.40 (m, 2H), 1.30 - 1.24 (m, 2H). 19 F NMR (377 MHz, CD3OD):δ -66.47, -112.31, -112.38, -184.66, -185.00. [ka] MS calculated: 670.2; MS found: 671.2 [M+H] +. 1 H NMR (400 MHz, CD3OD):δ 9.07 (d, J = 1.6 Hz, 1 H), 8.56 (s, 1 H), 7.64 - 7.55 (m, 1 H), 7.31 - 7.23 (m, 1 H), 7.23 - 7.15 (m, 1 H), 6.83 - 6.69 (m, 3 H), 4.94 - 4.91 (m, 1 H), 4.01 - 3.86 (m, 2 H), 3.28 - 3.20 (m, 2 H), 3.00 - 2.75 (m, 3 H), 2.31 (t, J = 11.6 Hz, 2 H), 2.10 - 1.78 (m, 5H), 1.48 - 1.42 (m, 2H), 1.27 - 1.22 (m, 2H). 19 F NMR (377 MHz, CD3OD):δ -66.58, -112.31, -112.38, -184.57, -184.68, -184.70, -184.95, -185.02.

[0276] Examples 29 and 30: Diastereomer 1 of 1-((2-((trans)-4-((R)-2-(4-chloro-2-fluorophenyl)-7-fluoro-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluoropiperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (29) and 1-((2-((trans)-4-((R)-2-(4-chloro-2-fluorophenyl)-7-fluoro-2-methylbenzo[d][1,3]dioxol-4-yl)-3-fluoropiperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile Diastereomer 2 of (30) [ka]

[0277] MS calculated value: 688.2; MS measured value: 689.4 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 9.09 (d, J = 2.0 Hz, 1 H), 8.58 (d, J = 2.0 Hz, 1 H), 7.62 (t, J = 8.4 Hz, 1 H), 7.33 (dd, J1= 2.0 Hz / J2= 11.2 Hz, 1 H), 7.26 (dd, J1= 2.0 Hz / J2= 8.4 Hz, 1 H), 6.81 - 6.65 (m, 2 H), 4.94 (dd, J1= 4.8 Hz / J2= 9.2 Hz, 0.5 H), 4.81 (dd, J1= 4.8 Hz / J2= 9.6 Hz, 0.5 H), 4.02 - 3.87 (m, 2 H), 3.28 (s, 3 H), 2.97 - 2.78 (m, 2 H), 2.36 - 2.26 (m, 2 H), 2.10 (s, 3 H), 2.02 - 1.93 (m, 1 H), 1.87 - 1.79 (m, 1 H), 1.49 - 1.44 (m, 2 H), 1.31 - 1.24 (m, 2 H). 19 F NMR (377 MHz, CD3OD): δ (-66.50), (-112.22), (-143.14), (-185.19).

change

[0278] Example 31: 1-((2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (31) [ka]

[0279] Starting from 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-1,2,3,6-tetrahydropyridine TFA salt, 1-((2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile was obtained in a manner similar to that of Example 1 (3.7 mg). MS calculated: 650.2; MS found: 651.2 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 9.17 (s, 1 H), 8.52 (s, 1 H), 7.58 (t, J = 8.4 Hz, 1 H), 7.31 - 7.18 (m, 2 H), 6.92 - 6.78 (m, 3 H), 6.43 (s, 1 H), 4.41 (s, 2 H), 3.74 (s, 2 H), 3.25 - 3.21 (m, 2 H), 3.13 (s, 2 H), 2.82 (s, 2 H), 2.05 (s, 3 H), 1.44 - 1.39 (m, 2 H), 1.28 - 1.24 (m, 2 H). 19 F NMR (377 MHz, CD3OD):δ (-66.56), (-112.46).

[0280] Example 32: 1-({2-[(4-{6-[(4-chloro-2-fluorophenyl)methoxy]pyridin-2-yl}piperidin-1-yl)methyl]-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl}methyl)cyclopropane-1-carbonitrile (32) [ka]

[0281] Starting from 2-((4-chloro-2-fluorobenzyl)oxy)-6-(piperidin-4-yl)pyridine hydrochloride, 1-({2-[(4-{6-[(4-chloro-2-fluorophenyl)methoxy]pyridin-2-yl}piperidin-1-yl)methyl]-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl}methyl)cyclopropane-1-carbonitrile (32) (7.2 mg, yield: 38.3%) was obtained using a method similar to that described in Example 1. MS calculated: 625.2; MS found: 626.2 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 9.21 (d, J = 2.0 Hz, 1 H), 8.50 (d, J = 1.6 Hz, 1 H), 7.62 (t, J = 3.8 Hz, 1 H), 7.52 (t, J = 4.0 Hz, 1 H), 7.27 - 7.19 (m, 2 H), 6.90 (d, J = 7.2 Hz, 1 H), 6.70 (d, J = 8.4 Hz, 1 H), 5.45 (s, 2 H), 4.55 - 4.45 (m, 2 H), 3.61 - 3.56 (m, 2 H), 3.17- 2.90 (m, 5 H), 2.28- 2.05 (m, 4 H), 1.44 - 1.39 (m, 2H), 1.33 - 1.25 (m, 2H), 19 F-NMR (377 MHz, CD3OD):δ -65.07, -117.58.

[0282] Example 33: 1-((2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (33) [ka] Starting from 1-(4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)-114-piperidin-1-yl) TFA salt, 1-((2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (23.2 mg, yield: 19.4%) was obtained using a method similar to Example 1. MS calculated: 643.1; MS found: 644.1 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 9.21 (s, 1 H), 8.50 (d, J = 1.6 Hz, 1 H), 7.54 (t, J = 8.4 Hz, 1 H), 7.46 - 7.42 (m, 1 H), 7.27 - 7.22 (m, 2 H), 6.93 - 6.86 (m, 1 H), 5.54 (s, 2 H), 4.57 (s, 2 H), 3.60 - 3.52 (m, 1 H), 3.36 - 3.33 (m,2 H), 3.27 - 3.23 (m, 2 H), 3.07 (s, 2 H), 2.20 - 2.03 (m, 4 H), 1.43 - 1.40 (m, 2 H), 1.34 - 1.28 (m, 2 H). 19 F NMR (377 MHz, CD3OD):δ -65.21, -86.99, -117.35.

[0283] Example 34: 1-({2-[(4-{2-[(4-chloro-2-fluorophenyl)methoxy]pyrimidin-4-yl}piperidin-1-yl)methyl]-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl}methyl)cyclopropane-1-carbonitrile (34) [ka] Starting from 2-[(4-chloro-2-fluorophenyl)methoxy]-4-(piperidin-4-yl)pyrimidine TFA salt, 1-({2-[(4-{2-[(4-chloro-2-fluorophenyl)methoxy]pyrimidin-4-yl}piperidin-1-yl)methyl]-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl}methyl)cyclopropane-1-carbonitrile (34) (6.5 mg, yield: 26.1%) was obtained in a similar manner. MS calculated: 626.2; MS found: 627.0 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 9.27 (s, 1 H), 8.57 (s, 1 H), 8.54 (d, J = 5.2 Hz, 1 H), 7.57 (t, J = 8.0 Hz, 1 H), 7.27 (t, J = 8.0 Hz, 2 H), 7.13 (d, J = 4.0 Hz, 1 H), 5.53 (s, 2 H), 4.80 (s, 2 H), 3.93 - 3.77 (m, 2 H), 3.46 - 3.30 (m, 2 H), 3.19 - 3.05 (m, 1 H), 3.07 (s, 2 H), 2.40 - 2.21 (m, 4 H), 1.50 - 1.42 (m, 2 H), 1.33 - 1.25 (m, 2 H). 19 F-NMR (377 MHz, CD3OD):δ -66.6, -76.95, -117.24.

[0284] Example 35: 1-({2-[(4-{2-[(4-chloro-2-fluorophenyl)methoxy]-5-fluoropyrimidin-4-yl}piperidin-1-yl)methyl]-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl}methyl)cyclopropane-1-carbonitrile (35) [ka]

[0285] Starting from 2-[(4-chloro-2-fluorophenyl)methoxy]-5-fluoro-4-(piperidin-4-yl)pyrimidine TFA salt, 1-({2-[(4-{2-[(4-chloro-2-fluorophenyl)methoxy]-5-fluoropyrimidin-4-yl}piperidin-1-yl)methyl]-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl}methyl)cyclopropane-1-carbonitrile (35) (19.5 mg, yield: 22.2%) was obtained in a similar manner. MS calculated: 644.2; MS found: 645.2 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 9.27 (s, 1 H), 8.57 (t, J = 2.0 Hz, 1 H), 8.48 (s, 1 H), 7.56 (t, J = 8.4 Hz, 1 H), 7.26 (t, J = 8.8 Hz, 2 H), 5.49 (s, 2 H), 4.80 (s, 2H), 3.94 - 3.76 (m, 2 H), 3.54 - 3.36 (m, 3 H), 3.06 (s, 2 H), 2.44 - 2.31 (m, 2 H), 2.27 - 2.14 (m, 2 H), 1.51 - 1.42 (m, 2 H), 1.32 - 1.24 (m, 2 H). 19 F-NMR (377 MHz, CD3OD):δ -66.68, -77.08, -117.25, -152.46.

[0286] Example 36: 1-((2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidin-2-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (36) [ka] Starting from 1-(4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidin-2-yl)-114-piperidin-1-yl) TFA salt, 1-((2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidin-2-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (16.6 mg) was obtained using a method similar to Example 1. MS calculated: 644.2; MS found: 645.2 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 9.19 (s, 1 H), 8.51 (s, 1 H), 8.39 (s, 1 H), 7.54 (t, J = 7.6 Hz, 1 H), 7.26 (t, J = 9.2 Hz, 2 H), 5.60 (s, 2 H), 4.44 (s, 2 H), 3.53 - 3.44 (m, 2 H), 3.17 - 3.13 (m, 1 H), 3.09 (s, 2 H), 3.05 - 2.99 (m, 2 H), 2.28 - 2.15 (m, 4 H), 1.46 - 1.38 (m, 1 H), 1.30 - 1.21 (m, 2 H). 19 F NMR (377 MHz, CD3OD-d4):δ -65.29, -116.87, -158.41.

[0287] Example 37: 1-({2-[(4-{2-[(4-chloro-2-fluorophenyl)methoxy]pyridin-3-yl}piperidin-1-yl)methyl]-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl}methyl)cyclopropane-1-carbonitrile (37) [ka] Starting from 2-((4-chloro-2-fluorobenzyl)oxy)-3-(piperidin-4-yl)pyridine HCl salt, 1-({2-[(4-{2-[(4-chloro-2-fluorophenyl)methoxy]pyridin-3-yl}piperidin-1-yl)methyl]-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl}methyl)cyclopropane-1-carbonitrile (37) (8.1 mg) was obtained using a method similar to that described in Example 1. MS calculated: 625.2; MS found: 626.2 [M+H] + . 1 H NMR (400 MHz, CDCl3):δ 8.99 (s, 1 H), 8.20 (s, 1 H), 8.11 (d, J=4.8 Hz, 1 H), 7.55-7.65 (m, 1 H), 7.35-7.45 (m, 1 H), 7.10-7.18 (m, 2 H), 6.97-7.03 (m, 1 H), 5.46 (s, 2 H), 4.47 (s, 2 H), 4.05 (s, 2 H), 3.01-3.24 (m, 3 H), 2.38-2.60 (m, 4 H), 2.10-2.21 (m, 2 H), 1.22-1.38 (m, 4 H). 19 F NMR(377 MHz, CDCl3): δ -64.62, -115.27.

[0288] Example 38: 1-{[2-({4-[3-(4-chloro-2-fluorophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (38) [ka] Starting from 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine hydrochloride, 1-{[2-({4-[3-(4-chloro-2-fluorophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (38) (19.7 mg) was obtained using a similar method. MS calculated: 652.2; MS found: 653.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 2.0 Hz, 1 H), 8.44 (d, J = 2.0 Hz, 1 H), 7.60 - 7.51 (m, 2 H), 7.43 (dd, J = 1.6 Hz / J = 8.4 Hz, 1 H), 6.88 - 6.77 (m, 3 H), 5.47 (dd, J = 1.6 Hz / J = 7.6 Hz, 1 H), 4.45 (dd, J = 2.0 Hz / J = 11.2 Hz, 1 H), 4.11 (dd, J = 8.0 Hz / J = 11.6 Hz, 1 H), 3.89 (brs, 2H), 3.18 (s, 2H), 3.05 - 2.95 (m, 2 H), 2.94 - 2.86 (m, 1 H), 2.40 - 2.27 (m, 2 H), 1.85 - 1.62 (m, 4 H), 1.40 - 1.36 (m, 2 H), 1.25 - 1.09 (m, 2 H). 19 F-NMR (377 MHz, DMSO-d6):δ -63.01, -115.09.

[0289] Example 39: 1-{[2-({4-[(2R)-2-(4-chlorophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (39) [ka] Starting from (R)-4-(2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine HCl salt, 1-{[2-({4-[(2R)-2-(4-chlorophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (39) (2.1 mg) was obtained using a similar method. MS calculated: 634.2; MS found: 635.2 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 9.20 (s, 1 H), 8.50 (d, J = 1.6 Hz, 1 H), 7.49 - 7.40 (m, 4 H), 6.89 - 6.82 (m, 3 H), 5.20 - 5.14 (m, 1 H), 4.57 (s, 2 H), 4.49 - 4.42 (m, 1 H), 4.06 - 4.00 (m, 1 H), 3.65 - 3.50 (m, 1 H), 3.25 - 3.12 (m, 4 H), 3.10 - 3.05 (m, 2 H), 2.20 - 1.90 (m, 4 H), 1.44 - 1.40 (m, 2 H), 1.30 - 1.26 (m, 2 H). 19 F-NMR (377 MHz, CD3OD):δ -65.07.

[0290] Example 40: 1-({2-[(4-{3-[(4-chloro-2-fluorophenyl)methoxy]-4-fluorophenyl}piperidin-1-yl)methyl]-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl}methyl)cyclopropane-1-carbonitrile (40) [ka] Starting from 4-{3-[(4-chloro-2-fluorophenyl)methoxy]-4-fluorophenyl}piperidine TFA salt, 1-({2-[(4-{3-[(4-chloro-2-fluorophenyl)methoxy]-4-fluorophenyl}piperidin-1-yl)methyl]-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl}methyl)cyclopropane-1-carbonitrile (40) (16.3 mg) was obtained using a similar method. MS calculated: 642.2; MS found: 643.3 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 9.20 (s, 1 H), 8.51 (s, 1 H), 7.53 (t, J = 8.2 Hz, 1 H), 7.28 - 7.22 (m, 2 H), 7.11 - 7.03 (m, 2 H), 6.93 - 6.87 (m, 1 H), 5.19 (s, 2 H), 4.49 (s, 2 H), 3.55 (d, J = 11.6 Hz, 2 H), 3.14 - 2.95 (m, 4 H), 2.90 - 2.77 (m, 1 H), 2.10 - 1.98 (m, 4 H), 1.47 - 1.40 (m, 2 H), 1.32 - 1.25 (m, 2 H). 19 F-NMR (377 MHz, CD3OD):δ -65.29, -117.60, -138.49.

[0291] Example 41: 1-({2-[(4-{3-[(4-chloro-2-fluorophenyl)methoxy]-4-fluorophenyl}piperazin-1-yl)methyl]-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl}methyl)cyclopropane-1-carbonitrile (41) [ka] Starting from 1-{3-[(4-chloro-2-fluorophenyl)methoxy]-4-fluorophenyl}piperazine TFA salt, 1-({2-[(4-{3-[(4-chloro-2-fluorophenyl)methoxy]-4-fluorophenyl}piperazin-1-yl)methyl]-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl}methyl)cyclopropane-1-carbonitrile (41) (14.8 mg) was obtained using a similar method. MS calculated: 643.2; MS found: 644.3 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 9.09 (d, J = 2.0 Hz, 1 H), 8.53 (d, J = 2.0 Hz, 1 H), 7.51 (t, J = 8.2 Hz, 1 H), 7.23 (d, J = 9.2 Hz, 2 H), 7.01 - 6.93 (m, 1 H), 6.75 (dd, J1= 7.2 Hz / J2= 2.8 Hz, 1 H), 6.58 - 6.50 (m, 1 H), 5.15 (s, 2 H), 4.01 (s, 2 H), 3.20 (s, 2 H), 3.20 -3.11 (m, 4 H), 2.90 - 2.74 (m, 4H), 1.47 - 1.41 (m, 2 H), 1.28 - 1.22 (m, 2 H). 19 F-NMR (377 MHz, CD3OD):δ -66.18, -117.58, -146.19.

[0292] Example 42: 1-({2-[(4-{4-chloro-3-[(4-chloro-2-fluorophenyl)methoxy]phenyl}piperazin-1-yl)methyl]-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl}methyl)cyclopropane-1-carbonitrile (42) [ka] Step A: 4-chloro-2-fluoro-1-((2-fluoro-5-iodophenoxy)methyl)benzene To a solution of 2-chloro-5-iodophenol (500 mg, 2.0 mmol) in THF (35 mL) were added 1-(bromomethyl)-4-chloro-2-fluorobenzene (437 mg, 2.0 mmol) and CsCO (2.57 g, 7.88 mmol). The mixture was stirred at rt 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 the filtrate was concentrated. The mixture was purified by silica gel column chromatography (PE:EA = 1:0) to give 4-chloro-2-fluoro-1-((2-fluoro-5-iodophenoxy)methyl)benzene (524 mg, yield: 92.1%). 1 H NMR (400 MHz, CD3OD):δ 7.64 -7.59 (m, 2 H), 7.52 (dd, J = 4.0 Hz / J = 10.0 Hz, 1 H), 7.39 - 7.34 (m, 2 H), 7.23 (d, J = 2.0 Hz, 1 H), 5.25 (s, 2 H).

[0293] Step B: tert-butyl 4-(4-chloro-3-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperazine-1-carboxylate A mixture of 4-chloro-2-fluoro-1-((2-fluoro-5-iodophenoxy)methyl)benzene (234 mg, 1.05 mmol), tert-butyl piperazine-1-carboxylate (196 mg, 1.05 mmol), Pd(dba) (97 mg, 0.11 mmol), Xantphos (122 mg, 0.21 mmol), and CsCO (1.03 g, 3.16 mmol) in dioxane (15 mL) was stirred at 110 °C for 8 h under Ar. The mixture was poured into water (50 mL) and extracted with EA (2 × 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (PE:EA = 15:1) to give tert-butyl 4-(4-chloro-3-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperazine-1-carboxylate (190 mg, yield: 40.0%). MS calculated: 454.1; MS found: 455.0 [M+H] + .

[0294] Step C: 1-{4-chloro-3-[(4-chloro-2-fluorophenyl)methoxy]phenyl}piperazine, TFA salt To a mixture of tert-butyl 4-(4-chloro-3-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperazine-1-carboxylate (190 mg, 0.42 mmol) in DCM (8 ml) was added TFA (2 ml) dropwise. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated with DCM to give 1-{4-chloro-3-[(4-chloro-2-fluorophenyl)methoxy]phenyl}piperazine, TFA salt (170 mg). MS calculated: 354.1; MS found: 355.2 [M+H] + .

[0295] Step D: 1-((2-((4-(4-chloro-3-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperazin-1-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile

[0296] A mixture of 1-{4-chloro-3-[(4-chloro-2-fluorophenyl)methoxy]phenyl}piperazine, TFA salt (170 mg, 0.48 mmol) and TEA (298 mg, 2.95 mmol) in DCM (20 mL) was stirred at room temperature for 0.5 hours. 1-((2-formyl-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (230 mg, 0.71 mmol) was added, and the mixture was stirred for 2 hours. NaBH(OAc)3 (500 mg, 2.36 mmol) was added, and the mixture was stirred at room temperature for 16 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 filtrate was concentrated to give 1-((2-((4-(4-chloro-3-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperazin-1-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (30 mg, yield: 7.7%). MS calculated: 660.1; MS found: 661.0 [M+H] + .

[0297] Step E: 1-({2-[(4-{4-chloro-3-[(4-chloro-2-fluorophenyl)methoxy]phenyl}piperazin-1-yl)methyl]-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl}methyl)cyclopropane-1-carbonitrile (42) A mixture of 1-((2-((4-(4-chloro-3-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperazin-1-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (30 mg, 0.05 mmol) and NH2NH2·H2O (2 drops) in EtOH (2 mL) was stirred at 70 °C for 1 h. The mixture was purified by prep-HPLC to give 1-({2-[(4-{4-chloro-3-[(4-chloro-2-fluorophenyl)methoxy]phenyl}piperazin-1-yl)methyl]-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl}methyl)cyclopropane-1-carbonitrile (42) (5.59 mg, yield: 17.0%). MS calculated: 659.2; MS found: 660.0 [M+H] + . HNMR (400 MHz, CD3OD):δ 9.10 (d, J = 2.0 Hz, 1 H), 8.55 (s, 1 H), 7.58 (t, J = 8.2 Hz, 1 H), 7.30 - 7.15 (m, 3 H), 6.71 (d, J = 2.4 Hz, 1 H), 6.60 - 6.53 (dd, J = 2.8 Hz / J = 8.8 Hz, 1 H), 5.16 (s, 2 H), 4.01 (s, 2 H), 3.28 - 3.20 (m, 6 H), 2.85 - 2.75 (m, 4 H), 1.46 - 1.39 (m, 2 H), 1.38 - 1.21 (m, 2 H). 19 F-NMR (377 MHz, CD3OD):δ -67.86, -117.60.

[0298] Example 43: 1-[(2-{[(2S)-4-{3-[(4-chloro-2-fluorophenyl)methoxy]-4-fluorophenyl}-2-methylpiperazin-1-yl]methyl}-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl)methyl]cyclopropane-1-carbonitrile (43) [ka] Starting from (3S)-1-{3-[(4-chloro-2-fluorophenyl)methoxy]-4-fluorophenyl}-3-methylpiperazine TFA salt, 1-[(2-{[(2S)-4-{3-[(4-chloro-2-fluorophenyl)methoxy]-4-fluorophenyl}-2-methylpiperazin-1-yl]methyl}-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl)methyl]cyclopropane-1-carbonitrile (43) (2.9 mg) was obtained using a similar method. MS calculated: 657.2; MS found: 658.3 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 9.11 (d, J = 2.0 Hz, 1 H), 8.52 (d, J = 1.6 Hz, 1 H), 7.52 (t, J = 8.4 Hz, 1 H), 7.23 (d, J = 9.2 Hz, 2 H), 7.01 - 6.93 (m, 1 H), 6.74 (dd, J1= 4.8 Hz / J2= 7.2 Hz, 1 H), 6.57 - 6.50 (m, 1 H), 5.15 (s, 2 H), 4.58 (d, J = 13.6 Hz, 1 H), 3.75 (d, J =13.2 Hz, 1 H), 3.49 - 3.40 (m, 1 H), 3.36 - 3.31 (m, 2 H), 3.23 - 3.15 (m, 1 H), 2.99 - 2.85 (m, 3 H), 2.81 - 2.59 (m, 2 H), 1.47 - 1.39 (m, 2 H), 1.36 (d, J = 6.4 Hz, 3 H), 1.27 - 1.22 (m, 2 H). 19 F-NMR (377 MHz, CD3OD):δ -66.03, -117.55, -146.11.

[0299] Example 44: 1-({2-[(4-{6-[(4-chloro-2-fluorophenyl)methoxy]-5-fluoropyridin-2-yl}piperazin-1-yl)methyl]-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl}methyl)cyclopropane-1-carbonitrile (44) [ka] Starting from 1-{6-[(4-chloro-2-fluorophenyl)methoxy]-5-fluoropyridin-2-yl}piperazine, TFA salt, 1-({2-[(4-{6-[(4-chloro-2-fluorophenyl)methoxy]-5-fluoropyridin-2-yl}piperazin-1-yl)methyl]-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl}methyl)cyclopropane-1-carbonitrile (44) (4.7 mg) was obtained using a similar method. MS calculated: 644.2; MS found: 645.1 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 8.98 (d, J = 1.6 Hz, 1 H), 8.38 (d, J = 1.6 Hz, 1 H), 7.54 (t, J = 8.4 Hz, 1 H), 7.50 - 7.42 (m, 2 H), 7.31 (dd, J = 8.0 Hz / J = 6.4 Hz, 1 H), 6.27 (d, J = 8.4 Hz, 1 H), 5.39 (s, 2 H), 3.70 (s, 2 H), 3.45 - 3.40 (m, 4 H), 3.20 - 3.11 (m, 2 H), 2.51 - 2.46 (m, 4 H), 1.38 - 1.32 (m, 2 H), 1.21 - 1.15 (m, 2 H). 19 F-NMR (377 MHz, CD3OD):δ -60.78, -115.19, -156.90.

[0300] Example 45: 1-((2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (45) [ka] Starting from 1-(4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidin-2-yl)-114-piperazin-1-yl) TFA salt, 1-((2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (4.0 mg) was obtained using a method similar to Example 1. MS calculated: 645.1; MS found: 646.1 [M+H] + . 1 H NMR (400 MHz, CD3OD-d4):δ 9.09 (s, 1 H), 8.54 (s, 1 H), 8.01 (s, 1 H), 7.50 (t, J = 7.6 Hz, 1 H), 7.27 - 7.21 (m, 2 H), 5.47 (s, 2 H), 3.94 (s, 2 H), 3.83 - 3.73 (m, 4 H), 3.25 (s, 2 H), 2.69 - 2.60 (m, 4 H), 1.47 - 1.42 (m, 2 H), 1.28 - 1.21 (m, 2 H). 19 F NMR(377 MHz, CD3OD-d4):δ (-66.25), (-117.15).

[0301] Example 46: (S)-1-((2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2-methylpiperazin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (46) [ka] Starting from 1-((2S)-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2-methyl-114-piperazin-1-yl) TFA salt, (S)-1-((2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2-methylpiperazin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (11.7 mg) was obtained. MS calculated: 640.2; MS found: 641.2 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 9.03 (s, 1 H), 8.34 (s, 1 H), 7.64 (t, J = 7.6 Hz, 1 H), 7.51 (t, J = 8 Hz, 1 H), 7.26 - 7.21 (m, 2 H), 6.91 (d, J = 7.2 Hz, 1 H), 6.71 (d, J =8.4 Hz, 1 H), 5.46 (s, 2 H), 4.64 - 4.52 (m, 2 H), 3.71 - 3.57 (m, 2 H), 3.23 - 3.13 (m, 1 H), 3.09 - 2.95 (m, 4 H), 2.33 - 2.22 (m, 2 H), 2.20 - 2.09 (m, 2 H), 1.44 - 1.29 (m, 2 H), 1.27 -1.21 (m, 2 H). 19 F NMR (377 MHz, CD3OD):δ -117.59.

[0302] Example 47: 1-{[2-({6-[(4-chloro-2-fluorophenyl)methoxy]-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridin]-1′-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (47) [ka] Starting from 2-[(4-chloro-2-fluorophenyl)methoxy]-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridine TFA salt, 1-{[2-({6-[(4-chloro-2-fluorophenyl)methoxy]-1',2',3',6'-tetrahydro-[2,4'-bipyridin]-1'-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (47) (2.8 mg) was obtained using a similar method. MS calculated: 623.2; MS found: 624.2 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 9.17 (s, 1 H), 8.53 (s, 1 H), 7.65 (t, J = 7.8 Hz, 1 H), 7.48 (t, J = 8.0 Hz, 1 H), 7.24 - 7.17 (m, 2 H), 7.15 - 7.08 (m, 1 H), 6.75 - 6.70 (m, 2 H), 5.44 (s, 2 H), 4.38 (s, 2 H), 3.72 (s, 2 H), 3.30 - 3.21 (m, 2 H), 3.13 (s, 2 H), 2.87 - 2.80 (s, 2 H), 1.45 - 1.38 (m, 2 H), 1.28 - 1.23 (m, 2 H). 19 F-NMR (377 MHz, CD3OD):δ -65.48, -117.67.

[0303] Example 48: 1-({2-[(4-{3-[(4-chloro-2-fluorophenyl)methoxy]-4-fluorophenyl}-1,2,3,6-tetrahydropyridin-1-yl)methyl]-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl}methyl)cyclopropane-1-carbonitrile (48) [ka] Starting from 4-{3-[(4-chloro-2-fluorophenyl)methoxy]-4-fluorophenyl}-1,2,3,6-tetrahydropyridine, TFA salt, 1-({2-[(4-{3-[(4-chloro-2-fluorophenyl)methoxy]-4-fluorophenyl}-1,2,3,6-tetrahydropyridin-1-yl)methyl]-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl}methyl)cyclopropane-1-carbonitrile (48) (31.8 mg) was obtained using a similar method. MS calculated: 640.2; MS found: 641.0 [M+H] + . 1 H NMR (477 MHz, CD3OD):δ 9.08 (s, 1 H), 8.46 (s, 1 H), 7.62 - 7.57 (m, 1 H), 7.51 (d, J = 10.0 Hz, 1 H), 7.38 - 7.28 (m, 2 H), 7.20 - 7.13 (m,1 H), 7.02 - 6.98 (m,1 H), 6.16 (s, 1 H), 5.23 (s, 2 H), 3.92 (s, 2 H), 3.20 (s, 4 H), 2.75 (s, 2 H), 2.50 - 2.43 (m, 2 H), 1.40 - 1.34 (m, 2 H), 1.24 - 1.20 (m, 2 H). 19 F-NMR (377 MHz, CD3OD):δ -63.44, -114.96, -136.51.

[0304] Example 49: (S)-3-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridazine (49) [ka] Step A: 6-hydroxy-5-methylpyridazine-3-carbonitrile A mixture of 6-chloro-4-methylpyridazin-3-ol (5.0 g, 34.5 mmol), Zn(CN) (5.24 g, 44.8 mmol), Pd(dba) (1.58 g, 1.72 mmol), and dppf (1.53 g, 2.76 mmol) in DMF (50 mL) was degassed and refilled with nitrogen three times. The reaction mixture was heated at 120 °C for 1.5 h. The resulting mixture was diluted with DCM (100 mL) and saturated aqueous NaHCO (100 mL). The aqueous layer was separated and extracted with DCM (100 mL * 3). The combined organic layers were dried, filtered, and concentrated. The residue was purified by silica gel column (PE / EtOAc = 100 / 1 to 2 / 1) to give 6-hydroxy-5-methylpyridazine-3-carbonitrile (4.5 g, 97% yield). 1 H NMR (400 MHz, DMSO-d6) δ 13.81 (s, 1H), 7.71 (d, J = 1.6 Hz, 1H), 2.07 (d, J = 1.2 Hz, 3H). LC-MS:m / z 136.0 (M+H) + .

[0305] Step B: 6-chloro-5-methylpyridazine-3-carbonitrile To a solution of 6-hydroxy-5-methylpyridazine-3-carbonitrile (4.5 g, 33.3 mmol) in ACN (50 mL) was added POCl (15.3 g, 100 mmol). The mixture was stirred at 80 °C for 4 h. The mixture was concentrated. The residue was diluted with EtOAc (100 mL) and poured into ice water (100 mL). The aqueous layer was extracted with EtOAc (100 mL * 3). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column (PE / EtOAc = 100 / 1 to 8 / 1) to give 6-chloro-5-methylpyridazine-3-carbonitrile (3.0 g, 59% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J = 0.8 Hz, 1H), 2.44 (d, J = 0.8 Hz, 3H). LC-MS:m / z 154.0 (M+H) + .

[0306] Step C: 5-methyl-6-vinylpyridazine-3-carbonitrile A solution of 6-chloro-5-methylpyridazine-3-carbonitrile (1.66 g, 10.9 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (5.01 g, 32.6 mmol), Pd(dppf)Cl·DCM (893 mg, 1.09 mmol), and KCO (4.49 g, 32.6 mmol) in dioxane / HO (30 mL / 3 mL) was degassed and refilled with N three times. The mixture was stirred at 80 °C for 2.5 h. The mixture was diluted with HO (50 mL) and extracted with EtOAc (50 mL * 3). The combined organic phase was washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column (PE / EtOAc=50 / 1 to 4 / 1) to give 5-methyl-6-vinylpyridazine-3-carbonitrile (1.08 g, 69% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J = 0.4 Hz, 1H), 7.16 (dd, J = 16.8, 10.8 Hz, 1H), 6.62 (dd, J = 17.2, 2.0 Hz, 1H), 5.87 (dd, J = 10.8, 2.0 Hz, 1H), 2.42 (d, J = 0.8 Hz, 3H). LC-MS:m / z 146.1 (M+H) + .

[0307] Step D: 6-formyl-5-methylpyridazine-3-carbonitrile 5-Methyl-6-vinylpyridazine-3-carbonitrile (1.08 g, 7.45 mmol) was dissolved in DCM (10 mL). The solution was cooled to -78 °C. Ozone was bubbled through the solution until it turned pale blue. The reaction mixture was quenched with dimethyl sulfide. The mixture was concentrated and purified on a silica gel column (PE / EtOAc = 30 / 1 to 2 / 1) to give 6-formyl-5-methylpyridazine-3-carbonitrile (150 mg, 14% yield). 1 H NMR (400 MHz, DMSO-d6) δ 10.35 (d, J = 0.8 Hz, 1H), 8.47 - 8.50 (m, 1H), 2.63 (d, J = 0.8 Hz, 3H). LC-MS:m / z 166.1 (M+18+H) + .

[0308] Step E: (S)-6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methylpyridazine-3-carbonitrile To a solution of 6-formyl-5-methylpyridazine-3-carbonitrile (197 mg, 1.34 mmol) and (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine (310 mg, 0.890 mmol) in DMF (3 mL) was added three drops of AcOH. The mixture was stirred at room temperature for 1 hour, and then NaBH(OAc) (377 mg, 1.78 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with HO (30 mL) and extracted with EtOAc (30 mL * 3). The organic layer was concentrated and purified by Prep-TLC (PE / EtOAc = 1 / 1) to give (S)-6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methylpyridazine-3-carbonitrile (200 mg, 47% yield). LC-MS: m / z 479.3 (M+H) + .

[0309] Step F: (S,Z)-6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-N'-hydroxy-5-methylpyridazine-3-carboximidamide A solution of (S)-6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methylpyridazine-3-carbonitrile (200 mg, 0.420 mmol), hydroxylamine hydrochloride (88.0 mg, 1.26 mmol) and TEA (85.0 mg, 0.840 mmol) in EtOH (5 mL) was stirred at 80° C. for 2 hours. The mixture was concentrated. The residue was diluted with HO (20 mL) and extracted with EtOAc (30 mL * 3). The combined organic layers were dried over anhydrous NaSO and concentrated to give (S,Z)-6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-N'-hydroxy-5-methylpyridazine-3-carboximidamide (crude, 210 mg). LC-MS: m / z 512.3 (M+H) + .

[0310] Step G: (S)-3-(6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methylpyridazin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole To a solution of (S,Z)-6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-N'-hydroxy-5-methylpyridazine-3-carboximidamide (crude product 210 mg, 0.410 mmol) in THF (5 mL) were added TFAA (123 mg, 0.585 mmol), TEA (0.5 mL), and MgSO4. The mixture was stirred at room temperature for 2 days. The mixture was filtered, and the filtrate was concentrated. The residue was purified by Prep-HPLC (0.1% NH4HCO3 in water and acetonitrile) to give (S)-3-(6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methylpyridazin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (60.0 mg, 24% yield over two steps). LC-MS: m / z 590.2 (M+H) + .

[0311] Step H: (S)-3-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridazine To a solution of (S)-3-(6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methylpyridazin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (65.0 mg, 0.110 mmol) in EtOH (5 mL) was added hydrazine monohydrate (98%, 55.0 mg, 1.10 mmol). The mixture was stirred at 80° C. for 2 hours. TLC showed the reaction was complete. The mixture was concentrated and purified by Prep-TLC (PE / EtOAc = 1 / 1) and Prep-HPLC (0.1% formic acid in water and acetonitrile) to give (S)-3-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridazine (18.5 mg, 29% yield). LC-MS: m / z 589.0 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.52 - 7.60 (m, 2H), 7.34 (dd, J = 8.4, 2.0 Hz, 1H), 6.77 - 6.81 (m, 2H), 6.71 - 6.76 (m, 1H), 3.94 (s, 2H), 2.92 (s, 2H), 2.61 - 2.72 (m, 1H), 2.58 (s, 3H), 2.24 - 2.34 (m, 2H), 2.02 (s, 3H), 1.66 - 1.78 (m, 4H).

[0312] Example 50: 3-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-4-methyl-6-(1H-1,2,3,4-tetrazol-5-yl)pyridazine (50) [ka] A solution of 6-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}-methyl)-5-methylpyridazine-3-carbonitrile (70 mg, 0.15 mmol) in toluene (1 mL) was treated with di-n-butyltin diacetate (103 mg, 0.29 mmol) and trimethylsilyl azide (67 mg, 0.58 mmol). The reaction mixture was stirred at 30° C. for 2.5 days. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC to give 3-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-4-methyl-6-(1H-1,2,3,4-tetrazol-5-yl)pyridazine (7.7 mg, 10.0%). LC-MS (ES + ): m / z 522.1 [MH + ]. 1 H NMR (400 MHz, DMSO-d6, ppm):δ 8.18 (s, 1H), 7.75-7.45 (m, 2H), 7.34 (d, J = 8.5 Hz, 1H), 6.99-6.59 (m, 3H), 4.50-4.22 (m, 2H), 3.12-3.02 (m, 2H), 2.92-2.72 (m, 4H), 2.48-2.46 (m, 3H), 2.03 (s, 3H), 1.99-1.80 (m, 4H).

[0313] Example 51: (S)-3-(6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methylpyridazin-3-yl)-1,2,4-oxadiazol-5(4H)-one (51) [ka] A mixture of (Z)-6-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-N'-hydroxy-5-methylpyridazine-3-carboximidamide (80 mg, 0.16 mmol), DBU (71 mg, 0.47 mmol), and CDI (51 mg, 0.31 mmol) in dioxane (3 mL). The reaction mixture was stirred at 80° C. for 5 hours under a N atmosphere. The reaction mixture was monitored by LC / MS. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DMF (2 mL) and purified by Prep-HPLC to give 3-[6-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-methylpyridazin-3-yl]-4H-1,2,4-oxadiazol-5-one (40 mg, 46.7%). LC-MS (ES + ): m / z 538.1 [MH + ]. 1 H NMR (400 MHz, DMSO-d6):δ 8.04 (s, 1H), 7.61-7.52 (m, 2H), 7.32-7.35 (m, 1H), 6.81-6.74 (m, 3H), 3.98 (s, 2H), 3.05-2.89 (m, 2H), 2.76-2.72 (m, 1H), 2.60-2.53 (m, 4H), 2.40-2.33 (m, 1H), 2.02 (s, 3H), 1.80-1.60 (m, 4H). 19 F NMR (377 MHz, DMSO-d6):δ -110.82.

[0314] Example 52: 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxa (4-yl)piperidin-1-yl}methyl)-3-methyl-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyrazine (52) [ka] Step A: Synthesis of 5-hydroxy-6-methylpyrazine-2-carbonitrile A three-necked flask equipped with a reflux condenser was charged with 5-bromo-3-methylpyrazin-2-ol (5.0 g, 26.4 mmol), zinc cyanide (4.1 g, 34.4 mmol), DMF (50 mL), Pd(dba) (1.2 g, 1.32 mmol), and dppf (1.2 g, 2.12 mmol). The flask was purged with nitrogen three times and maintained. The reaction mixture was stirred at 120 °C under a N atmosphere for 3 h. The reaction mixture was monitored by LC / MS. After cooling to room temperature, the reaction mixture was quenched with H0 (100 mL). The resulting mixture was extracted with EA (3 × 100 mL). The combined organic layers were washed with saturated NaHCO (aq, 2 × 100 mL) and then with brine (2 × 100 mL). The organic layer was dried over NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA / PE (3:2) to give 5-hydroxy-6-methylpyrazine-2-carbonitrile (1.7 g, 47.6%). LC-MS (ES - ): m / z 134.00 [MH + ].

[0315] Step B: Synthesis of 6-methyl-5-(morpholin-4-yl)pyridazine-3-carbonitrile A mixture of 5-hydroxy-6-methylpyrazine-2-carbonitrile (1.7 g, 12.6 mmol) and oxyphosphorus chloride (5.8 g, 37.7 mmol) in acetonitrile (20 mL) was stirred at 80 °C for 3 h under a N atmosphere. The reaction mixture was monitored by LC / MS. The reaction mixture was cooled to room temperature and then concentrated in vacuo. The residue was poured into water (100 mL) at room temperature. The resulting mixture was basified to pH = 8 with NaOH (aq., c = 1 M). The resulting mixture was extracted with EA (3 x 100 mL). The combined organic phases were washed with saturated aqueous NaHCO (2 x 50 mL) followed by brine (2 x 50 mL). The organic layer was dried over NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA / PE (1:9) to give 5-chloro-6-methylpyrazine-2-carbonitrile (1.1 g, 56.9%). LC-MS (ES + ): m / z 153.8 [MH + ].

[0316] Step C: Synthesis of 5-ethenyl-6-methylpyrazine-2-carbonitrile To a mixture of 5-chloro-6-methylpyrazine-2-carbonitrile (1.1 g, 7.16 mmol) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.7 g, 10.75 mmol) in dioxane / HO (5:1, 9.5 mL) was added Pd(dppf)Cl (0.5 g, 0.72 mmol) and KCO (3.0 g, 21.47 mmol). The reaction mixture was stirred at 90 °C in an oil bath under a N atmosphere for 2 h. The reaction mixture was monitored by LC / MS. The reaction mixture was cooled to room temperature and then quenched with HO (20 mL). The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with saturated brine (2 × 50 mL) and dried over NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA / PE (1:9) to give 5-ethenyl-6-methylpyrazine-2-carbonitrile (660 mg, 63.5%). LC-MS (ES + ): m / z 145.9 [MH + ].

[0317] Step D: Synthesis of 5-formyl-6-methylpyrazine-2-carbonitrile To a solution of sodium periodate (1827 mg, 8.54 mmol) in water (2 mL) was added dropwise a solution of 5-ethenyl-6-methylpyrazine-2-carbonitrile (620 mg, 4.27 mmol) in dioxane (4 mL), followed by the addition of KOsO (14.2 mg, 0.04 mmol). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with HO (10 mL). The resulting mixture was extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (1 × 20 mL) and dried over NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give 5-formyl-6-methylpyrazine-2-carbonitrile (220 mg, 32.1%).

[0318] Step E: Synthesis of 5-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-6-methylpyrazine-2-carbonitrile A stirred solution of 5-formyl-6-methylpyrazine-2-carbonitrile (198 mg, 1.35 mmol) and 4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidine; para-toluenesulfonate (350 mg, 0.67 mmol) in DCM (5 mL) was basified to pH = 8 with DIEA. The reaction mixture was stirred at room temperature for 2 hours. Then, NaBH(OAc) (428 mg, 2.02 mmol) was added to the above mixture. The reaction mixture was stirred at room temperature under a N atmosphere for another 1 hour. The reaction mixture was monitored by LC / MS. The reaction mixture was quenched with H O (10 mL). The resulting mixture was extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (1 × 10 mL) and dried over Na SO . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA:PE (2:3) to give 5-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-6-methylpyrazine-2-carbonitrile (300 mg, 80.5%). LC-MS (ES + ): m / z 479.0 [MH + ].

[0319] Step F: Synthesis of 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-methyl-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyrazine (52) 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-methyl-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyrazine (30.2 mg) was obtained in a similar manner to that in Example 49. LC-MS (ES + ): m / z 589.20 [MH + ]. 1 H NMR (400 MHz, DMSO-d6):δ 9.01 (s, 1H), 7.65-7.51 (m, 2H), 7.32-7.35 (m, 1H), 6.83-6.65 (m, 3H), 3.75 (s, 2H), 2.98-2.85 (m, 2H), 2.73 (s, 3H), 2.30-2.15 (m, 2H), 2.05-1.98 (m, 4H), 1.95-1.84 (m, 1H), 1.79-1.61 (m, 4H). 19 F NMR (376 MHz, DMSO-d6):δ -62.84, -110.47.

[0320] Example 53: 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-[(1-methoxycyclopropyl)methyl]-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridine (53) [ka] Step A: 2-(5-bromo-2-methylpyridin-3-yl)acetonitrile To a mixture of 5-bromo-3-(chloromethyl)-2-methylpyridine (0.80 g, 3.65 mmol) in CHCN under a N atmosphere was added TMSCN (543 mg, 5.48 mmol) and aqueous TBAF (5.50 mL, 1.0 M in THF). The mixture was stirred at 80 °C for 2 h. Water and EtOAc were added to the mixture, and the organic layer was separated, washed with brine, dried over NaSO, and the solvent was concentrated to dryness to give 2-(5-bromo-2-methylpyridin-3-yl)acetonitrile (700 mg, yield: 91.3%). MS calculated: 210.0; MS found: 210.9 [M+H] + .

[0321] Step B: 2-(5-bromo-2-methylpyridin-3-yl)acetic acid A mixture of 2-(5-bromo-2-methylpyridin-3-yl)acetonitrile (700 mg, 3.33 mmol) and H2SO4 / H2O (7 mL, v:v=1:1) was stirred at room temperature for 10 hours at 100 °C. Aqueous NaOH solution (15% NaOH in water) was added to adjust the pH of the mixture to 4.0-5.0. Then, EtOAc (200 mL) was added, followed by water (100 mL). The organic layer was separated, washed with brine, and dried over Na2SO4. The filtrate was concentrated to dryness to give 2-(5-bromo-2-methylpyridin-3-yl)acetic acid (600 mg, yield: 78.70%). MS calculated: 229.0; MS found: 229.9 [M+H] + .

[0322] Step C: Methyl 2-(5-bromo-2-methylpyridin-3-yl)acetate To a solution of 2-(5-bromo-2-methylpyridin-3-yl)acetic acid (600 mg, 2.63 mmol) in MeOH (15 mL) was added dropwise HCl / MeOH (25% HCl in MeOH) (1.2 mL, 31.59 mmol) at room temperature. The mixture was stirred at 80 °C for 3 h. The mixture was poured into aqueous NaHCO (30 mL) / water (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated to give methyl 2-(5-bromo-2-methylpyridin-3-yl)acetate (650 mg, crude). MS calculated: 243.0; MS found: 243.9 [M+H] + .

[0323] Step D: 1-((5-bromo-2-methylpyridin-3-yl)methyl)cyclopropan-1-ol To a solution of methyl 2-(5-bromo-2-methylpyridin-3-yl)acetate (650 mg, 2.67 mmol) in THF (100 mL) was added Ti(CHO(CH3)2)4 (7.5 mL, 26.7 mmol) at 0 °C. With stirring, EtMgBr (1 M in THF, 66.75 mL, 67.75 mmol) was added to the mixture at 0 °C for 20 min. The black mixture was stirred at room temperature for about 30 min. The reaction was quenched with 5 mL of aqueous H2SO4 (1 M in water). The mixture was poured into water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by pre-HPLC to give 1-((5-bromo-2-methylpyridin-3-yl)methyl)cyclopropan-1-ol (150 mg, yield: 23.3%). MS calculated: 241.0; MS found: 241.9 [M+H] + .

[0324] Step E: 5-Bromo-3-((1-methoxycyclopropyl)methyl)-2-methylpyridine To a mixture of 1-((5-bromo-2-methylpyridin-3-yl)methyl)cyclopropan-1-ol (150 mg, 0.622 mmol) in THF (30 mL) was added NaH (60% w / w) (75 mg, 1.87 mmol) at 0° C., and the mixture was stirred for 0.5 h. MeI (266 mg, 1.87 mmol) was added, and the mixture was stirred at room temperature for 16 h. The mixture was poured into water (30 mL) and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give 5-bromo-3-((1-methoxycyclopropyl)methyl)-2-methylpyridine (150 mg, yield: 94.3%). MS calculated: 255.0; MS found: 256.0 [M+H] + .

[0325] Step F: 5-((1-methoxycyclopropyl)methyl)-6-methylnicotinonitrile A mixture of 5-bromo-3-((1-methoxycyclopropyl)methyl)-2-methylpyridine (150 mg, 0.59 mmol), Zn(CN) (210 mg, 1.77 mmol), and Pd(PPh) (68 mg, 0.059 mmol) in DMF (5 mL) was stirred under Ar with microwave irradiation at 100 °C for 2 h. The mixture was poured into water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by pre-HPLC to give 5-((1-methoxycyclopropyl)methyl)-6-methylnicotinonitrile (53 mg, yield: 44.4%). MS calculated: 202.1; MS found: 203.4 [M+H] + .

[0326] Step G: N'-hydroxy-5-((1-methoxycyclopropyl)methyl)-6-methylnicotinimidamide A mixture of 5-((1-methoxycyclopropyl)methyl)-6-methylnicotinonitrile (53 mg, 0.262 mmol) and aqueous NHOH (50% NHOH in water) (173 mg, 2.62 mmol) in EtOH (5 mL) was stirred at 90 °C for 1 h. The mixture was concentrated to give N'-hydroxy-5-((1-methoxycyclopropyl)methyl)-6-methylnicotinimidamide (66 mg, crude). MS calculated: 235.1; MS found: 236.2 [M+H] + .

[0327] Step H: 3-(5-((1-methoxycyclopropyl)methyl)-6-methylpyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole To a solution of N'-hydroxy-5-((1-methoxycyclopropyl)methyl)-6-methylnicotinimidamide (66 mg, crude product) in THF (10 mL) was added TFAA (550 mg, 2.62 mmol) in THF (0.5 mL) dropwise at 0 °C. The mixture was stirred at room temperature for 36 h. The mixture was poured into aqueous sodium bicarbonate (100 mL) and extracted with EtOAc (2 x 120 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by prep-TLC to give 3-(5-((1-methoxycyclopropyl)methyl)-6-methylpyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (25 mg, yield: 30.5%). MS calculated: 313.1; MS found: 314.2 [M+H] + .

[0328] Step I: 3-((1-methoxycyclopropyl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)picolinaldehyde A mixture of 3-(5-((1-methoxycyclopropyl)methyl)-6-methylpyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (10 mg, 0.080 mmol) and SeO2 (37 mg, 0.80 mmol) in 1,4-dioxane (5 mL) was stirred at 80 °C for 16 h. The mixture was filtered, and the filtrate was concentrated to give 3-((1-methoxycyclopropyl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)picolinaldehyde (27 mg). MS calculated: 327.1; MS found: 328.2 [M+H] + .

[0329] Step J: (S)-3-(6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-((1-methoxycyclopropyl)methyl)pyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole A mixture of 3-(5-(2-methoxypropyl)-6-methylpyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (42 mg, 0.082 mmol) and TEA (0.06 mL, 0.41 mmol) in DCM (5 mL) was stirred at room temperature for 0.5 h. 3-(2-Methoxypropyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)picolinaldehyde (27 mg) was added, and the mixture was stirred for 2 h. NaBH(OAc)3 (70 mg, 0.328 mmol) was added, and the mixture was stirred at room temperature for 16 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 filtrate was concentrated. The residue was purified by pre-HPLC to give (S)-3-(6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-((1-methoxycyclopropyl)methyl)pyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (16 mg, yield: 29.6%). MS calculated: 658.2; MS found: 659.0 [M+H] + .

[0330] Step K: 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-[(1-methoxycyclopropyl)methyl]-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridine (53) A mixture of (S)-3-(6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-((1-methoxycyclopropyl)methyl)pyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (16 mg, 0.023 mmol) and NH2NH2·H2O (2 drops) in EtOH (1 mL) was stirred at 70 °C for 1 h. The mixture was purified by prep-HPLC to give 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-[(1-methoxycyclopropyl)methyl]-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridine (53) (2.03 mg, yield: 13.4%). MS calculated: 657.2; MS found: 658.3 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 9.11 (s, 1 H), 8.48 (s, 1 H), 7.61 (t, J = 8.4 Hz, 1 H), 7.30 (dd, J1= 8.8 Hz / J2= 12.8 Hz , 1 H), 7.22 (dd, J1= 6.4 Hz / J2= 7.6 Hz, 1 H), 6.85 - 6.73 (m, 3 H), 4.45 - 4.30 (m, 2 H), 3.58 - 3.50 (m, 2 H), 3.32 (s, 3 H), 3.16 (s, 2 H), 3.10 - 2.90 (m, 3 H), 2.30 - 2.10 (m, 2H), 2.08 - 1.96 (m, 5 H), 0.95 - 0.90 (m, 2 H), 0.71 - 0.66 (m, 2 H). 19 F-NMR (377 MHz, CD3OD):δ -65.12, -65.16, -112.23.

[0331] Example 54: 2-{[2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}-1λ 6 -Thietane-1,1-dione (54) [ka]

[0332] Step A: 2-((5-bromo-2-methylpyridin-3-yl)methyl)thietane 1,1-dioxide To a solution of thietane 1,1-dioxide (150 mg, 1.415 mmol) in THF (5 mL) was added n-BuLi (2.5 M in THF) (0.57 mL, 1.415 mmol) dropwise at −78° C. under Ar. The mixture was stirred at −78° C. for 15 minutes. 5-Bromo-3-(chloromethyl)-2-methylpyridine (156 mg, 0.707 mmol) in THF (5 mL) was added dropwise, and the mixture was stirred at −50° C. for 1 hour. The mixture was poured into water (12 mL) and filtered. The filtrate was purified by flash reverse-phase column chromatography to give 2-((5-bromo-2-methylpyridin-3-yl)methyl)thietane 1,1-dioxide (60 mg, yield: 29.3%). MS calculated: 289.0; MS found: 290.0 [M+H] + .

[0333] Step B: 5-((1,1-dioxidothietan-2-yl)methyl)-6-methylnicotinonitrile A mixture of 2-((5-bromo-2-methylpyridin-3-yl)methyl)thietane 1,1-dioxide (60 mg, 0.208 mmol), Zn(CN) (121 mg, 1.038 mmol), Zn (3 mg, 0.052 mmol), Pddba (8 mg, 0.0083 mmol), and dppf (9 mg, 0.0166 mmol) in NMP (1 mL) was stirred at 180 °C under Ar using microwave irradiation for 2 h. The mixture was filtered, and the residue was purified by silica gel column chromatography to give 5-((1,1-dioxidothietan-2-yl)methyl)-6-methylnicotinonitrile (15 mg, yield: 30.6%). MS calculated: 236.1; MS found: 237.2 [M+H] + .

[0334] Step C: 5-((1,1-dioxidothietan-2-yl)methyl)-6-formylnicotinonitrile A mixture of 5-((1,1-dioxidothietan-2-yl)methyl)-6-methylnicotinonitrile (15 mg, 0.063 mmol) and SeO2 (70 mg, 0.63 mmol) in 1,4-dioxane (5 mL) was stirred at 80 °C for 16 h. The mixture was filtered, and the filtrate was concentrated to give 5-((1,1-dioxidothietan-2-yl)methyl)-6-formylnicotinonitrile (10 mg, yield: 62.9%). MS calculated: 250.0; MS found: 251.1 [M+H] + .

[0335] Step D: 6-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-((1,1-dioxidothietan-2-yl)methyl)nicotinonitrile A mixture of (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine 4-methylbenzenesulfonate (21 mg, 0.04 mmol) and TEA (20 mg, 0.2 mmol) in DCM (3 mL) was stirred at room temperature for 0.5 h. 5-((1,1-dioxidothietan-2-yl)methyl)-6-formylnicotinonitrile (10 mg, 0.04 mmol) was added, and the mixture was stirred for 2 h. NaBH(OAc)3 (34 mg, 0.16 mmol) was added, and the mixture was stirred at room temperature for 16 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 filtrate was concentrated. The residue was purified by silica gel column chromatography to give 6-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-((1,1-dioxidothietan-2-yl)methyl)nicotinonitrile (10 mg, yield: 43%). MS calculated: 581.2; MS found: 582.3 [M+H] + .

[0336] Step E: 2-{[2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}-1λ 6 -Thietane-1,1-dione (54) 2-{[2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}-1λ 6-Thietane-1,1-dione (54) (0.93 mg) was obtained using a method similar to that described in Example 1. MS calculated: 691.2; MS found: 692.3 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 9.11 (s, 1 H), 8.39 (s, 1 H), 7.61 (t, J = 8.4 Hz, 1 H), 7.29 (d, J = 9.6 Hz, 1 H), 7.22 (d, J = 8.0 Hz, 1 H), 6.85 - 6.70 (m, 3 H), 4.56 (s, 2 H), 4.42 - 4.26 (m, 2 H), 4.14 - 3.94 (m, 3 H), 3.50 - 3.46 (m, 2 H), 3.00 - 2.80 (m, 2 H), 2.55 - 2.41 (m, 1 H), 2.24 - 2.10 (m, 3 H), 2.05 (s, 3 H), 2.05 - 1.93 (m, 3 H). 19 F-NMR (377 MHz, CD3OD):δ -65.21, -112.26.

[0337] Example 55: 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-(methanesulfonylmethyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridine (55) [ka] Step A: 5-Bromo-2-methyl-3-((methylsulfonyl)methyl)pyridine A mixture of 5-bromo-3-(chloromethyl)-2-methylpyridine (1.1 g, 5.0 mmol) and sodium methanesulfinate (765 mg, 7.5 mmol) in DMF (10 mL) was stirred at 65 °C for 1 h. The mixture was poured into water (200 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give 5-bromo-2-methyl-3-((methylsulfonyl)methyl)pyridine (810 mg, yield: 61.6%). MS calculated: 263.0; MS found: 263.9 [M+H] + .

[0338] Step B: 6-methyl-5-((methylsulfonyl)methyl)nicotinonitrile A mixture of 5-bromo-2-methyl-3-((methylsulfonyl)methyl)pyridine (410 mg, 1.56 mmol), Zn(CN) (547 mg, 4.68 mmol), and Pd(PPh) (180 mg, 0.156 mmol) in NMP (2 mL) was stirred under Ar at 180 °C using microwave irradiation for 2 h. The mixture was poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give 6-methyl-5-((methylsulfonyl)methyl)nicotinonitrile (850 mg, crude). MS calculated: 210.0; MS found: 210.9 [M+H]. + .

[0339] Step C: N'-hydroxy-6-methyl-5-((methylsulfonyl)methyl)nicotinimidamide A mixture of 6-methyl-5-((methylsulfonyl)methyl)nicotinonitrile (750 mg, 3.57 mmol) and aqueous NHOH (50% NHOH in water) (2.4 mL, 35.7 mmol) in EtOH (10 mL) was stirred at 90 °C for 1 h. The mixture was concentrated to give N'-hydroxy-6-methyl-5-((methylsulfonyl)methyl)nicotinimidamide (750 mg, crude). MS calculated: 243.1; MS found: 244.0 [M+H] + .

[0340] Step D: 3-(6-methyl-5-((methylsulfonyl)methyl)pyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole To a solution of N'-hydroxy-6-methyl-5-((methylsulfonyl)methyl)nicotinimidamide (750 mg, 3.09 mmol) in THF (10 mL) was added TFAA (2.2 mL, 15.4 mmol) in THF (2 mL) dropwise at 0 °C. The mixture was stirred at room temperature for 16 h. The mixture was poured into aqueous sodium bicarbonate (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give 3-(6-methyl-5-((methylsulfonyl)methyl)pyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (240 mg, yield: 21.4%). MS calculated: 321.0; MS found: 322.4 [M+H] + .

[0341] Step E: 3-((methylsulfonyl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)picolinaldehyde A mixture of 3-(6-methyl-5-((methylsulfonyl)methyl)pyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (120 mg, 0.374 mmol) and SeO (415 mg, 3.74 mmol) in 1,4-dioxane (5 mL) was stirred at 80 °C for 16 h. The mixture was filtered, and the filtrate was concentrated to give 3-((methylsulfonyl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)picolinaldehyde (126 mg, crude). MS calculated: 335.0; MS found: 336.0 [M+H] + .

[0342] Step F: (S)-3-(6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-((methylsulfonyl)methyl)pyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole A mixture of (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine 4-methylbenzenesulfonate (65 mg, 0.125 mmol) and TEA (63 mg, 0.627 mmol) in DCM (5 mL) was stirred at room temperature for 0.5 h. 3-((methylsulfonyl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)picolinaldehyde (42 mg, 0.125 mmol) was added, and the mixture was stirred for 2 h. NaBH(OAc)3 (106 mg, 0.5 mmol) was added, and the mixture was stirred at room temperature for 16 h. 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 filtrate was concentrated. The residue was purified by silica gel column chromatography to give (S)-3-(6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-((methylsulfonyl)methyl)pyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (83 mg, crude). MS calculated: 666.1; MS found: 667.2 [M+H] + .

[0343] Step G: 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-(methanesulfonylmethyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridine (55) A mixture of (S)-3-(6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-((methylsulfonyl)methyl)pyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (83 mg, 0.125 mmol) and NH2NH2·H2O (5 drops) in EtOH (2 mL) was stirred at 70 °C for 1 h. The mixture was purified by prep-HPLC to give 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-(methanesulfonylmethyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridine (55) (21.9 mg, yield: 26.4%). MS calculated: 665.1; MS found: 666.1 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 9.28 (d, J = 1.6 Hz, 1 H), 8.47 (d, J = 2.0 Hz, 1 H), 7.61 (t, J = 8.4 Hz, 1 H), 7.30 (dd, J1 = 2.0 Hz / J2 = 11.2 Hz, 1 H), 7.22 (dd, J = 1.2 Hz / J = 8.4 Hz, 1 H), 6.85 - 6.73 (m, 3 H), 4.82 (s, 2 H), 4.60 (s, 2 H), 3.65 - 3.53 (m, 2 H), 3.20 - 2.95 (m, 6 H), 2.30 - 2.13 (m, 2 H), 2.10 - 2.00 (m, 5 H). 19 F-NMR (377 MHz, CD3OD):δ -65.21, -112.22.

[0344] Example 56: (S)-2-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-N,N-dimethylacetamide (56) [ka]

[0345] Step A: tert-butyl 2-(2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)acetate A mixture of 3-bromo-2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridine (200 mg, 0.46 mmol), (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (1.18 g, 4.6 mmol), and Pd(pph3)4 (53 mg, 0.05 mmol) in THF (8 mL) was stirred at 70 °C in a microwave cube for 4 h. The mixture was poured into water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the residue was purified by prep-TLC (PE:EA = 5:1) to give tert-butyl 2-(2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)acetate (85 mg, yield: 39.2%). MS calculated: 472.2; MS found: 473.3 [M+H] + .

[0346] Step B: tert-butyl 2-(2-formyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)acetate A mixture of tert-butyl 2-(2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)acetate (30 mg, 0.06 mmol) and SeO (71 mg, 0.64 mmol) in 1,4-dioxane (3 mL) was stirred at 80 °C for 16 h. The mixture was filtered and the residue was concentrated to give tert-butyl 2-(2-formyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)acetate (25 mg, yield: 86.2%). MS calculated: 486.2; MS found: 487.3 [M+H] + .

[0347] Step C: tert-butyl (S)-2-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)acetate A mixture of (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine 4-methylbenzenesulfonate (29 mg, 0.06 mmol) and TEA (25 mg, 0.26 mmol) in DCM (5 mL) was stirred at room temperature for 0.5 hours. To the mixture was added tert-butyl 2-(2-formyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)acetate (25 mg, 0.05 mmol), and the mixture was stirred for 2 hours. To the mixture was added NaBH(OAC) (44 mg, 0.21 mmol), and the mixture was stirred at room temperature for 16 hours. 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 to give tert-butyl (S)-2-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)acetate (45 mg, yield: >99.9%). MS calculated: 817.3; MS found: 818.4 [M+H] + .

[0348] Step D: (S)-2-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)acetic acid A mixture of tert-butyl (S)-2-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)acetate (45 mg, 0.06 mmol) and TFA (1 mL) in DCM (2 mL) was stirred at room temperature for 1 hour. The mixture was poured into saturated aqueous NaHCO3 (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 give (S)-2-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)acetic acid (37 mg, yield: >99.9%). MS calculated: 631.2; MS found: 632.3 [M+H] + .

[0349] Step E: (S)-2-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-N,N-dimethylacetamide A mixture of the obtained (S)-2-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)acetic acid (37 mg, 0.06 mmol), DIEA (39 mg, 0.30 mmol), and dimethylamine (11 mg, 0.24 mmol) in DMF (3 mL) was stirred at room temperature for 5 minutes. HATU (45 mg, 0.12 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was purified by prep-HPLC to give compound 56 (2.35 mg, yield: 6.03%). MS calculated: 658.2; MS found: 659.4 [M+H] + . 1 H NMR (400 MHz, CD3OD-d4):δ 9.16 (s, 1 H), 8.27 (s, 1 H), 7.61 (t, J = 8.4 Hz, 1 H), 7.25 (dd, J = 10.8 Hz / J = 29.2 Hz, 2 H), 6.84 - 6.80 (m, 1 H), 6.75 (d, J = 8.0 Hz, 2 H), 4.39 - 4.24 (m, 1 H), 4.06 (s, 2 H), 3.64 - 3.61 (m, 3 H), 3.48 - 3.45 (m,2 H), 3.43 - 3.39 (m, 3 H), 3.03 - 2.99 (m, 3H), 2.99 - 2.95 (m, 1 H), 2.20 - 1.97 (m, 7 H). 19 F NMR (377 MHz, CD3OD-d4): δ (-74.04), (-76.04), (-112.25).

[0350] Example 57: 2-[(4-{6-[(4-chloro-2-fluorophenyl)methoxy]pyridin-2-yl}piperidin-1-yl)methyl]-3-(methanesulfonylmethyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridine (57) [ka] Step A: 3-(6-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-5-((methylsulfonyl)methyl)pyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole A mixture of 2-((4-chloro-2-fluorobenzyl)oxy)-6-(piperidin-4-yl)pyridine hydrochloride (45 mg, 0.12 mmol) and TEA (63 mg, 0.63 mmol) in DCM (5 mL) was stirred at room temperature for 0.5 h. 3-((methylsulfonyl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)picolinaldehyde (42 mg, 0.12 mmol) was added, and the mixture was stirred for 2 h. NaBH(OAc)3 (106 mg, 0.5 mmol) was added, and the mixture was stirred at room temperature for 16 h. The mixture was poured into water (50 mL), extracted with DCM (2 x 50 mL), and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give 3-(6-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-5-((methylsulfonyl)methyl)pyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (20 mg, yield: 25%). MS calculated: 639.1; MS found: 640.0 [M+H] + .

[0351] Step B: 2-[(4-{6-[(4-chloro-2-fluorophenyl)methoxy]pyridin-2-yl}piperidin-1-yl)methyl]-3-(methanesulfonylmethyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridine (57) A mixture of 3-(6-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-5-((methylsulfonyl)methyl)pyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (20 mg, 0.031 mmol) and NHNH·HO (2 drops) in EtOH (1 mL) was stirred at 70 °C for 1 h. The mixture was purified by prep-HPLC to give 2-[(4-{6-[(4-chloro-2-fluorophenyl)methoxy]pyridin-2-yl}piperidin-1-yl)methyl]-3-(methanesulfonylmethyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridine (57) (4.8 mg, yield: 23.9%). MS calculated: 638.2; MS found: 639.1 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 9.28 (d, J = 1.2 Hz, 1 H), 8.46 (s, 1 H), 7.63 (t, J = 8.0 Hz, 1 H), 7.51 (t, J = 8.4 Hz, 1 H), 7.28 - 7.18 (m, 2 H), 6.90 (d, J = 7.2 Hz, 1 H), 6.71 (d, J = 8.4 Hz, 1 H), 5.45 (s, 2 H), 4.62 (s, 2 H), 3.65 - 3.54 (m, 2 H), 3.27 - 3.20 (m, 2 H), 3.18 - 2.90 (m, 6 H), 2.30 - 2.10 (m, 2 H), 2.18 - 2.06 (m, 2 H). 19 F-NMR (377 MHz, CD3OD):δ -65.14, -117.55.

[0352] Example 58: 3-[6-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-(methanesulfonylmethyl)pyridin-3-yl]-2,5-dihydro-1,2,4-oxadiazol-5-one (58) [ka] A mixture of (S)-6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-N'-hydroxy-5-((methylsulfonyl)methyl)nicotinimidamide (10 mg, 0.017 mmol) and CDI (14 mg, 0.085 mmol) in THF (3 mL) was stirred at 50°C for 16 h. The mixture was purified by prep-HPLC to give 3-[6-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-(methanesulfonylmethyl)pyridin-3-yl]-2,5-dihydro-1,2,4-oxadiazol-5-one (58) (2.3 mg, yield: 21.9%). MS calculated: 614.1; MS found: 615.3 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 9.08 (s, 1 H), 8.31 (s, 1 H), 7.61 (t, J = 8.4 Hz, 1 H), 7.29 (d, J = 10.4 Hz, 1 H), 7.22 (d, J = 8.8 Hz, 1 H), 6.85 - 6.72 (m, 3 H), 4.55 (brs, 2 H), 3.60 - 3.45 (m, 2 H), 3.34 (s, 2 H), 3.09 (s, 3 H), 3.08 - 2.90 (m, 3 H), 2.28 - 2.10 (m, 2 H), 2.04 (s, 3 H), 2.10 - 1.97 (m, 2 H). 19 F NMR(377 MHz, CD3OD):δ -112.23.

[0353] Example 59: 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-[(ethanesulfonyl)methyl]-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridine (59) [ka] Step A: 5-Bromo-3-((ethylsulfonyl)methyl)-2-methylpyridine To a solution of 5-bromo-3-(chloromethyl)-2-methylpyridine (200 mg, 0.91 mmol) in DMF (10 mL) was added sodium ethanesulfinate (159 mg, 1.8 mmol) and stirred at 65 °C for 1 h. The mixture was poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated to give 5-bromo-3-((ethylsulfonyl)methyl)-2-methylpyridine (210 mg, 83.0% yield). MS calculated: 277.0; MS found: 277.8 [M+H]. + .

[0354] Step B: 5-((ethylsulfonyl)methyl)-6-methylnicotinonitrile A mixture of 5-bromo-3-((ethylsulfonyl)methyl)-2-methylpyridine (210 mg, 0.76 mmol), Zn(CN) (266 mg, 2.3 mmol), and Pd(PPh) (87 mg, 0.08 mmol) in DMF (5 mL) was stirred at 130 °C under Ar with microwave irradiation for 2 h. The mixture was filtered, and the residue was purified by silica gel column chromatography to give 5-((ethylsulfonyl)methyl)-6-methylnicotinonitrile (60 mg, yield: 35.3%). MS calculated: 224.1; MS found: 224.8 [M+H]. + .

[0355] Step C: 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-[(ethanesulfonyl)methyl]-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridine (59) 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-[(ethanesulfonyl)methyl]-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridine (59) (14.3 mg) was obtained using a method similar to that described in Example 55. MS calculated: 679.2; MS found: 680.3 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 9.27 (s, 1 H), 8.45 (d, J = 2.0 Hz, 1 H), 7.61 (t, J = 8.4 Hz, 1 H), 7.29 (dd, J = 8.4 Hz, 1.7 Hz, 1H), 7.22 (dd, J = 8 Hz, 1.6 Hz, 1H), 6.86 - 6.72 (m, 3 H), 4.65 - 4.80 (s, 2H), 4.51 (m, 2 H), 3.61 - 3.48 (m, 2 H), 3.27 - 3.17 (m, 2 H), 3.13 - 2.92 (m, 3 H), 2.30 - 2.13 (m, 2 H), 2.12 - 1.98 (m, 5 H), 1.43 (t, J = 7.6 Hz, 3 H). 19 F NMR(377 MHz, CD3OD):δ -65.23, -112.24.

[0356] Example 60: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(1-(methylsulfonyl)ethyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridine (60) [ka] Step A: Synthesis of 5-bromo-2-methyl-3-(1-(methylsulfonyl)ethyl)pyridine To a solution of 5-bromo-2-methyl-3-((methylsulfonyl)methyl)pyridine (100 mg, 0.38 mmol) in THF (5 mL) was added NaH (60%) (30 mg, 0.76 mmol) at 0° C., and the mixture was stirred for 0.5 h. MeI (65 mg, 0.46 mmol) was added to the mixture, and the mixture was stirred at room temperature for 16 h. The mixture was poured into water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the residue was concentrated. The residue was purified by silica gel column chromatography to give 5-bromo-2-methyl-3-(1-(methylsulfonyl)ethyl)pyridine (90 mg, yield: 85.5%). MS calculated: 277.0; MS found: 278.1 [M+H] + .

[0357] Step B: Synthesis of 6-methyl-5-(1-(methylsulfonyl)ethyl)nicotinonitrile A mixture of 5-bromo-2-methyl-3-(1-(methylsulfonyl)ethyl)pyridine (105 mg, 0.38 mmol), Zn(CN) (133 mg, 1.13 mmol), and Pd(PPh) (44 mg, 0.038 mmol) in NMP (2 mL) was stirred under Ar at 180 °C using a MW. The mixture was filtered and the residue was purified by silica gel column chromatography to give 6-methyl-5-(1-(methylsulfonyl)ethyl)nicotinonitrile (45 mg, yield: 53.2%). MS calculated: 224.1; MS found: 225.0 [M+H]. + .

[0358] Step C: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(1-(methylsulfonyl)ethyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridine 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(1-(methylsulfonyl)ethyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridine (21.0 mg) was obtained in a similar manner to that of Example 55. MS calculated: 679.2; MS found: 680.3 [M+H] + .

[0359] 1 H NMR (400 MHz, CD3OD-d4):δ 9.25 (s, 1 H), 8.67 (s, 1 H), 7.61 (t, J = 8.4 Hz, 1 H), 7.29 (dd, J = 1.6 Hz / J = 10.8 Hz, 1 H), 7.22 (d, J = 8.4 Hz, 1 H), 6.84 - 6.75 (m, 3 H), 5.06 - 5.00 (m, 1 H), 4.50 (brs, 2 H), 3.52 - 3.44 (m, 2 H), 3.03 (s, 3 H), 3.01 - 2.91 (m, 3 H), 2.23 - 2.13 (m, 2 H), 2.04 (s, 3 H), 2.02 - 1.97 (m, 2 H), 1.91 (d, J = 7.2 Hz, 3 H). 19 F NMR (377 MHz, CD3OD-d4):δ (-65.50), (-112.23).

[0360] Example 61: 2-[(4-{6-[(4-chloro-2-fluorophenyl)methoxy]-5-fluoropyridin-2-yl}piperidin-1-yl)methyl]-3-(methanesulfonylmethyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridine (61) [ka] Step A: 3-(6-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)piperidin-1-yl)methyl)-5-((methylsulfonyl)methyl)pyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole A mixture of 2-((4-chloro-2-fluorobenzyl)oxy)-3-fluoro-6-(piperidin-4-yl)pyridine 2,2,2-trifluoroacetate (40 mg, 0.089 mmol) and TEA (45 mg, 0.45 mmol) in DCM (5 mL) was stirred at room temperature for 0.5 h. 3-((methylsulfonyl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)picolinaldehyde (30 mg, 0.089 mmol) was added, and the mixture was stirred for 2 h. NaBH(OAc)3 (75 mg, 0.36 mmol) was added, and the mixture was stirred at room temperature for 16 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 filtrate was concentrated. The residue was purified by silica gel column chromatography to give 3-(6-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)piperidin-1-yl)methyl)-5-((methylsulfonyl)methyl)pyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (10 mg, yield: 17.0%). MS calculated: 657.1; MS found: 658.0 [M+H] + .

[0361] Step B: 2-[(4-{6-[(4-chloro-2-fluorophenyl)methoxy]-5-fluoropyridin-2-yl}piperidin-1-yl)methyl]-3-(methanesulfonylmethyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridine (61) A mixture of 3-(6-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)piperidin-1-yl)methyl)-5-((methylsulfonyl)methyl)pyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (10 mg, 0.015 mmol) and NHNH·HO (2 drops) in EtOH (1 mL) was stirred at 70 °C for 1 h. The mixture was purified by prep-HPLC to give 2-[(4-{6-[(4-chloro-2-fluorophenyl)methoxy]-5-fluoropyridin-2-yl}piperidin-1-yl)methyl]-3-(methanesulfonylmethyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridine (61) (3.1 mg, yield: 30.7%). MS calculated: 656.1; MS found: 657.3 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 9.26 (d, J = 1.2 Hz, 1 H), 8.46 (s, 1 H), 7.54 (t, J = 8.4 Hz, 1 H), 7.43 (dd, J = 8.0 Hz / J = 10.0 Hz, 1 H), 7.29 - 7.21 (m, 2 H), 6.89 (dd, J = 2.8 Hz / J = 8.0 Hz, 1 H), 5.53 (s, 2 H), 4.53 (s, 2 H), 3.56 - 3.46 (m, 2 H), 3.31 (s, 2 H), 3.09 (s, 3 H), 3.08 - 2.85 (m, 3H), 2.21 - 2.02 (m,4 H). 19 F NMR(377 MHz, CD3OD):δ -65.02, -117.28, 144.90.

[0362] Example 62: 1-{[3-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyrazin-2-yl]methyl}cyclopropane-1-carbonitrile (62) [ka] Step A: 6-chloro-3-methylpyrazine-2-carboxylate A mixture of methyl 3-bromo-6-chloropyrazine-2-carboxylate (5.0 g, 20.0 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (6.86 mL, 3.5 mol / L), Pd(dppf)Cl.sub.2·DCM (1.63 g, 2.00 mmol), and K.sub.2CO.sub.3 (5.52 g, 40.00 mmol) in dioxane (60 mL) was stirred at 80.degree. C. for 16 hours under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3.times.100 mL). The combined organic layers were washed with brine (2.times.60 mL) and dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (20:1) to give 6-chloro-3-methylpyrazine-2-carboxylate (1.6 g, yield: 44.1%). MS calculated: 186.0; MS found: 187.0 [M+H] + .

[0363] Step B: (6-chloro-3-methylpyrazin-2-yl)methanol To a solution of methyl 6-chloro-3-methylpyrazine-2-carboxylate (1.64 g, 8.82 mmol) in THF (20 mL), -65 oC gave DIBAL-H (35.3 mL, 1 mol / L in toluene). The resulting mixture was stirred at room temperature under N for 3 h. The reaction mixture was quenched with aqueous NaOH (2 M, 30 mL) at 0 °C, followed by the addition of HO (100 mL) and extraction with EA (3 x 60 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give (6-chloro-3-methylpyrazin-2-yl)methanol (910 mg, yield: 65.3%). MS calculated: 158.0; MS found: 159.0 [M+H] + .

[0364] Step C: 5-chloro-3-(chloromethyl)-2-methylpyrazine To a solution of (6-chloro-3-methylpyrazin-2-yl)methanol (910 mg, 5.8 mmol) in DCM (12 mL) was added SOCl (1.03 g, 8.7 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated NaHCO (20 mL) and then extracted with DCM (3 x 40 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (20:1) to give 5-chloro-3-(chloromethyl)-2-methylpyrazine (950 mg, yield: 93.7%). MS calculated: 176.0; MS found: 177.1 [M+H] + .

[0365] Step D: tert-butyl 1-((6-chloro-3-methylpyrazin-2-yl)methyl)cyclopropane-1-carboxylate To a solution of tert-butyl cyclopropanecarboxylate (1.15 g, 8.1 mmol) in THF (10 mL) was added dropwise LDA (5.4 mL, 2 mol / L in THF) under N at −65° C. The mixture was stirred at −65° C. for 1 h. 5-Chloro-3-(chloromethyl)-2-methylpyrazine (950 mg, 5.40 mmol) in THF (10 mL) was added dropwise. The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. The reaction mixture was washed with EA (50 mL), NH4Cl (aq, 20 mL) and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (PE / EA=10 / 1) to give tert-butyl 1-((6-chloro-3-methylpyrazin-2-yl)methyl)cyclopropane-1-carboxylate (560 mg, yield: 36.8%). MS calculated: 282.1; MS found: 283.1 [M+H] + .

[0366] Step E: tert-butyl 1-((6-cyano-3-methylpyrazin-2-yl)methyl)cyclopropane-1-carboxylate To a mixture of tert-butyl 1-((6-chloro-3-methylpyrazin-2-yl)methyl)cyclopropane-1-carboxylate (460 mg, 1.6 mmol) in NMP (4.0 mL) was added Zn(CN) (572 mg, 4.9 mmol) and Ruphos Pd G (136 mg, 0.16 mmol). The resulting mixture was stirred at 130 °C under Ar for 1 h. The reaction mixture was quenched with HO (20 mL) and then extracted with EA (2 x 20 mL). The combined organic layers were washed with brine (20 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give tert-butyl 1-((6-cyano-3-methylpyrazin-2-yl)methyl)cyclopropane-1-carboxylate (290 mg, yield: 65.2%). MS calculated: 273.2; MS found: 274.1 [M+H]+ .

[0367] Step F: 1-((6-cyano-3-methylpyrazin-2-yl)methyl)cyclopropane-1-carboxylic acid To a solution of tert-butyl 1-((6-cyano-3-methylpyrazin-2-yl)methyl)cyclopropane-1-carboxylate (270 mg, 0.99 mmol) in DCM (6.0 mL) was added TFA (2.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give crude 1-((6-cyano-3-methylpyrazin-2-yl)methyl)cyclopropane-1-carboxylic acid (340 mg, yield: 100%). MS calculated: 217.1; MS found: 218.0 [M+H] + .

[0368] Step G: 1-((6-cyano-3-methylpyrazin-2-yl)methyl)cyclopropane-1-carboxamide To a mixture of 1-((6-cyano-3-methylpyrazin-2-yl)methyl)cyclopropane-1-carboxylic acid (340 mg, 1.57 mmol) in DCM (6.0 mL) was added DIEA (608 mg, 4.71 mmol), NH4Cl (126 mg, 2.35 mmol), and HATU (775 mg, 2.04 mmol). The resulting mixture was stirred at rt under Ar for 2 h. The reaction mixture was quenched with HO (20 mL) and then extracted with EA (2 x 20 mL). After extraction with DCM (2 x 30 mL), the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3:1) to give 1-((6-cyano-3-methylpyrazin-2-yl)methyl)cyclopropane-1-carboxamide (250 mg, yield: 73.5%). MS calculated: 216.1; MS found: 217.1 [M+H] + .

[0369] Step H: 6-((1-cyanocyclopropyl)methyl)-5-methylpyrazine-2-carbonitrile To a mixture of 1-((6-cyano-3-methylpyrazin-2-yl)methyl)cyclopropane-1-carboxamide (230 mg, 1.06 mmol) in DCM (6.0 mL) was added Burgess reagent (818 mg, 3.19 mmol). The resulting mixture was stirred at rt under Ar for 16 h. The reaction mixture was quenched with HO (10 mL) and then extracted with DCM (2 x 20 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3:1) to give 6-((1-cyanocyclopropyl)methyl)-5-methylpyrazine-2-carbonitrile (65 mg, yield: 30.9%). MS calculated: 198.1; MS found: 199.1 [M+H] + .

[0370] Step I: 5-(bromomethyl)-6-((1-cyanocyclopropyl)methyl)pyrazine-2-carbonitrile

[0371] A mixture of 6-((1-cyanocyclopropyl)methyl)-5-methylpyrazine-2-carbonitrile (30 mg, 0.151 mmol), AIBN (12 mg, 0.075 mmol), and NBS (54 mg, 0.303 mmol) in DMF (1.5 mL) was stirred at 115 °C for 4 h under a N atmosphere. The reaction mixture was cooled to room temperature. The mixture was quenched with HO (5 mL) and extracted with EA (3 x 10 mL). The combined organic layers were washed with brine (10 mL). The organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (PE / EA = 2 / 1) to give 5-(bromomethyl)-6-((1-cyanocyclopropyl)methyl)pyrazine-2-carbonitrile (13 mg, yield: 31%).

[0372] Step J: (S)-5-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-6-((1-cyanocyclopropyl)methyl)pyrazine-2-carbonitrile To a solution of (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine (27 mg, 0.051 mmol, TsOH salt) in DMF (1.5 mL) was added DIEA (12 mg, 0.094 mmol) and 5-(bromomethyl)-6-((1-cyanocyclopropyl)methyl)pyrazine-2-carbonitrile (13 mg, 0.047 mmol). The reaction mixture was stirred at 70 °C for 1 h. The reaction mixture was cooled to room temperature. The mixture was quenched with HO (5 mL) and extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (5 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (PE / EA=4 / 1) to give (S)-5-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-6-((1-cyanocyclopropyl)methyl)pyrazine-2-carbonitrile (15 mg, yield: 58.6%). MS calculated: 543.2; MS found: 544.2 [M+H] + .

[0373] Step K: (S)-5-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-6-((1-cyanocyclopropyl)methyl)-N'-hydroxypyrazine-2-carboximidamide To a solution of (S)-5-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-6-((1-cyanocyclopropyl)methyl)pyrazine-2-carbonitrile (15 mg, 0.02 mmol) in ACN (1.5 mL) was added hydroxylamine hydrochloride (3.9 mg, 0.055 mmol) and TEA (8 mg, 0.081 mmol). The resulting mixture was stirred at 50 °C for 1 h. The reaction mixture was diluted with EA (10 mL) and washed with HO (5 mL). The organic layer was dried over NaSO and purified. The filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (DCM / MeOH=20 / 1) to give (S)-5-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-6-((1-cyanocyclopropyl)methyl)-N′-hydroxypyrazine-2-carboximidamide (13 mg, yield: 81.7%). MS calculated: 576.2; MS found: 577.2 [M+H] + .

[0374] Step L: (S)-1-((3-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyrazin-2-yl)methyl)cyclopropane-1-carbonitrile To a solution of (S)-5-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-6-((1-cyanocyclopropyl)methyl)-N'-hydroxypyrazine-2-carboximidamide (13 mg, 0.022 mmol) in THF (1.5 mL) was added TFAA (19 mg, 0.090 mmol). The resulting mixture was stirred at room temperature for 2 h, and then the reaction mixture was heated to 60°C for 12 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (5 mL) and extracted with EA (3 x 10 mL). The combined organic layers were washed with brine (5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM / MeOH=40 / 1) to give (S)-1-((3-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyrazin-2-yl)methyl)cyclopropane-1-carbonitrile (8.0 mg, yield: 54.2%). MS calculated: 654.2; MS found: 655.2 [M+H] + .

[0375] Step M: 1-{[3-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyrazin-2-yl]methyl}cyclopropane-1-carbonitrile (62) To a solution of (S)-1-((3-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyrazin-2-yl)methyl)cyclopropane-1-carbonitrile (8 mg, 0.012 mmol) in DMF (1 mL) was added hydrazine hydrate (2.4 mg, 0.049 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water (5 mL) and extracted with EA (3 x 10 mL). The combined organic layers were washed with brine (5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM / MeOH=50 / 1) to give 1-{[3-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyrazin-2-yl]methyl}cyclopropane-1-carbonitrile (62) (4.3 mg, yield: 53%). MS calculated: 653.2; MS found: 654.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6):δ 9.15 (s, 1 H), 7.51-7.60 (m, 2 H), 7.33 (dd, J=8.4 Hz, 1.6 Hz, 1 H), 6.70-6.81 (m, 3 H), 3.85 (s, 2 H), 3.37 (s, 2 H), 2.89-3.00 (m, 2 H), 2.62-2.72 (m, 1 H), 2.20-2.33 (m, 2 H), 2.02 (s, 3 H), 1.67-1.85 (m, 4 H), 1.35-1.42 (m, 2 H), 1.21-1.29 (m, 2 H). 19 F NMR (377 MHz, DMSO-d6):δ -63.52, -110.75.

[0376] Example 63: 1-((2-((4-(6-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyridin-2-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (63) [ka] Step A: 1-Bromo-4-chloro-2-(2,2-diethoxyethoxy)benzene To a solution of 2-bromo-5-chlorophenol (3.2 g, 15.5 mmol) in DMF (50 mL) were added K2CO3 (6.43 g, 46.6 mmol) and 2-bromo-1,1-diethoxyethane (6.1 g, 31.1 mmol). The resulting mixture was stirred at 110 °C for 16 h. The reaction mixture was quenched with HO (100 mL) and extracted with EA (2 x 200 mL). The combined organic layers were washed with brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to give 1-bromo-4-chloro-2-(2,2-diethoxyethoxy)benzene (4.8 g, yield: 97.0%).

[0377] Step B: 7-Bromo-4-chlorobenzofuran To a solution of 1-bromo-4-chloro-2-(2,2-diethoxyethoxy)benzene (4.6 g, 14.4 mmol) in DCE (50 mL) was added PPA (7.3 g, 21.7 mmol). The resulting mixture was stirred at 75 °C under N for 16 h. The reaction mixture was quenched with HO (100 mL) and extracted with EA (2 x 200 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA = 10 / 1 to give 7-bromo-4-chlorobenzofuran (2.3 g, yield: 68.0%). 1H NMR:(400 MHz, DMSO-d6):δ 8.26 (d, J=2.0 Hz, 1 H), 7.59 (m, 1 H), 7.33 (dd, J=1.2 Hz, 8.4 Hz, 1 H), 7.16 (m, 1 H).

[0378] Step C: Ethyl 4-chlorobenzofuran-7-carboxylate To a solution of 7-bromo-4-chlorobenzofuran (2.3 g, 9.8 mmol) in EtOH (40 mL) was added Pd(dppf)Cl (1.4 g, 2.0 mmol) and KOAc (2.9 g, 29.5 mmol). The resulting mixture was stirred at 75 °C under CO for 16 h. The reaction mixture was quenched with HO (50 mL) and extracted with EA (2 x 100 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 20 / 1) to give ethyl 4-chlorobenzofuran-7-carboxylate (840 mg, yield: 38.2%). MS calculated: 224.0; MS found: 224.9 [M+H] + .

[0379] Step D: (4-chlorobenzofuran-7-yl)methanol To a solution of ethyl 4-chlorobenzofuran-7-carboxylate (840 mg, 3.75 mmol) in THF (9 mL) was added LiBH (330 mg, 15.0 mmol). The resulting mixture was stirred at 40 °C under N for 3 h. The reaction mixture was quenched with HO (20 mL) and extracted with EA (2 x 40 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA = 10 / 1 to give (4-chlorobenzofuran-7-yl)methanol (606 mg, yield: 88.8%).

[0380] Step E: tert-butyl 4-(6-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyridin-2-yl)piperidine-1-carboxylate To a solution of (4-chlorobenzofuran-7-yl)methanol (250 mg, 1.37 mmol) in THF (8 mL) was added tert-butyl 4-(5-fluoro-6-hydroxypyridin-2-yl)piperidine-1-carboxylate (488 mg, 1.65 mmol) and PPh3 (720 mg, 2.75 mmol). To the mixture was added DIAD (555 mg, 2.75 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature under N2 for 3 h. The reaction mixture was quenched with HO (10 mL) and extracted with EA (2 × 20 mL). The combined organic layers were washed with brine (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=6 / 1) to give tert-butyl 4-(6-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyridin-2-yl)piperidine-1-carboxylate (410 mg, yield: 65%). MS calculated: 460.1; MS found: 460.9 [M+H] + .

[0381] Step F: 1-((2-((4-(6-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyridin-2-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile 1-((2-((4-(6-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyridin-2-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (21.9 mg) was obtained using a method similar to that described in Example 1. MS calculated: 665.2; MS found: 666.0 [M+H]+ . 1 H NMR (400 MHz, DMSO-d6):δ 9.05 (d, J=1.6 Hz, 1 H), 8.43 (d, J=2.0 Hz, 1 H), 8.17 (d, J=1.6 Hz, 1 H), 7.56-7.61 (m, 1 H), 7.45 (d, J=8.0 Hz, 1 H), 7.36 (d, J=8.0 Hz, 1 H), 7.05 ...

Claims

1. A compound having the following structure: Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 Table 26 Table 27 Table 28 Table 29 Table 30 Table 31 Table 32 Table 33 Table 34 Table 35 Table 36 Table 37 Table 38 Table 39 Table 40 Table 41 Table 42 Table 43 Table 44 Table 45 Table 46 or a pharmaceutically acceptable salt or solvate thereof.

2. 10. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

3. 3. The pharmaceutical composition of claim 2 for treating a GLP-1 related disease, disorder or condition.

4. The disease, disorder or condition is type 1 diabetes, type 2 diabetes, young-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), young-onset atypical diabetes (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of adults (LADA), obesity, weight gain due to use of other medications, gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, kidney disease, adipocyte dysfunction, or sleep apnea. , visceral fat accumulation, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, vascular restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial lipemia, metabolic acidosis, ketosis 4. The pharmaceutical composition of claim 3, wherein the therapeutic agent is selected from the group consisting of: diabetes, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, treatment of addiction, 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 pharmaceutical composition according to claim 2 for treating type 2 diabetes.

6. The pharmaceutical composition of claim 2 for regulating insulin levels in a patient.

7. The pharmaceutical composition of claim 2 for regulating glucose levels in a patient.

8. The pharmaceutical composition of any one of claims 3 to 7, administered in combination with another therapeutic method or agent.

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

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