Heterocyclic GLP-1 agonist

Abstract

We provide heterocyclic GLP-1 agonists. [Solution] The present invention relates to a GLP-1 agonist represented by the following formula and a pharmaceutical composition containing the same. TIFF2026063013000352.tif3083 In the formula, X 1 ~X 8 It is independently selected from the group consisting of C, CH, and N, however X 1 ~X 8 At least two of the elements, up to four of which are N, ring A and ring C may be substituted phenylene, 5-6 member heteroalylene, etc., and ring B is selected from (BI) and (B-II). JPEG2026063013000353.jpg28133

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefits of International Patent Application No. PCT / CN2020 / 105865 filed on 30 July 2020; and International Patent Application No. PCT / CN2020 / 087776 filed on 29 April 2020 (each of these is incorporated herein by reference in whole).

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

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

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

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

Summary of the Invention

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

[0007] Thus, Formula I:

Chemical Formula

Chemical Formula

[0008] A pharmaceutical composition is also provided comprising a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0009] Also provided herein is a method for treating type 2 diabetes in a patient requiring treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

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

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

[0012] In one embodiment, the method further includes obtaining a sample from the patient. In one embodiment, the sample is a bodily fluid sample. In one embodiment, the patient is about 40 to about 70 years old and is overweight or obese. In one embodiment, the patient weighs about 22 kg / m². 2 or having a body mass index (BMI) of approximately 30 kg / m². In one embodiment, the patient has a BMI of approximately 30 kg / m². 2 Having a BMI of or higher.

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

[0014] In one embodiment, the treatment method for type 2 diabetes includes reducing the HbA1c level. In one embodiment, the HbA1c level is reduced to about 5.7% or less.

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

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

[0017] In one embodiment, the treatment method for type 2 diabetes includes reducing BMI. In one embodiment, the BMI is approximately 25 kg / m². 2 Or reduce it to less than that.

[0018] In one embodiment, a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, is administered orally.

[0019] In one embodiment, the method for treating type 2 diabetes further comprises administering a further therapy or therapeutic agent to the patient. In one embodiment, the further therapy or therapeutic agent is selected from the group consisting of antidiabetic drugs, anti-obesity drugs, GLP-1 receptor agonists, non-alcoholic steatohepatitis (NASH) drugs, gastric electrical stimulation, dietary monitoring, physical activity, or any combination thereof. In one embodiment, the antidiabetic drug is selected from the group consisting of biguanides, sulfonylureas, glitazar, thiazolidinediones, dipeptidyl peptidase 4 (DPP-4) inhibitors, meglitinides, sodium-dependent glucose transporter 2 (SGLT2) inhibitors, glitazone, GRP40 agonists, glucose-dependent insulinotropic polypeptides (GIPs), insulin or insulin analogs, alpha-glucosidase inhibitors, sodium-dependent glucose transporter 1 (SGLT1) inhibitors, or any combination thereof. In one embodiment, the biguanide is metformin. In one embodiment, the anti-obesity drug is a neuropeptide Y receptor type 2 (NPYR2) agonist, an NPYR1 or NPYR5 antagonist, or a human proislet peptide. The following are selected from the group consisting of (HIP) peptides (HIP), cannabinoid receptor 1 (CB1R) antagonists, lipase inhibitors, melanocortin receptor 4 agonists, farnesoid X receptor (FXR) agonists, phentermine, zonisamide, norepinephrine / dopamine reuptake inhibitors, GDF-15 analogs, opioid receptor antagonists, cholecystokinin agonists, serotonergic agents, methionine aminopeptidase 2 (MetAP2) inhibitors, diethylpropion, fendimethrazine, benzfetamine, fibroblast growth factor receptor (FGFR) modifiers, AMP-activated protein kinase (AMPK) activators, sodium-glucose transporter 1 (SGLT-1) inhibitors, or any combination thereof.In one embodiment, the GLP-1 receptor agonist is selected from the group consisting of liraglutide, exenatide, dulaglutide, albiglutide, taspoglutide, lixisenatide, semaglutide, or any combination thereof. In one embodiment, the NASH treatment agent is selected from the group consisting of FXR agonists, PF-05221304, synthetic fatty acid bile conjugates, anti-lysyl oxidase analog 2 (LOXL2) monoclonal antibodies, caspase inhibitors, MAPK5 inhibitors, galectin 3 inhibitors, fibroblast growth factor 21 (FGF21) agonists, niacin analogs, leukotriene D4 (LTD4) receptor antagonists, acetyl-CoA carboxylase (ACC) inhibitors, ketohexokinase (KHK) inhibitors, ileal bile acid transporter (IBAT) inhibitors, apoptosis signal-regulated kinase 1 (ASK1) inhibitors, peroxisome proliferator-activated receptor (PPAR) agonists, diacylglycerol acyltransferase 2 (DGAT2) inhibitors, or any combination thereof. In one embodiment, the compound of formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, and further therapeutic agents are administered sequentially in any order as separate formulations.

[0020] Also provided herein is a method for regulating insulin levels in a patient requiring regulation, comprising administering to the patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In one embodiment, the regulation results in an increase in insulin levels.

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

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

[0023] All publications, patents, and patent applications described herein are incorporated by reference to the same extent as each publication, patent, or patent application has been 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 disclosures contained herein, this specification shall take precedence and / or supersede any such conflicting document.

[0024] Other features and advantages of the present invention will become apparent from the detailed description and drawings below, as well as from the claims. [Modes for carrying out the invention]

[0025] Detailed explanation Heterocyclic GLP-1 agonists are provided herein for use in the treatment of T2DM and other diseases in which activation of GLP-1 activity is beneficial.

[0026] definition When a number is given as a range, it is understood that all possible subranges within such a range, as well as any specific number within such a range, are included, regardless of whether the specific number or subrange is explicitly indicated.

[0027] As used herein, the term "halo" or "halogen" means -F (also referred herein as "fluoro" or "fluoro"), -Cl (also referred herein as "chloro" or "chloro"), -Br (also referred herein as "bromo" or "bromo"), and -I (also referred herein as "iodine" or "iodine").

[0028] As used herein, the term “alkyl” means a saturated linear or branched monovalent hydrocarbon group containing the indicated number of carbon atoms. For example, “C1-C6 alkyl” means a saturated linear or branched monovalent hydrocarbon group containing 1 to 6 carbon atoms. Non-limiting examples of alkyl include methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, 2-methyl-2-propyl, pentyl, neopentyl, and hexyl.

[0029] As used herein, the term “alkylene” means a divalent alkyl group containing the indicated number of carbon atoms. For example, “C1-C3 alkylene” means a divalent alkyl group having 1 to 3 carbon atoms (e.g., -CH2-, -CH(CH3)-, -CH2CH2-, or -CH2CH2CH2-). Similarly, the terms “cycloalkylene,” “heterocycloalkylene,” “arylene,” and “heteroarylene” mean divalent cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, respectively.

[0030] As used herein, the term “alkenyl” means a linear or branched monounsaturated hydrocarbon chain containing the indicated number of carbon atoms. For example, “C2-C6 alkenyl” means a linear or branched monounsaturated hydrocarbon chain containing 2 to 6 carbon atoms. Non-limiting examples of alkenyls include ethenyl, propenyl, butenyl, or pentenyl.

[0031] As used herein, the term “alkynyl” means a linear or branched diunsaturated hydrocarbon chain containing the indicated number of carbon atoms. For example, “C2-C6 alkynyl” means a linear or branched diunsaturated hydrocarbon chain containing 2 to 6 carbon atoms. Non-limiting examples of alkynyl include ethynyl, propynyl, butynyl, or pentynyl.

[0032] As used herein, the term “cycloalkyl” means a saturated or partially unsaturated cyclic hydrocarbon containing the indicated number of carbon atoms. For example, “C3-C6 cycloalkyl” means a saturated or partially unsaturated cyclic hydrocarbon having 3 to 6 ring carbon atoms. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl may also be partially unsaturated. Non-limiting examples of partially unsaturated cycloalkyl include cyclohexenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl, and the like. Cycloalkyl may contain multiple condensed and / or crosslinked rings. Non-limiting examples of condensed / crosslinked cycloalkyls include bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, and bicyclo[2.2.2]octane. Cycloalkyls also include spiro rings (e.g., spirocyclic birings in which two rings are simply bonded by one atom). Non-restrictive examples of spirocyclic cycloalkyl compounds include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, and spiro[5.5]undecane.

[0033] As used herein, the term “heterocycloalkyl” means a monocyclic, dicyclic, tricyclic, or polycyclic non-aromatic ring group containing the indicated number of ring atoms, having 1 to 3 heteroatoms (in the case of a monocyclic), 1 to 6 heteroatoms (in the case of a bicyclic), or 1 to 9 heteroatoms (in the case of a tricyclic or polycyclic) (e.g., a 3- to 8-membered monocyclic, an 8- to 12-membered bicyclic, or an 11- to 14-membered tricyclic ring group), wherein the heteroatoms are O, N, S, or S(O) 1~2A heterocycloalkyl group is selected from (for example, monocyclic, bicyclic, or tricyclic groups, each consisting of a carbon atom and 1-3, 1-6, or 1-9 heteroatoms (N, O, or S), respectively), where 0, 1, 2, or 3 atoms in each ring may be substituted by substituents. Examples of heterocycloalkyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, and tetrahydrofuranyl. Non-limiting examples of partially unsaturated heterocycloalkyl groups include dihydropyrrolyl, dihydropyridinyl, tetrahydropyridinyl, dihydrofuranyl, and dihydropyranyl. Heterocycloalkyl groups may contain multiple condensed and crosslinked rings. Non-limiting examples of condensed / crosslinked heterocyclils include 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, and 3-azabicyclo Examples include [3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, and 3-oxabicyclo[3.2.1]octane. Heterocycloalkyls also include spiro rings (for example, spiro-type dicyclic rings in which two rings are simply joined by one atom).Non-restrictive examples of spiro ring heterocycloalkyls include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, and 2-oxaspiro[2 Examples include pentane, 4-oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, and 3-oxa-9-azaspiro[5.5]undecane.

[0034] As used herein, the term "aryl" means a monocyclic, dicyclic, tricyclic, or polycyclic hydrocarbon group containing the indicated number of carbon atoms, wherein at least one ring in the group is aromatic (e.g., C6 monocyclic, C6). 10 Biring, or C 14 This refers to a tricyclic aromatic ring group. Examples of aryl groups include phenyl, naphthyl, and tetrahydronaphthyl.

[0035] As used herein, the term “heteroaryl” means a monocyclic, dicyclic, tricyclic, or polycyclic group having the indicated number of ring atoms (e.g., 5 to 6 ring atoms; e.g., 5, 6, 9, 10, or 14 ring atoms) and having 6, 10, or 14 pi electrons shared by a cyclic aryl, wherein at least one ring in the group is aromatic (it does not have to be a ring containing a heteroatom (e.g., tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl)), and at least one ring in the group contains one or more heteroatoms independently selected from the group consisting of N, O, and S. The heteroaryl group may be unsubstituted or substituted with one or more substituents. Examples of heteroaryls include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridadinyl, triazinyl, thiazolylbenzothienyl, benzoxadiazolyl, benzofuranil, benzimidazolyl, benzotriazolyl, sinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthylidinyl, prinyl, thienopyridinyl, pyrido[2, Examples include [3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chroman, 2,3-dihydrobenzo[b][1,4]diokine, benzo[d][1,3]dioxol, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]xatiin, and isoindoline.

[0036] As used herein, the term “haloalkyl” means an alkyl group as defined herein in which one or more hydrogen atoms are substituted with one or more halogen atoms. Non-limiting examples include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, chloromethyl, dichloromethyl, chloroethyl, trichloroethyl, bromomethyl, and iodomethyl.

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

[0038] As used herein, [ka] " indicates any single or double bond, such that the valence is acceptable. As used herein, [ka] The symbol indicates the bond point to the parent molecule.

[0039] As used herein, the term “compound” includes all stereoisomers, geometric isomers, tautomers, and isotopes of the structure shown. Compounds identified by name or structure as one specific tautomer form herein include other tautomer forms unless otherwise specified.

[0040] As used herein, when a ring is described as “aromatic,” it means that the ring has a continuous delocalized π-electron system. Typically, the number of extraplane π-electrons corresponds to Hückel’s rule (4n+2). Examples of such rings include benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, and isothiazole. When a ring group containing at least two rings is described as “aromatic,” it means that the ring group contains one or more aromatic rings. Therefore, when a ring group containing at least two rings is described as “non-aromatic,” it means that none of the constituent rings of the ring group are aromatic.

[0041] As used herein, when a ring is described as “partially unsaturated,” it means that the ring has one or more further degrees of unsaturation (in addition to the degree of unsaturation relating to the ring itself; for example, one or more double bonds between the constituent ring atoms), but the ring is not aromatic. Examples of such rings include cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like. When a ring group containing at least two rings is described as “partially unsaturated,” it means that the ring group contains one or more partially unsaturated rings, but none of the constituent rings of the ring group are aromatic.

[0042] As used herein, the term “carboxylic acid bioisoster” means a group that has chemical and physical similarities to a carboxylic acid, resulting in biological properties very similar to those of a carboxylic acid (see Lipinski, Annual Reports in Medicinal Chemistry, 1986, 21, p283 "Bioisosterism In Drug Design"; Yun, Hwahak Sekye, 1993, 33, pages 576-579 "Application Of Bioisosterism To New Drug Design"; Zhao, Huaxue Tongbao, 1995, pages 34-38 25 "Bioisosteric Replacement And Development Of Lead Compounds In Drug Design"; Graham, Theochem, 1995, 343, pages 105-109 "Theoretical Studies Applied To Drug Design: a initio Electronic Distributions In Bioisosteres"). Suitable carboxylic acid bioisosteres include sulfo, phosphono, alkylsulfonylcarbamoyl, tetrazolyl, arylsulfonylcarbamoyl, heteroarylsulfonylcarbamoyl, N-methoxycarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl, or heterocyclic phenols, such as 3-hydroxyisoxazolyl and 3-hydroxy-1-methylpyrazolyl.

[0043] As used herein, the term "tautomer" refers to a compound whose structure differs significantly in the arrangement of atoms, but which exists in an easily and rapidly equilibrium state. Compounds provided herein may be shown as different tautomers, and if a compound has tautomer forms, all tautomer forms are considered to be within the scope of the present invention. It is understood that the names of compounds do not exclude tautomers.

[0044] As used herein, the terms “GLP-1R” or “GLP-1 receptor” include, but are not limited to, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide chains, complementary sequences, peptides, polypeptides, proteins, homologous and / or orthologous GLP-1R molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.

[0045] As used herein, the term “GLP-1 related disease” includes, but is not limited to, all diseases, disorders, or illnesses in which modulation of glucagon-like peptide 1 (GLP-1) receptor signaling alters the pathophysiology and / or symptoms and / or progression of the disease.

[0046] As used herein, the terms “GLP-1 agonist” or “GLP-1RA” refer to agonists of the glucagon-like peptide-1 (GLP-1) receptor. GLP-1RAs enhance glucose-dependent insulin secretion; suppress inappropriately elevated glucagon levels in both fasting and postprandial states; and delay gastric emptying. Karla et al., Glucagon-like peptide-1 receptor agonists in the treatment of type 2 diabetes: Past, present, and future, Indian J Endocrinol Metab. 2016 Mar-Apr; 20(2): 254-267. GLP-1RAs have been shown to treat type 2 diabetes. Examples of GLP-1RAs include, but are not limited to, albiglutide (TANZEMM®), dulaglutide (LY2189265, TRULICITY®), efpeglenatide, exenatide (BYETTA®, BYDUREON®, exendin-4), liraglutide (VICTOZA®, NN2211), lixisenatide (LYXMMIA®), semaglutide (OZEMPIC®), tilzepatide, ZP2929, NNC0113-0987, BPI-3016, and TT401. For example, U.S. Patent Nos. 10,370,426; 10,308,700; 10,259,823; 10,208,019; 9,920,106; 9,839,664; 8,129,343; 8,536,122; 7,919,598; 6,414,126; 6,628,343; and RE453 See also further GLP-1 receptor agonists described in publications 13; and international publications WO2019 / 239319; WO2019 / 239371; WO2020 / 103815; WO2020 / 207474; WO20202 / 34726; WO2020 / 044266; WO2020117987; and WO2020263695.

[0047] As used herein, the term "pharmaceutically acceptable" means that a compound, or a salt thereof, or a composition thereof, is chemically and / or toxicologically compatible with other components, including the formulation, and / or the patient being treated.

[0048] As used herein, the term “therapeutic compound” includes, but is not limited to, all compounds of formula I, or their pharmaceutically acceptable salts or solvates (e.g., any one of the compounds of formula IA, IB, IB-1, IC, ID, IE, and IE-1, or their pharmaceutically acceptable salts or solvates), as well as all compositions (e.g., pharmaceutical compositions) in which a compound of formula I or its pharmaceutically acceptable salt or solvate (e.g., any one of the compounds of formula IA, IB, IB-1, IC, ID, IE, and IE-1, or their pharmaceutically acceptable salts or solvates) is a component of the composition.

[0049] The term "administer" or "to administer" means a method for imparting a dose of a compound or pharmaceutical composition to a vertebrate or invertebrate (including mammals, birds, fish, or amphibians). The method of administration can be varied depending on various factors, such as the components of the pharmaceutical composition, the site of the disease, and the severity of the disease.

[0050] As used herein, the terms “effective dose,” “effective dosage,” “pharmaceutically effective amount,” or “therapeutic effective dose” mean a sufficient amount of a chemical substance administered (e.g., a compound of formula I or one of its pharmaceutically acceptable salts or solvates (e.g., any one of the compounds of formulas IA, IB, IB-1, IC, ID, IE, and IE-1, or one of its pharmaceutically acceptable salts or solvates)) which may include reducing one or more symptoms of the disease or illness being treated to some extent, and potentially curing the disease. “Cure” means that the active symptoms of the disease are eliminated. Such results include reduction and / or mitigation of the signs, symptoms or etiology of the disease, or any other desired change in the biological system. For example, “effective dose” for therapeutic use is the amount of a composition containing the compounds disclosed herein required to provide a clinically significant reduction in disease symptoms. The appropriate “effective” dose in each case is determined using any appropriate technique, such as a dose-escalation study. In one embodiment, the “therapeutic effective amount” of a compound provided herein means the amount of the compound that is effective as monotherapy or in combination therapy.

[0051] The term “excipient” or “pharmaceutically acceptable excipient” means a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid extender, diluent, carrier, solvent, or capsule material. In some embodiments, each component is “pharmaceutically acceptable” in the sense that it is compatible with the other components of a pharmaceutical formulation and is suitable for use in contact with human and animal tissues or organs without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, and with a reasonable balance of benefits / risks. For example, Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical See Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0052] The term “pharmaceutical composition” means a mixture of a compound of formula I described herein or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formulas IA, IB, IB-1, IC, ID, IE, and IE-1, or a pharmaceutically acceptable salt or solvate thereof) and other chemical components (collectively referred to herein as “excipients”), such as carriers, stabilizers, diluents, dispersants, suspenders, and / or fillers. Pharmaceutical compositions facilitate the administration of compounds to living organisms. Many techniques for administering compounds exist, including, but are not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0053] In the context of treating a disease, disorder, or illness, the terms “to treat,” “treating,” and “treatment” include reducing or suppressing one or more symptoms of the disorder, disorder, or illness, or associated with the said disorder, disorder, or illness; or slowing the progression, spread, or worsening of the disease, disorder, or illness, or one or more symptoms thereof.

[0054] As used herein, the term “prevent” means to prevent the onset, recurrence, or spread of a disease or illness described herein, or any symptom thereof, in whole or in part.

[0055] As used herein, the terms “subject,” “patient,” or “individual” are interchangeable and mean any animal, including mammals, e.g., mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some embodiments, the terms “subject” mean, in particular, a mammalian subject for which diagnosis, prognosis, or treatment is desired or required. In some embodiments, the patient is a human. In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of a disease, disorder, or illness for which treatment and / or prevention is desired.

[0056] The terms "treatment plan" and "dosing regimen" are used interchangeably to mean the dosage and administration timing of each therapeutic agent in the combinations of the present invention.

[0057] 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 fixed combinations and unfixed combinations of active ingredients.

[0058] As used herein, the term "combination therapy" means the dosing regimens of two different therapeutically active agents (i.e., the components of said combination or the partners of the combination), said therapeutically active agents being administered together or separately, as desired by a healthcare provider or in accordance with a regulatory authority, as defined herein.

[0059] As used herein, the term "modulate" means to regulate or adjust (e.g., increase or decrease) and may include, for example, receptor activation, partial receptor activation or antagonism.

[0060] Compound Thus, Formula I:

Chemical Formula

Chemical Formula

[0061] In one embodiment, formula I: [ka] Equation I [In the formula, [ka] This indicates any single or double bond whose valence is acceptable; X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 Each of them is independently selected from the group consisting of C, CH, and N, however X 1 , X 2 , X 3 , X4 , X 5 , X 6 , X 7 , and X 8 At least two of these, and four or fewer, is N; T 1 It is a C(=O)OH or carboxylic acid bioisoster; T 2 (C1-C6) alkyl which may be appropriately substituted with (C3-C6) cycloalkyl, 3-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl, and each of the (C3-C6) cycloalkyl, 3-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl has 1-4 R x It may be replaced as appropriate; Each R x These are independently selected from the group consisting of OH, SH, CN, NO2, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C1-C6)cyanoalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C3-C6)cycloalkyl, amino, (C1-C6)alkylamino, and di(C1-C6)alkylamino; L 1 This is 1 to 3 R L It is a (C1-C3) alkylene which may be substituted as appropriate. L 2 is a bond, -O-, -S(O) 0-2 -, or -NH-; Each R L These are independently selected from the group consisting of halogens, (C1-C3)alkyls, and (C1-C3)haloalkyls; or A pair of R on the same or adjacent carbon atoms L These atoms, together with the atoms to which they are bonded, form a (C3-C6) cycloalkyl ring; Ring A is: 1 to 4 R Y Phenylene may be substituted as appropriate; 1 to 3 R YA 5-6 member heteroalylene which may be substituted as appropriate; 1 to 4 R Y Partially unsaturated monocyclic (C5-C8) cycloalkylenes, which may be substituted as appropriate; 1 to 4 R Y Partially unsaturated monocyclic 5- to 8-membered heterocycloalkylenes, which may be substituted as appropriate; [ka] (wherein n1 is 0, 1, or 2; W 1 CR Y1 or N; and W 2 CR Y2 or N); and [ka] (In the formula, W 3 C, CR Y3 , or N, L 3 is (C1-C3)alkylene, and each [ka] (These are, independently, single or double bonds, with acceptable valence.) It is selected from the group consisting of, mm is L 2 The bond point to is shown, and nn indicates the bond point to ring B; and R Y Each of these is independently selected from the group consisting of halogens, cyano, -OH, oxo, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; R Y1 , R Y2 , and R Y3 Each is independently selected from the group consisting of hydrogen, halogen, cyano, -OH, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; or W 1 However, CRY1 And W 2 However, CR Y2 If so, then R Y1 and R Y2 The groups can combine to form (C1-C4)alkylenes, and one of the CH2 units of the (C1-C4)alkylene is O, S, NH, and N(C 1-3 ) These may be appropriately substituted with heteroatoms selected from the group consisting of alkyl groups; Ring B is (B-Ia) and (B-IIa): [ka] It is selected from the group consisting of, in the formula, rr indicates a bond point to ring A; ss indicates a bond point to ring C; B 1 and B 2 These are independently -O- and -NR N -, and -C(R 1 Selected from a group consisting of )2-; Each R 1 These are independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, and halogen; R N This is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, C(=O)(C1-C6)alkyl, S(O)2(C1-C6)alkyl, and C(=O)O(C1-C6)alkyl; B 3 B 4 , and B 5 CH and CR are independent. a Selected from the group consisting of , and N; Each R a These are independently halogens, (C1-C6)alkyls, (C1-C3)alkyl(C3-C6)cycloalkyls, (C1-C3)alkyl(3-5 member heterocycloalkyls), and -C(O)NR 2 R 3 Selected from the group consisting of (C1-C6) fluoroalkyl groups; Each R 2 and R3 These are independently selected from the group consisting of H and (C1-C6) alkyl groups; R aa , R ab , and R ac Each is independently selected from the group consisting of H, (C1-C6) alkyl, and (C1-C6) haloalkyl; Ring C is phenyl, 5-6 member heteroaryl, (C3-C6) cycloalkyl, (C5-C 10 ) Selected from the group consisting of bicycloalkyl, 5-10 membered bicycloheteroaryl, and 3-6 membered heterocycloalkyl; Each R b These are independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, halogen, (C3-C6)cycloalkyl, and CN; and b is an integer selected from 0 to 3. Or pharmaceutically acceptable salts or solvates thereof are provided herein.

[0062] In another embodiment, formula IA: [ka] Formula IA [In the formula, [ka] This indicates any single or double bond whose valence is acceptable; X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 Each of them is independently selected from the group consisting of C, CH, and N, however X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8At least two of these, and four or fewer, is N; T 1 It is a C(=O)OH or carboxylic acid bioisoster; T 2 (C1-C6)alkyl which may be appropriately substituted with (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C3-C6)cycloalkyl, 3-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl, each of the (C3-C6)cycloalkyl, 3-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl has 1-4 R x It may be replaced as appropriate; Each R x These are independently selected from the group consisting of OH, SH, CN, NO2, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C1-C6)cyanoalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C3-C6)cycloalkyl, amino, (C1-C6)alkylamino, and di(C1-C6)alkylamino; L 1 This is 1 to 3 R L It is a (C1-C3) alkylene which may be appropriately substituted; L 2 is a bond, -O-, -S(O) 0-2 -, or -NH-; Each R L These are independently selected from the group consisting of halogens, (C1-C3)alkyls, and (C1-C3)haloalkyls; or A pair of R on the same or adjacent carbon atoms L These atoms, together with the atoms to which they are bonded, form a (C3-C6) cycloalkyl ring; Ring A is: 1 to 4 R Y Phenylene may be substituted as appropriate; 1 to 3 R Y A 5-6 member heteroalylene which may be substituted as appropriate; 1 to 4 RY Partially unsaturated monocyclic (C5-C8) cycloalkylenes, which may be substituted as appropriate; 1 to 4 R Y Partially unsaturated monocyclic 5- to 8-membered heterocycloalkylenes, which may be substituted as appropriate; [ka] (wherein n1 is 0, 1, or 2; W 1 CR Y1 or N; and W 2 CR Y2 or N); and [ka] (In the formula, W 3 C, CR Y3 , or N, L 3 is (C1-C3)alkylene, and each [ka] These are single or double bonds, independently of valence, provided that (1)W 3 The ring containing is partially unsaturated or (2)L 3 (This is a (C2-C3) alkylene.) It is selected from the group consisting of, mm is L 2 The bond point to is shown, and nn indicates the bond point to ring B; and R Y Each of these is independently selected from the group consisting of halogens, cyano, -OH, oxo, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; R Y3 This is selected from the group consisting of hydrogen, halogen, cyano, -OH, oxo, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; R Y1 and R Y2The following are independently selected from the group consisting of halogens, cyano, -OH, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; or R Y1 and R Y2 The groups combine to form a (C1-C4)alkylene, and one of the CH2 units of the (C1-C4)alkylene is O, S, NH, and N(C 1-3 ) These may be appropriately substituted with heteroatoms selected from the group consisting of alkyl groups; Ring B consists of (BI) and (B-II): [ka] It is selected from the group consisting of, in the formula, rr indicates a bond point to ring A; ss indicates a bond point to ring C; B 1 and B 2 These are independently -O- and -NR N -, and -C(R 1 Selected from a group consisting of )2-; B 6 is N or CR aa and; Each R 1 These are independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, and halogen; R N This is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, C(=O)(C1-C6)alkyl, S(O)2(C1-C6)alkyl, and C(=O)O(C1-C6)alkyl; B 3 B 4 , and B 5 CH and CR are independent. a Selected from the group consisting of , and N; Each R aThese are independently halogens, (C1-C6)alkyls, (C1-C3)alkyl(C3-C6)cycloalkyls, (C1-C3)alkyl(3-5 member heterocycloalkyls), and -C(O)NR 2 R 3 Selected from the group consisting of (C1-C6) fluoroalkyl groups; Each R 2 and R 3 These are independently selected from the group consisting of H and (C1-C6) alkyl groups; R aa , R ab , and R ac Each is independently selected from the group consisting of H, (C1-C6) alkyl, and (C1-C6) haloalkyl; Ring C is phenyl, 5-6 member heteroaryl, (C3-C6) cycloalkyl, (C5-C 10 ) Selected from the group consisting of bicycloalkyl, 5-10 membered bicycloheteroaryl, and 3-6 membered heterocycloalkyl; Each R b These are independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, halogen, (C3-C6)cycloalkyl, and CN; and b is an integer selected from 0 to 3. Or pharmaceutically acceptable salts or solvates thereof are provided herein.

[0063] In one embodiment, formula IA: [ka] Formula IA [In the formula, [ka] This indicates any single or double bond whose valence is acceptable; X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X7 , and X 8 Each of them is independently selected from the group consisting of C, CH, and N, however X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 At least two of these, and four or fewer, is N; T 1 It is a C(=O)OH or carboxylic acid bioisoster; T 2 (C1-C6) alkyl which may be appropriately substituted with (C3-C6) cycloalkyl, 3-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl, and each of the (C3-C6) cycloalkyl, 3-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl has 1-4 R x It may be replaced as appropriate; Each R x These are independently selected from the group consisting of OH, SH, CN, NO2, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C1-C6)cyanoalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C3-C6)cycloalkyl, amino, (C1-C6)alkylamino, and di(C1-C6)alkylamino; L 1 This is 1 to 3 R L It is a (C1-C3) alkylene which may be appropriately substituted; L 2 is a bond, -O-, -S(O) 0-2 -, or -NH-; Each R L These are independently selected from the group consisting of halogens, (C1-C3)alkyls, and (C1-C3)haloalkyls; or A pair of R on the same or adjacent carbon atoms LThese atoms, together with the atoms to which they are bonded, form a (C3-C6) cycloalkyl ring; Ring A is: 1 to 4 R Y Phenylene may be substituted as appropriate; 1 to 3 R Y A 5-6 member heteroalylene which may be substituted as appropriate; 1 to 4 R Y Partially unsaturated monocyclic (C5-C8) cycloalkylenes, which may be substituted as appropriate; 1 to 4 R Y Partially unsaturated monocyclic 5- to 8-membered heterocycloalkylenes, which may be substituted as appropriate; [ka] (wherein n1 is 0, 1, or 2; W 1 CR Y1 or N; and W 2 CR Y2 or N); and [ka] (In the formula, W 3 C, CR Y3 , or N, L 3 is (C1-C3)alkylene, and each [ka] These are single or double bonds, independently of valence, provided that (1)W 3 The ring containing is partially unsaturated or (2)L 3 It is a (C2-C3) alkylene; It is selected from the group consisting of, mm is L 2 The bond point to is shown, and nn indicates the bond point to ring B; and R YEach of these is independently selected from the group consisting of halogens, cyano, -OH, oxo, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; R Y3 This is selected from the group consisting of hydrogen, halogen, cyano, -OH, oxo, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; R Y1 and R Y2 The following are independently selected from the group consisting of halogens, cyano, -OH, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; or R Y1 and R Y2 The groups combine to form a (C1-C4)alkylene, and one of the CH2 units of the (C1-C4)alkylene is O, S, NH, and N(C 1-3 ) These may be appropriately substituted with heteroatoms selected from the group consisting of alkyl groups; Ring B is (B-Ia) and (B-IIa): [ka] It is selected from the group consisting of, in the formula, rr indicates a bond point to ring A; ss indicates a bond point to ring C; B 1 and B 2 These are independently -O- and -NR N -, and -C(R 1 Selected from a group consisting of )2-; Each R 1 These are independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, and halogen; R N This is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, C(=O)(C1-C6)alkyl, S(O)2(C1-C6)alkyl, and C(=O)O(C1-C6)alkyl; B 3 B 4 , and B 5 CH and CR are independent. a Selected from the group consisting of , and N; Each R a These are independently halogens, (C1-C6)alkyls, (C1-C3)alkyl(C3-C6)cycloalkyls, (C1-C3)alkyl(3-5 member heterocycloalkyls), and -C(O)NR 2 R 3 Selected from the group consisting of (C1-C6) fluoroalkyl groups; Each R 2 and R 3 These are independently selected from the group consisting of H and (C1-C6) alkyl groups; R aa , R ab , and R ac Each is independently selected from the group consisting of H, (C1-C6) alkyl, and (C1-C6) haloalkyl; Ring C is phenyl, 5-6 member heteroaryl, (C3-C6) cycloalkyl, (C5-C 10 ) Selected from the group consisting of bicycloalkyl, 5-10 membered bicycloheteroaryl, and 3-6 membered heterocycloalkyl; Each R b These are independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, halogen, (C3-C6)cycloalkyl, and CN; and b is an integer selected from 0 to 3. Or pharmaceutically acceptable salts or solvates thereof are provided herein.

[0064] Embodiments may include one or more of the features described below and / or in the claims.

[0065] In embodiments of formula I or IA, X 8 C is C; and X 5 It is C.

[0066] In embodiments of formula I or IA, X 3 It is C.

[0067] In embodiments of formula I or IA, X 2 It is N.

[0068] In embodiments of formula I or IA, X 4 It is N.

[0069] In embodiments of formula I or IA, X 3 C is X 2 is N; and X 4 It is N.

[0070] In embodiments of formula I or IA, X 7 It is CH.

[0071] In embodiments of formula I or IA, X 8 C is X 5 C is C; and X 7 It is CH.

[0072] In embodiments of formula I or IA, X 8 , X 5 , and X 3 C is X 2 and X 4 is N and X 7 CH is; and X 1 and X 6 It is independently CH or N. For example, X 1 and X 6 Both are CH. As another non-restrictive example, X 1 is N; and X 6 is CH. As yet another non-restrictive example, X 1 CH is; and X 6 It is N.

[0073] In embodiments of formula I or IA, X 8 , X5 , and X 3 C is X 7 and X 6 CH is; X 1 is N; and X 2 and X 4 It is N.

[0074] In embodiments of formula I or IA, X 8 , X 5 , and X 3 C is X 7 , X 6 , and X 1 CH is; and X 2 and X 4 It is N.

[0075] In one embodiment of formula I or IA, the [ka] The part is formula: [ka] This is shown.

[0076] In one embodiment of formula I or IA, the [ka] The part is formula: [ka] This is shown.

[0077] In one embodiment of formula I or IA, the [ka] The part is formula: [ka] This is shown.

[0078] In some embodiments of formula I or IA, T 1 This is C(=O)OH.

[0079] In some embodiments of formula I or IA, T 1 It is a carboxylic acid bioisoster.

[0080] In embodiments of formula I or IA (T 1 However, if it is a carboxylic acid bioisoster, T 1 This is a five-membered heteroaryl compound comprising 2 to 4 heteroatoms independently selected from the group consisting of N, O, and S, wherein the heteroaryl compound may be appropriately substituted with 1 to 4 substituents independently selected from the group consisting of hydroxyl, (C1-C6)alkyl, (C1-C6)haloalkyl, and halogen.

[0081] In some embodiments of formula I or IA, T 1 This is a tetrazolyl which may be appropriately substituted with one or two substituents independently selected from the group consisting of hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, and halogen. For example, T 1 teeth, [ka] It is selected from the group consisting of the following.

[0082] In some embodiments of formula I or IA, T 1 This is a triazolyl or oxadiazolyl which may be appropriately substituted with one or two substituents independently selected from the group consisting of (C1-C6) alkyl and hydroxy. For example, T 1 teeth, [ka] That is the case.

[0083] In some embodiments of formula I or IA, T 1This is a ring (e.g., a 4-6 membered ring, e.g., a 5-membered ring) containing 0-3 heteroatoms independently selected from the group consisting of N, O, and S, wherein the ring is substituted with 1-2 oxos and may be further appropriately substituted with 1-2 substituents independently selected from the group consisting of hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, and halogen. For example, T 1 teeth, [ka] That is the case.

[0084] In some embodiments of formula I or IA, T 1 is a (C1-C6) alkyl group that is substituted with 1 to 3 hydroxyls and may be further optionally substituted with 1 to 10 fluorols. In any of these embodiments, T 1 These are (C1-C6) alkyl groups substituted with 1 to 3 hydroxyls and 1 to 10 fluorols. For example, T 1 teeth, [ka] That is the case.

[0085] In some embodiments of formula I or IA, T 1 This is C(=O)NHS(O)2(C1-C4)alkyl. For example, T 1 This is C(=O)NHS(O)2Me.

[0086] In some embodiments of formula I or IA, T 1 The following: [ka] It is selected from the group consisting of the following.

[0087] In some embodiments of formula I or IA, T 2These are (C1-C3) alkyl groups substituted with (C1-C6) alkoxy, (C3-C6) cycloalkyl, 3-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl.

[0088] In some embodiments of formula I or IA, T 2 These are (C1-C3) alkyl groups substituted with (C3-C6) cycloalkyl groups, 3-6 member heterocycloalkyl groups, phenyl groups, or 5-6 member heteroaryl groups.

[0089] In some embodiments of formula I or IA, T 2 This is a (C1-C3) alkyl group substituted with a (C3-C6) cycloalkyl group or a 3- to 6-membered heterocycloalkyl group.

[0090] In some embodiments of formula I or IA, T 2 It is a (C1-C3) alkyl group substituted with a 3- to 6-membered heterocycloalkyl group.

[0091] In some embodiments of formula I or IA, T 2 It is a (C1-C3) alkyl group substituted with a 4-6 member heterocycloalkyl group.

[0092] In some embodiments of formula I or IA, T 2 It is a (C1-C3) alkyl group substituted with oxetanyl.

[0093] In some embodiments of formula I or IA, T 2 teeth, [ka] In one embodiment of formula I or IA, T 2 teeth, [ka] and; as well as T 2 The center of the solid has an (S) configuration.

[0094] In some embodiments of formula I or IA, T 2 teeth, [ka] That is the case.

[0095] In some embodiments of formula I or IA, T 2 is a (C1-C3) alkyl substituted with a (C1-C6) alkoxy. In one embodiment, T 2 is a (C1-C3)alkyl substituted with a (C1-C3)alkoxy. In one embodiment, T 2 is a (C2-C3)alkyl substituted with a (C1-C3)alkoxy. As a non-limiting example, T 2 It is CH2CH2OCH3.

[0096] As a non-limiting example, [ka] The part is, [ka] (for example, [ka] ) is possible.

[0097] As another non-limiting example, [ka] The part is, [ka] (for example, [ka] ) is possible.

[0098] In one embodiment of formula I or IA, L2 It is a combination.

[0099] In one embodiment of formula I or IA, L 1 This is CH2.

[0100] In one embodiment of formula I or IA, L 1 is CH2; and L 2 It is a combination.

[0101] In one embodiment of formula I, ring A is [ka] In one example, W 1 In one embodiment, W 2 CR Y2 In one example, R Y2 is hydrogen. In one embodiment, W 2 n1 is N. In one embodiment, n1 is 0. In another embodiment, n1 is 1.

[0102] In one embodiment of formula I, ring A is [ka] In one example, W 1 In one embodiment, W 2 CR Y2 In one example, R Y2 is hydrogen. In one embodiment, W 2 It is N.

[0103] As a non-restrictive example, ring A is, [ka] It is possible. As another non-restrictive example, ring A is [ka] It is possible.

[0104] In one embodiment of formula I, ring A is [ka] (for example, [ka] ) is. In one embodiment, W 1 In one embodiment, W 2 CR Y2 In one example, R Y This is a (C1-C3) alkyl group, for example, methyl.

[0105] As a non-limiting example of the above embodiment, ring A is [ka] (for example, [ka] ) is possible.

[0106] To avoid any doubt, ring A is, [ka] And; W 1 However, CR Y1 And; W 2 However, CR Y2 And; as well as R Y1 and R Y2 When the groups come together to form a (C1-C4) alkylene as defined herein, ring A is a bridging bicyclic ring group.

[0107] In one embodiment of formula IA, ring A is [ka] It is selected from the group consisting of the following.

[0108] In any of these embodiments, n1 is 0.

[0109] In one embodiment of formula I or IA, ring A is 1 to 4 R Y Phenylene which may be substituted as appropriate; and 1 to 3 R Y 5-6 member heteroalylenes which may be substituted as appropriate. It is selected from the group consisting of the following.

[0110] In one embodiment of formula I or IA, ring A is 1 to 4 R Y Phenylene which may be substituted as appropriate; and 1 to 3 R Y A 6-membered heteroalylene which may be substituted as appropriate. It is selected from the group consisting of, mm is a parameter or meta to nn.

[0111] In embodiments of formula I or IA, ring A has 1 to 2 R Y Phenylene which may be appropriately substituted with; mm is para or meta with respect to nn. In one embodiment, ring A has 1 to 2 R Y It is 1,4-phenylene, which may be appropriately substituted with. As a non-limiting example of the above embodiment, ring A is [ka] It is possible.

[0112] In one embodiment of formula I or IA, ring A is 1 to 4 R Y Partially unsaturated monocyclic (C5-C8) cycloalkylenes which may be appropriately substituted with; and 1 to 4 R Y Partially unsaturated monocyclic 5- to 8-membered heterocycloalkylenes which may be substituted as appropriate. It is selected from the group consisting of the following.

[0113] In one embodiment of formula I or IA, ring A is 1 to 4 R Y Partially unsaturated monocyclic C6 cycloalkylenes which may be appropriately substituted with; and 1 to 4 R Y Partially unsaturated monocyclic six-membered heterocycloalkylenes which may be substituted as appropriate. It is selected from the group consisting of and is parametric with respect to nn.

[0114] In one embodiment of formula I, L 1 is CH2; L 2 is a bond; and ring A is, [ka] (for example, [ka] ) is. As a non-limiting example of the above embodiment, ring A is, [ka] It is possible. As another non-restrictive example, ring A is [ka] It is possible. As yet another non-restrictive example, ring A is, [ka] (For example, R Y (This is a (C1-C3) alkyl group, for example, methyl.) It is possible.

[0115] In one embodiment of formula I or IA, L 1 is CH2; L 2 is a bond; and ring A is, 1 to 4 R Y Phenylene which may be substituted as appropriate; and 1 to 3 RY A 6-membered heteroalylene which may be substituted as appropriate. It is selected from the group consisting of, where mm is parametric or metametric with respect to nn.

[0116] In embodiments of formula I or IA, ring A has 1 to 2 R Y Phenylene which may be appropriately substituted with; mm is para or meta with respect to nn. As a non-limiting example of the above embodiment, ring A is [ka] It is possible.

[0117] In one embodiment of formula I or IA, B 6 CR aa In one embodiment of formula I or IA, B 6 It is N.

[0118] In one embodiment of formula I or IA, B 1 is -O-. In some embodiments of formula I or IA, B 1 -C(R 1 )2-(for example, -CH2-). In one embodiment of formula I or IA, B 1 is -N(R N )-(For example, NH).

[0119] In one embodiment of formula I or IA, B 2 is -O-. In some embodiments of formula I or IA, B 2 -C(R 1 )2-(for example, -CH2-). In one embodiment of formula I or IA, B 2 is -N(R N )-(For example, NH).

[0120] In embodiments of formula I or IA, R 1 is hydrogen. In some embodiments of formula I or IA, R 1is a (C1-C6) alkyl group. In some embodiments of formula I or IA, R 1 is a (C1-C6) haloalkyl. In some embodiments of formula I or IA, R 1 It is a halogen.

[0121] In embodiments of formula I or IA, R N In some embodiments of formula I or IA, R N is a (C1-C6) alkyl group. In some embodiments of formula I or IA, R N is a (C1-C6) haloalkyl. In some embodiments of formula I or IA, R N is a C(=O)(C1-C6) alkyl group. In some embodiments of formula I or IA, R N is a C(=O)O(C1-C6) alkyl group. In some embodiments of formula I or IA, R N It is an S(O)2(C1-C6) alkyl group.

[0122] In some embodiments of formula I or IA, ring B is [ka] (B-Ia) That is the case.

[0123] In some embodiments of formula I or IA, ring B is [ka] (B-IIa) That is the case.

[0124] In one embodiment of formula I or IA, B 1 is -O- and B 2 It is -O-.

[0125] In one embodiment of formula I or IA, B 1 is -O- and B 2 -NR N-(For example, -NH-).

[0126] In one embodiment of formula I or IA, B 1 is -O- and B 2 -C(R 1 )2-. For example, B 1 It can be -O-; and B 2 It can be -CH2-.

[0127] In one embodiment of formula I or IA, B 1 -C(R 1 )2- and B 2 is -O-. For example, B 1 It can be -CH2-; and B 2 It can be -O-.

[0128] In some embodiments of formula I or IA, ring B is [ka] (B-Ia) B 1 is -O- and B 2 It is -O-.

[0129] In some embodiments of formula I or IA, ring B is [ka] (B-IIa) B 1 is -O- and B 2 It is -O-.

[0130] In some embodiments of formula I or IA, ring B is [ka] (B-Ib) That is the case.

[0131] In one embodiment of formula I or IA, B 1 -C(R 1 )2-(for example, -CH2-). In one embodiment of formula I or IA, B 2 -C(R 1 )2- (for example, -CH2-).

[0132] In embodiments of formula I or IA, R aa is H. In some embodiments of formula I or IA, R aa is a (C1-C6) alkyl group. As a non-limiting example of the above embodiment, R aa is methyl. In some embodiments of formula I or IA, R ab is H. In some embodiments of formula I or IA, R ac H is H.

[0133] In embodiments of formula I or IA, R aa H is; R ab H is; as well as R ac is H. In some embodiments of formula I or IA, R aa is a (C1-C3) alkyl (e.g., methyl); R ab H is; as well as R ac H is H.

[0134] In one embodiment of formula I or IA, B 3 is CH. In some embodiments of formula I or IA, B 3 CR a In one embodiment of formula I or IA, B 3 It is N.

[0135] In one embodiment of formula I or IA, B 4 is CH. In some embodiments of formula I or IA, B 4 CR a In one embodiment of formula I or IA, B 4 It is N.

[0136] In one embodiment of formula I or IA, B 5 is CH. In some embodiments of formula I or IA, B 5 CR a In one embodiment of formula I or IA, B 5 It is N.

[0137] In one embodiment of formula I or IA, B 3 B 4 , and B 5 Independently, CH or CR a In one embodiment of formula I or IA, B 3 B 4 , and B 5 It is CH.

[0138] In one embodiment of formula I or IA, B 1 is -O- and; B 2 is -O- and B 3 B 4 , and B 5 Independently, CH or CR a In one example, B 3 B 4 , and B 5 is CH. In one embodiment, R aa H is; R ab H is; as well as R ac H is. In one example, B 6 CR aa In one example, R aa is a (C1-C3) alkyl (e.g., methyl); R ab H is; as well as R ac H is H.

[0139] In one embodiment of formula I or IA, B 1 is -O- and; B 2 -NR N -(for example, -NH-); and B 3 B 4 , and B5 Independently, CH or CR a In one example, B 3 B 4 , and B 5 is CH. In one embodiment, R aa H is; R ab H is; as well as R ac H is. In one example, B 6 CR aa In one example, R aa is a (C1-C3) alkyl (e.g., methyl); R ab H is; as well as R ac H is H.

[0140] In one embodiment of formula I or IA, B 1 is -O- and; B 2 is -CH2-; and B 3 B 4 , and B 5 Independently, CH or CR a In one example, B 3 B 4 , and B 5 is CH. In one embodiment, R aa H is; R ab H is; as well as R ac H is. In one example, B 6 CR aa In one example, R aa is a (C1-C3) alkyl (e.g., methyl); R ab H is; as well as R ac H is H.

[0141] In one embodiment of formula I or IA, B 1 is -CH2-; B 2 is -O- and B 3 B 4 , and B 5 Independently, CH or CR aIn one example, B 3 B 4 , and B 5 is CH. In one embodiment, R aa H is; R ab H is; as well as R ac H is. In one example, B 6 CR aa In one example, R aa is a (C1-C3) alkyl (e.g., methyl); R ab H is; as well as R ac H is H.

[0142] In one embodiment of formula I or IA, B 1 and B 2 is -O- and B 3 B 4 , and B 5 is CH. In some embodiments of formula I or IA, B 1 and B 2 One of them is -CH2-; B 1 and B 2 The other of these is -O-; and B 3 B 4 , and B 5 is CH. In one embodiment, B 6 CR aa In one example, R aa H is; R ab H is; as well as R ac is H. In one example, R aa is a (C1-C3) alkyl (e.g., methyl); R ab H is; as well as R ac H is H.

[0143] In some embodiments of formula I or IA, ring B is (B-Ia); R aa and B 2The carbon atom to which both are bonded has an (S)-configuration. In some embodiments of formula I or IA, ring B is (B-Ia); R aa and B 2 The carbon atom to which both are bonded has a (R)-configuration.

[0144] In some embodiments of formula I or IA, ring B is (B-II); B 6 CR aa And; R aa and B 1 The carbon atom to which both are bonded has an (S)- configuration.

[0145] In some embodiments of formula I or IA, ring B is (B-II); B 6 CR aa And; R aa and B 1 The carbon atom to which both are bonded has a (R)-configuration.

[0146] In some embodiments of formula I or IA, ring B is [ka] (B-Ia) And in the formula, B 3 B 4 , and B 5 Each of them is CH; B 1 and B 2 Each of them is -O-;R ac and R ab H is H, and R is R, respectively. aa is H or (C1-C3) alkyl (e.g., H or methyl). In one embodiment, R aa and B 2 A carbon atom to which both are bonded has a (R)- configuration. In one embodiment, R aa and B 2 The carbon atom to which both are bonded has an (S)- configuration. In one embodiment, R aa is H. In one example, R aaIt is methyl.

[0147] In some embodiments of formula I or IA, ring B is [ka] (B-IIa) And in the formula, B 3 B 4 , and B 5 Each of them is CH; B 1 and B 2 Each of them is -O-;R ac and R ab H is H, and R is R, respectively. aa is H or (C1-C3) alkyl. In one embodiment, R aa and B 1 The carbon atom to which both are bonded has an (S)- configuration. In one embodiment, R aa and B 1 A carbon atom to which both are bonded has a (R)- configuration. In one embodiment, R aa is H. In one example, R aa It is methyl.

[0148] In some embodiments of formula I or IA, ring B is [ka] Selected from the group consisting of the following. In one embodiment, the carbon atoms marked with * have the (R) configuration. In one embodiment, the carbon atoms marked with * have the (S) configuration.

[0149] In some embodiments of formula I or IA, ring C is selected from the group consisting of phenyl, 5-6 membered heteroaryls, and 5-10 membered bicycloheteraryls.

[0150] In some embodiments of formula I or IA, ring C is phenyl.

[0151] In an embodiment of formula I or IA, b is 1 to 3.

[0152] In one embodiment of formula I or IA, b is 2.

[0153] In an embodiment of formula I or IA, b is 1.

[0154] In some embodiments of formula I or IA, b is 0.

[0155] In some embodiments of formula I or IA, ring C is phenyl; and b is 2.

[0156] In an embodiment of formula I or IA, [ka] teeth, [ka] (for example, [ka] ,for example, [ka] )

[0157] In an embodiment of formula I or IA, [ka] teeth, [ka] (for example, [ka] )

[0158] In some embodiments of formula I or IA, ring C is phenyl; and b is 1.

[0159] In an embodiment of formula I or IA, [ka] teeth, [ka] (for example, [ka] )

[0160] In an embodiment of formula I or IA, [ka] teeth, [ka] (for example, [ka] )

[0161] In an embodiment of formula I or IA, [ka] teeth, [ka] (for example, [ka] )

[0162] In some embodiments of formula I or IA, ring C is phenyl; and b is 0.

[0163] In embodiments of formula I or IA, R b Each of these is independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, halogen, and CN.

[0164] In embodiments of formula I or IA, R b Each of these is independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, halogen, and CN.

[0165] In embodiments of formula I or IA, R b Each of these is independently selected from the group consisting of -F, -Cl, -CH3, -CF3, and CN.

[0166] In embodiments of formula I or IA, R b Each of these is independently selected from the group consisting of -F, -Cl, and CN.

[0167] In one embodiment of formula I or IA, the compound is of formula IB: [ka] Formula IB It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0168] In one embodiment of formula I or IA, the compound is formula IC: [ka] formula IC It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0169] In one embodiment of formula I or IA, the compound is formula ID: [ka] Expression ID It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0170] In one embodiment of formula I or IA, the compound is formula IE: [ka] Formula IE It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0171] In formulas IB, IC, ID, and IE, T 1 , T 2 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , L 1 , L 2 , ring A (including mm and nn), B 3 B 4 B 5 , R aa , R ab , R ac , ring C, R b , and b may be as defined for any of Formula I or IA in this specification.

[0172] In some embodiments of formula IB, IC, ID, or IE, B 3 B 4 , and B 5 CH and CR are independent of each other. a It is selected from the group consisting of the following.

[0173] In some embodiments of formula IB, IC, ID, or IE, B 3 B 4 , and B 5 It is CH.

[0174] In one embodiment of formula IB, IC, ID, or IE, R aa H is; as well as R ab and R ac H is H.

[0175] In one embodiment of formula IB, IC, ID, or IE, R aa is (C1-C3) alkyl (e.g., methyl); and R ab and R ac H is H.

[0176] In some embodiments of formula IB, IC, ID, or IE, X 8 , X 5 , and X 3 C is X 2 and X 4 is N and X 7 CH is; and X 1 and X 6 Independently, is CH or N. In some embodiments of formula IB, IC, ID, or IE, X 1 is N; and X 6 is CH. In some embodiments of formula IB, IC, ID, or IE, X 1 CH is; and X 6 is CH. In some embodiments of formula IB, IC, ID, or IE, X 1 CH is; and X 6 It is N.

[0177] In some embodiments of the formula IB, IC, ID, or IE, T 1 This is C(=O)OH.

[0178] In some embodiments of the formula IB, IC, ID, or IE, T 2 is a (C1-C3) alkyl substituted with a 4-6 member heterocycloalkyl group. In some embodiments of formula IB, IC, ID, or IE, T 2 is an oxetanyl-substituted (C1-C3) alkyl group. As a non-limiting example of the above embodiment, T 2 teeth, [ka] (For example, T 2The center of the solid may have an (S) configuration. It is possible.

[0179] In some embodiments of the formula IB, IC, ID, or IE, T 2 teeth, [ka] That is the case.

[0180] In some embodiments of the formula IB, IC, ID, or IE, T 2 is a (C1-C3) alkyl substituted with a (C1-C6) alkoxy. In one embodiment, T 2 is a (C1-C3)alkyl substituted with a (C1-C3)alkoxy. In one embodiment, T 2 is a (C2-C3)alkyl substituted with a (C1-C3)alkoxy. As a non-limiting example, T 2 It is CH2CH2OCH3.

[0181] In some embodiments of formula IB, IC, ID, or IE, L 2 It is a combination.

[0182] In some embodiments of formula IB, IC, ID, or IE, L 1 This is CH2.

[0183] In some embodiments of formula IB, IC, ID, or IE, L 1 is CH2; and L 2 It is a combination.

[0184] In one embodiment of formula IB, IC, ID, or IE, ring A is [ka] (for example, [ka] ) is. In one embodiment, W1 In one embodiment, W 2 CR Y2 In one example, R Y2 is hydrogen. In one embodiment, W 2 is N. As a non-restrictive example, ring A is [ka] It is possible. As another non-restrictive example, ring A is [ka] It is possible. As yet another non-restrictive example, ring A is, [ka] (For example, R Y (It is a (C1-C3) alkyl group.) It is possible.

[0185] In one embodiment of formula IB, IC, ID, or IE, ring A is 1 to 4 R Y Phenylene may be substituted as appropriate; 1 to 3 R Y A 5-6 member heteroalylene which may be substituted as appropriate; 1 to 4 R Y Partially unsaturated monocyclic (C5-C8) cycloalkylenes, which may be substituted as appropriate; 1 to 4 R Y Partially unsaturated monocyclic 5- to 8-membered heterocycloalkylenes, which may be substituted as appropriate; [ka] [wherein n1 is 0, 1, or 2; W 1 CR Y1 or N; and W 2 CR Y2 or N]; and [ka] [In the formula, W 3 C, CR Y3 , or N, L 3 These are (C1-C3) alkylenes, and each [ka] These are single or double bonds, independently of valence, provided that (1)W 3 The ring containing is partially unsaturated or (2)L 3 [This is (C2-C3) alkylene] It is selected from the group consisting of, in the formula, mm is L 2 The bond point to is shown, and nn indicates the bond point to ring B; and R Y Each of these is independently selected from the group consisting of halogens, cyano, -OH, oxo, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; R Y3 This is selected from the group consisting of hydrogen, halogen, cyano, -OH, oxo, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; R Y1 and R Y2 The following are independently selected from the group consisting of halogens, cyano, -OH, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; or R Y1 and R Y2 The groups combine to form a (C1-C4)alkylene, and one of the CH2 units of the (C1-C4)alkylene is O, S, NH, and N(C 1-3 ) These may be appropriately substituted with heteroatoms selected from the group consisting of alkyl groups.

[0186] In one embodiment of formula IB, IC, ID, or IE, ring A is [ka] It is selected from the group consisting of, in the formula, n1 is 0, 1, or 2; W 1 CR Y1 or N, and W 2 CR Y2 or N; and R Y1 and R Y2 The following are independently selected from the group consisting of halogens, cyano, -OH, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; or R Y1 and R Y2 The groups combine to form a (C1-C4)alkylene, and one of the CH2 units of the (C1-C4)alkylene is O, S, NH, and N(C 1-3 ) may be appropriately substituted with heteroatoms selected from the group consisting of alkyl groups. In one embodiment, n1 is 0.

[0187] In any of these embodiments, ring A is [ka] It is selected from the group consisting of the following.

[0188] In one embodiment of formula IB, IC, ID, or IE, ring A is [ka] And in the formula, W 3 C, CR Y3 , or N, L 3 is (C1-C3)alkylene, and each [ka] These are single or double bonds, independently of valence, provided that (1)W 3The ring containing is partially unsaturated or (2)L 3 It is a (C2-C3) alkylene.

[0189] In one embodiment of formula IB, IC, ID, or IE, ring A is 1 to 4 R Y Phenylene which may be substituted as appropriate; and 1 to 3 R Y 5-6 member heteroalylenes which may be substituted as appropriate. It is selected from the group consisting of the following.

[0190] In one embodiment of formula IB, IC, ID, or IE, ring A is 1 to 4 R Y Phenylene which may be substituted as appropriate; and 1 to 3 R Y A 6-membered heteroalylene which may be substituted as appropriate. It is selected from the group consisting of, where mm is parametric or metametric with respect to nn.

[0191] In one embodiment of formula IB, IC, ID, or IE, ring A is one to two R Y Phenylene which may be appropriately substituted with; mm is para or meta with respect to nn. In one embodiment, ring A has 1-2 R Y It is 1,4-phenylene, which may be appropriately substituted with. As a non-limiting example of the above embodiment, ring A is [ka] That is the case.

[0192] In one embodiment of formula IB, IC, ID, or IE, ring A is 1 to 4 R Y Partially unsaturated monocyclic (C5-C8) cycloalkylenes which may be appropriately substituted with; and 1 to 4 R Y Partially unsaturated monocyclic 5- to 8-membered heterocycloalkylenes which may be substituted as appropriate. It is selected from the group consisting of the following.

[0193] In one embodiment of formula IB, IC, ID, or IE, ring A is 1 to 4 R Y Partially unsaturated monocyclic C6 cycloalkylenes which may be appropriately substituted with; and 1 to 4 R Y Partially unsaturated monocyclic six-membered heterocycloalkylenes which may be substituted as appropriate. It is selected from the group consisting of the following. In one embodiment, mm is parametric with respect to nn.

[0194] In some embodiments of formula IB, IC, ID, or IE, L 1 is CH2; L 2 is a bond; and ring A is, [ka] (for example, [ka] ) is. As a non-limiting example of the above embodiment, ring A is, [ka] It is possible. As another non-restrictive example, ring A is [ka] It is possible. As yet another non-restrictive example, ring A is, [ka] (For example, R Y (It is a (C1-C3) alkyl group.) It is possible.

[0195] In some embodiments of formula IB, IC, ID, or IE, L 1 is CH2; L 2 is a bond; and ring A is, 1 to 4 RY Phenylene which may be substituted as appropriate; and 1 to 3 R Y 5-6 member heteroalylenes which may be substituted as appropriate. It is selected from the group consisting of the following.

[0196] In any of these embodiments, mm is meta or para with respect to nn. In one embodiment, ring A has 1 to 2 R Y Phenylene which may be appropriately substituted with; and mm is meta or para with respect to nn. In one embodiment, ring A is 1-2 R Y It is 1,4-phenylene, which may be appropriately substituted with. As a non-limiting example of the above embodiment, ring A is [ka] It is possible.

[0197] In some embodiments of formulas IB, IC, ID, or IE, ring C is phenyl.

[0198] In an embodiment of formula IB, IC, ID, or IE, b is 1 to 3.

[0199] In some embodiments of formula IB, IC, ID, or IE, b is 2.

[0200] In an embodiment of formula IB, IC, ID, or IE, b is 1.

[0201] In some embodiments of formulas IB, IC, ID, or IE, b is 0.

[0202] In some embodiments of formulas IB, IC, ID, or IE, ring C is phenyl; and b is 2.

[0203] In one embodiment of formula IB, IC, ID, or IE, [ka] teeth, [ka] (for example, [ka] ) For example, [ka] teeth, [ka] It is possible. As another non-limiting example, [ka] teeth, [ka] It is possible.

[0204] In one embodiment of formula IB, IC, ID, or IE, [ka] teeth, [ka] For example, [ka] teeth, [ka] It is possible.

[0205] In some embodiments of formulas IB, IC, ID, or IE, ring C is phenyl; and b is 1.

[0206] In one embodiment of formula IB, IC, ID, or IE, [ka] teeth, [ka] For example, [ka] teeth, [ka] It is possible.

[0207] In one embodiment of formula IB, IC, ID, or IE, [ka] teeth, [ka] For example, [ka] teeth, [ka] It is possible.

[0208] In one embodiment of formula IB, IC, ID, or IE, [ka] teeth, [ka] For example, [ka] teeth, [ka] It is possible. As another non-limiting example, [ka] teeth, [ka] It is possible. As another non-limiting example, [ka] teeth, [ka] It is possible. As another non-limiting example, [ka] teeth, [ka] It is possible.

[0209] In some embodiments of formulas IB, IC, ID, or IE, ring C is phenyl; and b is 0.

[0210] In one embodiment of formula IB, IC, ID, or IE, R b Each of these is independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, halogen, and CN.

[0211] In one embodiment of formula IB, IC, ID, or IE, R b Each of these is independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, halogen, and CN.

[0212] In one embodiment of formula IB, IC, ID, or IE, R b Each of these is independently selected from the group consisting of -F, -Cl, -CH3, -CF3, and CN.

[0213] In one embodiment of formula IB, IC, ID, or IE, R b Each of these is independently selected from the group consisting of -F, -Cl, and CN.

[0214] In one embodiment of formula IB, IC, ID, or IE, R aa The carbon atoms to which both the and ring C are bonded have the (S)-configuration. In some embodiments of formula IB, IC, ID, or IE, R aa The carbon atom to which both the ring C and the carbon atom are bonded has a (R)-configuration.

[0215] In one embodiment, the compound of formula I is formula IB-1: [ka] Formula IB-1 [In the formula, X 1 and X 6 It is independently either N or CH; T 2 (C1-C6)alkyl is a (C1-C3)alkyl substituted with (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C3-C6)cycloalkyl, 3-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl. Each of the (C3-C6) cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl may be appropriately substituted with 1 to 4 substituents independently selected from the group consisting of halogens, CN, and (C1-C6) alkyl groups; W 1 and W 2 It is independently either N or CH; R aa is H or (C1-C3) alkyl; Ring C is selected from the group consisting of phenyl and 6-membered heteroaryls; b is 0, 1, or 2; and R bEach of these is independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, halogen, and CN. It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0216] In one embodiment of formula IB: X 6 CH is; X 1 is N or CH; T 2 It is a (C1-C3) alkyl group substituted with a 3-6 member heterocycloalkyl group; Ring C is selected from the group consisting of phenyl and 6-membered heteroaryls; and b is either 1 or 2.

[0217] In one embodiment of formula IB: X 6 CH is; X 1 is N or CH; T 2 It is an oxetanyl-substituted (C1-C3) alkyl group; W 1 is N and W 2 CH is; R aa is H or methyl; The carbon atom of the ring is phenyl; b is 1 or 2; and R b Each of these is independently selected from the group consisting of -F, -Cl, -CH3, -CF3, and CN.

[0218] In one embodiment of formula IB: X 6 CH is; X 1 is N; T 2 teeth, [ka] and; W1 is N and W 2 CH is, R aa is H or methyl; Ring C is, [ka] and; as well R b Each of these is independently selected from the group consisting of -F, -Cl, -CH3, -CF3, and CN.

[0219] In one embodiment of formula IB, R aa The carbon atom to which it is bonded has a (R)-configuration.

[0220] In one embodiment of formula IB, R aa The carbon atom to which it is bonded has an (S)- configuration.

[0221] In one embodiment, the compound of formula I is formula IE-1: [ka] Formula IE-1 [In the formula, X 1 and X 6 It is independently either N or CH; T 2 (C1-C6)alkyl is a (C1-C3)alkyl substituted with (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C3-C6)cycloalkyl, 3-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl. Each of the (C3-C6) cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl may be appropriately substituted with 1 to 4 substituents independently selected from the group consisting of halogens, CN, and (C1-C6) alkyl groups; W 1 and W 2 It is independently either N or CH; R aais H or (C1-C3) alkyl; Ring C is selected from the group consisting of phenyl and 6-membered heteroaryls; b is 0, 1, or 2; and R b Each of these is independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, halogen, and CN. It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0222] In one embodiment of formula IE: X 6 CH is; X 1 is N or CH; T 2 It is a (C1-C3) alkyl group substituted with a 3-6 member heterocycloalkyl group; Ring C is selected from the group consisting of phenyl and 6-membered heteroaryls; and b is either 1 or 2.

[0223] In one embodiment of formula IE: X 6 CH is; X 1 is N or CH; T 2 It is an oxetanyl-substituted (C1-C3) alkyl group; W 1 is N and W 2 CH is; R aa is H or methyl; The carbon atom of the ring is phenyl; b is 1 or 2; and R b Each of these is independently selected from the group consisting of -F, -Cl, -CH3, -CF3, and CN.

[0224] In one embodiment of formula IE: X 6 CH is; X 1is N; T 2 teeth, [ka] and; W 1 is N and W 2 CH is; R aa is H or methyl; Ring C is, [ka] and; as well R b Each of these is independently selected from the group consisting of -F, -Cl, -CH3, -CF3, and CN.

[0225] In one embodiment of formula IE, R aa The carbon atom to which it is bonded has a (R)-configuration.

[0226] In one embodiment of formula IE, R aa The carbon atom to which it is bonded has an (S)- configuration.

[0227] In one embodiment, the compound is selected from the group consisting of the compounds listed in Table C1 or pharmaceutically acceptable salts or solvates thereof. Table C1 [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6]

[0228] In one embodiment, the compound is selected from the group consisting of the compounds listed in Table C2 or pharmaceutically acceptable salts or solvates thereof. Table C2 [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14]

[0229] The compounds of formula I include their pharmaceutically acceptable salts. Furthermore, the compounds of formula I also include other salts of such compounds that are not necessarily pharmaceutically acceptable, and may be useful as intermediate compounds for preparing and / or purifying the compounds of formula I and / or separating enantiomers of the compounds of formula I. Non-limiting examples of pharmaceutically acceptable salts of the compounds of formula I include trifluoroacetate.

[0230] Furthermore, the compounds of formula I or their salts may be isolated in the form of solvates, and it is understood that any such solvates fall within the scope of the present invention. For example, the compounds of formula I and their salts may exist in an unsolvated form, as well as in a solvated form with a pharmaceutically acceptable solvent, such as water or ethanol.

[0231] Pharmaceutical composition and administration When used as a pharmaceutical, compounds of formula I (including their pharmaceutically acceptable salts or solvates) can be administered in the form of pharmaceutical compositions. These compositions can be prepared by methods well known in the pharmaceutical field and can be administered by various routes depending on whether topical or systemic treatment is desired and the area to be treated. Administration may be topical (including transdermal, epidermal, ocular, and mucosal delivery including intranasal, vaginal, and rectal), pulmonary (e.g., inhalation or inhalation of powders or aerosols (including nebulizers); intratracheal or intranasal), oral, or parenteral. Oral administration may include formulations prepared for once-daily or twice-daily (BID) administration. Parenteral administration may include intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular injection or infusion; or intracerebral, e.g., subarachnoid or intraventricular administration. Parenteral administration may be in the form of a single rapid dose, or, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, droplets, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder, or oily bases, fillers, etc., may be required or desired.

[0232] Pharmaceutical compositions comprising, as an active ingredient, a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, in combination with one or more pharmaceutically acceptable excipients (carriers) are also provided herein. For example, pharmaceutical compositions prepared using a compound of formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, such compositions are suitable for topical administration. When preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by the excipient, or encapsulated in such a carrier, for example, in the form of a capsule, pouch, paper, or other container. When the excipient is provided as a diluent, it may be a solid, semi-solid, or liquid substance acting as a vehicle, carrier, or medium for the active ingredient. Therefore, the composition may be in the form of tablets, pills, powders, lozenges, pouches, cashews, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or in a liquid medium), ointments (e.g., containing 10% by weight of the active compound), soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaged powders. In one embodiment, the composition is formulated for oral administration. In one embodiment, the composition is a solid oral preparation. In one embodiment, the composition is formulated as a tablet or capsule.

[0233] Pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt or solvate thereof together with a pharmaceutically acceptable excipient are further provided herein. Pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt or solvate thereof as an active ingredient can be prepared by closely mixing the compound of formula I or a pharmaceutically acceptable salt or solvate thereof with a pharmaceutical carrier according to conventional pharmaceutical formulation techniques. The carrier can be in a wide range of forms depending on the desired route of administration (e.g., oral, parenteral). In one embodiment, the composition is a solid oral composition.

[0234] Appropriate pharmaceutically acceptable carriers are well known in the art. Some descriptions of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients (published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain).

[0235] Methods for formulating pharmaceutical compositions are described in numerous publications, including Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al; published by Marcel Dekker, Inc.

[0236] In some embodiments, the compound or pharmaceutical composition may be administered in combination with one or more conventional pharmaceutical excipients. Medicinally acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS), e.g., d-α-tocopherol polyethylene glycol 1000 succinic acid, surfactants used in pharmaceutical formulations, e.g., Tween, poloxamer or other similar polymer delivery matrices, serum proteins, e.g., human serum albumin, buffering substances, e.g., phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene polyoxypropylene block polymers, and lanolin. Cyclodextrins, such as α-, β-, and γ-cyclodextrins, or chemically modified derivatives, such as hydroxyalkylcyclodextrins (including 2- and 3-hydroxypropyl-β-cyclodextrin), or other solubilized derivatives, can also be used to enhance the delivery of the compounds described herein. Formulations of compositions can be prepared that contain the chemicals described herein in a balanced manner, comprising non-toxic excipients in an amount ranging from 0.005% to 100%. The intended compositions may contain the compounds provided herein in amounts ranging from 0.001% to 100%, 0.1% to 95% in one embodiment, 75% to 85% in another embodiment, and 20% to 80% in a further embodiment. Practical methods for preparing such formulations are known or obvious to those skilled in the art, e.g., Remington: The Science and Practice of Pharmacy, 22 nd See Edition (Pharmaceutical Press, London, UK. 2012).

[0237] In one embodiment, the compounds and pharmaceutical compositions described herein, or the pharmaceutical compositions thereof, may be administered to a patient in need via any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, intracervical, sinus, tracheal, intestinal, epidural, interstitial, intraperitoneal, intraarterial, intrabronchial, intrasacral, intracerebral, cisterna magna, coronary, intradermal, intratubular, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intravascular, intramedullary, intrasynovial, intratesticular, subarachnoid, intratubular, intratumoral, intrauterine, intravascular, intravenous, transnasal (e.g., intranasal), transnasal-gastric, oral, parenteral, transdermal, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, local, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and vaginal.

[0238] In some embodiments, the preferred route of administration is parenteral (e.g., intratumor). In some embodiments, a compound of formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formulas IA, IB, IB-1, IC, ID, IE, and IE-1, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition thereof, can be formulated for parenteral administration and can be formulated for injection via, for example, an intra-arterial, intrasternal, intracerebral, intravenous, intramuscular, subcutaneous, or intraperitoneal route. For example, such a composition can be prepared as either an injectable liquid solvent or suspension; a solid form suitable for use in preparing a solvent or suspension can also be prepared by adding a liquid before injection; and the formulation may be emulsified. The preparation of such formulations is known to those skilled in the art with regard to this disclosure. In some embodiments, a device is used for parenteral administration. For example, such a device may include a needle injector, a microneedle injector, a needleless injector, and an injection technique.

[0239] In one embodiment, pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersants; formulations (containing sesame oil, peanut oil, or propylene glycol solutions); and sterile powders for the immediate preparation of sterile injection solvents or dispersants. In one embodiment, the forms need to be sterile and fluid enough to be easily injected. In one embodiment, the forms need to be stable under manufacturing and storage conditions and must be resistant to contamination by microorganisms, such as bacteria and fungi.

[0240] In one embodiment, the carrier may also be a solvent or dispersion medium comprising, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. In one embodiment, proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the particle size required during dispersion, and by the use of a surfactant. In one embodiment, microbial activity can be prevented by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. In one embodiment, an isotonic agent, such as sugar or sodium chloride, may be included. In one embodiment, sustained absorption of the injectable composition can be achieved by the use of absorption-delaying agents, such as aluminum monostearate and gelatin, in the composition.

[0241] In one embodiment, a sterile injection solution is prepared by incorporating a required amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., any one of the compounds of formulas IA, IB, IB-1, IC, ID, IE, and IE-1, or a pharmaceutically acceptable salt or solvate thereof) in a suitable solvent into various other components listed above, and subsequently by sterile filtration as necessary. In one embodiment, a dispersant is prepared by incorporating various sterile active ingredients into a sterile vehicle containing a basic dispersion medium and other required components from those listed above. In one embodiment, a sterile powder is used for the preparation of a sterile injection solution. In one embodiment, the preparation method is a vacuum drying and freeze-drying technique to obtain a powder of the active ingredient and any further desired components from the previously sterile-filtered solution.

[0242] In some embodiments, pharmacoagulably acceptable excipients that can be used in rectal compositions as gels, creams, enemas, or rectal suppositories include, but are not limited to, cocoa butter glycerides, synthetic polymers, e.g., polyvinylpyrrolidone, PEG (e.g., PEG ointments), glycerin, glycerin gelatin, hydrogenated vegetable oils, poloxamer, polyethylene glycol and mixtures of fatty acid esters of polyethylene glycol of various molecular weights, Vaseline, anhydrous lanolin, shark liver oil, sodium saccharate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxide SBN, vanilla essential oil), aerosols, parabens in phenoxyethanol, sodium methyl p-oxobenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomer, Carbopol, methyl oxybenzoate, macrogol cetostearyl ether, and cocoyl phosphate. Caprylica plate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-methabites, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins, such as vitamins A and E, and potassium acetate, one or more of these.

[0243] In one embodiment, a suppository can be prepared by mixing a compound of formula I described herein or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formulas IA, IB, IB-1, IC, ID, IE, and IE-1, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition with a suitable non-irritating excipient or carrier that is solid at ambient temperature but liquid at body temperature, and therefore melts rectally to release the active compound, such as cocoa butter, polyethylene glycol, or suppository wax. In one embodiment, the composition for rectal administration is in the form of an enema.

[0244] In one embodiment, the compounds of formula I described herein or their pharmaceutically acceptable salts or solvates (e.g., any one of the compounds of formulas IA, IB, IB-1, IC, ID, IE, and IE-1, or their pharmaceutically acceptable salts or solvates) or their pharmaceutical compositions are formulated for local delivery to the gastrointestinal tract or GI tract by oral administration (e.g., solid or liquid formulations). In one embodiment, solid formulations for oral administration include capsules, tablets, pills, powders, and granules.

[0245] In one embodiment, a compound of formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formulas IA, IB, IB-1, IC, ID, IE, and IE-1, or a pharmaceutically acceptable salt or solvate thereof) is mixed with one or more pharmaceutically acceptable excipients, e.g., sodium citrate or dicalcium phosphate, and / or: a) fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) wetting agents, e.g., glycerol; d) disintegrants, e.g., agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicic acids, and sodium carbonate; e) solution retarding agents. f) an agent, e.g., paraffin; g) an absorption enhancer, e.g., a quaternary ammonium compound; h) a wetting agent, e.g., cetyl alcohol and glycerol monostearate; i) an absorbent, e.g., kaolin and bentonite clay; and i) a lubricant, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. For example, in the case of capsules, tablets and pills, the formulation may also contain a buffer. In some embodiments, similar types of solid compositions may be used in soft and hard gelatin capsules as fillers, e.g., excipients such as lactose or milk sugar, and high molecular weight polyethylene glycol, etc.

[0246] In one embodiment, the pharmaceutical composition is in the form of a unit formulation such as a pill or tablet, and therefore the composition may contain, together with a compound of formula I provided herein or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formulas IA, IB, IB-1, IC, ID, IE, and IE-1, or a pharmaceutically acceptable salt or solvate thereof), a diluent, such as lactose, sucrose, dicalcium phosphate, etc.; a lubricant, such as magnesium stearate, etc.; and a binder, such as starch, gum arabic, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, etc. In one embodiment, another solid formulation, powder, pill (marume), solution or suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) is encapsulated in a capsule (gelatin or cellulosic capsule). In some embodiments, unit formulations in which one or more of the compounds and pharmaceutical compositions or further active agents provided herein are physically separated, such as granular capsules and granular (or tablet in capsule) formulations; double-layer tablets; two-compartment gel capsules, etc. In some embodiments, enteric-coated or sustained-release oral formulations are also included.

[0247] In some embodiments, other physiologically acceptable compounds may include wetting agents, emulsifiers, dispersants, or preservatives that are particularly useful for preventing the growth or action of microorganisms. For example, a variety of preservatives are well known, including, for instance, phenol and ascorbic acid.

[0248] In some embodiments, the excipients are sterile and generally free of undesirable substances. For example, these compositions can be sterilized by conventional, well-known sterilization techniques. In some embodiments for various oral formulation excipients, such as tablets and capsules, sterilization is not required. For example, the United States Pharmacopeia / National Standard (USP / NF) standard may suffice.

[0249] In some embodiments, the compounds of formula I described herein or their pharmaceutically acceptable salts or solvates (e.g., any one of the compounds of formulas IA, IB, IB-1, IC, ID, IE, and IE-1, or their pharmaceutically acceptable salts or solvates), or the pharmaceutical compositions thereof, are formulated for ophthalmic use. In some embodiments, the ophthalmic composition may include, but is not limited to, one or more of the following: biscogen (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., Pluronic (triblock copolymer), cyclodextrin); and preservatives (e.g., benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxyloro complex; Allergan, Inc.)).

[0250] In some embodiments, the compounds of formula I described herein or their pharmaceutically acceptable salts or solvates (e.g., any one of the compounds of formulas IA, IB, IB-1, IC, ID, IE, and IE-1, or their pharmaceutically acceptable salts or solvates), or the pharmaceutical compositions thereof, are formulated for topical administration to the skin or mucous membranes (e.g., skin or transdermally). In some embodiments, the topical compositions may include ointments and creams. In some embodiments, the ointments are typically semi-solid preparations based on petrolatum or other petroleum derivatives. In some embodiments, the creams containing the selected active agent are typically viscous liquids or semi-solid emulsions, and are often either oil-in-water or water-in-oil. For example, the cream base is typically water-washable and comprises an oil phase, an emulsifier, and an aqueous phase. For example, the oil phase is also called the “internal” phase and generally consists of petrolatum and fatty alcohols, such as cetyl or stearyl alcohol, and the aqueous phase is usually not necessary but is generally present in greater volume than the oil phase and generally contains a wetting agent. In some embodiments, the emulsifier in the cream formulation is generally a nonionic, anionic, cationic, or amphoteric surfactant. In some embodiments, the ointment base, like other carriers or vehicles, needs to be inert, stable, non-irritating, and non-sensitizing.

[0251] In any of the embodiments described herein, the pharmaceutical composition may comprise one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradable poly(D,L-lactic acid-coglycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and a nanoporous particle-supporting lipid bilayer.

[0252] In one embodiment, the dose for a compound of formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formulas IA, IB, IB-1, IC, ID, IE, and IE-1, or a pharmaceutically acceptable salt or solvate thereof) is determined based on many factors, including, but not limited to, the patient's type, age, weight, sex, medical condition, severity of the patient's medical condition, route of administration, and the activity of the compound or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the appropriate dose for a particular situation can be determined by a person skilled in the pharmaceutical art. In one embodiment, the total daily dose may be divided and administered in portions throughout the day, or administered by means of continuous delivery.

[0253] In one embodiment, a compound of formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formulas IA, IB, IB-1, IC, ID, IE, and IE-1, or a pharmaceutically acceptable salt or solvate thereof) is administered in doses ranging from about 0.01 to about 1000 mg. For example, doses such as about 0.1 to about 30 mg, about 10 to about 80 mg, about 0.5 to about 15 mg, about 50 mg to about 200 mg, about 100 mg to about 300 mg, about 200 to about 400 mg, about 300 mg to about 500 mg, about 400 mg to about 600 mg, about 500 mg to about 800 mg, about 600 mg to about 900 mg, or about 700 mg to about 1000 mg. In one embodiment, the dose is a therapeutically effective dose.

[0254] In one embodiment, a compound of formula I described herein or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formulas IA, IB, IB-1, IC, ID, IE, and IE-1, or a pharmaceutically acceptable salt or solvate thereof) is present in amounts of about 0.0002 mg / Kg to about 100 mg / Kg (e.g., about 0.0002 mg / Kg to about 50 mg / Kg; about 0.0002 mg / Kg~about 25mg / Kg;about 0.0002mg / Kg~about 10mg / Kg;about 0.0002mg / Kg~about 5mg / Kg;about 0.0002mg / Kg~about 1mg / Kg;about 0.0002mg / Kg ~ approx. 0.5mg / Kg; approx. 0.0002mg / Kg ~ approx. 0.1mg / Kg; approx. 0.001mg / Kg ~ approx. 50mg / Kg; approx. 0.001mg / Kg ~ approx. 25mg / Kg; approx. 0.001mg / Kg ~About 10mg / Kg; Approx. 0.001mg / Kg ~ Approx. 5mg / Kg; Approx. 0.001mg / Kg ~ Approx. 1mg / Kg; Approx. 0.001mg / Kg ~ Approx. 0.5mg / Kg; Approx. 0.001mg / Kg ~ Approx. 0.1m g / 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 They are administered in doses of approximately mg / Kg to 1 mg / Kg; approximately 0.01 mg / Kg to 0.5 mg / Kg; approximately 0.01 mg / Kg to 0.1 mg / Kg; approximately 0.1 mg / Kg to 50 mg / Kg; approximately 0.1 mg / Kg to 25 mg / Kg; approximately 0.1 mg / Kg to 10 mg / Kg; approximately 0.1 mg / Kg to 5 mg / Kg; approximately 0.1 mg / Kg to 1 mg / Kg; approximately 0.1 mg / Kg to 0.5 mg / Kg). In one embodiment, a compound of formula I described herein or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formulas IA, IB, IB-1, IC, ID, IE, and IE-1, or a pharmaceutically acceptable salt or solvate thereof) is administered in a dose of approximately 100 mg / Kg.

[0255] In one embodiment, the dose of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formulas IA, IB, IB-1, IC, ID, IE, and IE-1, or a pharmaceutically acceptable salt or solvate thereof) may be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or not on a daily basis (e.g., every other day, every two days, every three days, once a week, twice a week, once every two weeks, or once a month).

[0256] In one embodiment, the duration of administration of a compound of formula I described herein or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formulas IA, IB, IB-1, IC, ID, IE, and IE-1, or a pharmaceutically acceptable salt or solvate thereof) is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer. In one embodiment, the period during which administration is discontinued is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer. In one embodiment, a compound of formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., any one of the compounds of formulas IA, IB, IB-1, IC, ID, IE, and IE-1, or a pharmaceutically acceptable salt or solvate thereof) is administered to a patient for a certain period, followed by a separation period during which administration of the compound of formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., any one of the compounds of formulas IA, IB, IB-1, IC, ID, IE, and IE-1, or a pharmaceutically acceptable salt or solvate thereof) is discontinued.In one embodiment, a compound of formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., any one of the compounds of formulas IA, IB, IB-1, IC, ID, IE, and IE-1, or a pharmaceutically acceptable salt or solvate thereof) is administered for a first period, followed by a second period after the first period, during which administration is discontinued, then a third period in which administration of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., any one of the compounds of formulas IA, IB, IB-1, IC, ID, IE, and IE-1, or a pharmaceutically acceptable salt or solvate thereof) is initiated, followed by a fourth period after the third period in which administration is discontinued. For example, the period of administration of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., any one of the compounds of formulas IA, IB, IB-1, IC, ID, IE, and IE-1, or a pharmaceutically acceptable salt or solvate thereof) followed by a period of discontinuation of administration is repeated for a predetermined or unspecified period. In one embodiment, the duration of administration is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In one embodiment, the period during which administration is discontinued is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer.

[0257] In one embodiment, a compound of formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formulas IA, IB, IB-1, IC, ID, IE, and IE-1, or a pharmaceutically acceptable salt or solvate thereof) is administered orally to a patient once or more daily (e.g., once daily, twice daily, three times daily, four times daily, or once daily).

[0258] In one embodiment, a compound of formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formulas IA, IB, IB-1, IC, ID, IE, and IE-1, or a pharmaceutically acceptable salt or solvate thereof) is administered parenterally to a patient once or more times daily (e.g., doses of 1 to 4 times daily, 2 times daily, 3 times daily, 4 times daily, or once daily).

[0259] In one embodiment, a compound of formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., any one of the compounds of formulas IA, IB, IB-1, IC, ID, IE, and IE-1, or a pharmaceutically acceptable salt or solvate thereof) is administered parenterally to the patient once a week.

[0260] Treatment method In some embodiments, the Disclosure features a method for treating a patient (e.g., a human) suffering from a disease, disorder, or illness in which the modulation of GLP-1R (e.g., inhibited or impaired, and / or increased or undesired GLP-1R) is beneficial in treating the disease, disorder, or the underlying pathology and / or symptoms and / or progression of the disease. In some embodiments, the methods described herein may include, or further include, one or more diseases related to, coexisting with, or secondary to one or more of the diseases described herein.

[0261] This specification provides a method for treating a GLP-1 related disorder, disorder, or illness, comprising administering an effective amount of a compound of formula I disclosed herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formulas IA, IB, IB-1, IC, ID, IE, and IE-1, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition, to a patient in need thereof.

[0262] In one embodiment, the diseases, disorders, or illnesses include, but are not limited to, type 1 diabetes, type 2 diabetes, juvenile-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), juvenile-onset atypical diabetes (YOAD), juvenile-onset adult-onset diabetes (MODY), adult latent autoimmune diabetes (LADA), obesity (including hypothalamic obesity and monogenic obesity), weight gain due to the use of other medications, idiopathic intracranial hypertension, Wolfram syndrome, Gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat accumulation, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral artery disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, restenosis, blood Embolism, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, alcohol intake disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, joints This includes inflammation, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, psychogenic polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, and polycystic ovary syndrome (PCOS).

[0263] In one embodiment, the diseases, disorders, or illnesses include, but are not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, idiopathic intracranial hypertension, Wolfram syndrome, weight gain due to the use of other medications, gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, gestational diabetes, kidney disease (e.g., acute kidney injury, tubular dysfunction, pro-inflammatory changes in the proximal tubules), adipocyte dysfunction, sleep apnea, visceral fat accumulation, eating disorders, cardiovascular diseases, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral artery disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, and hyper This includes blood glucose, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, alcohol intake disorders, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, psychogenic polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS), or any combination thereof.

[0264] In some embodiments, the diseases, disorders, or illnesses include, but are not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, idiopathic intracranial hypertension, Wolfram syndrome, weight gain due to the use of other medications, gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat accumulation, myocardial infarction, peripheral artery disease, stroke, transient ischemic attack, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, chronic renal failure, syndrome X, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, skin and connective tissue disorders, foot ulcers, or any combination thereof.

[0265] In some embodiments, the compounds and pharmaceutical compositions described herein, as well as methods for treating a patient, produce one or more of the following: a decrease in blood glucose levels (e.g., a decrease in blood glucose levels), a decrease in blood hemoglobin A1c (HbA1c) levels, promotion of insulin synthesis, activation of insulin secretion, an increase in the population of β-cells, regulation of gastric acid secretion, regulation of gastric emptying, a decrease in body mass index (BMI), and / or a decrease in glucagon production (e.g., levels). In some embodiments, the compounds and pharmaceutical compositions described herein, as well as methods for treating a patient, can produce a decrease in blood glucose levels, a decrease in blood hemoglobin A1c (HbA1c) levels, promotion of insulin synthesis, activation of insulin secretion, an increase in the population of β-cells, regulation of gastric acid secretion, regulation of gastric emptying, a decrease in body mass index (BMI), a decrease in glucagon production (e.g., levels), and any combination thereof. In some embodiments, the compounds and pharmaceutical compositions described herein, as well as methods for treating a patient, stabilize serum glucose and serum insulin levels (e.g., serum glucose and serum insulin concentrations). Also provided is a method for regulating glucose or insulin levels in a patient requiring regulation, comprising administering to the patient an effective amount of a compound of formula I described herein or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formulas IA, IB, IB-1, IC, ID, IE, and IE-1, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition thereof.

[0266] In one embodiment, a method is provided herein for reducing the risk of major cardiovascular events (MACE) in a patient requiring reduction (e.g., by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%), comprising administering to the patient an effective amount of a compound of formula I described herein or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formulas IA, IB, IB-1, IC, ID, IE, and IE-1, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition. In any of these embodiments, the patient is an adult diagnosed with type 2 diabetes mellitus (T2D). In one embodiment, the patient is an adult diagnosed with heart disease. In one embodiment, the patient is an adult diagnosed with both type 2 diabetes mellitus (T2D) and heart disease. In one embodiment, the patient is an adult diagnosed with type 2 diabetes mellitus (T2D). In one embodiment, the patient is an adult diagnosed with heart disease. In one embodiment, the patient has type 2 diabetes (T2D) and heart disease.

[0267] Indications Obesity In some embodiments, the disease, disorder, or condition is a disease, disorder, or condition associated with or related to obesity. Non-limiting examples of obesity and obesity-related conditions include symptomatic obesity, simple obesity, childhood obesity, morbid obesity, and abdominal obesity (central obesity characterized by abdominal fat accumulation). Non-limiting examples of symptomatic obesity include endocrine obesity (e.g., Cushing's syndrome, hypothyroidism, insulinoma, obese type 2 diabetes, pseudohypoparathyroidism, reproductive dysfunction), hypothalamic obesity, hereditary obesity (e.g., Prader-Willi syndrome, Laurence Moon-Beadle syndrome), and drug-induced obesity (e.g., steroid, phenothiazine, insulin, sulfonylurea, or beta-blocker-induced obesity).

[0268] In some embodiments, the disease, disorder, or condition is related to obesity. Examples of such diseases, disorders, or conditions include, but are not limited to, impaired glucose tolerance, diabetes (e.g., type 2 diabetes, obesity diabetes), lipid metabolism disorders, hyperlipidemia, hypertension, heart failure, hyperuricemia, gout, fatty liver (including non-alcoholic steatohepatitis (NASH)), coronary heart disease (e.g., myocardial infarction, angina pectoris), stroke (e.g., cerebral thrombosis, transient ischemic attack), bone or joint diseases (e.g., osteoarthritis of the knee, osteoarthritis of the hip, spondylitis degeneratively, lumbago), sleep apnea syndrome, obesity hypoventilation syndrome (Pickwick's syndrome), menstrual disorders (e.g., abnormal menstrual cycle, menstrual bleeding and cycle abnormalities, amenorrhea, abnormal circadian rhythms), visceral obesity syndrome, urinary incontinence, and metabolic syndrome. In some embodiments, the compounds and pharmaceutical compositions described herein can be used to treat patients exhibiting symptoms of both obesity and insulin deficiency.

[0269] diabetes In one embodiment, the disease, disorder, or disorder is diabetes mellitus. Non-limiting examples of diabetes mellitus include type 1 diabetes mellitus, type 2 diabetes mellitus (e.g., diet-dependent type 2 diabetes mellitus, sulfonylurea-dependent type 2 diabetes mellitus, more advanced stage type 2 diabetes mellitus, long-term insulin-dependent type 2 diabetes mellitus), diabetes mellitus (e.g., non-insulin-dependent diabetes mellitus, insulin-dependent diabetes mellitus), gestational diabetes mellitus, obesity-related diabetes mellitus, autoimmune diabetes mellitus, and prediabetes. In one embodiment, the disease, disorder, or disorder is type 2 diabetes mellitus (e.g., diet-dependent type 2 diabetes mellitus, sulfonylurea-dependent type 2 diabetes mellitus, more advanced stage type 2 diabetes mellitus, long-term insulin-dependent type 2 diabetes mellitus).

[0270] A method for treating diabetes in a patient is provided herein, comprising (a) determining that the patient has type 2 diabetes, and then (b) administering to the patient a therapeutically effective amount of a compound of formula I disclosed herein or a pharmaceutically acceptable salt or solvate thereof (e.g., any one of the compounds of formulas IA, IB, IB-1, IC, ID, IE, and IE-1, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition.

[0271] A method for treating type 2 diabetes in a patient is provided herein, comprising administering a therapeutically effective amount of a compound of formula I disclosed herein or a pharmaceutically acceptable salt or solvate thereof (e.g., any one of the compounds of formulas IA, IB, IB-1, IC, ID, IE, and IE-1, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition, to a patient identified or diagnosed with type 2 diabetes.

[0272] Also provided is a method for treating type 2 diabetes in a patient requiring treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula I disclosed herein or a pharmaceutically acceptable salt or solvate thereof (for example, any one compound of formulas IA, IB, IB-1, IC, ID, IE, and IE-1, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition thereof.

[0273] In one embodiment, compounds, pharmaceutical compositions, and methods for treating patients with the disease, illness, or disorder described herein (e.g., type 2 diabetes) reduce fasting blood glucose levels. In one embodiment, compounds, pharmaceutical compositions, and methods for treating patients with the disease, illness, or disorder described herein (e.g., type 2 diabetes) reduce non-fasting blood glucose levels. In one embodiment, compounds, pharmaceutical compositions, and methods for treating patients with the disease, illness, or disorder described herein (e.g., type 2 diabetes) reduce HbA1c levels. In one embodiment, compounds, pharmaceutical compositions, and methods for treating patients with the disease, illness, or disorder described herein (e.g., type 2 diabetes) reduce glucagon levels. In one embodiment, compounds, pharmaceutical compositions, and methods for treating patients with the disease, illness, or disorder described herein (e.g., type 2 diabetes) increase insulin levels. In one embodiment, compounds, pharmaceutical compositions, and methods for treating patients with the disease, illness, or disorder described herein (e.g., type 2 diabetes) reduce BMI.

[0274] In one embodiment, a reduction in fasting blood glucose levels of approximately 5% to approximately 95% is demonstrated by the treatment of type 2 diabetes. A reduction in fasting blood glucose levels of approximately 15% to approximately 80% is demonstrated by the treatment of type 2 diabetes. A reduction in fasting blood glucose levels of approximately 25% to approximately 60% is demonstrated by the treatment of type 2 diabetes. In one embodiment, a reduction in fasting blood glucose levels to approximately 126 mg / dL or less, approximately 110 mg / dL or less, or approximately 90 mg / dL or less is demonstrated by the treatment of type 2 diabetes.

[0275] In one embodiment, a reduction of approximately 5% to approximately 95% in non-fasting blood glucose levels is demonstrated by the treatment of type 2 diabetes. A reduction of approximately 15% to approximately 80% in non-fasting blood glucose levels is demonstrated by the treatment of type 2 diabetes. A reduction of approximately 25% to approximately 60% in non-fasting blood glucose levels is demonstrated by the treatment of type 2 diabetes. In one embodiment, a reduction of non-fasting blood glucose levels to approximately 200 mg / dL or less, approximately 150 mg / dL or less, or approximately 130 mg / dL or less is demonstrated by the treatment of type 2 diabetes.

[0276] In one embodiment, a reduction in HbA1c levels of approximately 5% to approximately 95% is shown by treatment of type 2 diabetes. A reduction in HbA1c levels of approximately 15% to approximately 80% is shown by treatment of type 2 diabetes. A reduction in HbA1c levels of approximately 25% to approximately 60% is shown by treatment of type 2 diabetes. In one embodiment, a reduction in HbA1c levels of approximately 6.5% or less, approximately 6.0% or less, or approximately 5.0% or less is shown by treatment of type 2 diabetes.

[0277] In one embodiment, a decrease in glucagon levels of approximately 5% to approximately 95% is shown by the treatment of type 2 diabetes. A decrease in glucagon levels of approximately 15% to approximately 80% is shown by the treatment of type 2 diabetes. A decrease in glucagon levels of approximately 25% to approximately 60% is shown by the treatment of type 2 diabetes. An increase in insulin levels of approximately 5% to approximately 95% is shown by the treatment of type 2 diabetes. An increase in insulin levels of approximately 15% to approximately 80% is shown by the treatment of type 2 diabetes. An increase in insulin levels of approximately 25% to approximately 60% is shown by the treatment of type 2 diabetes.

[0278] In one embodiment, a BMI reduction of approximately 5% to approximately 95% is shown by the treatment of type 2 diabetes. A BMI reduction of approximately 15% to approximately 80% is shown by the treatment of type 2 diabetes. A BMI reduction of approximately 25% to approximately 60% is shown by the treatment of type 2 diabetes. In one embodiment, a BMI reduction of approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% is shown by the treatment of type 2 diabetes. In one embodiment, a BMI reduction of approximately 40 or less, approximately 30 or less, or approximately 20 or less is shown by the treatment of type 2 diabetes.

[0279] In one embodiment, the disease, disorder, or impairment is related to diabetes (e.g., complications of diabetes). Non-limiting examples of disorders related to diabetes include obesity, obesity-related disorders, metabolic syndrome, neuropathy, renal impairment (e.g., diabetic nephropathy), retinopathy, diabetic cardiomyopathy, cataracts, macrovascular disorders, osteopenia, hyperosmolar diabetic coma, infections (e.g., respiratory infections, urinary tract infections, gastrointestinal infections, skin and soft tissue infections, lower extremity infections), diabetic gangrene, xerostomia, hearing impairment, cerebrovascular disorders, diabetic cachexia, delayed wound healing, diabetic dyslipidemia, peripheral circulatory disorders, cardiovascular risk factors (e.g., coronary artery disease, peripheral artery disease, cerebrovascular disease, hypertension, and risk factors associated with uncontrolled cholesterol and / or lipid levels, and / or inflammation), NASH, fractures, and cognitive impairment.

[0280] Other non-limiting examples of diabetes-related disorders include prediabetes, hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, hyper-LDL cholesterolemia, hypo-LDL cholesterolemia, postprandial dyslipidemia), metabolic syndrome (e.g., metabolic disorders in which GLP-1R activation is beneficial, metabolic syndrome X), hypertension, impaired glucose tolerance (IGT), insulin resistance, and sarcopenia.

[0281] In one embodiment, the disease, disorder, or condition is diabetes and obesity. In one embodiment, the compounds described herein are useful for improving the therapeutic efficacy of metformin.

[0282] Damage to metabolically important tissues In one embodiment, the disease, disorder, or impairment is a disorder of metabolically important tissues. Non-limiting examples of metabolically important tissues include the liver, fat, pancreas, kidneys, and intestines.

[0283] In one embodiment, the disease, disorder, or disorder is a fatty liver disease. Fatty liver diseases include, but are not limited to, non-alcoholic fatty liver disease (NAFLD), steatohepatitis, non-alcoholic steatohepatitis (NASH), fatty liver disease resulting from hepatitis, fatty liver disease resulting from obesity, fatty liver disease resulting from diabetes, fatty liver disease resulting from insulin resistance, fatty liver disease resulting from hypertriglyceridemia, abetalipoproteinemia, hyperlipoproteinemia, glycogen storage disease, Weber-Christian disease, Wollman disease, acute fatty liver of pregnancy, and lipodystrophy.

[0284] Non-alcoholic fatty liver disease (NAFLD) is a set of disorders that occur in the absence of alcohol abuse and are typically characterized by the presence of fatty liver (fat in the liver). NAFLD is thought to be associated with various diseases, such as metabolic syndrome (including obesity, diabetes, and hypertriglyceridemia) and insulin resistance. It can cause liver disease in adults and children and can eventually lead to cirrhosis (Skelly et al., J Hepatol 2001; 35: 195-9; Chitturi et al., Hepatology 2002; 35(2):373-9). The severity of NAFLD ranges from relatively benign, mostly isolated macrodrip fatty liver (i.e., non-alcoholic fatty liver or NAFL) to non-alcoholic steatohepatitis (NASH) (Angulo et al., J Gastroenterol Hepatol 2002; 17 Suppl:S186-90).

[0285] Other non-limiting examples of disorders of metabolically important tissues include arthropathy (e.g., osteoarthritis, secondary osteoarthritis), fatty liver (e.g., liver); fibrosis (e.g., liver); cirrhosis (e.g., liver); gallstones; gallbladder disease; gastroesophageal reflux; sleep apnea; hepatitis; fatty liver; bone disorders characterized by changes in bone metabolism, e.g., osteoporosis (including postmenopausal osteoporosis), decreased bone strength, osteopenia, Paget's disease, osteolytic metastases in cancer patients, osteodystrophy in liver disease and changes in bone metabolism caused by renal failure or hemodialysis, fractures, bone surgery, aging, pregnancy, protection from fractures, and malnutrition; polycystic ovary syndrome; renal diseases (e.g., chronic renal failure, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease); muscular dystrophy, angina pectoris, acute or chronic diarrhea, testicular dysfunction, respiratory dysfunction, frailty, sexual dysfunction (e.g., erectile dysfunction), and geriatric syndromes. In one embodiment, the compounds and pharmaceutical compositions described herein can be used to treat surgical trauma by improving postoperative recovery and / or preventing catabolic reactions resulting from surgical trauma.

[0286] Cardiovascular and vascular diseases In one embodiment, the disease, disorder, or condition is a cardiovascular disease. Non-limiting examples of cardiovascular diseases include congestive heart failure, atherosclerosis, arteriosclerosis, coronary heart disease, coronary artery disease, congestive heart failure, coronary heart disease, hypertension, heart failure, cerebrovascular disease (e.g., cerebral infarction), vascular dysfunction, myocardial infarction, elevated blood pressure (e.g., 130 / 85 mmHg or higher), and pro-thrombus formation conditions (e.g., high levels of fibrinogen or plasminogen activator inhibitors in the blood).

[0287] In one embodiment, the disease, disorder, or disability is related to a vascular disease. Non-limiting examples of vascular diseases include peripheral vascular disease, megavascular complications (e.g., stroke), vascular dysfunction, peripheral artery disease, abdominal aortic aneurysm, carotid artery disease, cerebrovascular disease (e.g., cerebral infarction), pulmonary embolism, chronic venous insufficiency, severe limb ischemia, retinopathy, renal impairment, and neurological disorders.

[0288] Neurological diseases In one embodiment, the disease, disorder, or disability is a neurological disorder (e.g., a neurodegenerative disorder) or a mental disorder. Non-limiting examples of neurological disorders include idiopathic intracranial hypertension (IIH), cerebral insulin resistance, mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), anxiety, dementia (e.g., senile dementia), traumatic brain injury, Huntington's disease, tardive dyskinesia, hyperkinesia, mania, Morbus Parkinson's disease, Steel-Richard syndrome, Down syndrome, myasthenia gravis, neurotrauma, traumatic brain injury, vascular amyloidosis, cerebral hemorrhage with amyloidosis, encephalitis, Friedreich's ataxia, acute confusional disorder, amyotrophic lateral sclerosis (ALS), glaucoma, and apoptosis-mediated degenerative diseases of the central nervous system (e.g., Creutzfeldt-Jakob disease, bovine spongiform encephalopathy (mad cow disease), and chronic wasting syndrome). For example, see U.S. Publication No. 20060275288A1.

[0289] In one embodiment, the disease, disorder, or disorder is idiopathic hypertension. Idiopathic hypertension is characterized by increased intracranial pressure and papilledema. See, for example, Virdee et al. Ophthalmol Ther. 2020; 9(4):767-781. In one embodiment, the compounds, pharmaceutical compositions, and methods described herein reduce cerebrospinal fluid secretion in patients with idiopathic hypertension. In one embodiment, the compounds, pharmaceutical compositions, and methods described herein reduce intracranial pressure in patients with idiopathic hypertension. In one embodiment, the compounds, pharmaceutical compositions, and methods described herein reduce one or more symptoms in patients with idiopathic hypertension. Symptoms of idiopathic hypertension may include severe headache and visual impairment. In one embodiment, the patient with idiopathic hypertension is female. In one embodiment, the patient with idiopathic intracranial hypertension is approximately 20 to 30 years old. In another embodiment, the patient with idiopathic intracranial hypertension is obese.

[0290] In one embodiment, the disease, disorder, or disability is Wolfram syndrome. Wolfram syndrome is caused by biallelic mutations in the Wolframin ER transmembrane glycoprotein (Wfs1) gene. See, for example, Seppa et al. Sci Rep 9, 15742 (2019). Wolfram syndrome may present first as diabetes, followed by symptoms of optic nerve atrophy, hearing loss, and neurodegeneration. Patients with Wolfram syndrome may exhibit symptoms of ataxia due to brainstem atrophy, sleep apnea, dysphagia, hearing loss, and loss of taste. In one embodiment, the compounds, pharmaceutical compositions, and methods described herein reduce neuroinflammation in patients with Wolfram syndrome. In one embodiment, the neuroinflammation is reduced in the lower olivary gland of the patient. In one embodiment, the compounds, pharmaceutical compositions, and methods described herein reduce retinal ganglion cell death in patients with Wolfram syndrome. In one embodiment, the compounds, pharmaceutical compositions, and methods described herein reduce axonal degeneration in patients with Wolfram syndrome. In one embodiment, the compounds, pharmaceutical compositions, and methods described herein reduce one or more symptoms (e.g., any of the symptoms described herein) in patients with Wolfram syndrome.

[0291] Non-limiting examples of mental disorders include drug addiction / indulgence (narcotics and amphetamines) and attention deficit hyperactivity disorder (ADHD). The compounds and pharmaceutical compositions described herein may be useful in improving behavioral responses to addictive substances, reducing drug dependence, preventing relapse of substance abuse, and alleviating anxiety caused by the absence of certain addictive substances. See, for example, U.S. Publication No. 20120021979A1.

[0292] In one embodiment, the compounds and pharmaceutical compositions described herein are useful for improving learning and memory by enhancing neuroplasticity and cell differentiation, and for maintaining dopamine neurons and motor function in Morbus Parkinson's disease.

[0293] Insulin-related In one embodiment, the disease, disorder, or impairment is poor fasting blood glucose (IFG), fasting hyperglycemia (IFG), hyperglycemia, insulin resistance (impaired glucose homeostasis), hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hypoglycemic state, insulin resistance syndrome, paresthesia caused by hyperinsulinemia, hyperlipidemia, hypercholesterolemia, poor wound healing, leptin resistance, glucose intolerance, elevated fasting glucose, dyslipidemia (e.g., atherosclerotic dyslipidemia characterized by hyperlipidemia, high triglycerides, and low HDL cholesterol), glucagonoma, hyperuricemia, hypoglycemia (e.g., nocturnal hypoglycemia), and insulin-related concomitant comatose endpoint.

[0294] In some embodiments, the compounds and pharmaceutical compositions described herein can reduce or delay the progression of pre-diabetes with poor fasting blood glucose levels or hyperglycemia.

[0295] autoimmune disease In some embodiments, the disease, disorder, or condition is an autoimmune disease. Non-limiting examples of autoimmune diseases include multiple sclerosis and experimental autoimmune encephalomyelitis, and autoimmune diseases may be associated with immune rejection, graft-versus-host disease, uveitis, optic neuropathy, optic neuritis, transverse myelitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, myasthenia gravis, and Graves' disease. See, for example, U.S. Publication No. 20120148586A1.

[0296] Gastrointestinal disorders In some embodiments, the disease, disorder, or disorder is a disorder relating to the stomach or intestines. Non-limiting examples of these disorders include ulcers of any etiology (e.g., gastric ulcer, Zollinger-Ellison syndrome, drug-induced ulcer, infection or other pathogen-related ulcer), gastrointestinal disorders, malabsorption, short bowel syndrome, duct-blind syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), celiac disease, hypogammaglobulinemia, chemotherapy and / or radiotherapy-induced mucositis and diarrhea, gastroenteritis, short bowel syndrome, ulcerative colitis, gastric mucosal injury (e.g., aspirin-induced gastric mucosal injury), small intestinal mucosal injury, and cachexia (e.g., cancer cachexia, tuberculous cachexia, cachexia associated with hematological disorders, cachexia associated with endocrine disorders, cachexia associated with infections, and cachexia caused by acquired immunodeficiency syndrome).

[0297] body weight In some embodiments, the compounds and pharmaceutical compositions described herein can be used in patients (e.g., patients in need) to reduce body weight (e.g., excess weight), prevent weight gain, induce weight loss, reduce body fat, or reduce food intake. In some embodiments, the patient's weight gain may be due to excessive food intake or an unbalanced diet, or it may be due to concomitant medications (e.g., insulin sensitivity improving agents having PPARγ agonist-like activity, such as troglitazone, rosiglitazone, englitazone, siglitazone, pioglitazone, etc.). In some embodiments, the weight gain may be weight gain before becoming obese, or it may be weight gain in obese patients. In some embodiments, the weight gain may also be drug-induced weight gain or weight gain after quitting smoking. In some embodiments, the weight gain may be caused by the use of steroids or antipsychotics.

[0298] In one embodiment, the disease, disorder, or disorder is an eating disorder, such as binge eating, overeating, bulimia, forced eating, or symptomatic obesity, such as Prader-Willi syndrome and Valde-Biedl syndrome.

[0299] Inflammatory diseases In one embodiment, the disease, disorder, or condition is an inflammatory disease. Non-limiting examples of inflammatory diseases include rheumatoid arthritis, spondylitis degenerative, osteoarthritis, lumbago, gout, postoperative or post-traumatic inflammation, abdominal distension, neuralgia, pharyngitis, cystitis, pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory bowel disease), inflammation of metabolically important tissues (including the liver, fat, pancreas, kidneys, and intestines), and pro-inflammatory conditions (e.g., elevated levels of pro-inflammatory cytokines or markers such as C-reactive proteins in the blood).

[0300] cancer In one embodiment, the disease, disorder, or disorder is cancer. Suitable examples of cancer include breast cancer (e.g., invasive ductal carcinoma, non-invasive ductal carcinoma, inflammatory breast cancer), prostate cancer (e.g., hormone-dependent prostate cancer, hormone-independent prostate cancer), pancreatic cancer (e.g., pancreatic ductal carcinoma), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, malignant mesothelioma), colon cancer (e.g., gastrointestinal stromal tumor), rectal cancer (e.g., gastrointestinal Stromal tumors), colorectal cancer (e.g., familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumors), small intestine cancer (e.g., non-Hodgkin lymphoma, gastrointestinal stromal tumors), esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer (e.g., nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer), salivary gland cancer, brain tumors (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma), schwannoma, liver cancer (e.g., primary liver cancer) Cancer (extrahepatic cholangiocarcinoma), kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter), cholangiocarcinoma, endometrial cancer, cervical cancer, ovarian cancer (e.g., ovarian epithelial carcinoma, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian tumor with low malignancy), bladder cancer, urethral cancer, skin cancer (e.g., intraocular melanoma, Merkel cell carcinoma), hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer (e.g., medullary thyroid carcinoma), This includes parathyroid cancer, nasal cavity cancer, sinus cancer, bone tumors (e.g., osteosarcoma, Ewing's tumor, uterine sarcoma, soft tissue sarcoma), angiofibroma, retinal sarcoma, penile cancer, testicular tumor, pediatric solid tumors (e.g., Wilms' tumor, pediatric renal tumor), Kaposi's sarcoma, Kaposi's sarcoma caused by AIDS, maxillary sinus tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia).

[0301] Hypothalamic-pituitary disorder In one embodiment, the disease, disorder, or disorder is related to the hypothalamic-pituitary-gonadal axis. For example, the disease, disorder, or disorder is related to the hypothalamic-pituitary-ovarian axis. In another example, the disease, disorder, or disorder is related to the hypothalamic-pituitary-testicular axis. Disorders of the hypothalamic-pituitary-gonadal axis include, but are not limited to, reproductive dysfunction, polycystic ovary syndrome, hypothyroidism, hypopituitarism, sexual dysfunction, and Cushing's disease.

[0302] In one embodiment, a disease, disorder, or condition related to diabetes is related to the hypothalamic-pituitary-gonadal axis.

[0303] Lung disease In one embodiment, the disease, disorder, or impairment is related to a lung disease. Lung diseases include, but are not limited to, asthma, idiopathic pulmonary fibrosis, pulmonary hypertension, obstructive sleep apnea syndrome, and chronic obstructive pulmonary disease (COPD) (e.g., emphysema, chronic bronchitis, and refractory (irreversible) asthma).

[0304] In one embodiment, a disease, disorder, or condition associated with diabetes is a lung disease.

[0305] Combination therapy In some embodiments, this disclosure includes both monotherapy regimens and combination therapy regimens.

[0306] In one embodiment, the method described herein may further include administering one or more additional therapies (e.g., one or more additional therapeutic agents and / or one or more therapeutic regimens) in combination with the administration of the compound described herein.

[0307] In one embodiment, the methods described herein include administering the compounds described herein in combination with one or more of the following: dietary therapy (e.g., dietary monitoring for diabetes), exercise therapy (e.g., physical activity), blood glucose monitoring, gastric electrical stimulation (e.g., TANTALUS®), and dietary modifications.

[0308] In one embodiment, a compound of formula I described herein (e.g., any one of the compounds of formulas IA, IB, IB-1, IC, ID, IE, and IE-1, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutically acceptable salt or solvate thereof, may be administered in combination with one or more further therapeutic agents.

[0309] Representative additional treatments include, but are not limited to, anti-obesity drugs, drugs for diabetes, drugs for diabetic complications, drugs for hyperlipidemia, antihypertensives, diuretics, chemotherapeutic drugs, immunotherapeutic drugs, anti-inflammatory drugs, antithrombotic drugs, antioxidants, drugs for osteoporosis, vitamins, drugs for dementia, drugs for erectile dysfunction, drugs for frequent urination or urinary incontinence, drugs for NAFLD, drugs for NASH, and drugs for voiding disorders.

[0310] In one embodiment, the one or more further therapeutic agents include, for example, those useful as anti-obesity agents. Non-limiting examples include monoamine reuptake inhibitors (e.g., tramadol, phentermine, sibutramine, mazindol, fluoxetine, tesofensin), serotonin 2C receptor agonists (e.g., lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptor modifiers, GABA modifiers (e.g., topiramates) (including GABA receptor agonists (e.g., gabapentin, pregabalin)), neuropeptide Y antagonists (e.g., berneperito), peptide YY or its analogues. Cannabinoid receptor antagonists (e.g., rimonabant, taranabant), ghrelin antagonists, ghrelin receptor antagonists, ghrelin acylates inhibitors, opioid receptor antagonists (e.g., GSK-1521498, naltrexone), orexin receptor antagonists, melanocortin 4 receptor agonists, 11β-hydroxysteroid dehydrogenase inhibitors (e.g., AZD-4017, BVT-3498, INCB-13739), pancreatic lipase inhibitors (e.g., (e.g., orlistat, cetilistat), β3 agonists (e.g., N-5984), diacylglycerol acyltransferase 1 (DGAT1) inhibitors, acetyl-CoA carboxylase (ACC) inhibitors (e.g., compounds described in WO2020 / 234726, WO2020 / 044266, and U.S. Patent No. 8,859,577), stearate-CoA desaturate inhibitors, microsomal triglyceride transport protein inhibitors (e.g., R-256918), sodium glucose transporter 2 (SGL) T-2) inhibitors (e.g., JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, remogliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, cergliflozin etabonate, remogliflozin etabonate, or erzgliflozin), SGLT-1 inhibitors, MCR-4 agonists, monoamine reuptake inhibitors, melanocyte-stimulating hormone analogs, 5HT2c agonists, galanin antagonists,Appetite suppressants (e.g., bombesin agonists), thyromimetic agents, dehydroepiandrosterone or its analogues, human agouti-related protein (AGRP) inhibitors, neuromedin U agonists, NFK inhibitors (e.g., HE-3286), PPAR agonists (e.g., GFT-505, DRF-11605, gemfibrozil, fenofibrate, paraglitazone, siglitazone, dalglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone, CLX-0940, GW-1536, GW-1929, GW-2) 433, KRP-297, L-796449, LR-90, MK-0767, and SB-219994), phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate, trodasquemin), GPR119 agonists (e.g., compounds listed in PSN-821, MBX-2982, APD597, WO2010 / 140092, WO2010 / 128425, WO2010 / 128414, WO2010 / 106457), glucokinase activators (e.g., pyragliatin, Compounds listed in AZD-1656, AZD6370, TTP-355, TTP-399, TTP547, ARRY403, MK-0599, TAK-329, AZD5658 or GKM-001, WO2010 / 103437, WO2010 / 103438, WO2010 / 013161, WO2007 / 122482, WO2006 / 112549, WO2007 / 028135, WO2008 / 047821, WO2008 / 050821, WO2008 / 136428 and WO2008 / 156757), rep Tin, leptin derivatives (e.g., metreleptin), leptin resistance improvers, CNTF (ciliary neurotrophic factor), BDNF (brain-derived neurotrophic factor), cholecystokinin agonists, amylin preparations (e.g., plumlintide, AC-2307), neuropeptide Y agonists (e.g., PYY3-36, PYY3-36 derivatives, obineptide, TM-30339, TM-30335), oxinmodulin (OXM) preparations, appetite suppressants (e.g., ephedrine), FGF21 preparations (e.g.,Animal FGF21 preparations extracted from bovine or porcine pancreas; human FGF21 preparations genetically synthesized using E. coli or yeast; fragments or derivatives of FGF21), appetite suppressants (e.g., P-57), human proislet peptides. Peptides (HIP), melanocortin receptor 4 agonists (e.g., cetomelanotide), melanin-concentrating hormone receptor 1 antagonists, serotonergic agents (e.g., sibutramine, lorcaserin), farnesoid X receptor (FXR) agonists (e.g., obeticholic acid, tropifexor, cilofexol, LY2562175, Met409, TERN-101, EDP305, compounds listed in WO2020 / 234726 and WO2020 / 044266), phentermine, zonisamide, norepinephrine / dopamine reuptake inhibitors Examples include harmful agents (e.g., bupropion), GDF-15 analogs, methionine aminopeptidase 2 (MetAP2) inhibitors (e.g., veroranib or ZGN-1061), diethylpropion, fendimethrazine, benzfetamine, fibroblast growth factor receptor (FGFR) modifiers, biotin, MAS receptor modifiers, glucagon receptor agonists, CCKa agonists (e.g., compounds listed in WO2005 / 116034 and U.S. Publication No. 2005 / 0287100), and AMP-activated protein kinase (AMPK) activators.

[0311] In one embodiment, the one or more further therapeutic agents include, for example, agents useful as antidiabetic agents. Non-limiting examples include insulin and insulin preparations (e.g., animal insulin preparations extracted from bovine or porcine pancreas; human insulin preparations genetically synthesized using E. coli or yeast; zinc insulin; protamine zinc insulin; insulin fragments or derivatives (e.g., INS-1), oral insulin preparations, synthetic human insulin), insulin sensitivity enhancers (e.g., pioglitazone or its salts), biguanides (e.g., metformin, buformin or its salts (e.g., hydrochloride)). (Fumarate, succinate), glucagon analogs (e.g., any of the glucagon analogs listed in WO2010 / 011439), drugs that antagonize the action of glucagon or reduce glucagon secretion, sulfonylurea drugs (e.g., chloropropamide, trazamide, glimepiride, tolbutamide, glibenclamide, gliclazide, acetohexamide, glyclopyramide, glibzol, glibrid, glipizide), thiazolidinedione drugs (e.g., rosiglitazone, robeglitazone, troglitazone) (e.g., paraglitazone, riboglitazone, lobeglitazone or pioglitazone), glitazar (e.g., alleglitazar, chiglitazar, saroglitazal, mulaglitazal, tesaglitazal), SGLT2 inhibitors (e.g., JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, THR1474, TS-071, ISIS388626, LX4211, remogliflozin, empagliflozin) , canagliflozin, ipragliflozin, tofogliflozin, cergliflozin etabonate, remogliflozin etabonate, erzgliflozin (compounds listed in WO2010 / 023594), GPR40 agonists (e.g., FFAR1 / FFA1 agonists, e.g., fasiglifam), α-glucosidase inhibitors (e.g., adiposin, camiglibose, pradymycin-Q, salvostatin, voglibose, acarbose, miglitol, emiglitate), insulin secretagogues, e.g.,Dietary glucose regulators (sometimes called "short-acting secretagogues"), e.g., meglitinides (e.g., repaglinide and nateglinide), cholinesterase inhibitors (e.g., donepezil, galantamine, rivastigmine, tacrine), NMDA receptor antagonists, GLP-1 / GIP receptor dual agonists (e.g., LBT-2000, ZPD1-70), GLP-1R agonists (e.g., exenatide, liraglutide, albiglutide, dulaglutide, albiglutide, taspoglutide, lixisenatide, semaglutide, AVE-001) Examples include 0, 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, omaligliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, ALS2-0426, TA-6666, TS-021, KRP-104, trelagliptin).

[0312] In one embodiment, the one or more further therapeutic agents include, for example, drugs useful for treating NAFL and NASH. Non-limiting examples include FXR agonists (e.g., obeticholic acid), PF-05221304, PPARα / δ agonists (e.g., ellafibrano), synthetic fatty acid bile conjugates (e.g., aramchol), anti-lysyl oxidase analog 2 (LOXL2) monoclonal antibodies (e.g., simtuzumab), caspase inhibitors (e.g., emricasan), MAPK5 inhibitors (e.g., GS-4997), galectin 3 inhibitors (e.g., GR-MD-02), and line Fibroblast growth factor 21 (FGF21) (e.g., BMS-986036), niacin analogs (e.g., ARJ3037MO), leukotriene D4 (LTD4) receptor antagonists (e.g., tipercast), acetyl-CoA carboxylase (ACC) inhibitors (e.g., NDI010976, and compounds described in WO2009 / 144554, WO2003 / 072197, WO2009 / 144555, and WO2008 / 065508), ketohexokinase (KHK) inhibitors (WO2020 / Compounds listed in 234726), apoptosis signal-regulated kinase 1 (ASK1) inhibitors, ileal bile acid transporter (IBAT) inhibitors, chemokine receptor 2 (CCR2) and CCR5 dual antagonists (e.g., senicliviroc), diacylglycerol acyltransferase 2 (DGAT2) inhibitors (e.g., compounds listed in WO2020 / 234726 and U.S. Publication No. 20180051012), CB1 receptor antagonists, anti-CB1R antibodies, glycyrrhizin, Schisandra, ASCO Examples include rubic acid, glutathione, silymarin, lipoic acid, and d-alpha-tocopherol, ascorbic acid, glutathione, vitamin B complexes, glitazone / thiazolidinediones (e.g., troglitazone, rosiglitazone, pioglitazone, paraglitazone, riboglitazone, robeglitazone), metformin, cysteamine, sulfonylurea, alpha-glucosidase inhibitors, meglitinides, vitamin E, tetrahydrolipustatin, milk thistle protein, antiviral agents, and antioxidants.

[0313] In one embodiment, the one or more further therapeutic agents include, for example, drugs useful for treating diabetic complications. Non-limiting examples include aldose reductase inhibitors (e.g., torrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat, lidrestat), these neurotrophic factors and growth factors (e.g., NGF, NT-3, BDNF, neurotrophic synthesis / secretion-promoting agents described in WO2001 / 14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxyl)propyl]oxazole), compounds described in WO2004 / 039365), PKC inhibitors (e.g., ru Examples include boxistaurine mesylate, AGE inhibitors (e.g., ALT946, N-phenacylthiazolium bromide (ALT766), EXO-226, pyridrine, pyridoxamine), serotonin and norepinephrine reuptake inhibitors (e.g., duloxetine), sodium channel inhibitors (e.g., lacosamide), reactive oxygen species scavengers (e.g., thioctic acid), cerebral vasodilators (e.g., tiapride, mexiletine), somatostatin receptor agonists (e.g., BIM23190), and apoptosis signal-regulated kinase 1 (ASK-1) inhibitors.

[0314] In one embodiment, the one or more further therapeutic agents include, for example, drugs useful for treating hyperlipidemia. Non-limiting examples include HMG-COA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or salts thereof (e.g., sodium salts, calcium salts)), squalene synthase inhibitors (e.g., compounds described in WO97 / 10224, e.g., N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-yl]acetyl Examples include piperidine-4-acetic acid, fibrate compounds (e.g., bezafibrate, clofibrate, cinfibrate, clinofibrate), anion exchange resins (e.g., cholestyramine), nicotinic acid drugs (e.g., nicomole, niceritrol, niaspan), phytosterols (e.g., soysterol, gamma-oryzanol (γ-oryzanol)), cholesterol absorption inhibitors (e.g., Zetia), CETP inhibitors (e.g., dalcetrapib, anacetrapib), and omega-3 fatty acid preparations (e.g., omega-3 fatty acid ethyl ester 90).

[0315] In one embodiment, the one or more further therapeutic agents include, for example, drugs useful as antihypertensive agents. Non-limiting examples include angiotensin-converting enzyme inhibitors (e.g., captopril, zofenopril, hosinopril, enalapril, ceranopril, cilazapril, delapril, pentopril, quinapril, ramipril, lisinopril), and angiotensin II antagonists (e.g., candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, val These include sartans (e.g., telmisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil, azilsartan, azilsartan medoxomil), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine, cilnidipine), and beta-blockers (e.g., metoprolol, atenolol, propranolol, carvedilol, pindolol).Further non-exclusive examples of antihypertensive drugs include diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrine, tricrynafen, chlorthalidone, torsemide, furosemide, musolimine, bumetanide, musolimine, amiloride, spironolactone), alpha-adrenergic blockers, beta-adrenergic blockers, calcium thi These include channel blockers (e.g., diltiazem, verapamil, nifedipine, and amlodipine), vasodilators (e.g., hydralazine), renin inhibitors, AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan), ET receptor antagonists (e.g., citaxsentan, atrasentan, compounds disclosed in U.S. Patent Nos. 5,612,359 and 6,043,265), ET / AII dual antagonists (e.g., compounds disclosed in WO2000 / 01389), neutral endopeptidase (NEP) inhibitors, If channel blockers (IV channel blockers) such as ivabradine, and vasopeptidase inhibitors (NEP-ACE dual inhibitors) (e.g., gemopatrilate and nitrates).

[0316] In one embodiment, the one or more further therapeutic agents include, for example, drugs useful as diuretics. Non-limiting examples include xanthine derivatives (e.g., sodium salicylate theobromine, calcium salicylate theobromine), thiazide drugs (e.g., etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penfluthiazide, polythiazide, meticlothiazide), anti-aldosterone drugs (e.g., spironolactone, triamterene), carbonic anhydrase inhibitors (e.g., acetazolamide), and chlorobenzenesulfonamide drugs (e.g., chlorthalidone, mefluside, indapamide).

[0317] In one embodiment, the one or more further therapeutic agents include, for example, drugs useful as immunotherapeutic agents. Non-limiting examples include microbial or bacterial compounds (e.g., muramyl dipeptide derivatives, picibanil), polysaccharides having immunosuppressive activity (e.g., lentinan, schizophyllan, krestin), cytokines obtained by genetic manipulation (e.g., interferons, interleukins (IL), e.g., IL-1, IL-2, IL-12), and colony-stimulating factors (e.g., granulocyte colony-stimulating factor, erythropoietin).

[0318] In one embodiment, the one or more further therapeutic agents include, for example, drugs useful as antithrombotic agents. Non-limiting examples include heparin (e.g., heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarin (e.g., warfarin potassium); antithrombin drugs (e.g., argatroban, dabigatran, boroarginine derivatives, boropeptides, heparin, hirudin, and melagan); FXa inhibitors (e.g., Rivaroxaban, apixaban, edoxaban, YM150, compounds described in WO2002 / 06234, WO2004 / 048363, WO2005 / 030740, WO2005 / 058823, and WO2005 / 113504), thrombolytic agents (e.g., anistreplase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), urokinase, tysokinase, alteplase, nateplase, These include monteplase, pamiteplase, factor VIla inhibitors, PAI-1 inhibitors, alpha-2 plasmin inhibitors, and anisoylated plasminogen streptokinase activator complexes, and platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cilostazol, ethyl icosapentate, beraprost sodium, and sarpogrelate hydrochloride).

[0319] In one embodiment, the one or more further therapeutic agents include, for example, drugs useful for treating osteoporosis. Non-limiting examples include alfacalcidol, calcitriol, elcatonin, salmoncalcitonin, estriol, ipriflavone, disodium pamidronate, sodium alendronate hydrate, disodium incadronate, and disodium risedronate. Suitable examples of vitamins include vitamin B1 and vitamin B12. Suitable examples of drugs for treating erectile dysfunction include apomorphine and sildenafil citrate. Suitable examples of drugs for treating frequent urination or urinary incontinence include flavoxate hydrochloride, oxybutynin hydrochloride, and propiverine hydrochloride. Suitable examples of drugs for treating urinary disorders include acetylcholinesterase inhibitors (e.g., distigmine). Suitable examples of anti-inflammatory drugs include nonsteroidal anti-inflammatory drugs, such as aspirin, acetaminophen, and indomethacin.

[0320] Other exemplary therapeutic agents include drugs that regulate hepatic glucose balance (e.g., fructose 1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glycogen synthase kinase inhibitors, glucokinase activators), drugs designed to treat complications of persistent hyperglycemia (e.g., aldose reductase inhibitors, epalrestat and ranirestat), drugs used to treat complications associated with microvascular complications, and drugs for treating dyslipidemia (e.g., HMG-COA reductase inhibitors, statins, e.g., rosuvastatin, pravastatin, pitavastatin, lovastatin, atorvastatin). Simvastatin, fluvastatin, itavastatin, ZD-4522), HMG-CoA synthase inhibitors, cholesterol-lowering drugs, bile acid scavengers (e.g., cholestyramine, questran, colestipol, and coleseveram), cholesterol absorption inhibitors (e.g., plant sterols such as phytosterols), cholesteryl ester transfer protein (CETP) inhibitors, ileal bile acid transport system inhibitors (IBAT inhibitors), diacylglycerol acyltransferase 1 (DGAT1) inhibitors (e.g., compounds described in AZD7687, LCQ908, WO2009 / 016462, WO2010 / 086820), monoacylglycerol O-acyltransferase inhibitors, α-amylase inhibitors (e.g., tendamistat, trestatin, AL-3688), α-glucoside hydrolase inhibitors, SIRT-1 activators, c-Jun N-terminal kinase (JNK) inhibitors, VPAC2 receptor agonists, TGR5 receptor modifiers (e.g., the compounds listed), GPBAR1 receptor modifiers, GPR120 modifiers, high-affinity nicotinic acid receptor (HM74A) activators, carnitine palmitoyltransferase enzyme inhibitors, mineralocorticoid receptor inhibitors, TORC2 inhibitors, fatty acid synthase inhibitors, serine palmitoyltransferase inhibitors, GPR81 modifiers, GPR39 modifiers, GPR43 modifiers, GPR41 modifiers, GPR105 modifiers, Kv1.3 modifiers, retinol-binding protein 4 modifiers, somatostatin receptor modifiers, PDHK2 modifiers, PDHK4 modifiers, MAP4K4 inhibitors,IL1 family modifiers (e.g., ILI beta modifier), ACAT inhibitors, MTP inhibitors (e.g., diriotapide, mitratapide, and implitapide), lipoxygenase inhibitors, PCSK9 modifiers (e.g., alirocumab and evolocumab), RXR alpha modifier, cysteamine, cystamine, RNA antisense constructs for inhibiting protein tyrosine phosphatase PTPRU, vitamin B complex, pentraxin protein, protein tyrosine phosphatase-1B (PTP-1B) inhibitors (e.g., trodasquemin, hyrtiosal extract, and compounds described in Zhang et al. Drug Discovery Today. 2007, 12(9-10): 373-381), ezitimbe, betaine, pentoxifylline, alpha delta-9 desaturase Desaturase), BCKDK inhibitors, branched-chain alpha-keto acid dehydrogenase (BCBK) inhibitors, PNPLA3 inhibitors, FGF19 analogs, SCD1 inhibitors, bile acid binding resins, nicotinic acid (niacin) and its analogs, antioxidants (e.g., probucol), omega-3 fatty acids, antihypertensives, e.g., adrenergic receptor antagonists, e.g., beta-blockers (e.g., atenolol), alpha-blockers (e.g., doxazosin), and mixed alpha / beta-blockers (e.g., labetalol), adrenergic receptor agonists, e.g., alpha-2 agonists (e.g., clonidine), angiotensin-converting enzyme (AC) E) Inhibitors (e.g., lisinopril), calcium channel blockers (e.g., dihydropyridine (e.g., nifedipine), phenylalkylamines (e.g., verapamil), and benzothiazepines (e.g., diltiazem), angiotensin II receptor antagonists (e.g., candesartan), aldosterone receptor antagonists (e.g., eplerenone, spironolactone), centrally acting adrenergic drugs (e.g., centrally acting alpha agonists (e.g., clonidine)), diuretics (e.g., furosemide, torsemide, bumetanide, ethacrine), thiazide diuretics (e.g., chlorothiazide),Hydrochlorothiazide, benzthiazide, hydroflumethiazide, bendroflumethiazide, meticlothiazide, polythiazide, trichlormethiazide, indapamide), phthalomidine diuretics (e.g., chlorthalidone, metrazone), quinazoline diuretics (e.g., quinazoline), potassium-sparing diuretics (e.g., triamterene and amiloride), thyroid receptor agonists (e.g., compounds listed in WO2020 / 117987), hemostatic modifiers (including antithrombotic agents (e.g., fibrinolytic activator)), thrombin antagonists, VI Factor Ia inhibitors, anticoagulants (e.g., vitamin K antagonists, e.g., warfarin), heparin and its low molecular weight analogs, factor Xa inhibitors, and direct thrombin inhibitors (e.g., argatroban), antiplatelet agents (e.g., cyclooxygenase inhibitors (e.g., aspirin), nonsteroidal anti-inflammatory drugs (NSAIDS), thromboxane-A2 receptor antagonists (e.g., ifetroban), thromboxane-A2 synthase inhibitors, PDE inhibitors (e.g., pletar, dipyridamole)), purine receptor antagonists (e.g., For example, P2Y1 and P2Y12), adenosine diphosphate (ADP) receptor inhibitors (e.g., clopidogrel), phosphodiesterase inhibitors (e.g., cilostazol), glycoprotein IIB / IIA inhibitors (e.g., tyrofiban, eptifivatide, and absiximab), adenosine reuptake inhibitors (e.g., dipyridamole), noradrenergic agonists (e.g., phentermine), serotonergic agonists (e.g., sibutramine, lorcaserin), diacylglycerol acyltransferase (DGAT) inhibitors, feeding behavior enhancers, pi Rubinate dehydrogenase kinase (PDK) modifiers, serotonin receptor modifiers, monoamine transport modifiers, e.g., selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine), norepinephrine reuptake inhibitors (NARIs), norepinephrine-serotonin reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs) (e.g., troxatone and amyflamin), compounds described in WO2007 / 013694, WO2007 / 018314, WO2008 / 093639 and WO2008 / 099794,GPR40 agonists (e.g., faciglifam or its hydrate, compounds described in WO2004 / 041266, WO2004 / 106276, WO2005 / 063729, WO2005 / 063725, WO2005 / 087710, WO2005 / 095338, WO2007 / 013689 and WO2008 / 001931), SGLT-1 inhibitors, adiponectin or its agonists, IKK inhibitors Harmful agents (e.g., AS-2868), somatostatin receptor agonists, ACC2 inhibitors, cachexia-improving agents (e.g., cyclooxygenase inhibitors, e.g., indomethacin), progesterone derivatives (e.g., megestrol acetate), glucocorticoids (e.g., dexamethasone), metoclopramide drugs, tetrahydrocannabinol drugs, drugs to improve lipid metabolism (e.g., eicosapentaenoic acid), growth hormones Antibodies against Lumont, IGF-1, cachexia inducers TNF-α, LIF, IL-6, and oncostatin M, metabolic-improving proteins or peptides, e.g., glucokinase (GK), glucokinase regulatory protein (GKRP), uncoupling proteins 2 and 3 (UCP2 and UCP3), peroxisome proliferator-activated receptor α (PPARα), MC4r agonists, insulin receptor agonists, PDE5 inhibitors, glycation inhibitors (e.g., ALT-711), nerve regeneration promoters (e.g., Y-128, VX853, prosaptide), antidepressants (e.g., desipramine, amitriptyline, imipramine), antiepileptic drugs (e.g., lamotrigine, trireptal, Keppra, Zonegran, pregabalin, harkoseride, carbamazepine), antiarrhythmic drugs (e.g., K, +Channel openers (mexiletine, propafenone, metoprolol, atenolol, carvadiol, propranolol, sotalol, dofetilide, amiodarone, azimilide, ibutilide, diltiazem, and verapamil), acetylcholine receptor ligands (e.g., ABT-594), endothelin receptor antagonists (e.g., ABT-627), narcotic analgesics (e.g., morphine), α2 receptor agonists (e.g., Clonidine), local anesthetics (e.g., capsaicin), anxiolytics (e.g., benzothiazepines), phosphodiesterase inhibitors (e.g., sildenafil), dopamine receptor agonists (e.g., apomorphine), cytotoxic antibodies (e.g., T cell receptor and IL-2 receptor specific antibodies), B cell depletion therapy drugs (e.g., anti-CD20 antibodies (e.g., rituximab), i-BLyS antibodies), drugs that affect T cell migration (e.g., anti-integrin alpha-4 / beta-1 antibodies (e.g., taisotherapy) Drugs acting on immunophyllines (e.g., cyclosporine, tacrolimus, sirolimus, rapamycin), interferons (e.g., IFN-β), immunomodulators (e.g., glatiramer), TNF-binding proteins (e.g., circulating receptors), immunosuppressants (e.g., mycophenolic acid), metaglidacen, AMG-131, paraglitazone, MBX-2044, riboglitazone, alleglitazar, tiglitazar, Examples include saroglitazal, mulaglitazal, tesaglitazal, lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, exenatide, exendin-4, memantine, midazolam, ketoconazole, ethyl eicosapentate, clonidine, azosemide, isosorbide, ethacrine, pyretanide, bumetanide, etoposide, piroxicam, NO donors (e.g., nitrate esters), and NO promoters (e.g., phosphodiesterase inhibitors).

[0321] In one embodiment, the further therapeutic agent or regimen is administered to the patient before contact with or administration of the compound and pharmaceutical composition (for example, about 1 hour, about 6 hours, about 12 hours, about 24 hours, about 48 hours, about 1 week, or about 1 month prior).

[0322] In one embodiment, the further therapeutic agent or regimen is administered to the patient almost simultaneously with the contact or administration of the compound and pharmaceutical composition. As an example, the further therapeutic agent or regimen, as well as the compound and pharmaceutical composition, are administered to the patient simultaneously in the same formulation. As another example, the further therapeutic agent or regimen, as well as the compound and pharmaceutical composition, are administered to the patient simultaneously in separate formulations.

[0323] In one embodiment, the method described herein further includes the step of identifying patients (e.g., subjects) who require such treatment (e.g., by a blood assay, a body mass index, or other conventional method known in the art).

[0324] In one embodiment, the method described herein further includes the step of identifying a patient (e.g., a patient) suffering from one of the diseases, disorders, or illnesses provided herein (e.g., GLP-1 related disease, disorder, or illness).

[0325] In one embodiment, the method described herein further includes the step of identifying a patient (e.g., a patient) who has type 2 diabetes. In one embodiment, determining a patient who has type 2 diabetes includes performing assays to determine hemoglobin A1c (HbA1c) levels, fasting blood glucose, non-fasting blood glucose, or any combination thereof. In one embodiment, the HbA1c level is about 6.5% to about 24.0%. In one embodiment, the HbA1c level is about 6.5% or higher. In one embodiment, the HbA1c level is about 8.0% or higher. In one embodiment, the HbA1c level is about 10.0% or higher. In one embodiment, the HbA1c level is about 12.0% or higher. In one embodiment, the HbA1c level is about 14.0% or higher. In one embodiment, the HbA1c level is about 16.0% or higher. In one embodiment, the HbA1c level is approximately 18.0% or higher. In another embodiment, the HbA1c level is approximately 20.0% or higher. In yet another embodiment, the HbA1c level is approximately 22.0% or higher. In yet another embodiment, the HbA1c level is approximately 24.0% or higher.

[0326] In one embodiment, the fasting blood glucose level is approximately 120 mg / dL or higher to approximately 750 mg / dL or higher. In another embodiment, the fasting blood glucose level is approximately 200 mg / dL or higher to approximately 500 mg / dL or higher. In yet another embodiment, the fasting blood glucose level is approximately 300 mg / dL or higher to approximately 700 mg / dL or higher.

[0327] In one embodiment, the non-fasting blood glucose level is approximately 190 mg / dL or higher to approximately 750 mg / dL or higher. In another embodiment, the non-fasting blood glucose level is approximately 250 mg / dL or higher to approximately 450 mg / dL or higher. In yet another embodiment, the non-fasting blood glucose level is approximately 400 mg / dL or higher to approximately 700 mg / dL or higher.

[0328] In one embodiment, determining whether a patient has type 2 diabetes further includes determining the patient's BMI. In one embodiment, the patient's BMI is approximately 22 kg / m². 2 Or more, up to approximately 100 kg / m 2 or greater. In one embodiment, the patient's BMI is approximately 30 kg / m². 2 Or more, up to approximately 90 kg / m³ 2 or greater. In one embodiment, the patient's BMI is approximately 40 kg / m². 2 Or more, up to approximately 80 kg / m³ 2 or greater. In one embodiment, the patient's BMI is approximately 50 kg / m². 2 Or more, up to approximately 70 kg / m³ 2 Or more.

[0329] In one embodiment, further factors (e.g., risk factors) used to determine whether a patient has type 2 diabetes include the patient's age and ethnicity. In one embodiment, the patient's age is about 10 years or older. In one embodiment, the patient's age is about 15 years or older. In one embodiment, the patient's age is about 20 years or older. In one embodiment, the patient's age is about 25 years or older. In one embodiment, the patient's age is about 30 years or older. In one embodiment, the patient's age is about 35 years or older. In one embodiment, the patient's age is about 40 years or older. In one embodiment, the patient's age is about 42 years or older. In one embodiment, the patient's age is about 44 years or older. In one embodiment, the patient's age is about 46 years or older. In one embodiment, the patient's age is about 48 years or older. In one embodiment, the patient's age is about 50 years or older. In one embodiment, the patient's age is about 52 years or older. In one embodiment, the patient's age is approximately 54 years or older. In one embodiment, the patient's age is approximately 56 years or older. In one embodiment, the patient's age is approximately 58 years or older. In one embodiment, the patient's age is approximately 60 years or older. In one embodiment, the patient's age is approximately 62 years or older. In one embodiment, the patient's age is approximately 64 years or older. In one embodiment, the patient's age is approximately 66 years or older. In one embodiment, the patient's age is approximately 68 years or older. In one embodiment, the patient's age is approximately 70 years or older. In one embodiment, the patient's age is approximately 72 years or older. In one embodiment, the patient's age is approximately 74 years or older. In one embodiment, the patient's age is approximately 76 years or older. In one embodiment, the patient's age is approximately 78 years or older.In one embodiment, the patient's age is approximately 80 years or older. In one embodiment, the patient's age is approximately 85 years or older. In one embodiment, the patient's age is approximately 90 years or older. In one embodiment, the patient's age is approximately 95 years or older. In one embodiment, the patient's ethnicity may be African American, Native American or Alaskan Native, Asian American, Hispanic or Latino American, or Native Hawaiian or Pacific Islander.

[0330] In one embodiment, the patient is a pediatric patient. As used herein, the term “pediatric patient” means a patient who is 21 years of age or younger at the time of diagnosis or treatment. The term “pediatric” can be further divided into various subgroups, including neonates (from birth to 1 month of age); infants (1 month to 2 years of age); children (2 years to 12 years of age); and adolescents (12 years to 21 years of age, including but not limited to 22 years of age) (Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WB Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; (1994.) In one embodiment, a pediatric patient is from birth to 28 days old, from 29 days old to 2 years old, from 2 years old to 12 years old, or from 12 years old to 21 years old (including but not limited to 22 years old). In another embodiment, a pediatric patient is from birth to 28 days old, from 29 days old to 1 year old, from 1 month old to 4 months old, from 3 months old to 7 months old, from 6 months old to 1 year old, from 1 year old to 2 years old, from 2 years old to 3 years old, from 2 years old to 7 years old, from 3 years old to 5 years old, from 5 years old to 10 years old, from 6 years old to 13 years old, from 10 years old to 15 years old, or from 15 years old to 22 years old. In another embodiment, the patient is an adult patient. [Examples]

[0331] The present invention is further described in the following embodiments and is not limited to the scope of the invention as described in the claims.

[0332] General Information: All evaporation was performed using a rotary evaporator under reduced pressure. Analytical samples were dried at room temperature under reduced pressure (1–5 mmHg). Thin-layer chromatography (TLC) was performed on silica gel plates, and spots were visualized with UV light (214 and 254 nm). Purification by column and flash chromatography was performed using silica gel (100–200 mesh). Solvent systems are reported as mixtures (by volume). NMR spectra were recorded using a Bruker 400 or Varian (400 MHz) spectrometer. 1 The H chemical shift is reported as a δ value (ppm) using a deuterated solvent as an internal standard. The data are reported as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quadruplet, br=broad signal, m=multilet), coupling constant (Hz), and integration. LCMS spectra are obtained using a SHIMADZU LC20-MS2020 or Agilent 1260 series 6125B mass spectrometer or Agilent 1200 series 6110 or 6120 mass spectrometer by electrospray ionization, unless otherwise indicated.

[0333] Example 1 3-((S)-oxetane-2-ylmethyl)-2-((4-(2-phenyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 101a) [ka] [ka] Step A: 2-(2,6-dibromophenoxy)-1-phenylethanone [ka] To a solution of 2-bromo-1-phenylethanone (3.90 g, 19.8 mmol, 1.1 equivalent) and 2,6-dibromophenol (4.50 g, 18.0 mmol, 1.0 equivalent) in DMSO (30 mL), NaOH (870 mg, 19.8 mmol, 1.1 equivalent) was added. The resulting mixture was stirred at room temperature under an N2 atmosphere for 2 hours. The reaction mixture was diluted with water (60 mL) and extracted with ethyl ether (3 x 80 mL). The organic layers were combined, washed with saline solution (30 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography (eluted at PE / siRNA = 10 / 1) to obtain the title compound 2-(2,6-dibromophenoxy)-1-phenylethanone as a white solid (3.50 g, yield 53%). 1 H NMR (400 MHz, CDCl3) δ ppm 8.01 - 8.03 (m, 2H), 7.59 - 7.64 (m, 1H), 7.48 - 7.55 (m, 4H), 6.93 (t, J = 8.0 Hz, 1H), 5.28 (s, 2H).

[0334] Step B: 2-(2,6-dibromophenoxy)-1-phenylethane-1-ol [ka] To a solution of 2-(2,6-dibromophenoxy)-1-phenylethanone (3.50 g, 9.41 mmol, 1.0 equivalent) in MeOH (100 mL), NaBH4 (712 mg, 18.8 mmol, 2.0 equivalents) was added. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (10 mL) and the MeOH was evaporated. The resulting mixture was extracted by DCM (3 x 80 mL). The organic layers were combined, washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated to obtain the crude product, the title compound 2-(2,6-dibromophenoxy)-1-phenylethane-1-ol, as a white solid (2.80 g, yield 80%). The crude product was used directly in the next step without purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.65 (d, J = 8.0 Hz, 2H), 7.44 - 7.46 (m, 2H), 7.34 - 7.37 (m, 2H), 7.26 - 7.30 (m, 1H), 7.02 (t, J = 8.0 Hz, 1H), 5.69 (d, J = 4.0 Hz, 1H), 4.08 (dd, J = 9.2, 7.2 Hz, 1H), 3.95 (dd, J = 9.2, 4.8 Hz, 1H).

[0335] Step C: tert-butyl 4-(3-bromo-2-(2-hydroxy-2-phenylethoxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate [ka] A mixture of 2-(2,6-dibromophenoxy)-1-phenylethane-1-ol (1.45 g, 3.90 mmol, 1.0 equivalent), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.20 g, 3.90 mmol, 1.0 equivalent), Pd(dppf)Cl2.DCM (320 mg, 0-390 mmol, 0.1 equivalent), and K2CO3 (1.6 g, 11.7 mmol, 3.0 equivalent) in dioxane / H2O (15 mL / 7 mL) was stirred at 85°C for 2 hours under an N2 atmosphere. The reaction mixture was filtered through Celite and extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, washed with saline solution (20 mL), dried over anhydrous sodium 2SO4, and concentrated. The residue was purified by flash chromatography (eluting at PE / siRNA = 10 / 1) to obtain the title compound tert-butyl 4-(3-bromo-2-(2-hydroxy-2-phenylethoxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate as a colorless oil (850 mg, yield 46%). 1H NMR (400 MHz, CDCl3) δ ppm 7.47 (dd, J = 8.0, 1.6 Hz, 1H), 7.26 - 7.40 (m, 5H), 7.09 (dd, J = 8.0, 1.6 Hz, 1H), 6.96 (t, J = 8.0 Hz, 1H), 5.80 (s, 1H), 5.07 (d, J = 8.0 Hz, 1H), 4.00 - 4.02 (m, 3H), 3.86 - 3.91 (m, 1H), 3.56 (t, J = 4.0 Hz, 2H), 3.17 (d, J = 1.6 Hz, 1H), 2.43 (d, J = 8.0 Hz, 2H), 1.50 (s, 9H).

[0336] Step D: tert-butyl 4-(2-phenyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate [ka] A mixture of tert-butyl 4-(3-bromo-2-(2-hydroxy-2-phenylethoxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (850 mg, 1.80 mmol, 1.0 equivalent), CuI (684 mg, 3.60 mmol, 2.0 equivalents), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (511 mg, 3.60 mmol, 2.0 equivalents), and Cs2CO3 (1.76 g, 5.40 mmol, 3.0 equivalents) in DMF (10 mL) was stirred at 110 °C for 2 hours under an N2 atmosphere by microwave irradiation. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography (eluting at PE / siRNA = 10 / 1) to obtain the title compound tert-butyl 4-(2-phenyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate as a colorless oil (280 mg, yield 39%). 1H NMR (400 MHz, CDCl3) δ ppm 7.29 - 7.37 (m, 5H), 6.85 (dd, J = 8.0, 2.0 Hz, 1H), 6.77 (t, J = 8.0 Hz, 1H), 6.70 (dd, J = 8.0, 2.0 Hz, 1H), 5.76 (s, 1H), 5.04 (dd, J = 8.0, 2.4 Hz, 1H), 4.31 (dd, J = 12.0, 2.4 Hz, 1H), 3.98 (d, J = 2.0 Hz, 2H), 3.93 (dd, J = 8.0, 2.4 Hz, 1H), 3.52 - 3.57 (m, 2H), 2.45 (s, 2H), 1.42 (s, 9H).

[0337] Step E: tert-butyl 4-(2-phenyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-(2-phenyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (280 mg, 0.710 mmol, 1.0 equivalent) in MeOH (15 mL), Pd / C (28.0 mg, 10 wt%) was added under N2. The resulting mixture was degassed three times with H2 and repacked. The mixture was then stirred at room temperature under an H2 atmosphere for 12 hours. The reaction mixture was filtered through Celite and concentrated to obtain the title compound tert-butyl 4-(2-phenyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate as a white solid (260 mg, yield 93%). The title compound was used directly in the next step without purification. 1H NMR (400 MHz, CDCl3) δ ppm 7.37 - 7.43 (m, 5H), 6.83 - 6.88 (m, 2H), 6.76 (dd, J = 8.0, 2.4 Hz, 1H), 5.11 (dd, J = 8.0, 2.4 Hz, 1H), 4.40 (dd, J = 11.6, 2.4 Hz, 1H), 4.24 (d, J = 13.2 Hz, 2H), 4.00 (dd, J = 11.2, 8.8 Hz, 1H), 3.05 (tt, J = 12.0, 3.2 Hz, 1H), 2.82 (tt, J = 12.8, 2.8 Hz, 1H), 1.77 - 1.86 (m, 2H), 1.55 - 1.68 (m, 2H), 1.48 (d, J = 9.0 Hz, 9H).

[0338] Step F: 4-(2-phenyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine hydrochloride [ka] A solution of tert-butyl 4-(2-phenyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate (260 mg, 0.66 mmol, 1.0 equivalent) in HCl-dioxane solution (4 M, 10 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated until dry to obtain the title compound 4-(2-phenyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine (220 mg, 100% yield) as a white solid. LC-MS: m / z 296.1 (M+H) + .

[0339] Step G: Ethyl 3-((S)-oxetane-2-ylmethyl)-2-((4-(2-phenyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate [ka] A mixture of 4-(2-phenyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine hydrochloride (66.0 mg, 0.200 mmol, 1.0 equivalent), (S)-ethyl 2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (62.0 mg, 0.200 mmol, 1.0 equivalent), and K2CO3 (55.0 mg, 0.400 mmol, 2.0 equivalent) in DMF (2 mL) was stirred at 60°C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, washed with saline solution (10 mL), dried over anhydrous sodium 2 SO4, and concentrated. The residue was purified by flash chromatography (eluted at DCM / MeOH = 50 / 1) to obtain the title compound ethyl 3-((S)-oxetane-2-ylmethyl)-2-((4-(2-phenyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate as a colorless gum (40.0 mg, yield 35%). LC-MS: m / z 569.1 (M+H) + .

[0340] Step H: 3-((S)-oxetane-2-ylmethyl)-2-((4-(2-phenyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ka] To a solution of ethyl 3-((S)-oxetane-2-ylmethyl)-2-((4-(2-phenyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (40.0 mg, 0.0700 mmol, 1.0 equivalent) in MeOH / H2O (3 mL / 0-3 mL), NaOH (28.0 mg, 0.700 mmol, 10.0 equivalent) was added. The resulting mixture was stirred at 30°C for 2 hours. The reaction mixture was then adjusted to pH = 5-7 with HCOOH and concentrated. The residue was purified by preparative HPLC to obtain the title compound 3-((S)-oxetane-2-ylmethyl)-2-((4-(2-phenyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid as a white solid (22.0 mg, yield 58%). 1 H NMR (400 MHz, CDCl3) δ ppm 8.21 (d, J = 8.0 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.36 - 7.43 (m, 5H), 6.79 - 6.88 (m, 3H), 5.25 - 5.27 (m, 1H), 5.11 (dd, J = 8.0, 2.4 Hz, 1H), 4.98 (dd, J = 16.0, 8.0 Hz, 1H), 4.85 (dd, J = 16.0, 4.0 Hz, 1H), 4.63 (dd, J = 16.0, 8.0 Hz, 1H), 4.39 - 4.43 (m, 2H), 4.05 - 4.16 (m, 2H), 4.00 (dd, J = 11.4, 9.0 Hz, 1H), 2.93 - 3.07 (m, 3H), 2.74 - 2.82 (m, 1H), 2.35 - 2.53 (m, 3H), 1.71 - 1.89 (m, 4H). LC-MS: m / z 541.1(M+H) + .

[0341] Example 2 2-((4-(2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3-((S)-oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 104a) [ka] Step A: 2-Bromo-1-(4-chloro-2-fluorophenyl)ethanone [ka] To a solution of 1-(4-chloro-2-fluorophenyl)ethenone (8.50 g, 49.4 mmol, 1.0 equivalent) in acetic acid (150 mL), 4-(dimethylamino)pyridine tribromide (19.7 g, 54.3 mmol, 1.1 equivalent) was added. The resulting mixture was stirred at room temperature for 24 hours. Water (150 mL) was added, and the mixture was stirred for 30 minutes. The precipitate was collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound 2-bromo-1-(4-chloro-2-fluorophenyl)ethenone as a white solid (10.0 g, yield 81%). 1 H NMR (400 MHz, CDCl3) δ ppm 7.94 (t, J = 8.0 Hz, 1H), 7.67 (dd, J = 11.2, 2.0 Hz, 1H), 7.47(dd, J = 8.0, 2.0 Hz, 1H), 4.84 (d, J = 2.0 Hz, 2H).

[0342] Step B: 1-(4-chloro-2-fluorophenyl)-2-(2,6-dibromophenoxy)ethanone [ka] A suspension of the compounds 2-bromo-1-(4-chloro-2-fluorophenyl)ethanone (10.0 g, 40.0 mmol, 1.1 equivalent), 2,6-dibromophenol (9.10 g, 36.4 mmol, 1.0 equivalent), and K2CO3 (5.50 g, 40.0 mmol, 1.1 equivalent) in acetone (150 mL) was stirred at 70 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by flash chromatography (eluted at PE / siRNA = 10 / 1) to obtain the title compound 1-(4-chloro-2-fluorophenyl)-2-(2,6-dibromophenoxy)ethanone as a white solid (8.00 g, yield 48%). 1 H NMR (400 MHz, CDCl3) δ ppm 8.07 (t, J = 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.31 (dd, J = 8.4, 2.0 Hz, 1H), 7.21 (dd, J = 10.8, 2.0 Hz, 1H), 6.92 (t, J = 8.0 Hz, 1H), 5.19 (d, J = 3.6 Hz, 2H).

[0343] 2-((4-(2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3-((S)-oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 104a) [ka] Following the procedure of Example 1 (steps B to H in Scheme 1), the compound of Example 2 (compound 104a) was synthesized from 1-(4-chloro-2-fluorophenyl)-2-(2,6-dibromophenoxy)ethanone obtained in step B. 1H NMR (400 MHz, CDCl3) δ ppm 8.18 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 8.4 Hz, 2H), 7.45 (t, J = 8.0 Hz, 1H), 7.20 (dd, J = 8.0, 1.6 Hz, 1H), 7.14 (dd, J = 8.0, 1.6 Hz, 1H), 6.80 - 6.85 (m, 3H), 5.39 (dd, J = 8.0, 1.6 Hz, 1H), 5.24 - 5.25 (m, 1H), 4.99 (dd, J = 14.8, 6.0 Hz, 1H), 4.86 (d, J = 14.0 Hz, 2H), 4.60 (dd, J = 14.4, 7.6 Hz, 1H), 4.44 (dd, J = 11.2, 2.0 Hz), 4.36 - 4.41 (m, 1H), 4.12 - 4.22 (m, 2H), 3.94 (dd, J = 12.0, 8.0 Hz, LC-MS: m / z 593.2(M+H) + .

[0344] The (R)- and (S)-isomers of compound 104a were obtained by chiral resolution, and the chiral centers were confirmed by chiral synthesis. Conditions for chiral partitioning: Column: ChiralPak AD-H, Daicel Chemical Industries, Ltd, 250*30mm ID5um Mobile phase A: Supercritical CO2, Mobile phase B: Ethanol (0.1% NH3H2O) A:B=60:40(50ml / min) Column temperature: 38℃ Nozzle pressure: 100 Bar; Wavelength: 220nm

[0345] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 104b) [ka] 1 H NMR (400 MHz, CDCl3) δ ppm 8.20 (dd, J = 13.2, 8.0 Hz, 2H), 7.46 (t, J = 8.0 Hz, 1H), 7.21 (dd, J = 8.4, 2.0 Hz, 1H), 7.15 (dd, J = 10.0, 2.0 Hz, 1H), 6.81 - 6.87 (m, 3H), 5.40 (dd, J = 8.4, 2.0 Hz, 1H), 5.23 - 5.28 (m, 1H), 4.97 (dd, J = 14.8, 6.4 Hz, 1H), 4.84 (dd, J = 15.2, 3.6 Hz, 1H), 4.65 (q, J = 6.8 Hz, 1H), 4.39 - 4.47 (m, 2H), 4.11 (dd, J = 18.4, 14.0 Hz, 2H), 3.94 (dd, J = 11.2, 8.4 Hz, 1H), 2.93 - 3.09 (m, 3H), 2.75 - 2.82 (m, 1H), 2.39 - 2.53 (m, 3H), 1.77 - 1.92 (m, 4H). LC-MS: m / z 593.2(M+H) + .

[0346] 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 104c) [ka] 1H NMR (400 MHz, CDCl3) δ ppm 8.19 (dd, J = 13.2, 8.0 Hz, 2H), 7.46 (t, J = 8.0 Hz, 1H), 7.20 (dd, J = 8.4, 2.0 Hz, 1H), 7.15 (dd, J = 10.0, 2.0 Hz, 1H), 6.80 - 6.87 (m, 3H), 5.40 (dd, J = 8.4, 2.0 Hz, 1H), 5.25 - 5.27 (m, 1H), 4.96 (dd, J = 14.8, 6.0 Hz, 1H), 4.84 (dd, J = 14.4, 3.2 Hz, 1H), 4.64 (q, J = 7.2 Hz, 1H), 4.38 - 4.47 (m, 2H), 4.10 (s, 2H), 3.95 (dd, J = 11.2, 8.4 Hz, 1H), 2.92 - 3.06 (m, 3H), 2.75 - 2.84 (m, 1H), 2.35 - 2.51 (m, 3H), 1.73 - 1.89 (m, 4H). LC-MS: m / z 593.2 (M+H) + .

[0347] Example 3 2-[[4-[2-(4-chloro-2-fluorophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]phenyl]methyl]-3-(oxetane-2-ylmethyl)imidazo[4,5-b]pyridine-5-carboxylic acid (compound 107a) [ka] [ka] Step A: 1-(4-chloro-2-fluorophenyl)-2-(2,6-dibromophenoxy)ethanol [ka] To a solution of 1-(4-chloro-2-fluorophenyl)-2-(2,6-dibromophenoxy)ethanone (16.2 g, 38.35 mmol) in EtOH (200 mL), NaBH4 (2.90 g, 76.69 mmol) was added and the mixture was stirred at 25°C for 2 hours. TLC showed that the starting material was completely consumed. The mixture was quenched with water (150 mL) and concentrated to obtain a brown mixture. The mixture was extracted with ELISA (150 mL x 2). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated to obtain 1-(4-chloro-2-fluorophenyl)-2-(2,6-dibromophenoxy)ethanol (16.0 g, crude composition) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.60 - 7.67 (m, 3 H) 7.29 - 7.42 (m, 2 H) 7.02 (t, J=8.0 Hz, 1 H) 5.94 (d, J=5.2 Hz, 1 H) 5.25 - 5.33 (m, 1 H) 4.06 - 4.13 (m, 1 H) 3.93 - 4.02 (m, 1 H).

[0348] Step B: 5-bromo-2-(4-chloro-2-fluorophenyl)-2,3-dihydro-1,4-benzodioxin [ka] To a solution of 1-(4-chloro-2-fluorophenyl)-2-(2,6-dibromophenoxy)ethanol (16.0 g, 37.69 mmol) in toluene (300 mL), 1,10-phenanthroline (1.36 g, 7.54 mmol), CuI (717.85 mg, 3.77 mmol), and Cs2CO3 (36.84 g, 113.08 mmol) were added. The mixture was stirred at 100°C for 16 hours. TLC showed that the starting materials were completely consumed. The mixture was quenched with water (150 mL) and concentrated to obtain a brown mixture. The mixture was extracted with ELISA (150 mL x 2). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated to obtain 5-bromo-2-(4-chloro-2-fluorophenyl)-2,3-dihydro-1,4-benzodioxin (13.53 g, crude product) as a brown oily substance. 1 H NMR (400 MHz, CD3OD) δ ppm 7.49 (t, J=8.0 Hz, 1 H) 7.26 - 7.32 (m, 2 H) 7.18 - 7.23 (m, 1 H) 7.07 - 7.17 (m, 2 H) 6.95 (dd, J=8.4, 1.2 Hz, 1 H) 6.75 - 6.82 (m, 1 H) 5.41 (dd, J=8.4, 2.4 Hz, 1 H) 4.52 (dd, J=11.2, 2.4 Hz, 1 H) 4.05 - 4.14 (m, 1 H).

[0349] Step H Methyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate [ka] To a solution of methyl 2-(4-bromophenyl)acetate (1.00 g, 4.37 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (1.16 g, 4.58 mmol) in dioxane (12 mL), Pd(dppf)Cl2 (159.71 mg, 218.27 mmol) and KOAc (1.29 g, 13.10 mmol) were added under N2. The suspension was stirred at 80°C for 2 hours. The dark mixture was diluted with water (10 mL) and extracted twice with ethyl acetate (10 mL). The organic layer was concentrated to obtain the crude product (1.66 g) as a dark, gum-like substance. The crude product was purified by Combi-flash (silica gel, ethyl acetate in petroleum ether, 0-10%) to obtain methyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (980.0 mg, yield 81.3%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 7.78 - 7.79 (m, 2 H) 7.27 - 7.31 (m, 2 H) 3.69 (s, 3 H) 3.65 (s, 2 H) 1.35 (s, 12 H).

[0350] Step C Methyl 2-[4-[2-(4-chloro-2-fluorophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]phenyl]acetate [ka] To a solution of 5-bromo-2-(4-chloro-2-fluorophenyl)-2,3-dihydro-1,4-benzodioxin (360 mg, 1.05 mmol) and methyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (289.3 mg, 1.05 mmol) in dioxane (4 mL), K2CO3 (434.44 mg, 3.14 mmol), Pd(dppf)Cl2 (76.67 mg, 104.78 mL), and H2O (1.2 mL) were added under N2. The mixture was stirred at 80°C for 1 hour. The dark mixture was diluted with water (5 mL) and extracted twice with ethyl acetate (5 mL). The organic layer was concentrated to obtain a crude product (510 mg) as a dark, gum-like substance. The crude product was purified by Combi-flash (silica gel, ethyl acetate in petroleum ether, 0-15%) to obtain methyl 2-[4-[2-(4-chloro-2-fluorophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]phenyl]acetate (358.0 mg, yield 82.7%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ ppm 7.47 - 7.57 (m, 3 H) 7.33-7.38 (m, 2 H) 7.25 (dd, J=8.4, 1.2 Hz, 1 H) 7.16 (d, J=10.0 Hz, 1 H) 6.95 - 7.02 (m, 3 H) 5.47 (dd, J=8.4, 2.0 Hz, 1 H) 4.44 (dd, J=11.2, 2.0 Hz, 1 H) 3.96 (dd, J=11.2, 8.4 Hz, 1 H) 3.72 (s, 3 H) 3.68 (s, 2 H).

[0351] Step D: 2-[4-[2-(4-chloro-2-fluorophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]phenyl]acetic acid [ka] To a solution of methyl 2-[4-[2-(4-chloro-2-fluorophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]phenyl]acetate (350.0 mg, 847.79 ml) in MeOH (2 mL) and THF (3 mL), LiOH.H2O (106.73 mg, 2.54 mmol) in H2O (1 mL) was added. The solution was stirred at 15°C for 16 hours. The colorless solution was treated with 1N HCl to adjust the pH to 5. The solution was concentrated to remove MeOH. The white suspension was diluted with water (2 mL) and extracted twice with ethyl acetate (3 mL). The organic layer was concentrated to obtain 2-[4-[2-(4-chloro-2-fluorophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]phenyl]acetic acid (340.0 mg, crude product) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.17 (br s, 1 H) 7.52 - 7.60 (m, 2 H) 7.43 - 7.49 (m, 2 H) 7.40 (dd, J=8.4, 1.6 Hz, 1 H) 7.27-7.33 (m, 2 H) 6.92 - 7.01 (m, 3 H) 5.52 (dd, J=8.0, 2.0 Hz, 1 H) 4.47 (dd, J=11.6, 2.4 Hz, 1 H) 4.14 (dd, J=11.6, 8.0 Hz, 1 H) 3.60 (s, 2 H).

[0352] Step E: 2-[4-[2-(4-chloro-2-fluorophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]phenyl]acetyl chloride [ka] To a solution of 2-[4-[2-(4-chloro-2-fluorophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]phenyl]acetic acid (170.0 mg, 426.27 ml) in DCM (3 mL), oxalyl dichloride (135.26 mg, 1.07 mmol) and one drop of DMF were added. The solution was stirred at 30°C for 0.5 hours. The yellow solution was concentrated to obtain 2-[4-[2-(4-chloro-2-fluorophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]phenyl]acetyl chloride (180.0 mg, crude product) as a yellow solid.

[0353] Step F Methyl 5-[[2-[4-[2-(4-chloro-2-fluorophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]phenyl]acetyl]amino]-6-[[(2S)-oxetane-2-yl]methylamino]pyridine-2-carboxylate [ka] To a solution of methyl 5-amino-6-[[(2S)-oxetan-2-yl]methylamino]pyridine-2-carboxylate (102.35 mg, 431.39 ml) and TEA (218.26 mg, 2.16 mmol) in DCM (1 mL), 2-[4-[2-(4-chloro-2-fluorophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]phenyl]acetyl chloride (180.0 mg, 431.39 ml) in DCM (1 mL) was added. The resulting yellow solution was stirred at 25°C for 16 hours. The yellow solution was diluted with MeOH (1 mL) and concentrated to obtain a crude product (355 mg) as a yellow gum-like substance. The crude product was purified by Combi-flash (silica gel, ethyl acetate in petroleum ether, 50-100%) to obtain methyl 5-[[2-[4-[2-(4-chloro-2-fluorophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]phenyl]acetyl]amino]-6-[[(2S)-oxetane-2-yl]methylamino]pyridine-2-carboxylate (53.0 mg, yield 20.2%) as a yellow gum-like substance. LCMS m / z 640.1 (M+Na) + .

[0354] Step G 2-[[4-[2-(4-chloro-2-fluorophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]phenyl]methyl]-3-(oxetan-2-ylmethyl)imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 107a) [ka] To a suspension of methyl 5-[[2-[4-[2-(4-chloro-2-fluorophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]phenyl]acetyl]amino]-6-[[(2S)-oxetane-2-yl]methylamino]pyridine-2-carboxylate (50.08 mg, 81.0-3 umol) in i-PrOH (1 mL), t-BuOK (18.18 mg, 162.06 umol) was added. The suspension was stirred at 85°C for 0.5 hours under N2. The suspension was treated with 1N HCl to adjust the pH to 7, concentrated, and the solvent was removed. The crude product was purified by preparative HPLC (column: Phenomenex Gemini C18 250*50mm*10um; mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 23%-43%, 10 min). The fraction was lyophilized to obtain 2-[[4-[2-(4-chloro-2-fluorophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]phenyl]methyl]-3-(oxetan-2-ylmethyl)imidazo[4,5-b]pyridine-5-carboxylic acid (10.19 mg, yield 20.2%) as a white solid. 1 H NMR (400 MHz, CD3OD) δ ppm 8.05 - 8.15 (m, 2 H) 7.41 - 7.58 (m, 3 H) 7.26 - 7.34 (m, 4 H) 6.90 - 7.03 (m, 3 H) 5.42 - 5.49 (m, 1 H) 5.17 - 5.26 (m, 0.6 H) 4.54 - 4.72 (m, 3.3 H) 4.37 - 4.50 (m, 2.3 H) 3.98 - 4.06 (m, 1 H) 3.70 (t, J=6.4 Hz, 0.6 H) 2.62 - 2.80 (m, 0.7 H) 2.42 - 2.53 (m, 1.3 H). 19 F NMR (377 MHz, CD3OD) δ ppm -117.932.

[0355] Example 4 2-((4-(2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperazine-1-yl)methyl)-3-((S)-oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 108a) [ka] Step A: tert-butyl(1-(4-chloro-2-fluorophenyl)-2-(2,6-dibromophenoxy)ethoxy)dimethylsilane [ka] A solution of 1-(4-chloro-2-fluorophenyl)-2-(2,6-dibromophenoxy)ethanol (4.20 g, 10.0 mmol), TBSCl (3.75 g, 25.0 mmol), and imidazole (2.04 g, 30.0 mmol) in DCM (100 mL) was stirred at room temperature under an N2 atmosphere for 12 hours. Water (150 mL) was added, and the mixture was extracted with DCM (3 x 100 mL). The organic layers were combined, washed with saline solution (80 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (PE / siRNA = 10 / 1) to obtain the title compound tert-butyl(1-(4-chloro-2-fluorophenyl)-2-(2,6-dibromophenoxy)ethoxy)dimethylsilane (5.00 g, yield 93%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 7.57 (t, J = 8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.14 (dd, J = 8.0, 2.0 Hz, 1H), 7.03 (dd, J = 9.6, 2.0 Hz, 1H), 6.81 (t, J = 8.0 Hz, 1H), 5.49 (dd, J = 7.2, 4.0 Hz, 1H), 4.09 (dd, J = 8.8, 7.2 Hz, 1H), 3.91 (dd, J = 8.0, 4.0 Hz, 1H), 0.90 (s, 9H), 0.17 (s, 3H), 0.04 (s, 3H).

[0356] Step B: tert-butyl 4-(3-bromo-2-(2-((tert-butyldimethylsilyl)oxy)-2-(4-chloro-2-fluorophenyl)ethoxy)phenyl)piperazine-1-carboxylate [ka] The compounds tert-butyl(1-(4-chloro-2-fluorophenyl)-2-(2,6-dibromophenoxy)ethoxy)dimethylsilane (4.90 g, 9.14 mmol), tert-butyl piperazine-1-carboxylate (1.87 g, 10.0 mmol), Pd2(dba)3 (833 mg, 0.910 mmol), BINAP (566 mg, 0.910 mmol), and in dry toluene (100 mL): t A mixture of BuONa (1.75 g, 18.3 mmol) was stirred at 100°C for 3 hours under an N2 atmosphere. The reaction mixture was filtered through Celite and washed with ELISA (100 mL). The organic layer was concentrated and purified by flash chromatography (PE / ELISA = 10 / 1) to obtain the title compound tert-butyl 4-(3-bromo-2-(2-((tert-butyldimethylsilyl)oxy)-2-(4-chloro-2-fluorophenyl)ethoxy)phenyl)piperazine-1-carboxylate (2.60 g, yield 44%) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ ppm 7.57 (t, J = 8.0 Hz, 1H), 7.15 - 7.19 (m, 2H), 7.04 (dd, J = 9.6, 2.0 Hz, 1H), 6.88 (t, J = 8.0 Hz, 1H), 6.80 (dd, J = 8.0, 1.6 Hz, 1H), 5.46 (dd, J = 8.0, 4.0 Hz, 1H), 4.19 (dd, J = 8.4, 8.0 Hz, 1H), 3.85 (dd, J = 8.0, 4.0 Hz, 1H), 3.54 (br.s, 4H), 2.99 - 3.06 (m, 4H), 1.51 (s, 9H), 0.91 (s, 9H), 0.15 (s, 3H), 0.05 (s, 3H).

[0357] Step C: tert-butyl 4-(3-bromo-2-(2-(4-chloro-2-fluorophenyl)-2-hydroxyethoxy)phenyl)piperazine-1-carboxylate [ka] The compound tert-butyl 4-(3-bromo-2-(2-((tert-butyldimethylsilyl)oxy)-2-(4-chloro-2-fluorophenyl)ethoxy)phenyl)piperazine-1-carboxylate (2.60 g, 4.05 mmol) in THF (20 mL) and t A mixture of Bu4NF (1M, 8.10 mL, 8.10 mmol) was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with siRNA (3 x 30 mL). The organic layers were combined, washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (PE / siRNA = 5 / 1) to obtain the title compound tert-butyl 4-(3-bromo-2-(2-(4-chloro-2-fluorophenyl)-2-hydroxyethoxy)phenyl)piperazine-1-carboxylate (1.49 g, yield 70%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ ppm 7.40 (t, J = 8.0 Hz, 1H), 7.23 - 7.27 (m, 1H), 7.04 (dd, J = 8.0, 2.0 Hz, 1H), 6.97 (dd, J = 10.0, 2.0 Hz, 1H), 6.92 (d, J = 4.0 Hz, 2H), 6.48 (d, J = 1.2 Hz, 1H), 5.15 (d, J = 9.6 Hz, 1H), 4.63 (dd, J = 11.2, 1.6 Hz, 1H), 3.50 - 3.58 (m, 5H), 3.06 - 3.11 (m, 2H), 2.83 - 2.85 (m, 2H), 1.38 (s, 9H).

[0358] Step D: tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperazine-1-carboxylate [ka] tert-Butyl 4-(3-bromo-2-(2-(4-chloro-2-fluorophenyl)-2-hydroxyethoxy)phenyl)piperazine-1-carboxylate (750 mg, 1.40 mmol), CuI (530 mg, 2.80 mmol), (1S,2S)-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine (400 mg, 2.80 mmol), and Cs2CO3 (1.38 g, 4.20 mmol) in dry DMF (10 mL) were stirred at 110 °C for 2 h by microwave irradiation under a N2 atmosphere. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (PE / EtOAc = 5 / 1) to give the title compound tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperazine-1-carboxylate (360 mg, 58% yield) as a colorless oil. LC-MS: m / z 449.1 (M+H) + .

[0359] Step E: 1-(2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperazine

Chem.

[0360] Step F: Methyl 2-((4-(2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperazine-1-yl)methyl)-3-((S)-oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate [ka] A mixture of compounds 1-(2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperazine (104 mg, 0-300 mmol), (S)-methyl 2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (93.0 mg, 0-300 mmol), and K2CO3 (85.0 mg, 0.600 mmol) in DMF (2 mL) was stirred at 60°C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layer was washed with saline solution (10 mL), dried over anhydrous sodium 2 SO4, filtered, and concentrated. The residue was purified by flash chromatography (DCM / MeOH = 50 / 1) to obtain the title compound methyl 2-((4-(2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperazine-1-yl)methyl)-3-((S)-oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (80.0 mg, yield 44%) as a colorless oil. LC-MS: m / z 608.1(M+H) + .

[0361] Step G: 2-((4-(2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperazine-1-yl)methyl)-3-((S)-oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 108a) [ka] A solution of the compound methyl 2-((4-(2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperazine-1-yl)methyl)-3-((S)-oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (80.0 mg, 0.130 mmol) and NaOH (52.0 mg, 1.30 mmol) in MeOH / H2O (5 mL / 1 mL) was stirred at 40°C for 1.5 hours. The reaction mixture was acidified to pH=5 with HCOOH and concentrated. The residue was purified by preparative HPLC to obtain the title compound 2-((4-(2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperazine-1-yl)methyl)-3-((S)-oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (35.0 mg, yield 45%) as a white solid. LC-MS: m / z 594.2 (M+H) + . 1 H NMR (400 MHz, CDCl3) δ ppm 8.21 (s, 2H), 7.46 (t, J = 8.0 Hz, 1H), 7.21 (dd, J = 8.0, 1.6 Hz, 1H), 7.13 (dd, J = 10.0, 2.0 Hz, 1H), 6.83 (t, J = 8.0 Hz, 1H), 6.71 (dd, J = 8.0, 1.2 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 5.39 (dd, J = 8.0, 1.6 Hz, 1H), 5.26 - 5.27 (m, 1H), 4.84 - 5.00 (m, 2H), 4.62 (dd, J = 14.0, 7.2 Hz, 1H), 4.50 (dd, J = 11.2, 2.0 Hz, 1H), 4.36 - 4.42 (m, 1H), 4.14 - 4.22(m, 2H), 3.98 (dd, J = 11.2, 8.8 Hz, 1H), 3.13 (br.s, 4H), 2.73 - 2.83 (m, 5H), 2.44 - 2.52 (m, 1H).

[0362] Example 5 2-((4-(2-(4-chlorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3-((S)-oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 128a) [ka] Step A: 2-(4-chlorophenyl)-1-(2,6-dibromophenoxy)propane-2-ol [ka] To a solution of 1-(4-chlorophenyl)-2-(2,6-dibromophenoxy)ethanone (1.90 g, 4.69 mmol) in THF (30 mL), MeMgCl (3.0 M, 4.7 mL in THF) was added dropwise at 0°C under an N2 atmosphere. The mixture was then stirred overnight at room temperature. The reaction mixture was quenched with saturated NH4Cl aqueous solution (3 mL) and extracted with EA (3 × 10 mL). The organic layers were washed together with water (10 mL) and saline solution (10 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography (eluted at PE / siRNA = 10 / 1) to obtain the title compound 2-(4-chlorophenyl)-1-(2,6-dibromophenoxy)propan-2-ol (1.77 g, yield 90%) as a white solid. LC-MS: m / z 402.9 (M-17) +

[0363] Step B: tert-butyl 4-(3-bromo-2-(2-(4-chlorophenyl)-2-hydroxypropoxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate [ka] A mixture of 2-(4-chlorophenyl)-1-(2,6-dibromophenoxy)propan-2-ol (700 mg, 1.67 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (566 mg, 1.84 mmol, 1.1 equivalents), Pd(dppf)Cl2 (122 mg, 0.167 mmol), and K2CO3 (460 mg, 3.34 mmol) in dioxane / H2O (19 mL / 1.9 mL) was stirred at 85°C for 3 hours under an N2 atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was diluted with ELISA (50 mL). The organic layer was washed with water (2 × 20 mL) and saline solution (20 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by flash chromatography (eluting at PE / ÃO = 10 / 1) to obtain the title compound tert-butyl 4-(3-bromo-2-(2-(4-chlorophenyl)-2-hydroxypropoxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate as a colorless oil (560 mg, yield 64%). 1 H NMR (400 MHz, CDCl3) δ ppm 7.40 - 7.49 (m, 3H), 7.29 - 7.36 (m, 2H), 7.06 (dd, J = 7.6, 1.6 Hz, 1H), 6.95 (t, J = 7.6 Hz, 1H), 5.73 - 5.76 (m, 1H), 4.02 - 4.05 (m, 2H), 3.99 (d, J = 8.8 Hz, 1H), 3.86 (d, J = 8.8 Hz, 1H), 3.50 - 3.56 (m, 2H), 2.30 - 2.34 (m, 2H), 1.61 (s, 3H), 1.52 (s, 9H).

[0364] Step C: tert-butyl 4-(2-(4-chlorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate [ka] tert-Butyl 4-(3-bromo-2-(2-(4-chlorophenyl)-2-hydroxypropoxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (320 mg, 0.612 mmol), CuI (117 mg, 0.612 mmol), (1S,2S)-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine (174 mg, 1.23 mmol), and Cs2CO3 (399 mg, 1.22 mmol) in DMF (7 mL) was stirred at 120 °C for 3.5 h by microwave irradiation under a N2 atmosphere. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography (eluting with PE / EtOAc = 10 / 1) to give the title compound, tert-butyl 4-(2-(4-chlorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate as a white solid (120 mg, 45% yield). 1 1H NMR (400 MHz, CDCl3) δ ppm 7.37 - 7.43 (m, 2H), 7.30 - 7.37 (m, 2H), 6.91 (dd, J = 8.0, 2.0 Hz, 1H), 6.84 (t, J = 8.0 Hz, 1H), 6.73 (dd, J = 7.2, 1.6 Hz, 1H), 5.74 - 5.79 (m, 1H), 4.21 (d, J = 11.6 Hz, 1H), 4.09 (d, J = 11.6 Hz, 1H), 3.90 - 4.04 (m, 2H), 3.54 - 3.69 (m, 2H), 2.35 -2.52 (m, 2H), 1.61 (s, 3H), 1.48 (s, 9H). LC-MS: m / z 386.2 (M-55) + .

[0365] Step D: tert-butyl 4-(2-(4-chlorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate

Chemical Structure

[0366] Step E: 4-(2-(4-chlorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine hydrochloride [ka] A solution of tert-butyl 4-(2-(4-chlorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate (120 mg, 0.270 mmol) in HCl-dioxane solution (4 M, 3 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated until dry to obtain the title compound 4-(2-(4-chlorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine hydrochloride (130 mg) as a white solid. LCMS: m / z 344.1 (M+H) + .

[0367] Step F: Methyl 2-((4-(2-(4-chlorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3-((S)-oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate [ka] A mixture of 4-(2-(4-chlorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine hydrochloride (130 mg, 0-378 mmol), (S)-methyl 2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (123 mg, 0.415 mmol), and K2CO3 (104 mg, 0.756 mmol) in DMF (4 mL) was stirred at 60°C for 3 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 10 mL). The organic layers were combined, washed with saline solution (10 mL), dried over anhydrous sodium 2SO4, and concentrated. The residue was purified by preparative HPLC to obtain the title compound methyl 2-((4-(2-(4-chlorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3-((S)-oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (70.0 mg, yield 34%) as a white solid. 11H NMR (400 MHz, CDCl3) δ ppm 8.08 (dd, J = 17.2, 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 4.4 Hz, 2H), 6.75 (t, J = 4.4 Hz, 1H), 5.23 - 5.28 (m, 1H), 4.98 (dd, J = 14.4, 8.4 Hz, 1H), 4.89 (dd, J = 14.4, 3.2 Hz, 1H), 4.58 - 4.63 (m, 1H), 4.32 - 4.44 (m, 1H), 4.18 - 4.25 (m, 1H), 4.09 (d, J = 11.2 Hz, 1H), 4.05 (s, 2H), 4.01 (s, 3H), 2.85 - 3.00 (m, 3H), 2.74 - 2.78 (m, 1H), 2.44 - 2.58 (m, 1H), 2.20 - 2.38 (m, 2H), 1.78 - 1.84 (m, 1H), 1.67 - 1.73 (m, 3H), 1.60 (s, 3H). LC-MS: m / z 603.2 (M+H) + .

[0368] Step G: 2-((4-(2-(4-chlorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3-((S)-oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

Chem.

[0369] The following compounds were synthesized using the corresponding starting materials according to the same method shown in Example 5.

[0370] 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3-((S)-oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 127a) [ka] 1H NMR (400MHz, CD3OD) δ ppm 8.22-8.02 (m, 2H), 7.42 (t, J = 8.0 Hz, 1H), 7.24 (dd, J = 12.0, 4.0 Hz, 1H), 7.12 (dd, J = 8.0, 4.0 Hz, 1H), 6.94-6.82 (m, 2H), 6.77-6.71 (m, 1H), 5.30-5.27 (m, 1H), 5.05-4.95 (m, 1H), 4.85-4.78 (m, 1H), 4.71-4.55 (m, 2H), 4.47-4.42 (m, 1H), 4.34-4.19 (m, 2H), 4.13 (d, J = 12.0 Hz, 1H), 3.31-3.16 (m, 2H), 3.01-2.88 (m, 1H), 2.84-2.73 (m, 1H), 2.68-2.45 (m, 3H), 1.92-1.67 (m, 4H), 1.63 (s, 3H). LC-MS: m / z 607.1 (M+H) + . 19 F NMR (377 MHz, CD3OD) δ ppm -112.78.

[0371] Example 6: 2-((4-((R)-2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3-((S)-oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 111b) [ka] [ka] Step A: 1-(4-chlorophenyl)-2-(2,6-dibromophenoxy)ethanone [ka] To a solution of 2-bromo-1-(4-chlorophenyl)ethanone (5.00 g, 21.5 mmol) and 2,6-dibromophenol (5.43 g, 21.5 mmol) in acetone (70 mL), K2CO3 (5.95 g, 43.0 mmol) was added. The resulting mixture was stirred at room temperature under an N2 atmosphere for 2 hours. The reaction mixture was quenched with water (140 mL), and a large amount of solid material appeared. The mixture was filtered. The filtered cake was washed with water (20 mL) and dried under reduced pressure to obtain the title compound 1-(4-chlorophenyl)-2-(2,6-dibromophenoxy)ethanone as a white solid (8.00 g, yield 92.5%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.02 - 8.09 (m, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.58 - 7.67 (m, 2H), 7.10 (t, J = 8.0 Hz, 1H), 5.37 (s, 2H).

[0372] Step B: (R)-1-(4-chlorophenyl)-2-(2,6-dibromophenoxy)ethanol [ka] To a solution of TEA (20 mL) and formic acid (4 mL), (S,S)-TS-DEPN-Ru-Cl-(p-cymene) (158 mg, 0.247 mmol) was added all at once at room temperature. The mixture was then stirred at room temperature for 1 hour. 1-(4-chlorophenyl)-2-(2,6-dibromophenoxy)ethanone (2.00 g, 4.94 mmol) was added. The resulting mixture was stirred at room temperature for 4 hours. The solution was quenched with water (30 mL), and a large precipitate was formed. The mixture was filtered. The filtered cake was washed with water (15 mL) and dried under reduced pressure to obtain the crude product, which was purified by flash chromatography (eluting at PE / siRNA = 10 / 1) to obtain the title compound (R)-1-(4-chlorophenyl)-2-(2,6-dibromophenoxy)ethanol (1.90 g, ee% 100%, yield 95%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.64 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.02 (t, J = 8.0 Hz, 1H), 5.79 (d, J = 4.4 Hz, 1H), 5.05 (dd, J = 11.2, 5.6 Hz, 1H), 4.06 (dd, J = 9.2, 6.8 Hz, 1H), 3.95 (dd, J = 9.6, 5.6 Hz, 1H).

[0373] Step C: (R)-tert-butyl 4-(3-bromo-2-(2-(4-chlorophenyl)-2-hydroxyethoxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate [ka] A mixture of (R)-1-(4-chlorophenyl)-2-(2,6-dibromophenoxy)ethanol (1.90 g, 4.70 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.75 g, 5.65 mmol), Pd(dppf)Cl2 (344 mg, 0.47 mmol), and K2CO3 (1.30 g, 9.40 mmol) in dioxane / H2O (60 mL / 8 mL) was stirred at 85°C for 3 hours under an N2 atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was diluted with ELISA (50 mL). The organic layer was washed with water (2 × 20 mL) and saline solution (20 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography (eluting at PE / siRNA = 10 / 1) to obtain the title compound (R)-tert-butyl 4-(3-bromo-2-(2-(4-chlorophenyl)-2-hydroxyethoxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate as a colorless oil (1.26 g, yield 53%). 1H NMR (400 MHz, CD3OD) δ ppm 7.48 (dd, J = 8.0, 1.6 Hz, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.13 (dd, J = 7.6, 1.6 Hz, 1H), 6.99 (t, J = 8.0 Hz, 1H), 5.78 (brs, 1H), 4.99 - 5.02 (m, 1H), 3.97 - 3.98 (m, 2H), 3.93 - 3.96 (m, 1H), 3.82 - 3.84 (m, 1H), 3.46 - 3.53 (m, 2H), 2.29 - 2.44 (m, 3H), 1.50 (s, 9H).

[0374] Step D: (R)-tert-butyl 4-(2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate [ka] (R)-tert-butyl 4-(3-bromo-2-(2-(4-chlorophenyl)-2-hydroxyethoxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (600 mg, 1.18 mmol), CuI (225 mg, 1.18 mmol), (1S,2S)-N in DMF (15 mL) 1 ,N 2 A mixture of -dimethylcyclohexane-1,2-diamine (337 mg, 2.37 mmol) and Cs2CO3 (772 mg, 2.37 mmol) was stirred at 110°C for 2.5 hours under an N2 atmosphere by microwave irradiation. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 30 mL). The organic layers were washed together with saline solution (30 mL), dried over anhydrous sodium 2SO4, and concentrated. The residue was purified by flash chromatography (eluting at PE / ethyl acetate = 10 / 1) to obtain the title compound (R)-tert-butyl 4-(2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate as a yellow oil (640 mg, yield 100%, excess weight). 1H NMR (400 MHz, CDCl3) δ ppm 7.35 - 7.42 (m, 4H), 6.92 (dd, J = 8.0, 1.6 Hz, 1H), 6.85 (t, J = 7.6 Hz, 1H), 6.79 (dd, J = 7.6, 1.6 Hz, 1H), 5.84 (brs, 1H), 5.11 (dd, J = 8.8, 2.4 Hz, 1H), 4.37 (dd, J = 11.6, 2.4 Hz, 1H), 4.04 - 4.07 (m, 2H), 3.96 (dd, J = 11.6, 8.8 Hz, 1H), 3.60 - 3.63 (m, 2H), 2.49 - 2.52 (m, 2H), 1.50 (s, 9H).

[0375] Step E: (R)-tert-butyl 4-(2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate [ka] To a solution of (R)-tert-butyl 4-(2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (640 mg, 1.50 mmol) in MeOH (15 mL), PtO2 (34.0 mg) was added under N2. The resulting mixture was degassed three times with H2 and repacked. Subsequently, the mixture was stirred at room temperature under an H2 atmosphere for 12 hours. The reaction mixture was filtered through Celite and concentrated to obtain the title compound (R)-tert-butyl 4-(2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate as a white solid (620 mg, yield 96%). The title compound was used directly in the next step without purification.

[0376] Step F: (R)-4-(2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine hydrochloride [ka] A solution of (R)-tert-butyl 4-(2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate (600 mg, 1.40 mmol) in HCl-dioxane solution (4 M, 10 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated until dry to obtain the title compound (R)-4-(2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine hydrochloride (500 mg, yield 98%) as a white solid. LCMS: m / z 330.2 (M+H) + .

[0377] Step G: Methyl 2-((4-((R)-2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3-((S)-oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate [ka] A mixture of (R)-4-(2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine hydrochloride (500 mg, 1.52 mmol), (S)-methyl 2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (494 mg, 1.67 mmol), and K2CO3 (420 mg, 3.04 mmol) in DMF (10 mL) was stirred at 60°C for 3 hours. The reaction mixture was diluted with water (30 mL) and extracted with ELISA (3 × 15 mL). The organic layers were combined, washed with saline solution (10 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography (eluted at DCM / MeOH = 50 / 1) to obtain the title compound methyl 2-((4-((R)-2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3-((S)-oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate as a colorless gum (743 mg, yield 83%). 11H NMR (400 MHz, CDCl3) δ ppm 8.08 (dd, J = 16.4, 8.0 Hz, 2H), 7.38 (dd, J = 16.0, 8.8 Hz, 4H), 6.81 - 6.86 (m, 3H), 5.24 - 5.26 (m, 1H), 5.09 (dd, J = 8.8, 2.0 Hz, 1H), 4.89 - 5.02 (m, 2H), 4.60 (dd, J = 14.0, 7.6 Hz, 1H), 4.36 - 4.40 (m, 2H), 4.07 (s, 2H), 4.01 (s, 3H), 3.95 (dd, J = 11.2, 8.8 Hz, 1H), 2.99 (brs, 3H), 2.73 - 2.81 (m, 1H), 2.47 - 2.56 (m, 1H), 2.31 - 2.37 (m, 2H), 1.68 - 1.92 (m, 4H). LC-MS: m / z 589.2 (M+H) + .

[0378] Step H: 2-((4-((R)-2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3-((S)-oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

Chem.

[0379] 2-((4-((S)-2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3-(((S)-oxetane-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 111c) was synthesized according to the method shown in Example 6 using N-[(1R,2R)-2-amino-1,2-diphenyl-ethyl]-4-methylbenzenesulfonamide; chlororuthenium; and 1-isopropyl-4-methylbenzene in step B. [ka] 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.12 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.47 - 7.50 (m, 4H), 6.79 - 6.84 (m, 3H), 5.25 (dd, J = 8.0, 2.0 Hz, 1H), 5.14 - 5.21 (m, 1H), 4.86 (dd, J = 14.8, 6.4 Hz, 1H), 4.73 (dd, J = 14.8, 4.0 Hz, 1H), 4.48 - 4.52 (m, 2H), 4.35 - 4.40 (m, 1H), 4.05 (dd, J = 11.2, 8.4 Hz, 1H), 3.99 (d, J = 13.6 Hz, 1H), 3.92 (d, J = 13.6 Hz, 1H), 2.66 - 2.99 (m, 5H), 2.20 - 2.26 (m, 2H), 1.58 - 1.75 (m, 4H). LC-MS: m / z 575.2 (M+H) + .

[0380] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-1-((S)-oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 120b) was synthesized according to the method shown in Example 6 using 1-(4-chloro-2-fluorophenyl)-2-(2,6-dibromophenoxy)ethenone and N-[(1S,2S)-2-amino-1,2-diphenyl-ethyl]-4-methylbenzenesulfonamide; chlororuthenium; and 1-isopropyl-4-methylbenzene in step B. [ka] 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.70 (brs, 1H), 8.26 (s, 1H), 7.79 (dd, J = 8.4, 1.6 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.57-7.51 (m, 2H), 7.38 (dd, J = 8.4, 2.0 Hz, 1H), 6.84-6.78 (m, 3H), 5.43 (dd, J = 8.0, 2.2 Hz, 1H), 5.15-5.04 (m, 1H), 4.83-4.77 (m, 1H), 4.69-4.63 (m, 1H), 4.53-4.47 (m, 2H), 4.41-4.33 (m, 1H), 4.13 (dd, J = 11.6, 8.2 Hz, 1H), 3.94 (d, J = 13.6 Hz, 1H), 3.78 (d, J = 13.6 Hz, 1H), 3.00 (d, J = 11.2 Hz, LC-MS: m / z 592.2 (M+H) + .

[0381] 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-1-((S)-oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 120c) was synthesized according to the method shown in Example 6 using 1-(4-chloro-2-fluorophenyl)-2-(2,6-dibromophenoxy)ethenone and N-[(1R,2R)-2-amino-1,2-diphenyl-ethyl]-4-methylbenzenesulfonamide; chlororuthenium; and 1-isopropyl-4-methylbenzene in step B. [ka] 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.75 (brs, 1H), 8.30 (s, 1H), 7.82 (d, J = 8.0, 1H), 7.73-7.60 (m, 1H), 7.58-7.50 (m, 2H), 7.39 (dd, J = 8.4, 1.8 Hz, 1H), 6.88-6.78 (m, 3H), 5.43 (dd, J = 8.0, 1.6 Hz, 1H), 5.12-5.04 (m, 1H), 4.87-4.76 (m, 1H), 4.72-4.63 (m, 1H), 4.56-4.44 (m, 2H), 4.41-4.33 (m, 1H), 4.13 (dd, J = 11.2, 8.0 Hz, 1H), 4.04-3.64 (m, 2H), 3.32-3.19 (m, 2H), 3.07-2.85 (m, 2H), 2.78-2.63 (m, 1H), 2.47-2.21 (m, 2H), 1.83-1.63 (m, 4H). LC-MS: m / z 592.1 (M+H) + .

[0382] Example 7 2-((4-((R)-2-(4-cyanophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 118b) [ka] Step A: (R)-5-bromo-2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin [ka] A mixture of (R)-1-(4-chlorophenyl)-2-(2,6-dibromophenoxy)ethane-1-ol (7.60 g, 18.8 mmol), CuI (359 mg, 1.88 mmol), 1,10'-phenanthroline (678 mg, 3.76 mmol), and Cs2CO3 (12.3 g, 37.6 mmol) in anhydrous toluene (115 mL) was stirred overnight at 120 °C under an N2 atmosphere. The reaction mixture was filtered, and the filtrate was washed with ethyl acetate (3 × 30 mL). The organic layers were combined, concentrated, and purified by flash chromatography (eluting at PE / DCM = 10 / 1) to obtain the title compound (R)-5-bromo-2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin as a white solid (3.39 g, yield 56%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.52 (s, 4H), 7.18 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.84 (t, J = 8.0 Hz, 1H), 5.33 (dd, J = 8.0, 2.0 Hz, 1H), 4.57 (dd, J = 11.6, 2.0 Hz, 1H), 4.19 (dd, J = 11.6, 8.0 Hz, 1H).

[0383] Step B: tert-butyl (R)-4-(2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate [ka] Zinc powder (11.5 g, 175 mmol) was suspended in DMA (30 mL), and a solution of chlorotrimethylsilane / 1,2-dibromoethane (7:5 w / w, 3.1 g) was added by syringe over several minutes. The temperature was raised to 60°C, and the mixture was stirred for 15 minutes. The reaction mixture was allowed to cool to room temperature, and a solution of tert-butyl 4-iodopiperidine-1-carboxylate (5.16 mol, 49.5 g) in DMA (80 mL) was added over 5 minutes. The temperature was raised again to 66°C, and the mixture was stirred for a further 2 hours to obtain (1-(tert-butoxycarbonyl)piperidine-4-yl)zinc(II) iodide as a 1.2 M solution in DMA. To a solution of (R)-5-bromo-2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin (20.0 g, 61.4 mmol) in DMA (50 mL), PdCl2 (dppf) (1.50 g, 1.84 mmol) and CuI (702 mg, 3.68 mmol) were added. The mixture was degassed three times with N2 and refilled. The above zinc reagent was added, and the mixture was heated at 90°C for 4 hours. The reaction product was then cooled, and saturated NH4Cl aqueous solution (250 mL) and HCl (250 mL) were added. The mixture was filtered through Celite and washed with water (100 mL) and HCl (100 mL). The organic layer was separated, and the aqueous layer was extracted with HCl (200 mL x 3). The extracts were combined, washed with saturated NaHCO3 solution and saline solution, dried over Na2SO4, filtered, and concentrated. The resulting oily substance was purified by flash chromatography using silica gel (siRNA / petroleum ether = 1 / 80 to 1 / 50) to obtain tert-butyl (R)-4-(2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate (21.5 g, 50.0 mmol, yield 82%) as a white solid. 11H NMR (400 MHz, CDCl3) δ ppm 7.35 - 7.41 (m, 4H), 6.86 (d, J = 4.4 Hz, 2H), 6.75 - 6.79 (m, 1H), 5.10 (dd, J = 8.8, 2.0 Hz, 1H), 4.38 (dd, J = 11.2, 2.4 Hz, 1H), 4.24 (d, J = 12.4 Hz, 2H), 3.96 (dd, J = 11.2, 7.6 Hz, 1H), 3.01 - 3.07 (m, 1H), 2.82 (t, J = 12.8 Hz, 1H), 1.76 - 1.85 (m, 2H), 1.56 - 1.68 (m, 3H), 1.48 (s, 9H). LC-MS: m / z 374.2 (M-55) + .

[0384] Step C: tert-butyl (R)-4-(2-(4-cyanophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate

Chem.

[0385] 2-((4-((R)-2-(4-cyanophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3-(((S)-oxetane-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 118b) was synthesized using tert-butyl (R)-4-(2-(4-cyanophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate in step F, according to the method shown in Example 6. [ka] 1 H NMR (400 MHz, DMSO-d6) δ ppm 13.06 (br.s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 8.0Hz, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 6.81 - 6.8 (m, 3H), 5.38 (dd, J = 7.6, 1.6 Hz, 1H), 5.11 - 5.24 (m, 1H), 4.80 - 4.85 (m, 1H), 4.73 (dd, J = 14.8, 3.6 Hz, 1H), 4.44 - 4.59 (m, 2H), 4.36 - 4.38 (m, 1H), 4.09 (dd, J = 11.2, 8.0 Hz, 1H), 3.96 (dd, J = 12, 7.2 Hz, 2H), 2.68 - 2.99 (m, 5H), 2.15 - 2.35 (m, 2H), 1.53 - 1.80 (m, 4H). LC-MS: m / z 566.6 (M+H) + .

[0386] 2-((4-((R)-2-(4-cyanophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 129a) was synthesized according to the method shown in Example 6, using tert-butyl (R)-4-(2-(4-cyanophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate in step F and methyl (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate in step G. [ka] 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.26 (s, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 7.6 Hz, 2H), 7.63 (d, J = 8.0 Hz, 1H), 6.77 - 6.92 (m, 3H), 5.38 (d, J = 7.2 Hz, 1H), 5.08 - 5.11 (m, 1H), 4.80 (dd, J = 14.8, 6.4 Hz, 1H), 4.66 (d, J = 15.6 Hz, 1H), 4.49 - 4.56 (m, 2H), 4.33 - 4.42 (m, 1H), 4.05 - 4.16 (m, 1H), 3.94 (d, J = 14.0 Hz, 1H), 3.79 (d, J = 14.0 Hz, 1H), 3.00 (d, J = 10.0 Hz, 1H), 2.86 - 2.89 (m, LC-MS: m / z 565.6 (M+H) + .

[0387] Example 8 2-((4-(2-(4-chloro-3-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 113a) [ka] Step A: 2-Bromo-1-(4-chloro-3-fluorophenyl)ethane-1-one [ka] To a solution of 1-(4-chloro-3-fluorophenyl)ethane-1-one (3.00 g, 17.4 mmol) in AcOH (30 mL), 4-(dimethylamino)pyridine tribromide (6.96 g, 19.2 mmol) was added. The resulting mixture was stirred overnight at room temperature under a N2 atmosphere. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 30 mL). The organic layers were washed together with saline solution (30 mL), dried over anhydrous sodium 2SO4, and concentrated. The residue was purified by flash chromatography (eluted at PE / ethyl acetate = 20 / 1) to obtain the title compound 2-bromo-1-(4-chloro-3-fluorophenyl)ethane-1-one as a white solid (4.30 g, 98% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.00 - 8.03 (m, 1H), 7.77 - 7.89 (m, 2H), 4.96 (s, 2H).

[0388] Step B: 1-(4-chloro-3-fluorophenyl)-2-(2,6-dibromophenoxy)ethane-1-one [ka] To a solution of 2-bromo-1-(4-chloro-3-fluorophenyl)ethane-1-one (3.20 g, 12.8 mmol) and 2,6-dibromophenol (3.22 g, 12.8 mmol) in acetone (40 mL), K2CO3 (3.50 g, 25.6 mmol) was added. The resulting mixture was stirred at room temperature under an N2 atmosphere for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was diluted with siRNA (50 mL). The organic layer was washed with water (2 × 20 mL) and saline solution (20 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography (eluted at PE / siRNA = 15 / 1) to obtain the title compound 1-(4-chloro-3-fluorophenyl)-2-(2,6-dibromophenoxy)ethane-1-one as a white solid (5.00 g, yield 92%). LCMS: m / z 420.2 (M+H) + .

[0389] Step C: 1-(4-chloro-3-fluorophenyl)-2-(2,6-dibromophenoxy)ethane-1-ol [ka] To a solution of 1-(4-chloro-3-fluorophenyl)-2-(2,6-dibromophenoxy)ethane-1-one (5.00 g, 11.8 mmol), NaBH4 (896 mg, 23.7 mmol) was added at 0°C. The resulting mixture was warmed to room temperature and stirred for 2 hours. The reaction product was quenched with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The organic layers were combined, washed with saline solution (30 mL), dried over anhydrous sodium 2SO4, and concentrated. The residue was purified by flash chromatography (eluted at PE / ethyl acetate = 15 / 1) to obtain the title compound 1-(4-chloro-3-fluorophenyl)-2-(2,6-dibromophenoxy)ethane-1-ol as a white solid (5.00 g, yield 92%). 1H NMR (400 MHz, CD3OD) δ ppm 7.56 (d, J = 8.0 Hz, 2H), 7.45 (t, J = 8.0 Hz, 1H), 7.38 (dd, J = 10.0, 2.0 Hz, 1H), 7.29 (dd, J = 8.4, 2.0 Hz, 1H), 6.95 (t, J = 8.0 Hz, 1H), 5.15 (t, J = 6.0 Hz, 1H), 4.15 (dd, J = 9.2, 6.4 Hz, 1H), 4.04 (dd, J = 8.8, 5.2 Hz, 1H).

[0390] 2-((4-(2-(4-chloro-3-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 113a) was synthesized using 1-(4-chloro-3-fluorophenyl)-2-(2,6-dibromophenoxy)ethane-1-ol in step C, according to the method shown in Example 6. [ka] 1H NMR (400 MHz, CD3OD) δ ppm 8.09 - 8.16 (m, 2H), 7.51 (t, J = 8.0 Hz, 1H), 7.37 (dd, J = 10.0, 1.6 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 6.76 - 6.91 (m, 3H), 5.25 - 3.01 (m, 1H), 5.17 - 5.20 (m, 1H), 4.95 - 5.00 (m, 1H), 4.87 - 4.88 (m, 1H), 4.61 - 4.66 (m, 1H), 4.26 - 4.49 (m, 5H), 4.01 (dd, J = 11.2, 8.0 Hz, 1H), 3.35 - 3.38 (m, 1H), 3.03 - 3.06 (m, 1H), 2.76 - 2.81 (m, 1H), 2.64 - 2.72 (m, 2H), 2.50 - 2.55 (m, 1H), 1.89 - 1.94 (m, 4H). LC-MS: m / z 593.2 (M+H) + .

[0391] The following compounds were synthesized using the corresponding starting materials according to the method shown in Example 8.

[0392] 2-((4-(2-(2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 109a) [ka] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.03 (dd, J = 30.8, 8.0 Hz, 2H), 7.44 - 7.54 (m, 2H), 7.27 - 7.31 (m, 2H), 6.79 - 6.86 (m, 3H), 5.43 (dd, J = 8.4, 2.0 Hz, 1H), 5.20 (s, 1H), 4.78 - 4.81 (m, 2H), 4.50 - 4.54 (m, 2H), 4.32 (s, 1H), 4.13 - 4.16 (m, 1H), 3.91 (dd, J = 34.0, 14.0Hz, 2H), 2.89 - 3.01 (m, 4H), 2.67 - 2.68 (m, 1H), 2.19 - 2.28 (m, 2H), 1.62 - 1.75 (m, 4H). LC-MS: m / z 559.2 (M+H) + .

[0393] 2-((4-(2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 111a) [ka] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.48 - 7.50 (m, 4H), 6.79 - 6.86 (m, 3H), 5.25 (dd, J = 8.0, 2.0 Hz, 1H), 5.16 - 5.19 (m, 1H), 4.84 - 4.89 (m, 1H), 4.74 (dd, J = 14.8, 3.6 Hz, 1H), 4.48 - 4.52 (m, 2H), 4.34 - 4.40 (m, 1H), 4.05 (dd, J = 11.6, 8.4 Hz, 1H), 4.00 (dd, J = 13.6, 4.0 Hz, 1H), 3.92 (dd, J = 13.6, 4.4 kHz, 1H), 2.66 - 2.99 (m, 5H), 2.20 - 2.29 (m, 2H), 1.61 - 1.74 (m, 4H). LC-MS: m / z 575.2 (M+H) + .

[0394] 3-(((S)-oxetan-2-yl)methyl)-2-((4-(2-(p-tolyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 116a) [ka] 1H NMR (400 MHz, CD3OD) δ ppm 8.11 - 8.15 (m, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 6.77 - 6.86 (m, 3H), 5.25 - 5.31 (m, 1H), 5.07 (dd, J = 8.8, 2.0 Hz, 1H), 4.94 - 4.99 (m, 1H), 4.85 - 4.88 (s, 2H), 4.64 (dd, J = 14.0, 7.6 Hz, 1H), 4.31 - 4.46 (m, 4H), 3.99 (dd, J = 11.2, 8.4 Hz, 1H), 3.38 - 3.41 (m, 2H), 3.05 - 3.08 (m, 1H), 2.76 - 2.81 (m, 3H), 2.50 - 2.55 (m, 1H), 2.35 (s, 3H), 1.90 - 1.94 (m, 4H). LC-MS: m / z 555.2 (M+H) + .

[0395] 2-((4-(2-(3-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 112a) [ka] 1H NMR (400 MHz, DMSO-d6) δ ppm 13.04 (s, 1H), 8.06 - 8.17 (m, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.43 - 7.46 (m, 3H), 6.79 - 6.84 (m, 3H), 5.26 (dd, J = 8.0, 2.0 Hz, 1H), 5.11 - 5.22 (m, 1H), 4.78 - 4.92 (m, 1H), 4.74 (dd, J = 14.4, 4.4 Hz, 1H), 4.42 - 4.56 (m, 2H), 4.33 - 4.42 (m, 1H), 4.08 (dd, J = 11.6, 8.4 Hz, 1H), 3.88 - 4.03 (m, 2H), 2.68 - 2.99 (m, 5H), 2.21 - 2.29 (d, J = 13.2 Hz, 2H), 1.53 - 1.79 (m, 4H). LC-MS: m / z 575.2 (M+H) + .

[0396] 2-((4-(2-(4-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 117a) [ka] 1H NMR (400 MHz, DMSO-d6) δ ppm 13.01 (br.s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.53 (dd, J = 8.4, 5.6 Hz, 2H), 7.26 (t, J = 9.2 Hz, 2H), 6.62 - 6.92 (m, 3H), 5.13 - 5.27 (m, 2H), 4.72 - 4.89 (m, 2H), 4.45 - 4.54 (m, 2H), 4.33 - 4.42 (m, 1H), 3.90 - 4.10 (m, 3H), 2.83 - 3.01 (m, LC-MS: m / z 559.2 (M+H) + .

[0397] 2-((4-(2-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 119a) [ka] 1H NMR (400 MHz, DMSO-d6) δ ppm 13.12 (br.s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 6.80 - 6.86 (m, 3H), 5.38 (d, J = 6.0 Hz, 1H), 5.15 - 5.19 (m, 1H), 4.80 - 4.94 (m, 1H), 4.74 (dd, J = 14.8, 3.6 Hz, 1H), 4.47 - 4.57 (m, 2H), 4.29 - 4.43 (m, 1H), 4.09 (dd, J = 11.6, 8.0 Hz, 1H), 3.91 - 4.15 (m, 2H), 2.79 - 2.99 (m, 3H), 2.65 - 2.75 (m, 1H), 2.45 - 2.55 (m, 1H), 2.21 - 2.29 (m, 2H), 1.60 - 1.81 (m, 4H). LC-MS: m / z 609.2 (M+H) + .

[0398] 2-((4-(2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 115a) [ka] 1H NMR (400 MHz, DMSO-d6) δ ppm 12.78 (br.s, 1H), 8.27 (s, 1H), 7.80 (dd, J = 8.4, 1.6 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.37 - 7.56 (m, 4H), 6.64 - 7.00 (m, 3H), 5.25 (dd, J = 8.4, 2.4 Hz, 1H), 5.07 - 5.14 (m, 1H), 4.81 (dd, J = 14.8, 6.4 Hz, 1H), 4.66 (d, J = 13.6 Hz, 1H), 4.46 - 4.53 (m, 2H), 4.35 - 4.42 (m, 1H), 4.05 (dd, J = 11.2, 8.4 Hz, 1H), 3.95 (dd, J = 13.6, 5.2 Hz, 1H), 3.79 (dd, J = 13.6, 5.2 Hz, 1H), 3.01 (d, J = 10.4 Hz, LC-MS: m / z 574.2 (M+H) + .

[0399] 2-((4-(2-(4-cyanophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 118a) [ka] 1H NMR (400 MHz, DMSO-d6) δ ppm 13.06 (br.s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 6.80 - 6.85 (m, 3H), 5.38 (dd, J = 7.6, 1.6 Hz, 1H), 5.11 - 5.24 (m, 1H), 4.80 - 4.90 (m, 1H), 4.73 (dd, J = 14.8, 3.6 Hz, 1H), 4.44 - 4.59 (m, 2H), 4.36 - 4.38 (m, 1H), 4.09 (dd, J = 11.2, 8.0 Hz, 1H), 3.95 (ddd, J = 16.8, 12, 4.8 Hz, 2H), 2.68 - 2.99 (m, 5H), 2.15 - 2.35 (m, 2H), 1.53 - 1.80 (m, 4H). LC-MS: m / z 566.6 (M+H) + .

[0400] The (S)-isomer of compound 118a can be obtained by chiral resolution.

[0401] 2-((4-((S)-2-(4-cyanophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 118c) [ka] 1H NMR (400 MHz, DMSO-d6) δ ppm 13.06 (br.s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 6.81 - 6.85 (m, 3H), 5.38 (dd, J = 7.6, 1.6 Hz, 1H), 5.11 - 5.24 (m, 1H), 4.80 - 4.90 (m, 1H), 4.73 (dd, J = 14.8, 3.6 Hz, 1H), 4.44 - 4.59 (m, 2H), 4.36 - 4.38 (m, 1H), 4.09 (dd, J = 11.2, 8.0 Hz, 1H), 3.96 (dd, J = 31.6, 13.6 Hz, 2H), 2.68 - 2.99 (m, 5H), 2.15 - 2.35 (m, 2H), 1.49 - 1.80 (m, 4H). LC-MS: m / z 566.6 (M+H) + .

[0402] Example 9 2-(((2S)-4-(2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2-methylpiperazine-1-yl)methyl)-3-(((S)-oxetane-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 114a) [ka] Step A: tert-butyl (1-(4-chlorophenyl)-2-(2,6-dibromophenoxy)ethoxy)dimethylsilane [ka] A solution of 1-(4-chlorophenyl)-2-(2,6-dibromophenoxy)ethan-1-ol (2.00 g, 4.95 mmol), TBSCl (1.87 g, 12.4 mmol), and imidazole (1.01 g, 14.8 mmol) in DCM (40 mL) was stirred at room temperature for 12 h under a N2 atmosphere. Water (100 mL) was added and the mixture was extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (PE / EtOAc = 10 / 1) to afford the title compound tert-butyl (1-(4-chlorophenyl)-2-(2,6-dibromophenoxy)ethoxy)dimethylsilane (2.80 g, yield 100%, weight over) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 7.47 (d, J = 8.0 Hz, 2H), 7.36 - 7.39 (m, 2H), 7.25 - 7.31 (m, 2H), 6.80 (t, J = 8.0 Hz, 1H), 5.18 (dd, J = 6.8, 4.8 Hz, 1H), 4.09 (dd, J = 8.4, 6.8 Hz, 1H), 3.85 (dd, J = 8.8, 4.8 Hz, 1H), 0.91 (s, 9H), 0.16 (s, 3H), 0.07 (s, 3H).

[0403] Step B: tert-butyl (2S)-4-(3-bromo-2-(2-((tert-butyldimethylsilyl)oxy)-2-(4-chlorophenyl)ethoxy)phenyl)-2-methylpiperazine-1-carboxylate [Chemical formula] tert-Butyl (1-(4-chlorophenyl)-2-(2,6-dibromophenoxy)ethoxy)dimethylsilane (840 mg, 1.61 mmol), tert-butyl (S)-2-methylpiperazine-1-carboxylate (355 mg, 1.77 mmol, 1.1 eq), Pd2(dba)3 (147 mg, 0.161 mmol), BINAP (100 mg, 0.160 mmol), and tA mixture of BuONa (309 g, 3.22 mmol) was stirred at 110°C for 3 hours under an N2 atmosphere. The reaction mixture was filtered through Celite and diluted with siRNA (30 mL). The organic layers were washed together with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (PE / siRNA = 10 / 1) to obtain tert-butyl (2S)-4-(3-bromo-2-(2-((tert-butyldimethylsilyl)oxy)-2-(4-chlorophenyl)ethoxy)phenyl)-2-methylpiperazine-1-carboxylate (220 mg, yield 22%) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ ppm 7.35 - 7.41 (m, 2H),7.29 - 7.32 (m, 2H), 7.20 (dt, J = 8.0, 1.2 Hz, 1H), 6.88 (td, J = 8.0, 2.4 Hz, 1H), 6.77 - 6.80 (m, 1H), 5.18 (dd, J = 8.0, 3.6 Hz, 0.5H), 5.14 (t, J = 6.4 Hz, 0.5H), 4.32 - 4.36 (m, 1.5H), 4.04 (dd, J = 8.4, 6.8 Hz, 0.5H), 3.86 - 3.92 (m, 1H), 3.65 - 3.68 (m, 1.5H), 3.26 - 3.33 (m, 1H), 3.13 - 3.16 (m, 1H), 3.01 - 3.03 (m, 1H), 2.88 (dd, J = 7.2, 3.6 Hz, 0.5H), 2.76 - 2.83 (m, 1H), 2.36 - 2.48 (m, 1H), 1.49 (d, J = 2.4 Hz, 9H), 1. 29 (d, J = 6.8 Hz, 1.5H), 1.20 (d, J = 6.8 Hz, 1.5H), 0.89 (s, 9H), 0.11 (s, 2.7 H), 0.07 (s, 1.5 H), 0.02 (s, 1.2 H), 0.11 (s, 0.6 H).

[0404] Step C: tert-butyl (2S)-4-(3-bromo-2-(2-(4-chlorophenyl)-2-hydroxyethoxy)phenyl)-2-methylpiperazine-1-carboxylate [ka] THF (8 mL) contains ert-butyl (2S)-4-(3-bromo-2-(2-((tert-butyldimethylsilyl)oxy)-2-(4-chlorophenyl)ethoxy)phenyl)-2-methylpiperazine-1-carboxylate (322 mg, 0.500 mmol), and t A mixture of Bu4NF (1M, 1mL, 1 mmol) was stirred at room temperature for 2 hours. The reaction mixture was diluted with ELISA (3 x 10 mL). The organic layers were combined, washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (PE / ELISA = 5 / 1) to obtain the title compound tert-butyl (2S)-4-(3-bromo-2-(2-(4-chlorophenyl)-2-hydroxyethoxy)phenyl)-2-methylpiperazine-1-carboxylate (260 mg, yield 97.2%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.29 - 7.36 (m, 5H), 6.95 - 7.02 (m, 2H), 5.04 (dd, J = 9.6, 2.4 Hz, 0.5H), 4.90 (dd, J = 9.6, 2.4 Hz, 0.5H), 4.62 (dd, J = 11.2, 2.8 Hz, 0.5H), 4.58 (dd, J = 10.8, 2.4 Hz, 0.5H), 4.33 - 4.38 (m, 1H), 4.02 (d, J = 13.6 Hz, 0.5H), 3.96 (d, J = 13.6 Hz, 0.5H), 3.84 (dd, J = 10.4, 10.0 Hz, 0.5H), 3.70 (dd, J = 11.2, 10.0 Hz, 0.5H), 3.49 (d, J = 9.6 Hz, 0.5H), 3.19 - 3.38 (m, 2.5H), 2.89 (dd, J = 11.6, 7.6, 0.5H), 2.80 (dd, J = 11.6, 2.8 Hz, 0.5H), 2.75 (dd, J = 11.6, 4.0 Hz, 0.5H), 2.61 (td, J = 12.0, 3.2 Hz, 0.5H), 1.49 (s, 9H), 1.45 (d, J = 7.2 Hz, 1.5 H), 1.40 (d, J = 6.8 Hz, 1.5H).

[0405] Step D: tert-butyl (2S)-4-(2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2-methylpiperazine-1-carboxylate [ka] The compounds tert-butyl (2S)-4-(3-bromo-2-(2-(4-chlorophenyl)-2-hydroxyethoxy)phenyl)-2-methylpiperazine-1-carboxylate (260 mg, 0.480 mmol), CuI (185 mg, 0.970 mmol), and (1S,2S)-N in dried DMF (10 mL) 1 ,N 2A solution of -dimethylcyclohexane-1,2-diamine (138 mg, 0.970 mmol) and Cs2CO3 (317 mg, 0.970 mmol) was stirred at 110°C for 2.5 hours under an N2 atmosphere by microwave irradiation. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, washed with brine (30 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated. The residue was purified by flash chromatography (PE / ethyl acetate = 5 / 1) to obtain the title compound tert-butyl (2S)-4-(2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2-methylpiperazine-1-carboxylate (56.4 mg, yield 26%) as a colorless oil. LCMS: m / z 445.2 (M+H) + .

[0406] 2-(((2S)-4-(2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2-methylpiperazine-1-yl)methyl)-3-(((S)-oxetane-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 9, Compound 114a) was synthesized using tert-butyl (2S)-4-(3-bromo-2-(2-(4-chlorophenyl)-2-hydroxyethoxy)phenyl)-2-methylpiperazine-1-carboxylate in step F, according to the method shown in Example 6. [ka] 1H NMR (400 MHz, CD3OD) δ ppm 8.12 - 8.17 (m, 2H), 7.43 (q, J = 8.8 Hz, 4H), 6.80 (t, J = 8.8 Hz, 1H), 6.66 (dd, J = 8.0, 1.6 Hz, 1H), 6.54 - 6.61 (m, 1H), 5.29 - 5.34 (m, 1H), 5.15 (td, J = 8.4, 2.4 Hz, 1H), 4.97 (d, J = 4.0 Hz, 2H), 4.72 (d, J = 14.0 Hz, 1H), 4.59 (dd, J = 13.2, 8.0 Hz, 1H), 4.41 - 4.51 (m, 1H), 4.26 - 4.31 (m, 1H), 3.96 - 4.02 (m, 1H), 3.83 - 3.86 (m, 1H), 3.39 - 3.42 (m, 1H), 3.17 - 3.23 (m, 1H), 2.87 - 2.89 (m, 2H), 2.71 - 2.83 (m, 2H), 2.64 - 2.67 (m, 2H), 2.45 - 2.52 (m, 1H), 1.23 - 1.29 (m, 3H). LC-MS: m / z 590.2 (M+H) + .

[0407] Example 10 2-((4-(2-(4-chloro-2-fluorophenyl)chroman-5-yl)piperazine-1-yl)methyl)-3-((S)-oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 123a) [ka] [ka] Step A: (E)-1-(2-bromo-6-hydroxyphenyl)-3-(4-chloro-2-fluorophenyl)propa-2-en-1-one [ka] A solution of 1-(2-bromo-6-hydroxyphenyl)ethanone (950 mg, 4.42 mmol), 4-chloro-2-fluorobenzaldehyde (1.05 g, 6.63 mmol), and KOH (1.12 g, 20.0 mmol) in EtOH (7 mL) was stirred overnight at 35°C. The mixture was acidified with HCOOH and extracted with DCM (50 mL x 3). The organic layer was washed with saline solution, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography using silica gel (eluted at PE / Â=19 / 1) to obtain (E)-1-(2-bromo-6-hydroxyphenyl)-3-(4-chloro-2-fluorophenyl)propa-2-en-1-one (1.26 g, yield 75%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ ppm10.58 (s, 1H), 7.82 (d, J = 15.6 Hz, 1H), 7.69 (d, J = 15.6 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.14 - 7.25 (m, 4H), 6.99 (dd, J = 7.6, 2.0 Hz, 1H).

[0408] Step B: 5-Bromo-2-(4-chloro-2-fluorophenyl)chroman-4-one [ka] A solution of (E)-1-(2-bromo-6-hydroxyphenyl)-3-(4-chloro-2-fluorophenyl)propa-2-en-1-one (1.2 g, 3.2 mmol, 1.0 equivalent) in EtOH (15 mL) and H2SO4 (3 mL) was stirred overnight at 80°C. The mixture was extracted with DCM (50 mL x 3), washed with saline solution, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography using silica gel (eluted at PE / siRNA = 97 / 3) to obtain 5-bromo-2-(4-chloro-2-fluorophenyl)chroman-4-one (570 mg, yield 47%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.55 (t, J = 8.0 Hz, 1H), 7.34 (dd, J = 7.6, 1.2 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.22 - 7.26 (m, 1H), 7.15 (dd, J = 10.0, 2.0 Hz, 1H), 7.04 (dd, J = 8.0, 1.2 Hz, 1H), 5.72 (dd, J = 12.8, 3.2 Hz, 1H), 3.06 (dd, J = 16.4, 12.8 Hz, 1H), 2.96 (dd, J = 16.4, 3.2 Hz, 1H).

[0409] Step C: 5-Bromo-2-(4-chloro-2-fluorophenyl)chroman [ka] A solution of 5-bromo-2-(4-chloro-2-fluorophenyl)chroman-4-one (35.0 mg, 0.0980 mmol) and Et3SiH (46.0 mg, 0.393 mmol) in TFA (5 mL) was stirred at room temperature for 3 hours. The mixture was filtered and concentrated. The residue was purified by flash chromatography using silica gel (eluted with 100% PE) to obtain 5-bromo-2-(4-chloro-2-fluorophenyl)chroman (30.0 mg, yield 90%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 7.45 (t, J = 8.0 Hz, 1H), 7.15 - 7.20 (m, 2H), 7.11 (dd, J = 10.0, 2.0 Hz, 1H), 7.00 (t, J = 8.0 Hz, 1H), 6.86 (dd, J = 8.4, 1.2 Hz, 1H), 5.25 (dd, J = 10.4, 2.4 Hz, 1H), 2.81 - 2.91 (m, 2H), 2.24 - 2.34 (m, 1H), 1.94 - 2.05 (m, 1H).

[0410] Step D: tert-butyl 4-(2-(4-chloro-2-fluorophenyl)chroman-5-yl)piperazine-1-carboxylate [ka] A mixture of 5-bromo-2-(4-chloro-2-fluorophenyl)chroman (200 mg, 0.590 mmol), tert-butylpiperazine-1-carboxylate (121 mg, 0.650 mmol), Pd2(dba)3 (54.0 mg, 0.0590 mmol), BINAP (37.0 mg, 0.0590 mmol), and tBuONa (113 mg, 1.18 mmol) in dry toluene (5 mL) was stirred at 100 °C for 3 hours under N2. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography using silica gel (PE / Â=93 / 7) to obtain tert-butyl 4-(2-(4-chloro-2-fluorophenyl)chroman-5-yl)piperazine-1-carboxylate (130 mg, yield 50%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 7.46 (t, J = 8.0 Hz, 1H), 7.06 - 7.18 (m, 3H), 6.70 (dd, J = 8.4, 1.2 Hz, 1H), 6.62 (dd, J = 8.0, 1.2 Hz, 1H), 5.35 (dd, J = 10.0, 2.4 Hz, 1H), 3.46 - 3.64 (m, 4H), 2.86 - 3.02 (m, 3H), 2.70 - 2.83 (m, 3H), 2.21 - 2.30 (m, 1H), 1.86 - 1.98 (m, 1H).

[0411] 2-((4-(2-(4-chloro-2-fluorophenyl)chroman-5-yl)piperazine-1-yl)methyl)-3-((S)-oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 10, Compound 123a) was synthesized using tert-butyl 4-(2-(4-chloro-2-fluorophenyl)chroman-5-yl)piperazine-1-carboxylate in step F, according to the method shown in Example 6. [ka] 1 H NMR (400 MHz, CDCl3) δ ppm 8.18 - 8.25 (m, 2H), 7.46 (t, J = 8.0 Hz, 1H), 7.16 (dd, J = 8.4, 2.0 Hz, 1H), 7.08 - 7.14 (m, 3H), 6.66 (dd, J = 20.4, 8.0 Hz, 2H), 5.35 (dd, J = 10.0, 2.4 Hz, 2H), 5.22 - 5.30 (m, 1H), 4.80 - 5.01 (m, 2H), 4.61 - 4.69 (m, 1H), 4.34 - 4.44 (m, 1H), 4.14 (br.s, 2H), 3.07 (s, 2H), 2.63 - 2.95 (m, 9H), 2.42 - 2.53 (m, 1H), 2.20 - 2.30 (m, 1H), 1.87 - 1.95 (m, 1H). LC-MS: m / z 592.2(M+H) + .

[0412] 2-((4-(2-(4-chloro-2-fluorophenyl)chroman-5-yl)piperidine-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 105a) was synthesized using tert-butyl 4-(2-(4-chloro-2-fluorophenyl)chroman-5-yl)piperazine-1-carboxylate in step F, according to the method shown in Example 6. [ka] 1H NMR (400 MHz, CDCl3) δ ppm 8.19 (dd, J = 10.8, 8.4 Hz, 2H), 7.47 (t, J = 8.0 Hz, 1H), 7.08 - 7.18 (m, 3H), 6.86 (dd, J = 7.6, 1.2 Hz, 1H), 6.78 (dd, J = 8.4, 1.2 Hz, 1H), 5.24 - 5.29 (m, 2H), 4.99 (dd, J = 15.2, 6.4 Hz, 1H), 4.86 (dd, J = 14.8, 3.2 Hz, 1H), 4.60 - 4.65 (m, 1H), 4.38 - 4.43 (m, 1H), 4.16 (dd, J = 20.4, 14.0 Hz, 2H), 3.10 - 3.16 (m, 2H), 2.68 - 2.94 (m, 4H), 2.26 - 2.53 (m, 4H), 1.75 - 2.04 (m, 5H). LC-MS: m / z = 519.2 (M+H) + .

[0413] Example 11 2-((4-(3-(4-chloro-2-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-yl)piperidine-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 124a) [ka] Step A: 2-(2-bromo-6-nitrophenoxy)-1-(4-chloro-2-fluorophenyl)ethane-1-one [ka] A mixture of 2-bromo-6-nitrophenol (1.09 g, 5.00 mmol), 2-bromo-1-(4-chloro-2-fluorophenyl)ethane-1-one (1.38 g, 5.50 mmol), and NaOH (202 mg, 5.50 mmol) in DMSO (5 mL) was stirred at 20°C for 3 hours. LC-MS indicated completion of the reaction. The mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 5:1) to obtain 2-(2-bromo-6-nitrophenoxy)-1-(4-chloro-2-fluorophenyl)ethane-1-one (1.28 g, 3.30 mmol, yield 66%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ ppm 8.01 - 8.10 (m, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.31 (dd, J = 8.4, 1.6 Hz, 1H), 7.15 - 7.24 (m, 2H), 5.39 (d, J = 3.6 Hz, 2H). LC-MS: m / z = 388.0, 390.0 (M+H) + .

[0414] Step B: 8-Bromo-3-(4-chloro-2-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine [ka] To a solution of 2-(2-bromo-6-nitrophenoxy)-1-(4-chloro-2-fluorophenyl)ethane-1-one (1.04 g, 2.67 mmol) in toluene (9 mL) and isopropanol (6 mL), Pt / C (5% Pt, 104 mg) was added. The mixture was heated at 60°C for 12 hours. LC-MS indicated that the starting material had been consumed. The mixture was filtered. The filtrate was concentrated and purified by silica gel column chromatography (PE / EA = 20:1) to obtain 8-bromo-3-(4-chloro-2-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (765 mg, 2.23 mmol, yield 84%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.38 (t, J = 8.0 Hz, 1H), 7.03 - 7.21 (m, 2H), 6.95 (dd, J = 7.6, 1.6 Hz, 1H), 6.70 (t, J = 8.0 Hz, 1H), 6.63 (dd, J LC-MS: m / z = 342.0, 344.0 (M+H) + .

[0415] Step C: tert-butyl 4-(3-(4-chloro-2-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate [ka] 10 mL of 1,4-dioxane and 3 mL of H2O containing 8-bromo-3-(4-chloro-2-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (665 mg, 1.94 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (905 mg, 2.92 mmol), and Pd(dppf)Cl 2. A mixture of CH2Cl2 (159 mg, 0.194 mmol) and K2CO3 (805 mg, 5.83 mmol) was stirred at 85°C for 3 hours under an argon atmosphere. LC-MS indicated completion of the reaction. The mixture was diluted with ethyl acetate (30 mL) and washed with water (30 mL). The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 5:1) to obtain tert-butyl 4-(3-(4-chloro-2-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate (842 mg, 1.89 mmol, yield 98%) as a yellow solid. 1H NMR 00 MHz, CDCl3) δ ppm 7.41 (t, J = 7.8 Hz, 1H), 7.10 - 7.17 (m, 2H), 6.78 (t, J = 7.8 Hz, 1H), 6.55 - 6.67 (m, 2H), 5.78 (br.s, 1H), 4.87 (dd, J = 6.4, 3.02Hz, 1H), 4.33 (dd, J = 10.8, 3.2 Hz, 1H), 4.00 - 4.05 (m, 3H), 3.58 (br.s, 2H), 2.48 (br.s, 2H), 1.48 (s, 9H). LC-MS: m / z = 445.2 (M+H) + .

[0416] Step D: tert-butyl 4-(3-(4-chloro-2-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-(3-(4-chloro-2-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate (250 mg, 0.560 mmol) in ethyl acetate (3 mL), PtO2 (5% Pt, 46.0 mg) was added. The mixture was stirred at room temperature under an H2 atmosphere for 3 hours. LC-MS indicated completion of the reaction. The mixture was filtered. The filtrate was concentrated and purified by silica gel column chromatography (PE / EA = 5:1) to obtain tert-butyl 4-(3-(4-chloro-2-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-yl)piperidine-1-carboxylate (247 mg, 0.497 mmol, yield 88.7%) as a yellow solid. LCMS: m / z = 391.2 (M-55) + .

[0417] 2-((4-(3-(4-chloro-2-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-yl)piperidine-1-yl)methyl)-3-(((S)-oxetane-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 124a) was synthesized using tert-butyl 4-(3-(4-chloro-2-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-yl)piperidine-1-carboxylate in step F, according to the method shown in Example 6. [ka] 1 H NMR (400 MHz, CDCl3) δ ppm 8.20 (dd, J = 13.6, 8.0 Hz, 2H), 7.40 (t, J = 8.0 Hz, 1H), 7.09 - 7.17 (m, 2H), 6.79 (t, J = 7.6 Hz, 1H), 6.64 (dd, J = 7.6, 1.2 Hz, 1H), 6.57 (dd, J = 7.6, 1.2 Hz, 1H), 5.21 - 5.30 (m, 1H), 4.97 (dd, J = 14.8, 6.4 Hz, 1H), 4.79 - 4.91 (m, 2H), 4.64 (m, 1H), 4.42 (m, 1H), 4.34 (dd, J = 10.4, 2.8 Hz, 1H), 4.09 (s, 2H), 4.02 (dd, J = 10.4, 6.8 Hz, 1H), 2.90 - 3.08 (m, 3H), 2.72 - 2.86 (m, 1H), 2.43 - 2.54 (m, 1H), 2.28 - 2.43 (m, 2H), 1.70 - 1.91 (m, 4H). LC-MS: m / z = 592.2 (M+H) + .

[0418] Example 12 2-((4-(3-(2-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-yl)piperidine-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 125a) [ka] Step A: tert-butyl 4-(3-(2-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-(3-(4-chloro-2-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate (100 mg, 0.225 mmol) in methanol (2 mL), Pd / C (5% Pd, 14.0 mg) was added. The mixture was stirred at room temperature under an H2 atmosphere for 3 hours. LC-MS indicated completion of the reaction. The mixture was filtered. The filtrate was concentrated and purified by silica gel column chromatography (PE / EA = 5:1) to obtain tert-butyl 4-(3-(2-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-yl)piperidine-1-carboxylate (84.0 mg, 0.188 mmol, yield 84%) as a yellow solid. LCMS: m / z = 357.2 (M-56) +

[0419] 2-((4-(3-(2-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-yl)piperidine-1-yl)methyl)-3-(((S)-oxetane-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 125a) was synthesized using tert-butyl 4-(3-(2-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-yl)piperidine-1-carboxylate in step F, according to the method shown in Example 6. [ka] 1 H NMR (400 MHz, CDCl3) δ ppm 8.20 (dd, J = 13.2, 8.0 Hz, 2H), 7.43 -7.49 (m, 1H), 7.27 - 7.33 (m, 1H), 7.12 -7.19 (m, 1H), 7.04 - 7.12 (m, 1H), 6.79 (t, J = 7.6 Hz, 1H), 6.63 (dd, J = 7.6, 1.2 Hz, 1H), 6.57 (dd, J = 7.6, 1.2 Hz, 1H), 5.20 - 5.30 (m, 1H), 4.80 - 5.05 (m, 3H), 4.58 - 4.69 (m, 1H), 4.33 - 4.47 (m, 2H), 4.10 (s, 2H), 4.04 (dd, J = 10.4, 7.2 Hz, 1H), 2.89 - 3.12 (m, 3H), 2.73 - 2.87 (m, 1H), 2.25 - 2.58 (m, 3H), 1.62 - 2.00 (m, 4H). LC-MS: m / z = 558.2 (M+H) + .

[0420] Example 13: 2-((4-(3-(4-chloro-2-fluorophenyl)chroman-8-yl)piperidine-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 106a) [ka] Step A: 2-(2-bromo-6-(hydroxymethyl)phenoxy)-1-(4-chloro-2-fluorophenyl)ethane-1-one [ka] To a solution of 2-bromo-1-(4-chloro-2-fluorophenyl)ethane-1-one (3.22 g, 12.8 mmol, synthesized according to step A of Example 8) in DMSO (60 ml), NaOH (564 mg, 14.1 mmol) and 2-bromo-6-(hydroxymethyl)phenol (2.60 g, 12.8 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours. The solution was diluted with water (40 ml) and extracted with ethyl acetate (3 × 50 ml). The organic layers were combined, washed with brine (50 ml), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (eluted at PE / ethyl acetate = 7 / 1-4 / 1) to obtain the title compound 2-(2-bromo-6-(hydroxymethyl)phenoxy)-1-(4-chloro-2-fluorophenyl)ethane-1-one as a white solid (2.75 g, yield 57%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.97 (t, J = 8.4 Hz, 1H), 7.66 (dd, J = 11.2, 1.6 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.49 (dd, J = 8.4, 1.6 Hz, 1H), 7.45 (d, J = 6.4 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 5.20 - 5.23 (m, 2H), 4.55 - 4.59 (m, 2H).

[0421] Step B: (3-Bromo-2-(2-(4-chloro-2-fluorophenyl)-2-oxoethoxy)benzyl)triphenylphosphonium bromide [ka] A mixture of 2-(2-bromo-6-(hydroxymethyl)phenoxy)-1-(4-chloro-2-fluorophenyl)ethane-1-one (2.75 g, 7.35 mmol) and Ph3P.HBr (2.52 g, 7.35 mmol) in CH3CN (95 ml) was stirred at 90°C for 16 hours under an N2 atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash chromatography (eluting at DCM / MeOH = 6 / 1 to 5 / 1) to obtain the title compound (3-bromo-2-(2-(4-chloro-2-fluorophenyl)-2-oxoethoxy)benzyl)triphenylphosphonium bromide as a yellow solid (2.02 g, yield 39%). 1 H NMR (400 MHz, CDCl3) δ ppm 7.96 (t, J = 8.0 Hz, 1H), 7.75 - 7.85 (m, 9H), 7.61 - 7.66 (m, 6H), 7.49 - 7.51 (m, 1H), 7.43 - 7.46 (m, 1H), 7.30 (dd, J = 8.4, 2.0 Hz, 1H), 7.19 (dd, J = 10.8, 2.0 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 5.81 (d, J = 14.8 Hz, 2H), 5.08 (d, J = 3.2 Hz, 2H).

[0422] Step C: 8-Bromo-3-(4-chloro-2-fluorophenyl)-2H-chromene [ka] To a solution of (3-bromo-2-(2-(4-chloro-2-fluorophenyl)-2-oxoethoxy)benzyl)triphenylphosphonium bromide (2.02 mg, 2.89 mmol) in EtOH (40 mL), a 1 M solution of EtONa in EtOH (3.18 mL, 3.18 mmol) was added. The reaction mixture was stirred at room temperature under a N2 atmosphere for 16 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 × 40 mL). The organic layers were washed with saline solution (60 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography (eluting at PE / ethyl acetate = 10 / 1 to 6 / 1) to obtain the title compound 8-bromo-3-(4-chloro-2-fluorophenyl)-2H-chromene as a yellow solid (815 mg, yield 83%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.53 - 7.60 (m, 2H), 7.45 (dd, J = 8.0, 1.2 Hz, 1H), 7.38 (dd, J = 8.4, 2.0 Hz, 1H), 7.24 (dd, J = 7.2, 1.2 Hz, 1H), 6.99 (s, 1H), 6.91 (t, J = 7.6 Hz, 1H), 5.18 (s, 2H).

[0423] 2-((4-(3-(4-chloro-2-fluorophenyl)chroman-8-yl)piperidine-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 106a) was synthesized using 8-bromo-3-(4-chloro-2-fluorophenyl)-2H-chromene in step C, according to the method shown in Example 11. [ka] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.10 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.45 (dd, J = 10.4, 2.0 Hz, 1H), 7.38 (t, J = 8.4 Hz, 1H), 7.28 (dd, J = 8.4, 2.0 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.96 (d, J = 7.2 Hz, 1H), 6.83 (t, J = 7.6 Hz, 1H), 5.14 - 5.19 (m, 1H), 4.85 (dd, J = 14.8, 6.4 Hz, 1H), 4.73 (dd, J = 14.8, 4.0 Hz, 1H), 4.67 - 4.52 (m, 1H), 4.28 - 4.43 (m, 2H), 4.12 (t, J = 10.0 Hz, 1H), 3.94 (dd, J = 29.6, 13.6 Hz, LC-MS: m / z 591.2 (M+H) + .

[0424] 2-((4-(3-(2-fluorophenyl)chroman-8-yl)piperidine-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 122a) was synthesized according to the method shown in Example 13 above. [ka] 1H NMR (400 MHz, DMSO-d6) δ ppm 13.03 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.29 - 7.40 (m, 2H), 7.15 - 7.26 (m, 2H), 7.03 (d, J = 7.2 Hz, 1H), 6.96 (d, J = 7.2 Hz, 1H), 6.82 (t, J = 7.6 Hz, 1H), 5.13 - 5.24 (m, 1H), 4.87 (dd, J = 14.4, 6.4 Hz, 1H), 4.74 (dd, J = 14.8, 4.4 Hz, 1H), 4.47 - 4.52 (m, 1H), 4.32 - 4.42 (m, 2H), 4.13 (t, J = 10.0 Hz, 1H), 3.97 (q, J = 13.8 Hz, 2H), 3.44 - 3.48 (m, 1H), 2.66 - 3.11 (m, 7H), 2.19 - 2.34 (m, 2H), 1.65 - 1.71 (m, 4H). LC-MS: m / z 557.2 (M+H) + .

[0425] Example 14 2-((4-(2-(3-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 121a) [ka] Step A: tert-butyl 4-(3-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperazine-1-carboxylate [ka] To a solution of 8-bromo-3-(4-chloro-2-fluorophenyl)-2H-chromene (230 mg, 0.680 mmol) in toluene (8 ml), tert-butylpiperazine-1-carboxylate (252 mg, 1.36 mmol), t-BuONa (130 mg, 1.36 mmol), BINAP (96.0 mg, 0.160 mmol), and Pd2(dba)3 (72.0 mg, 0.0800 mmol) were added. The mixture was stirred at 110°C for 16 hours under an N2 atmosphere. The mixture was diluted with water (30 mL) and extracted with  (3 × 20 mL). The organic layers were washed with saline solution (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (eluting at PE / siRNA = 10 / 1-4 / 1) to obtain the title compound tert-butyl 4-(3-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperazine-1-carboxylate as a white solid (220 mg, yield 73%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.56 (t, J = 7.6 Hz, 1H), 7.52 (dd, J = 11.6, 2.4 Hz, 2H), 7.35 (dd, J = 8.4, 2.0 Hz, 1H), 6.95 (s, 1H), 6.79 - 6.92 (m, 3H), 5.04 (s, 2H), 3.46 (t, J = 9.6 Hz, 4H), 2.93 (t, J = 9.6 Hz, 4H), 1.42 (s, 9H).

[0426] 2-((4-(3-(4-chloro-2-fluorophenyl)chroman-8-yl)piperazine-1-yl)methyl)-3-(((S)-oxetane-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 121a) was synthesized using tert-butyl 4-(3-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperazine-1-carboxylate in step F, according to the method shown in Example 6. [ka] 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.13 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.45 (dd, J = 10.2, 2.0 Hz, 1H), 7.37 (t, J = 8.4 Hz, 1H), 7.28 (dd, J = 8.0, 2.0 Hz, 1H), 6.73 - 6.81 (m, 3H), 5.11- 5.22 (m, 1H), 4.85 (dd, J = 14.4, 4.4 Hz, 1H), 4.72 (dd, J = 14.4, 3.6 Hz, 1H), 4.46 - 4.51 (m, 1H), 4.32 - 4.37 (m, 3H), 4.10 (t, J = 9.6 Hz, 1H), 3.94 - 4.05 (m, 2H), 3.40 - 3.46 (m, 2H), 2.91 - 3.06 (m, 6H), 2.63 - 2.77 (m, 4H). LC-MS: m / z 592.2 (M+H) + .

[0427] Example 15 (S)-2-((4-(2-(4-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline-5-yl)piperidine-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ka] Step A: tert-butyl 4-(1,2,3,4-tetrahydroisoquinoline-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate [ka] To a mixture of 5-bromo-1,2,3,4-tetrahydroisoquinoline (1.00 g, 4.71 mmol), Pd(dppf)Cl2.DCM (385 mg, 0.471 mmol), and Na2CO3 (1.00 g, 9.43 mmol) in dioxane (20 mL) and H2O (2 mL), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.70 g, 5.50 mmol) was added. The mixture was purged with N2 and stirred overnight at 90°C. The mixture was diluted with water (40 mL) and extracted with ELISA (3 x 40 mL). The organic layers were combined, washed with saline solution (30 mL), dried over anhydrous sodium 2SO4, concentrated, and purified by flash chromatography to obtain tert-butyl 4-(1,2,3,4-tetrahydroisoquinoline-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate as a brown solid (940 mg, yield 63%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.09 (t, J = 7.6 Hz, 1H), 6.94 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 5.52 (s, 1H), 3.94 (s, 2H), 3.90 (s, 2H), 3.52 (t, J = 5.6 Hz, 2H), 2.94 (t, J = 5.6 Hz, 2H), 2.61 (t, J = 5.6 Hz, 2H), 2.24 (br.s, 2H), 1.42 (s, 9H). LC-MS: m / z 315.2 (M+H) + .

[0428] Step B: tert-butyl 4-(1,2,3,4-tetrahydroisoquinoline-5-yl)piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-(1,2,3,4-tetrahydroisoquinoline-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (940 mg, 2.99 mmol) in MeOH (50 mL), Pd / C (5% Pd, 940 mg) was added. The mixture was stirred under H2 at room temperature for 2 days. The mixture was filtered and concentrated to obtain the title compound tert-butyl 4-(1,2,3,4-tetrahydroisoquinoline-5-yl)piperidine-1-carboxylate as a brown solid (629 mg, yield 67%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.04 - 7.10 (m, 2H), 6.87 - 6.90 (m, 1H), 4.07 (d, J = 10.8 Hz, 2H), 3.35 (br.s, 2H), 3.05 (t, J = 6.0 Hz, LC-MS: m / z 317.2 (M+H) + .

[0429] Step C: tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-5-yl)piperidine-1-carboxylate [ka] A mixture of tert-butyl 4-(1,2,3,4-tetrahydroisoquinoline-5-yl)piperidine-1-carboxylate (629 mg, 1.99 mmol), Pd2(dba)3 (182 mg, 0.20 mmol), BINAP (248 mg, 0.40 mmol), and t-BuONa (382 mg, 3.98 mmol) in toluene (20 mL) was to which 1-bromo-4-chlorobenzene (570 mg, 2.98 mmol) was added. The mixture was purged with N2 and stirred overnight at 110°C. The mixture was filtered and concentrated. The residue was purified by flash chromatography to obtain the title compound tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-5-yl)piperidine-1-carboxylate as a brown solid (321 mg, yield 39%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.24 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 7.6 Hz, 1H), 7.05 - 7.10 (m, 2H), 7.00 (d, J = 8.8 Hz, 2H), 4.37 (s, 2H), 4.08 (d, J = 10.4 Hz, 2H), 3.54 (t, J = 5.6 Hz, 2H), 2.83 - 2.93 (m, 5H), 1.64 - 1.68 (m, 2H), 1.44 - 1.51 (m, 2H), 1.42 (s, 9H). LC-MS: m / z 371.2 (M-55) + .

[0430] (S)-2-((4-(2-(4-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline-5-yl)piperidine-1-yl)methyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was synthesized according to the method of Example 6 using tert-butyl 4-(2-(4-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline-5-yl)piperidine-1-carboxylate in step F. [ka] 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.11 - 7.18 (m, 2H), 7.05 (d, J = 15.2 Hz, 1H), 6.99 (d, J = 8.8 Hz, 2H), 5.16 - 5.19 (m, 1H), 4.87 (dd, J = 14.4, 6.4 Hz, 1H), 4.74 (dd, J = 14.4, 4.0 Hz, 1H), 4.47 - 4.51 (m, 1H), 4.36 - 4.39 (m, 3H), 3.98 (q, J = 14.4 Hz, 2H), 3.48 - 3.54 (m, 2H), 2.89 - 3.01 (m, 4H), 2.66 - 2.75 (m, 2H), 2.55 - 2.60 (m, 1H), 2.24 - 2.33 (m, 2H), 1.66 - 1.68 (m, 4H). LCMS: m / z = 572.6 (M+H) + .

[0431] Example 16 3-(((S)-oxetan-2-yl)methyl)-2-((4-(2-phenylchroman-5-yl)piperidine-1-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 102a) [ka] Step A: 5-bromo-2-phenylchroman-4-ol [ka] 5-Bromo-2-phenylchroman-4-one (820 mg, 2.71 mmol) (synthesized according to the method shown in Example 10 using benzaldehyde in Step A) was dissolved in 15 mL of MeOH, and NaBH4 (206 mg, 5.42 mmol) was slowly added at 0°C. The reaction mixture was stirred at room temperature for 6 hours. The MeOH was removed, the residue was diluted with water (10 mL), and extracted with ethyl acetate (10 mL x 3). The organic layer was dried over Na2SO4, concentrated, and purified by flash chromatography using silica gel (eluting at PE / ethyl acetate = 10 / 1) to obtain the title compound 5-bromo-2-phenylchroman-4-ol (764 mg, yield 92%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ ppm 7.31 - 7.50 (m, 5H), 7.18 - 7.26 (m, 1H), 7.06 - 7.14 (m, 1H), 6.93 - 6.96 (m, 1H), 5.00 - 5.31 (m, 2H), 2.94 (s, 1H), 2.56 - 2.66 (m, 1H), 2.30 - 2.56 (m, 1H).

[0432] Step B: 5-bromo-2-phenylchromane [ka] To a solution of 5-bromo-2-phenylchroman-4-ol (764 mg, 2.50 mmol) in THF (2 mL) at 0°C, Et3SiH (1 mL) was added. The solution was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography using silica gel (eluting at heptane / Â=20 / 1) to obtain the title compound 5-bromo-2-phenylchroman (530 mg, yield 73%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.26 - 7.43 (m, 5H), 7.16 (dd, J = 8.0, 1.2 Hz, 1H), 7.00 (t, J = 8.0 Hz, 1H), 6.94 (t, J = 8.4 Hz, 1H), 5.00 (dd, J = 10.4, 2.4 Hz, 1H), 2.85 - 2.90 (m, 2H), 2.22 - 2.30 (m, 1H), 2.04 - 2.14 (m, 1H).

[0433] Step C: tert-butyl 4-(2-phenylchroman-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate [ka] To a solution of 5-bromo-2-phenylchroman (200 mg, 0.692 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (428 mg, 1.38 mmol) in dioxane / H2O (3 mL / 0.2 mL), Pd(PPh3)4 (80.0 mg, 0.0692 mmol) and K2CO3 (191 mg, 1.38 mmol) were added. The mixture was degassed three times with N2 and refilled. The reaction mixture was stirred in a microwave reactor at 80°C for 2 hours. The mixture was cooled, concentrated under reduced pressure, and purified by flash chromatography using silica gel (eluting at heptane / siRNA = 20 / 1 to 3 / 2) to obtain the title compound tert-butyl 4-(2-phenylchroman-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (240 mg, yield 88%) as a yellow solid. LCMS: m / z 336.2 (M-55) + .

[0434] 3-(((S)-oxetane-2-yl)methyl)-2-((4-(2-phenylchroman-5-yl)piperidine-1-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 102a) was synthesized using tert-butyl 4-(2-phenylchroman-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate in step E, according to the method shown in Example 13. [ka] 1 H NMR (400 MHz, DMSO-d6) δ ppm 13.06 (br.s, 1H),8.11 - 8.17 (m, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.37 - 7.44 (m, 4H), 7.31 - 7.34 (m, 1H), 7.07 (t, J = 8.0 Hz, 1H), 6.82 (d, J = 7.2 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 5.15 - 5.21 (m, 1H), 5.03 (d, J = 8.4 Hz, 1H), 4.87 (dd, J = 14.8, 6.4 Hz, 1H), 4.75 (dd, J = 14.4, 8.0 Hz, 1H), 4.50 (dd, J = 13.6, 7.6 Hz, 1H), 4.38 (dd, J = 14.8, 6.0 Hz, 1H), 3.92 - 4.03 (m, 2H), 2.93 - 3.00 (m, 2H), 2.78 - 2.87 (m, 2H), 2.67 - 2.73 (m, 2H), 2.53 - 2.55 (m, 1H), 2.19 - 2.32 (m, 3H), 1.91 - 2.04 (m, 1H), 1.61 - 1.71 (m, 4H). LC-MS: m / z 539.2 (M+H) + .

[0435] 3-(((S)-oxetan-2-yl)methyl)-2-((4-(3-phenylchroman-8-yl)piperidine-1-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 103a) was synthesized using 2-bromo-1-phenylethane-1-one in step A, according to the method shown in Example 13. [ka] 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 4.4 Hz, 4H), 7.23 - 7.30 (m, 1H), 7.02 (d, J = 7.2 Hz, 1H), 6.95 (d, J = 6.8 Hz, 1H), 6.81 (t, J = 7.6 Hz, 1H), 5.10 - 5.24 (m, 1H), 4.86 (dd, J = 14.8, 6.4 Hz, 1H), 4.74 (dd, J = 14.8, 4.4 Hz, 1H), 4.45 - 4.57 (m, 1H), 4.30 - 4.42 (m, 2H), 4.07 (t, J = 10.0 Hz, 1H), 3.96 (q, J = 14.0 Hz, 2H), 3.13 - 3.24 (m, 2H), 3.01 - 3.11 (m, 1H), 2.82 - 3.00 (m, 4H), 2.63 - 2.76 (m, 1H), 2.17 - 2.31 (m, 2H), 1.53 - 1.80 (m, 4H). LC-MS: m / z 539.2 (M+H) + .

[0436] Example 17 2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 130a) [ka] Step A: 2-Bromo-1-(4-chloro-2-fluorophenyl)ethane-1-one To a solution of 1-(4-chloro-2-fluorophenyl)ethane-1-one (1.73 g, 10.0 mmol) in AcOH (10 ml), 4-(dimethylamino)pyridinetribromide (4.00 g, 11.0 mmol) was added. The reaction mixture was stirred at room temperature for 40 hours. Water (50 mL) was added, and the mixture was filtered. The filtered cake was washed with water and then dried under reduced pressure to obtain the title compound 2-bromo-1-(4-chloro-2-fluorophenyl)ethane-1-one (2.30 g, yield 92%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ ppm 7.91 (t, J = 8.0 Hz, 1H), 7.28 (dd, J = 8.4, 1.6 Hz, 1H), 7.22 (dd, J = 10.8, 2.0 Hz, 1H), 4.48 (d, J = 2.4 Hz, 2H).

[0437] Step B: 2-(4-chloro-2-fluorophenyl)-2-oxoethyl acetate To a solution of 2-bromo-1-(4-chloro-2-fluorophenyl)ethane-1-one (2.00 g, 8.00 mmol) in THF (30 mL, dry), CH3COOK (1.57 g, 16.0 mmol) and 18-crown-6 (1.06 g, 4.00 mmol) were added. The mixture was stirred at 60°C for 2 hours. The solvent was removed, and the residue was purified by flash chromatography using silica gel (eluting at PE / siRNA = 20 / 1) to obtain the title compound 2-(4-chloro-2-fluorophenyl)-2-oxoethyl acetate (1.00 g, yield 56%) as a yellow liquid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.90 (t, J = 8.0 Hz, 1H), 7.70 (dd, J = 10.8, 1.6 Hz, 1H), 7.49 (dd, J = 8.8, 2.0 Hz, 1H), 5.25 (d, J = 3.2 Hz, 2H), 2.14 (s, 3H).

[0438] Step C: 1-(4-chloro-2-fluorophenyl)ethane-1,2-diol To a solution of 2-(4-chloro-2-fluorophenyl)-2-oxoethyl acetate (810 mg, 3.52 mmol) in MeOH (15 mL), NaBH4 (200 mg, 5.28 mmol) was added at 0°C. The mixture was stirred at room temperature for 2 hours. The mixture was quenched with H2O (10 mL) at 0°C and extracted with ethyl acetate (50 mL x 3). The organic layer was washed with saline solution, dried over Na2SO4, concentrated, and purified by flash chromatography using silica gel (eluting at PE / ethyl acetate = 30 / 1) to obtain the title compound 1-(4-chloro-2-fluorophenyl)ethane-1,2-diol (610 mg, yield 91%) as a yellow liquid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.50 (t, J = 8.0 Hz, 1H), 7.33 (dd, J = 10.4, 2.0 Hz, 1H), 7.27 (dd, J = 8.8, 2.0 Hz, 1H), 5.46 (d, J = 4.8 Hz, 1H), 4.75 - 4.84 (m, 2H), 3.41 - 3.47 (m, 2H).

[0439] Step D: 2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-2-fluorophenyl)ethane-1-ol To a solution of 1-(4-chloro-2-fluorophenyl)ethane-1,2-diol (1.70 g, 9.04 mmol) in DMF (20 mL), TBSCl (1.64 g, 10.9 mmol) and imidazole (923 mg, 13.6 mmol) were added at 0°C. The mixture was stirred overnight at room temperature. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with water and saline solution, dried over Na2SO4, concentrated, and purified by flash chromatography using silica gel (eluting at PE / ethyl acetate = 10 / 1) to obtain the title compound 2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-2-fluorophenyl)ethane-1-ol (2.10 g, yield 78%) as a yellow liquid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.50 (t, J = 8.4 Hz, 1H), 7.33 (dd, J = 10.4, 2.0 Hz, 1H), 7.28 (dd, J = 8.8, 2.0 Hz, 1H), 5.52 (d, J = 4.8 Hz, 1H), 4.83 (q, J = 5.6 Hz, 1H), 3.68 (dd, J = 10.4, 6.0 Hz, 1H), 3.58 (dd, J = 10.4, 5.6 Hz, 1H), 0.78 (s, 9H), - 0.06 (s, 3H), - 0.09 (s, 3H).

[0440] Step E: tert-butyl(2-(4-chloro-2-fluorophenyl)-2-(2,6-dibromophenoxy)ethoxy)dimethylsilane To a solution of 2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-2-fluorophenyl)ethane-1-ol (500 mg, 1.65 mmol) in THF (5 mL), NaH (264 mg, 6.60 mmol) was added at -10 °C. After 30 minutes, 1,3-dibromo-2-fluorobenzene (419 mg, 1.65 mmol) was added. The mixture was stirred overnight at room temperature. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was dried over Na₂SO₄, concentrated, and purified by flash chromatography using silica gel (eluted with PE) to obtain the title compound tert-butyl(2-(4-chloro-2-fluorophenyl)-2-(2,6-dibromophenoxy)ethoxy)dimethylsilane (406 mg, yield 46%) as a yellow liquid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.72 (t, J = 8.4 Hz, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.45 (dd, J = 10.4, 2.0 Hz, 1H), 7.37 (dd, J = 8.4, 2.0 Hz, 1H), 7.00 (t, J = 8.0 Hz, 1H), 5.68 (t, J = 5.6 Hz, 1H), 4.16 (dd, J = 10.4, 6.4 Hz, 1H), 3.91 - 3.95 (m, 1H), 0.68 (s, 9H), - 0.09 (s, 3H), -0.12 (s, 3H).

[0441] Step F: 2-(4-chloro-2-fluorop...

Claims

1. Formula I: 【Chemistry 1】 Equation I [In the formula, 【Chemistry 2】 This indicates any single or double bond whose valence is acceptable; X １ 、X ２ 、X ３ 、X ４ 、X ５ 、X ６ 、X ７ 、and X ８ each of which is independently selected from the group consisting of C, CH, and N, provided that X １ 、X ２ 、X ３ 、X ４ 、X ５ 、X ６ 、X ７ 、and X ８ are at least two of them, and four or less are N; T １ It is a C(=O)OH or carboxylic acid bioisoster; T ２ is, (C １ -C ６ ) Alkoxy, (C １ -C ６ ) Haloalkoxy, (C ３ -C ６ ) They may be appropriately substituted with cycloalkyl, 3-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl (C １ -C ６ ) alkyl, and the (C ３ -C ６ Each of the cycloalkyl, 3-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl groups contains 1-4 R ｘ It is also acceptable if it is replaced as appropriate; Each R ｘ These are independently OH, SH, CN, NO ２ , halogen, (C １ -C ６ ) alkyl, (C ２ -C ６ ) Alkenil, (C ２ -C ６ ) Alkinyl, (C １ -C ６ ) Haloalkyl, (C １ -C ６ ) cyanoalkyl, (C １ -C ６ ) Hydroxyalkyl, (C １ -C ６ ) Alkoxy, (C １ -C ６ ) Haloalkoxy, (C ３ -C ６ ) Cycloalkyl, amino, (C １ -C ６ ) alkylamino and di(C １ -C ６ ) Selected from the group consisting of alkylaminos; L １ This is a bond or 1 to 3 R Ｌ It may be replaced as appropriate (C １ -C ３ ) is alkylene; L ２ is a bond, -O-, -S(O) ０－２ -, or -NH-; Each R Ｌ These are, independently, halogen, (C １ -C ３ ) alkyl, and (C １ -C ３ ) Selected from the group consisting of haloalkyl groups; or A pair of R on the same or adjacent carbon atoms Ｌ Each atom, together with the atom it is bonded to, (C ３ -C ６ ) forming a cycloalkyl ring; Ring A is, 1 to 4 R Ｙ Phenylene may be substituted as appropriate; ・ 1 to 3 R Ｙ A 5-6 member heteroalylene which may be substituted as appropriate; 1 to 4 R Ｙ A partially unsaturated monocyclic (C) which may be appropriately substituted. ５ -C ８ ) Cycloalkylene; 1 to 4 R Ｙ Partially unsaturated monocyclic 5- to 8-membered heterocycloalkylenes which may be substituted as appropriate; ・ 【Transformation 3】 (wherein n1 is 0, 1, or 2; W １ CR Ｙ１ or N; and W ２ CR Ｙ２ or N); and ・ 【Chemistry 4】 (In the formula, W ３ C, CR Ｙ３ , or N, L ３ is, (C １ -C ３ ) is alkylene, and each 【Transformation 5】 (These are, independently, single or double bonds, with acceptable valence.) It is selected from the group consisting of, mm is L ２ The bond point to is shown, and nn indicates the bond point to ring B; and R Ｙ Each of which is independently selected from the group consisting of halogen, cyano, -OH, oxo, (C １ -C ６ alkyl, (C １ -C ３ haloalkyl, (C １ -C ３ alkoxy, and (C １ -C ３ haloalkoxy; R Ｙ１ 、 R Ｙ２ 、 and R Ｙ３ are each independently selected from the group consisting of hydrogen, halogen, cyano, -OH, (C １ -C ６ ) alkyl, (C １ -C ３ ) haloalkyl, (C １ -C ３ ) alkoxy, and (C １ -C ３ ) haloalkoxy; or W １ However, CR Ｙ１ And, W ２ However, CR Ｙ２ If so, the R Ｙ１ and R Ｙ２ The base is (C １ -C ４ ) can form alkylene, and the (C １ -C ４ ) Alkilen CH ２ One of the units is O, S, NH, and N(C) １－３ ) These may be appropriately substituted with heteroatoms selected from the group consisting of alkyl groups; Ring B is (B-I) and (B-II): 【Transformation 6】 It is selected from the group consisting of, rr indicates a bond point to ring A; ss indicates a bond point to ring C; B １ and B ２ These are independently -O- and -NR Ｎ -, and -C(R １ ) ２ Selected from the group consisting of: B ６ is N or CR ａａ And; Each R １ Independently, hydrogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) Selected from the group consisting of haloalkyls and halogens; R Ｎ is hydrogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) Haloalkyl, C(=O)(C １ -C ６ ) alkyl, S(O) ２ (C １ -C ６ ) alkyl, and C(=O)O(C １ -C ６ ) Selected from the group consisting of alkyl groups; B ３ , B ４ , and B ５ CH, CR ａ Selected from the group consisting of , and N; Each R ａ These are, independently, halogen, (C １ -C ６ ) alkyl, (C １ -C ３ ) Alkyl (C ３ -C ６ ) Cycloalkyl, (C １ -C ３ ) Alkyl (3-5 member heterocycloalkyl), -C(O)NR ２ R ３ , and (C １ -C ６ ) Selected from the group consisting of fluoroalkyl; Each R ２ and R ３ H and (C １ -C ６ ) Selected from the group consisting of alkyl groups; R ａａ , R ａｂ , and R ａｃ These are H and (C) respectively, independently. １ -C ６ ) alkyl, and (C １ -C ６ ) Selected from the group consisting of haloalkyl; Ring C is phenyl, 5-6 member heteroaryl, (C ３ -C ６ ) Cycloalkyl, (C ５ -C １０ ) Selected from the group consisting of bicycloalkyl, 5-10 membered bicycloheteroaryl, and 3-6 membered heterocycloalkyl; Each R ｂ (C １ -C ６ ) alkyl, (C １ -C ６ ) Haloalkyl, (C １ -C ６ ) Alkyl, halogen, (C ３ -C ６ ) Selected from the group consisting of cycloalkyl and CN; and b is an integer selected from 0 to 3. The compound indicated by or its pharmaceutically acceptable salt or solvate.

2. Formula IA: 【Transformation 7】 Formula IA [In the formula, 【Transformation 8】 This indicates any single or double bond whose valence is acceptable; X １ , X ２ , X ３ , X ４ , X ５ , X ６ , X ７ , and X ８ Each of them is independently selected from the group consisting of C, CH, and N, except X １ , X ２ , X ３ , X ４ , X ５ , X ６ , X ７ , and X ８ At least two of these, and four or fewer, is N; T １ It is a C(=O)OH or carboxylic acid bioisoster; T ２ is, (C １ -C ６ ) Alkoxy, (C １ -C ６ ) Haloalkoxy, (C ３ -C ６ ) They may be appropriately substituted with cycloalkyl, 3-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl (C １ -C ６ ) alkyl, and the (C ３ -C ６ Each of the cycloalkyl, 3-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl groups contains 1-4 R ｘ It is also acceptable if it is replaced as appropriate; Each R ｘ These are independently OH, SH, CN, NO ２ , halogen, (C １ -C ６ ) alkyl, (C ２ -C ６ ) Alkenil, (C ２ -C ６ ) Alkinyl, (C １ -C ６ ) Haloalkyl, (C １ -C ６ ) cyanoalkyl, (C １ -C ６ ) Hydroxyalkyl, (C １ -C ６ ) Alkoxy, (C １ -C ６ ) Haloalkoxy, (C ３ -C ６ ) Cycloalkyl, amino, (C １ -C ６ ) alkylamino and di(C １ -C ６ ) Selected from the group consisting of alkylaminos; L １ This is a bond or 1 to 3 R Ｌ It may be replaced as appropriate (C １ -C ３ ) is alkylene; L ２ is a bond, -O-, -S(O) ０－２ -, or -NH-; Each R Ｌ These are, independently, halogen, (C １ -C ３ ) alkyl, and (C １ -C ３ ) Selected from the group consisting of haloalkyl groups; or A pair of R on the same or adjacent carbon atoms Ｌ Each atom, together with the atom it is bonded to, (C ３ -C ６ ) forming a cycloalkyl ring; Ring A is, 1 to 4 R Ｙ Phenylene may be substituted as appropriate; ・ 1 to 3 R Ｙ A 5-6 member heteroalylene which may be substituted as appropriate; 1 to 4 R Ｙ A partially unsaturated monocyclic (C) which may be appropriately substituted. ５ -C ８ ) Cycloalkylene; 1 to 4 R Ｙ Partially unsaturated monocyclic 5- to 8-membered heterocycloalkylenes which may be substituted as appropriate; ・ 【Chemistry 9】 (wherein n1 is 0, 1, or 2; W １ CR Ｙ１ or N; and W ２ CR Ｙ２ or N); and ・ 【Chemistry 10】 (In the formula, W ３ C, CR Ｙ３ , or N, L ３ is, (C １ -C ３ ) is alkylene, and each 【Chemistry 11】 These are, independently, single or double bonds with acceptable valence, provided that (1) W ３ The ring containing (2)L is partially unsaturated or ３ is, (C ２ -C ３ (It is alkylene.) It is selected from the group consisting of, mm is L ２ The bond point to is shown, and nn indicates the bond point to ring B; and R Ｙ Each of these is independently a halogen, cyano, -OH, oxo, (C １ -C ６ ) alkyl, (C １ -C ３ ) Haloalkyl, (C １ -C ３ )alkoxy, and (C １ -C ３ ) Selected from the group consisting of haloalkoxys; R Ｙ３ (C) １ -C ６ ) alkyl, (C １ -C ３ ) Haloalkyl, (C １ -C ３ )alkoxy, and (C １ -C ３ ) Selected from the group consisting of haloalkoxys; R Ｙ１ and R Ｙ２ These are, independently, halogen, cyano, -OH, (C １ -C ６ ) alkyl, (C １ -C ３ ) Haloalkyl, (C １ -C ３ )alkoxy, and (C １ -C ３ ) Selected from the group consisting of haloalkoxys; or R Ｙ１ and R Ｙ２ The base is (C １ -C ４ ) forms alkylene, and the (C １ -C ４ ) Alkilen CH ２ One of the units is O, S, NH, and N(C) １－３ ) These may be appropriately substituted with heteroatoms selected from the group consisting of alkyl groups; Ring B is (B-I) and (B-II): 【Chemistry 12】 It is selected from the group consisting of, rr indicates a bond point to ring A; ss indicates a bond point to ring C; B １ and B ２ These are independently -O- and -NR Ｎ -, and -C(R １ ) ２ Selected from the group consisting of: B ６ is N or CR ａａ And; Each R １ Independently, hydrogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) Selected from the group consisting of haloalkyls and halogens; R Ｎ is hydrogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) Haloalkyl, C(=O)(C １ -C ６ ) alkyl, S(O) ２ (C １ -C ６ ) alkyl, and C(=O)O(C １ -C ６ ) Selected from the group consisting of alkyl groups; B ３ , B ４ , and B ５ CH, CR ａ Selected from the group consisting of , and N; Each R ａ These are, independently, halogen, (C １ -C ６ ) alkyl, (C １ -C ３ ) Alkyl (C ３ -C ６ ) Cycloalkyl, (C １ -C ３ ) Alkyl (3-5 member heterocycloalkyl), -C(O)NR ２ R ３ , and (C １ -C ６ ) Selected from the group consisting of fluoroalkyl; Each R ２ and R ３ H and (C １ -C ６ ) Selected from the group consisting of alkyl groups; R ａａ , R ａｂ , and R ａｃ These are H and (C) respectively, independently. １ -C ６ ) alkyl, and (C １ -C ６ ) Selected from the group consisting of haloalkyl; Ring C is phenyl, 5-6 member heteroaryl, (C ３ -C ６ ) Cycloalkyl, (C ５ -C １０ ) Selected from the group consisting of bicycloalkyl, 5-10 membered bicycloheteroaryl, and 3-6 membered heterocycloalkyl; Each R ｂ (C １ -C ６ ) alkyl, (C １ -C ６ ) Haloalkyl, (C １ -C ６ ) Alkyl, halogen, (C ３ -C ６ ) Selected from the group consisting of cycloalkyl and CN; and b is an integer selected from 0 to 3. The compound indicated by or its pharmaceutically acceptable salt or solvate.

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

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

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

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

7. X ２ However, N is X ３ However, C is; and X ４ The compound according to any one of claims 1 to 6, wherein N is present.

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

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

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

11. X １ However, N is; and X ６ The compound according to claim 9, wherein the compound is CH.

12. X １ However, CH is; and X ６ The compound according to claim 9, wherein N is present.

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

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

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

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

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

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

19. T ２ but, 【Chemistry 13】 The compound according to any one of claims 1 to 18. 【Request Item 20】 【Chemistry 14】 The compound according to claim 19, wherein the stereocenter has an (S) configuration.

21. L ２ The compound according to any one of claims 1 to 20, wherein the compound is bonded.

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

23. L １ However, CH ２ is; and L ２ The compound according to any one of claims 1 to 22, wherein the bond is a combination.

24. Ring A is 【Chemistry 15】 The compound according to any one of claims 1 or 3 to 23.

25. W １ The compound according to claim 24, wherein N is present.

26. W ２ However, CR Ｙ２ The compound according to claim 24 or 25.

27. R Ｙ２ The compound according to claim 26, wherein the compound is hydrogen.

28. W ２ The compound according to any one of claims 24 to 25, wherein N is present.

29. The compound according to any one of claims 24 to 28, wherein n1 is 0.

30. The compound according to any one of claims 24 to 28, wherein n1 is 1.

31. Ring A is 【Chemistry 16】 The compound according to any one of claims 1, 3 to 27, or 29.

32. Ring A is 【Chemistry 17】 The compound according to any one of claims 1, 3 to 27, or 30.

33. Ring A is [Chemistry 18] The compound according to any one of claims 1, 3 to 25, or 28 to 29.

34. Ring A is 1 to 4 R Ｙ Phenylene which may be substituted as appropriate; and 1 to 3 R Ｙ Five- to six-membered heteroalylenes which may be substituted as appropriate. A compound according to any one of claims 1 to 23, selected from the group consisting of the following.

35. Ring A is 1 to 4 R Ｙ Phenylene which may be substituted as appropriate; and 1 to 3 R Ｙ A six-membered heteroalylene which may be substituted as appropriate. A compound according to any one of claims 1 to 23 or 34, selected from the group consisting of, wherein mm is para or meta with respect to nn.

36. Ring A has 1 to 2 R Ｙ The compound according to any one of claims 1 to 23 or 34 to 35, wherein phenylene may be appropriately substituted with; mm is para or meta with respect to nn.

37. Ring A has 1 to 2 R Ｙ The compound according to any one of claims 1 to 23 or 34 to 36, wherein 1,4-phenylene may be appropriately substituted with 1,4-phenylene.

38. Ring A is 【Chemistry 19】 The compound according to any one of claims 1 to 23 or 34 to 37.

39. Ring A is 1 to 4 R Ｙ A partially unsaturated monocyclic (C) which may be appropriately substituted. ５ -C ８ ) Cycloalkylenes; and 1 to 4 R Ｙ Partially unsaturated monocyclic 5- to 8-membered heterocycloalkylenes which may be substituted as appropriate. A compound according to any one of claims 1 to 23, selected from the group consisting of the following.

40. Ring A is 1 to 4 R Ｙ Partially unsaturated monocyclic C, which may be appropriately substituted. ６ Cycloalkylenes; and 1 to 4 R Ｙ A partially unsaturated monocyclic six-membered heterocycloalkylene which may be substituted as appropriate. The compound according to claim 39, selected from the group consisting of the above, wherein mm is para with respect to nn.

41. L １ However, CH ２ And; L ２ However, it is a bond; and ring A is, 【Chemistry 20】 The compound according to any one of claims 1 to 20.

42. Ring A is 【Chemistry 21】 The compound according to claim 41.

43. Ring A is 【Chemistry 22】 And; as well as R Ｙ However, (C １ -C ３ The compound according to claim 41, wherein it is alkyl.

44. Ring A is 【Chemistry 23】 The compound according to claim 41.

45. L １ However, CH ２ And; L ２ However, it is a bond; and ring A is, 1 to 4 R Ｙ Phenylene which may be substituted as appropriate; and 1 to 3 R Ｙ A six-membered heteroalylene which may be substituted as appropriate. A compound according to any one of claims 1 to 20, selected from the group consisting of the above, wherein mm is para or meta with respect to nn.

46. Ring A has 1 to 2 R Ｙ The compound according to claim 45, wherein phenylene may be appropriately substituted with, and mm is para or meta with respect to nn.

47. Ring A is 【Chemistry 24】 The compound according to claim 46.

48. Ring B is 【Chemistry 25】 (B-Ia) The compound according to any one of claims 1 to 47.

49. Ring B is 【Chemistry 26】 (B-IIa) The compound according to any one of claims 1 to 47.

50. B １ The compound according to any one of claims 1 to 49, wherein the compound is -O-.

51. B １ However, -C(R １ ) ２ - The compound according to any one of claims 1 to 49.

52. B １ However, -CH ２ - The compound according to any one of claims 1 to 49 or 51.

53. B ２ The compound according to any one of claims 1 to 52, wherein the compound is -O-.

54. B ２ However, -C(R １ ) ２ - The compound according to any one of claims 1 to 52.

55. B ２ However, -CH ２ - The compound according to any one of claims 1 to 52 or 54.

56. B ２ However, -NR Ｎ - The compound according to any one of claims 1 to 52.

57. B ２ The compound according to any one of claims 1 to 52 or 56, wherein the compound is -NH-.

58. B １ However, -O- and B ２ The compound according to any one of claims 1 to 49, wherein the compound is -O-.

59. B １ However, -O- and B ２ However, -NR Ｎ - The compound according to any one of claims 1 to 49.

60. B １ However, -O- and B ２ The compound according to any one of claims 1 to 49 or 59, wherein the compound is -NH-.

61. B １ However, -O- and B ２ However, -C(R １ ) ２ - The compound according to any one of claims 1 to 49.

62. B １ However, -O- and B ２ However, -CH ２ - The compound according to any one of claims 1 to 49 or 61.

63. B １ However, -C(R １ ) ２ - and; as well as B ２ The compound according to any one of claims 1 to 49, wherein the compound is -O-.

64. B １ However, -CH ２ - and; as well as B ２ The compound according to any one of claims 1 to 49 or 63, wherein the compound is -O-.

65. Ring B is 【Chemistry 27】 (B-Ib) The compound according to any one of claims 1 to 48.

66. B １ However, -C(R １ ) ２ - The compound according to claim 65.

67. B ２ However, -C(R １ ) ２ - The compound according to claim 65 or 66.

68. R ａａ The compound according to any one of claims 1 to 64, wherein H is present.

69. R ａａ However, (C １ -C ６ The compound according to any one of claims 1 to 64, wherein it is alkyl.

70. R ａａ The compound according to any one of claims 1 to 64 or 69, wherein the compound is methyl.

71. R ａｂ The compound according to any one of claims 1 to 70, wherein H is present.

72. R ａｃ The compound according to any one of claims 1 to 71, wherein H is present.

73. R ａａ However, it is H; R ａｂ However, H is; and R ａｃ The compound according to any one of claims 1 to 64, wherein H is present.

74. R ａａ However, (C １ -C ３ ) is alkyl; R ａｂ However, H is; and R ａｃ The compound according to any one of claims 1 to 64, wherein H is present.

75. B ３ , B ４ , and B ５ However, independently, CH or CR ａ The compound according to any one of claims 1 to 74.

76. B ３ , B ４ , and B ５ The compound according to any one of claims 1 to 75, wherein the compound is CH.

77. B ６ However, CR ａａ B １ However, it is -O-; B ２ However, -O- and B ３ , B ４ , and B ５ However, independently, CH or CR ａ The compound according to any one of claims 1 to 49.

78. B ６ However, CR ａａ B １ However, it is -O-; B ２ However, it is -NH-; and B ３ , B ４ , and B ５ However, independently, CH or CR ａ The compound according to any one of claims 1 to 49.

79. B ６ However, CR ａａ B １ However, it is -O-; B ２ However, -CH ２ - and; as well as B ３ , B ４ , and B ５ However, independently, CH or CR ａ The compound according to any one of claims 1 to 49.

80. B ６ However, CR ａａ B １ However, -CH ２ - and; B ２ However, -O- and B ３ , B ４ , and B ５ However, independently, CH or CR ａ The compound according to any one of claims 1 to 49.

81. B ３ , B ４ , and B ５ The compound according to any one of claims 77 to 80, wherein the compound is CH.

82. B ６ However, CR ａａ B １ and B ２ However, -O- and B ３ , B ４ , and B ５ The compound according to any one of claims 1 to 49, wherein the compound is CH.

83. B ６ However, CR ａａ B １ and B ２ One of them is -O-; B １ and B ２ The other side is -CH ２ - or -NH-; and B ３ , B ４ , and B ５ The compound according to any one of claims 1 to 49, wherein the compound is CH.

84. R ａａ However, it is H; R ａｂ However, H is; and R ａｃ The compound according to any one of claims 77 to 83, wherein H is present.

85. R ａａ However, (C １ -C ３ ) is alkyl; R ａｂ However, H is; and R ａｃ The compound according to any one of claims 77 to 83, wherein H is present.

86. Ring B is 【Chemistry 28】 (B-Ia) And in the formula, B ３ , B ４ , and B ５ However, each is CH; B １ and B ２ However, each of them is -O-; R ａｃ and R ａｂ However, each is H; and R ａａ However, H or (C １ -C ３ The compound according to any one of claims 1 to 48, wherein it is alkyl.

87. Ring B is (B - I); B ６ However, CR ａａ And; as well as R ａａ and B ２ The compound according to any one of claims 1 to 48, 50 to 64, or 68 to 86, wherein the carbon atom to which both are bonded has an (S)- configuration.

88. Ring B is (B - I); B ６ However, CR ａａ And R ａａ and B ２ The compound according to any one of claims 1 to 48, 50 to 64, or 68 to 86, wherein the carbon atom to which both are bonded has an (R)- configuration.

89. Ring B is 【Chemistry 29】 (B-IIa) And in the formula, B ３ , B ４ , and B ５ However, each is CH; B １ and B ２ However, each of them is -O-; R ａｃ and R ａｂ However, each is H; and R ａａ However, H or (C １ -C ３ The compound according to any one of claims 1 to 48, wherein it is alkyl.

90. Ring B is (B-II); B ６ However, CR ａａ And; as well as R ａａ and B １ The compound according to any one of claims 1 to 47, 49 to 64, 68 to 85, or 89, wherein the carbon atom to which both are bonded has an (S)- configuration.

91. Ring B is (B-II); B ６ However, CR ａａ And; as well as R ａａ and B １ The compound according to any one of claims 1 to 47, 49 to 64, 68 to 85, or 89, wherein the carbon atom to which both are bonded has an (R)- configuration.

92. Ring B is 【Transformation 30】 A compound according to any one of claims 1 to 47, selected from the group consisting of the following.

93. The compound according to claim 92, wherein the carbon atom marked with an asterisk has an (R)- configuration.

94. The compound according to claim 92, wherein the carbon atom marked with an asterisk has an (S)- configuration.

95. The compound according to any one of claims 1 to 94, wherein ring C is selected from the group consisting of phenyl, 5-6 membered heteroaryl, and 5-10 membered bicycloheteraryl.

96. The compound according to any one of claims 1 to 95, wherein ring C is phenyl.

97. The compound according to any one of claims 1 to 96, wherein b is 1 to 3.

98. The compound according to any one of claims 1 to 97, wherein b is 2.

99. The compound according to any one of claims 1 to 97, wherein b is 1.

100. The compound according to any one of claims 1 to 96, wherein b is 0.

101. The compound according to any one of claims 1 to 98, wherein ring C is phenyl; and b is 2. 【Request Item 102】 【Chemistry 31】 but, 【Chemistry 32】 The compound according to any one of claims 1 to 98 or 101. 【Request Item 103】 【Chemistry 33】 but, 【Transformation 34】 The compound according to any one of claims 1 to 98 or 101.

104. The compound according to any one of claims 1 to 97 or 99, wherein ring C is phenyl; and b is 1. 【Request Item 105】 【Chemistry 35】 but, 【Transformation 36】 The compound according to any one of claims 1 to 97, 99, or 104. 【Request Item 106】 【Chemistry 37】 but, 【Transformation 38】 The compound according to any one of claims 1 to 97, 99, or 104. 【Request Item 107】 【Chemistry 39】 but, 【Chemistry 40】 The compound according to any one of claims 1 to 97, 99, or 104.

108. The compound according to any one of claims 1 to 96 or 100, wherein ring C is phenyl; and b is 0.

109. R ｂ Each of them independently, (C １ -C ６ ) alkyl, (C １ -C ６ ) Haloalkyl, (C １ -C ６ ) A compound according to any one of claims 1 to 108, selected from the group consisting of alkoxy, halogen, and CN.

110. R ｂ Each of these independently produces -F, -Cl, and -CH. ３ , -CF ３ The compound according to claim 109, selected from the group consisting of , and CN.

111. R ｂ The compound according to claim 109 or 110, wherein each of is independently selected from the group consisting of -F, -Cl, and -CN.

112. The aforementioned compound is of formula IB: 【Chemistry 41】 Formula IB The compound according to claim 1, which is a compound represented by or a pharmaceutically acceptable salt thereof.

113. The compound has the formula IC: 【Chemistry 42】 Formula IC The compound according to claim 1, which is a compound represented by or a pharmaceutically acceptable salt thereof.

114. The aforementioned compound has formula ID: 【Chemistry 43】 Expression ID The compound according to claim 1, which is a compound represented by or a pharmaceutically acceptable salt thereof.

115. The aforementioned compound is given by formula IE: 【Chemistry 44】 Formula IE The compound according to claim 1, which is a compound represented by or a pharmaceutically acceptable salt thereof.

116. B ３ , B ４ , and B ５ However, independently, CH and CR ａ A compound according to any one of claims 112 to 115, selected from the group consisting of the following.

117. B ３ , B ４ , and B ５ The compound according to any one of claims 112 to 116, wherein the compound is CH.

118. R ａａ However, H is; and R ａｂ and R ａｃ The compound according to any one of claims 112 to 117, wherein H is present.

119. R ａａ However, (C １ -C ３ ) is alkyl; and R ａｂ and R ａｃ The compound according to any one of claims 112 to 117, wherein H is present.

120. X ８ , X ５ , and X ３ However, C is X ２ and X ４ However, N is X ７ However, CH is; and X １ and X ６ The compound according to any one of claims 112 to 119, wherein the compound is independently CH or N.

121. X １ However, N is; and X ６ The compound according to claim 120, wherein the compound is CH.

122. X １ However, CH is; and X ６ The compound according to claim 120, wherein the compound is CH.

123. X １ However, CH is; and X ６ The compound according to claim 120, wherein N is present.

124. T １ The compound according to any one of claims 112 to 123, wherein the compound is C(=O)OH.

125. T ２ However, it is substituted with a 4-6 member heterocycloalkyl group (C １ -C ３ The compound according to any one of claims 112 to 124, wherein it is alkyl.

126. T ２ However, it is substituted with oxetanyl (C １ -C ３ The compound according to claim 125, wherein it is alkyl.

127. T ２ but, 【Chemistry 45】 The compound according to claim 126.

128. T ２ The compound according to claim 127, wherein the stereocenter has an (S) configuration.

129. L １ However, CH ２ And; L ２ However, it is a bond; and ring A is, 【Chemistry 46】 The compound according to any one of claims 112 to 128.

130. Ring A is 【Chemistry 47】 The compound according to claim 129.

131. Ring A is 【Chemistry 48】 And; as well as R Ｙ However, (C １ -C ３ The compound according to claim 129, wherein it is alkyl.

132. Ring A is 【Chemistry 49】 The compound according to claim 129.

133. L １ However, CH ２ And; L ２ However, it is a bond; and ring A is, 1 to 4 R Ｙ Phenylene which may be substituted as appropriate; and 1 to 3 R Ｙ Five- to six-membered heteroalylenes which may be substituted as appropriate. A compound according to any one of claims 112 to 128, selected from the group consisting of the following.

134. The compound according to claim 133, wherein mm is meta or para with respect to nn.

135. Ring A has 1 to 2 R Ｙ The compound according to claim 113 or 134, wherein phenylene may be appropriately substituted with, and mm is meta or para with respect to nn.

136. Ring A has 1 to 2 R Ｙ The compound according to claim 135, wherein 1,4-phenylene may be appropriately substituted with phenylene.

137. Ring A is [Transformation 50] The compound according to claim 136.

138. The compound according to any one of claims 112 to 137, wherein ring C is phenyl.

139. The compound according to any one of claims 112 to 138, wherein b is 1 to 3.

140. The compound according to claim 139, wherein b is 2.

141. The compound according to claim 139, wherein b is 1.

142. The compound according to any one of claims 112 to 138, wherein b is 0.

143. The compound according to any one of claims 112 to 139, wherein ring C is phenyl; and b is 2. 【Request Item 144】 【Chemistry 51】 but, 【Chemistry 52】 The compound according to any one of claims 112 to 139 or 143. 【Request Item 145】 【Chemistry 53】 but, 【Chemistry 54】 The compound according to any one of claims 112 to 139 or 143.

146. The compound according to any one of claims 112 to 138, wherein ring C is phenyl; and b is 1. 【Request Item 147】 【Chemistry 55】 but, 【Transformation 56】 The compound according to any one of claims 112 to 138 or 146. 【Request Item 148】 【Chemistry 57】 but, 【Transformation 58】 The compound according to any one of claims 112 to 138 or 146. 【Request Item 149】 【Chemistry 59】 but, 【Transformation 60】 The compound according to any one of claims 112 to 138 or 146.

150. The compound according to any one of claims 112 to 138, wherein ring C is phenyl; and b is 0.

151. R ｂ Each of them independently, (C １ -C ６ ) alkyl, (C １ -C ６ ) Haloalkyl, (C １ -C ６ ) A compound according to any one of claims 112 to 149, selected from the group consisting of alkoxy, halogen, and CN.

152. R ｂ Each of these independently produces -F, -Cl, and -CH. ３ , -CF ３ The compound according to claim 151, selected from the group consisting of , and CN.

153. R ｂ The compound according to claim 151 or 152, wherein each of is independently selected from the group consisting of -F, -Cl, and CN.

154. The aforementioned R ａａ The compound according to any one of claims 112 to 153, wherein the carbon atom to which both the ring C is bonded has an (S)- configuration.

155. The aforementioned R ａａ The compound according to any one of claims 112 to 153, wherein the carbon atom to which both the ring C is bonded has an (R)- configuration.

156. The compound according to any one of claims 1 to 155, wherein the compound represented by formula I is selected from the group consisting of the compounds of Table C1 and Table C2 or pharmaceutically acceptable salts or solvates thereof.

157. A pharmaceutical composition comprising a compound according to any one of claims 1 to 156 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

158. A method for treating type 2 diabetes in a patient requiring treatment, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 156 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 157.

159. A method for treating type 2 diabetes in a patient, comprising administering to a patient identified or diagnosed with type 2 diabetes in a therapeutically effective amount of a compound according to any one of claims 1 to 156 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 157.

160. A method for treating diabetes in patients, a) Determine that the patient has type 2 diabetes; then b) A method comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 156 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 157.

161. The method according to any one of claims 158 to 160, wherein the step of determining that the patient has type 2 diabetes includes performing an assay to determine the level of an analyte in a sample from a sample from the patient, wherein the analyte is selected from the group consisting of hemoglobin A1c (HbA1c), fasting blood glucose, non-fasting blood glucose, or any combination thereof.

162. The method according to claim 161, wherein the HbA1c level is approximately 6.5% or higher.

163. The method according to any one of claims 161 to 162, wherein the fasting blood glucose level is approximately 126 mg / dL or higher.

164. The method according to any one of claims 161 to 162, wherein the non-fasting blood glucose level is about 200 mg / dL or higher.

165. The method according to any one of claims 158 to 164, further comprising obtaining a sample from the patient.

166. The method according to claim 165, wherein the sample is a body fluid sample.

167. The method according to any one of claims 158 to 166, wherein the patient is approximately 40 to approximately 70 years old and is overweight or obese.

168. The aforementioned patient weighed approximately 22 kg / m². ２ The method according to any one of claims 158 to 167, wherein the body mass index (BMI) is or higher.

169. The aforementioned patient weighed approximately 30 kg / m². ２ The method according to any one of claims 158 to 168, wherein the BMI is or greater.

170. The method according to any one of claims 158 to 169, wherein the treatment of type 2 diabetes includes reducing fasting blood glucose levels.

171. The method according to claim 170, wherein the fasting blood glucose level is reduced to about 100 mg / dL or less.

172. The method according to any one of claims 158 to 171, wherein the treatment of type 2 diabetes includes a reduction in HbA1c levels.

173. The method according to claim 172, wherein the HbA1c level is reduced to approximately 5.7% or less.

174. The method according to any one of claims 158 to 173, wherein the treatment of type 2 diabetes includes reducing glucagon levels.

175. The method according to any one of claims 158 to 174, wherein the treatment of type 2 diabetes includes increasing insulin levels.

176. The method according to any one of claims 158 to 175, wherein the treatment of type 2 diabetes includes a reduction in BMI.

177. The aforementioned BMI is approximately 25 kg / m². ２ The method according to claim 176, which reduces the amount to or less than that.

178. The method according to any one of claims 158 to 177, wherein the compound according to any one of claims 1 to 156 or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition according to claim 157, is administered orally.

179. The method according to any one of claims 158 to 178, further comprising administering a further therapy or therapeutic agent to the patient.

180. The method according to claim 179, wherein the further therapy or therapeutic agent is selected from the group consisting of antidiabetic drugs, anti-obesity drugs, GLP-1 receptor agonists, non-alcoholic steatohepatitis (NASH) treatments, gastric electrical stimulation, dietary monitoring, physical activity, or any combination thereof.

181. The method according to claim 180, wherein the antidiabetic drug is selected from the group consisting of biguanides, sulfonylureas, glitazar, thiazolidinediones, dipeptidyl peptidase 4 (DPP-4) inhibitors, meglitinides, sodium-dependent glucose transporter 2 (SGLT2) inhibitors, glitazone, GRP40 agonists, glucose-dependent insulinotropic polypeptides (GIP), insulin or insulin analogs, alpha-glucosidase inhibitors, sodium-dependent glucose transporter 1 (SGLT1) inhibitors, or any combination thereof.

182. The method according to claim 181, wherein the biguanide is metformin.

183. The aforementioned anti-obesity drug is a neuropeptide Y receptor type 2 (NPYR2) agonist, an NPYR1 or NPYR5 antagonist, or a human proislet peptide. The method according to claim 180, comprising a peptide (HIP), a cannabinoid receptor type 1 (CB1R) antagonist, a lipase inhibitor, a melanocortin receptor 4 agonist, a farnesoid X receptor (FXR) agonist, phentermine, zonisamide, norepinephrine / dopamine reuptake inhibitor, a GDF-15 analog, an opioid receptor antagonist, a cholecystokinin agonist, a serotonergic agent, a methionine aminopeptidase 2 (MetAP2) inhibitor, diethylpropion, fendimethrazine, benzfetamine, a fibroblast growth factor receptor (FGFR) modifier, an AMP-activated protein kinase (AMPK) activator, a sodium-glucose transporter 1 (SGLT-1) inhibitor, or any combination thereof, selected from the group.

184. The method according to claim 180, wherein the GLP-1 receptor agonist is selected from the group consisting of liraglutide, exenatide, dulaglutide, albiglutide, taspoglutide, lixisenatide, semaglutide, or any combination thereof.

185. The method according to claim 180, wherein the NASH therapeutic agent is selected from the group consisting of FXR agonists, PF-05221304, synthetic fatty acid bile conjugates, anti-lysyl oxidase analog 2 (LOXL2) monoclonal antibodies, caspase inhibitors, MAPK5 inhibitors, galectin 3 inhibitors, fibroblast growth factor 21 (FGF21) agonists, niacin analogs, leukotriene D4 (LTD4) receptor antagonists, acetyl-CoA carboxylase (ACC) inhibitors, ketohexokinase (KHK) inhibitors, ileal bile acid transporter (IBAT) inhibitors, apoptosis signal-regulated kinase 1 (ASK1) inhibitors, peroxisome proliferator-activated receptor (PPAR) agonists, diacylglycerol acyltransferase 2 (DGAT2) inhibitors, or any combination thereof.

186. The method according to any one of claims 179 to 185, wherein a compound according to any one of claims 1 to 156 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 157, and a further therapeutic agent are administered sequentially in any order as separate formulations.

187. A method for regulating insulin levels in a patient requiring adjustment, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 156 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 157.

188. The method according to claim 187, wherein the adjustment results in an increase in insulin levels.

189. A method for regulating glucose levels in a patient requiring adjustment, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 156 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 157.

190. The method according to claim 189, wherein the adjustment results in a decrease in glucose levels.

191. A method for treating a GLP-1 related disease, disorder, or illness, comprising administering an effective amount of a compound according to any one of claims 1 to 156 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 157, to a patient in need thereof.

192. The aforementioned diseases, disorders, or illnesses include type 1 diabetes, type 2 diabetes, juvenile-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), juvenile-onset atypical diabetes (YOAD), juvenile-onset adult-onset diabetes (MODY), adult latent autoimmune diabetes (LADA), obesity, weight gain due to the use of other medications, idiopathic intracranial hypertension, Wolfram syndrome, gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, and gestational diabetes. Kidney disease, adipocyte dysfunction, sleep apnea, visceral fat accumulation, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral artery disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, vascular restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial hyperlipidemia The method according to claim 191, selected from the group consisting of: disease, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, alcohol intake disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, treatment of addiction, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, psychogenic polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof.

193. The aforementioned diseases, disorders, or illnesses include type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat accumulation, eating disorders, cardiovascular diseases, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral artery disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, and The method according to claim 192, selected from the group consisting of: impaired blood sugar intake, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, psychogenic polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS), idiopathic intracranial hypertension, Wolfram syndrome, or any combination thereof.

194. The method according to claim 193, wherein the disease, disorder, or illness includes, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other drugs, gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat accumulation, myocardial infarction, peripheral artery disease, stroke, transient ischemic attack, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, chronic renal failure, syndrome X, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, skin and connective tissue disorders, foot ulcers, idiopathic intracranial hypertension, Wolfram syndrome, or any combination thereof.

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