Heterocyclic GLP-1 agonist

Abstract

The present disclosure provides a compound of formula (I): TIFF2023513272000257.tif3657 formula (I) (including pharmaceutically acceptable salts and solvates thereof) and pharmaceutical compositions containing the same.

Description

Technical Field

[0001] Cross - reference to related applications This application claims the benefit of International Patent Application No. PCT / CN2020 / 109304, filed on August 14, 2020; and International Patent Application PCT / CN2020 / 074537, filed on February 7, 2020 (each of which is hereby incorporated by reference in its entirety).

[0002] Technical Field The present disclosure relates to GLP - 1 agonists, pharmaceutical compositions, and methods of using the same.

Background Art

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

[0004] Diabetes refers to a group of metabolic diseases characterized by persistent hyperglycemia. The most common type, type 2 diabetes mellitus (T2DM), is an acquired disease that accounts for more than 90% of diabetes cases. Typical onset occurs in obese or sedentary adults and begins with insulin resistance. Lifestyle changes can be useful in the management of this disease, but T2DM patients may need to take diabetes therapeutics, including, inter alia, 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 significantly reduced in the case of T2DM (in all cases), but GLP-1 retains its insulin secretory properties even when the endocrine pancreatic response to GIP is effectively abolished. Thus, incretin mimetics and other GLP-1-based therapies can assist in activating insulin production in patients with T2DM.

Summary of the Invention

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

[0007] Thus, formula (I):

Chemical Formula

Chem.

Chem.

Chemical formula

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

[0009] A method for treating type 2 diabetes in a patient in need of 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, is also provided herein.

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

[0011] A method for treating diabetes in a patient, 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, is also provided. In certain embodiments, 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 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 certain embodiments, the HbA1c level is about 6.5% or greater. In certain embodiments, the fasting blood glucose level is about 126 mg / dL or greater. In certain embodiments, the non-fasting blood glucose level is about 200 mg / dL or greater.

[0012] In certain embodiments, the method further includes obtaining a sample from the patient. In certain embodiments, the sample is a body fluid sample. In certain embodiments, the patient is about 40 to about 70 years old and is overweight or obese. In certain embodiments, the patient has a body mass index (BMI) of about 22 kg / m 2 or greater. In certain embodiments, the patient has a body mass index (BMI) of about 30 kg / m2 having a BMI of 25 or more.

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

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

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

[0016] In certain embodiments, the method for treating type 2 diabetes comprises reducing the insulin level.

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

[0018] In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, is administered orally.

[0019] In certain embodiments, the method for treating type 2 diabetes further comprises administering an additional therapy or therapeutic agent to the patient. In certain embodiments, the additional therapy or therapeutic agent is selected from the group consisting of antidiabetic agents, anti-obesity agents, GLP-1 receptor agonists, non-alcoholic steatohepatitis (NASH) therapeutic agents, gastric electrical stimulation, dietary monitoring, physical activity, or any combination thereof. In certain embodiments, the antidiabetic agent is selected from the group consisting of biguanides, sulfonylureas, glitazars, thiazolidinediones, dipeptidyl peptidase 4 (DPP-4) inhibitors, meglitinides, sodium-dependent glucose transporter 2 (SGLT2) inhibitors, glitazones, GRP40 agonists, glucose-dependent insulinotropic polypeptide (GIP), insulin or insulin analogs, alpha-glucosidase inhibitors, sodium-dependent glucose transporter 1 (SGLT1) inhibitors, or any combination thereof. In certain embodiments, the biguanide is metformin. In certain embodiments, the anti-obesity agent is selected from the group consisting of neuropeptide Y receptor type 2 (NPYR2) agonists, NPYR1 or NPYR5 antagonists, human proislet peptide (HIP), cannabinoid receptor type 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, serotoninergic agents, methionine aminopeptidase 2 (MetAP2) inhibitors, diethylpropion, fenfluramine, benzphetamine, fibroblast growth factor receptor (FGFR) modifiers, AMP-activated protein kinase (AMPK) activators, sodium-glucose transporter 1 (SGLT-1) inhibitors, or any combination thereof.In certain embodiments, the GLP-1 receptor agonist is selected from the group consisting of liraglutide, exenatide, dulaglutide, albiglutide, taspoglutide, lixisenatide, semaglutide, or any combination thereof. In certain embodiments, the NASH therapeutic agent is an FXR agonist, PF-05221304, a synthetic fatty acid bile conjugate, an anti-lysyl oxidase-like 2 (LOXL2) monoclonal antibody, a caspase inhibitor, a MAPK5 inhibitor, a galectin-3 inhibitor, a fibroblast growth factor 21 (FGF21) agonist, a niacin analog, a leukotriene D4 (LTD4) receptor antagonist, an acetyl-CoA carboxylase (ACC) inhibitor, a ketohexokinase (KHK) inhibitor, an ileal bile acid transporter (IBAT) inhibitor, an apoptosis signal-regulating kinase 1 (ASK1) inhibitor, a peroxisome proliferator-activated receptor (PPAR) agonist, a diacylglycerol acyltransferase 2 (DGAT2) inhibitor, or any combination thereof. In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, and a further therapeutic agent are administered sequentially in any order as separate formulations.

[0020] Also provided herein is a method for modulating insulin levels in a patient in need thereof, the method 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 certain embodiments, the modulation results in an increase in insulin levels.

[0021] Also provided herein is a method for modulating glucose levels in a patient in need thereof, the method 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 certain embodiments, the modulation results in a decrease in glucose levels.

[0022] A method for treating a GLP-1 related disease, disorder, or illness, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, is also provided herein. In certain embodiments, the disease, disorder, or illness is type 1 diabetes, type 2 diabetes, juvenile-onset type 2 diabetes, fulminant type 1 diabetes (type 1b), young-onset atypical diabetes (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes in adults (LADA), obesity, weight gain due to the use of other agents, 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 arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial disorder, vascular compliance disorder, restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorder, insulin resistance, hepatic insulin resistance, alcohol intake disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataract, glomerulosclerosis, arthritis, osteoporosis, treatment of poisoning, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, psychogenic polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof.In certain embodiments, the disease, disorder, or illness is selected from the group consisting of type 2 diabetes, juvenile-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, abnormal glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic kidney disease, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina, 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 fatty liver disease (NASH), non-alcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS), or any combination thereof. In certain embodiments, the disease, disorder, or illness includes, but is not limited to, type 2 diabetes, juvenile-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, abnormal glucose metabolism, insulin resistance, hepatic insulin resistance, chronic kidney disease, syndrome X, angina, 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 cited herein are incorporated herein by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent that any incorporated publications, patents, and patent applications conflict with the disclosure contained herein, the present specification shall control and / or be ranked superior to such conflicting documents.

[0024] Other features and advantages of the invention will be apparent from the following detailed description, drawings, and claims.

Mode for Carrying Out the Invention

[0025] Detailed Description Heterocyclic GLP-1 agonists are provided herein for use in the treatment of type 2 diabetes (T2DM) and other diseases where activation of GLP-1 activity is useful.

[0026] Definitions When a numerical value is described as a range, all possible sub-ranges within such range, as well as descriptions of specific numerical values within such range, are understood to be included regardless of whether a specific numerical value or specific sub-range is explicitly indicated.

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

[0028] As used herein, the term "alkyl" means a saturated straight-chain or branched-chain monovalent hydrocarbon group containing the indicated number of carbon atoms. For example, "C 1-6"Alkyl" means a saturated straight-chain or branched-chain monovalent hydrocarbon group having 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 containing the indicated number of carbon atoms. For example, "C 1-3 alkylene" means a divalent alkyl having 1 to 3 carbon atoms (e.g., -CH2-, -CH(CH3)-, -CH2CH2-, or -CH2CH2CH2-).

[0030] As used herein, the term "alkenyl" means a straight-chain or branched monovalent unsaturated hydrocarbon chain containing the indicated number of carbon atoms. For example, "C 2-6 alkenyl" means a straight-chain or branched monovalent unsaturated hydrocarbon chain having 2 to 6 carbon atoms. Non-limiting examples of alkenyl include ethenyl, propenyl, butenyl, or pentenyl.

[0031] As used herein, the term "alkynyl" means a straight-chain or branched divalent unsaturated hydrocarbon chain containing the indicated number of carbon atoms. For example, "C 2-6 alkynyl" means a straight-chain or branched divalent unsaturated 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 saturated cyclic hydrocarbon containing the indicated number of carbon atoms. For example, "C 3-6"Cycloalkyl" means a saturated or partially saturated cyclic hydrocarbon having 3 to 6 ring carbon atoms. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl may include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyl include bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, and the like. Cycloalkyl also includes spiro rings (e.g., a spiro bicyclic ring where two rings are joined by a single atom). Non-limiting examples of spiro ring cycloalkyl include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like.

[0033] As used herein, the term "heterocyclic" means a monocyclic, bicyclic, tricyclic, or polycyclic non-aromatic ring group (e.g., a 3- to 8-membered monocyclic, 8- to 12-membered bicyclic, or 11- to 14-membered tricyclic ring group) containing the indicated number of ring atoms, having 1 to 3 heteroatoms (in the case of a monocyclic ring), 1 to 6 heteroatoms (in the case of a bicyclic ring), or 1 to 9 heteroatoms (in the case of a tricyclic or polycyclic ring), wherein the heteroatoms are selected from O, N, or S (e.g., in the case of a monocyclic, bicyclic, or tricyclic ring, carbon atoms and 1 to 3, 1 to 6, or 1 to 9 heteroatoms (N, O, or S), respectively), and 0, 1, 2, or 3 atoms of each ring may be substituted by a substituent. Examples of heterocyclic groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Heterocyclic may include multiple fused and bridged rings. Non-limiting examples of fused / bridged heterocyclics include 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, and the like. Heterocyclic also includes spiro rings (e.g., spirobicyclic rings where two rings are simply joined by one atom).Non-limiting examples of spirocyclic heterocycles include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[2.2]pentane, 4-oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane, and the like.

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

[0035] As used herein, the term "heteroaryl" means a monocyclic, bicyclic, 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), wherein at least one ring in the group is aromatic (it is not necessary for the ring containing heteroatoms (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 heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiadiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolylbenzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chroman, 2,3-dihydrobenz[b][1,4]dioxin, benz[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenz[b][1,4]xathiin, isoindoline, and the like.

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

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

[0038] As used herein, "

Chem.

Chem.

[0039] As used herein, the term "compound" is taken to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structure shown. A compound of the present specification identified by name or structure as a particular tautomeric form is taken to include other tautomeric forms unless otherwise indicated.

[0040] As used herein, the term "tautomer" means a compound in which the structure of the compound is significantly different in the arrangement of atoms but exists in an easy and rapid equilibrium. The compounds provided herein may be shown as different tautomers. When a compound has a tautomeric form, all tautomeric forms are considered to be within the scope of the present invention, and it is understood that the name of the compound does not exclude tautomers.

[0041] As used herein, the term "GLP-1R" or "GLP-1 receptor" is meant to include, but is not limited to, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and / or orthologous GLP-1R molecules, isoforms, precursors, variants, mutants, derivatives, splice variants, alleles, different species, and active fragments thereof.

[0042] As used herein, the term "GLP-1 related disease" is meant to include, but is not limited to, all diseases, disorders, or illnesses in which the regulation of glucagon-like peptide 1 (GLP-1) receptor signaling can alter the pathophysiology and / or symptoms and / or progression of the disease, disorder, or illness.

[0043] As used herein, the term "GLP-1 agonist" or "GLP-1RA" means an agonist of the glucagon-like peptide 1 (GLP-1) receptor. GLP-1RA enhances glucose-dependent insulin secretion, suppresses inappropriately elevated glucagon levels in both fasting and postprandial states, and delays gastric emptying. Karla et al., Glucagon-like peptide-1 receptor agonists in the treatment of type 2 diabetes: Past, present, and future, Indian J Endocrinol Metab. 2016 Mar-Apr; 20(2): 254-267. GLP-1RA has been shown to treat type 2 diabetes. Examples of GLP-1RA include, but are not limited to, albiglutide (TANZEΜM (registered trademark)), dulaglutide (LY2189265, TRULICITY (registered trademark)), efpeglenatide, exenatide (BYETTA (registered trademark), BYDUREON (registered trademark), exendin-4), liraglutide (VICTOZA (registered trademark), NN2211), lixisenatide (LYXΜMIA (registered trademark)), semaglutide (OZEMPIC (registered trademark)), tirzepatide, ZP2929, NNC0113-0987, BPI-3016, and TT401. See, 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 RE45313; and International Publications WO2019 / 239319; WO2019 / 239371; WO2020 / 103815; WO2020 / 207474; WO20202 / 34726; WO2020 / 044266; WO2020117987; and WO2020263695 for further GLP-1 receptor agonists.

[0044] As used herein, the term "pharmaceutically acceptable" indicates that a compound, or a salt or composition thereof, is chemically and / or toxicologically compatible with other ingredients in a formulation and / or with a patient being treated.

[0045] As used herein, the term "therapeutic compound" includes, but is not limited to, all compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof (e.g., any one compound of formula (IA), (IB), (IC), (ID), and (IE), or pharmaceutically acceptable salts or solvates thereof), and all compositions (e.g., pharmaceutical compositions) in which a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formula (IA), (IB), (IC), (ID), and (IE), or pharmaceutically acceptable salts or solvates thereof) is a constituent.

[0046] The term "administer" or "administering" means a method for delivering a dose of a compound or pharmaceutical composition to a vertebrate or invertebrate (including mammals, birds, fish, or amphibians). The method of administration can vary depending on various factors such as the components of the pharmaceutical composition, the site of the disease, and the severity of the disease.

[0047] As used herein, the terms "effective amount", "effective dosage", "pharmaceutically effective amount", or "therapeutically effective amount" mean a sufficient amount of a chemical substance (e.g., a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (e.g., any one of the compounds of formula (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof)) administered to reduce to some extent one or more of the symptoms of the disease or disorder being treated and may include curing the disease. "Curing" means removing the symptoms of an active disease. The results include alleviation and / or mitigation of the signs, symptoms or causes of the disease, or any other desired change in the biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant reduction in the symptoms of the disease. The appropriate "effective" amount in each case is determined using any appropriate technique, such as a dose escalation study. In certain embodiments, a "therapeutically effective amount" of a compound provided herein means the amount of the compound effective as monotherapy or in combination therapy.

[0048] The term "excipient" or "pharmaceutically acceptable excipient" means a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid bulking agent, diluent, carrier, solvent, or encapsulating material. In certain embodiments, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and suitable for use in contact with human and animal tissues or organs without undue toxicity, irritation, allergic response, immunogenicity, or other problems or complications, and a reasonable benefit / risk ratio. See, 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 Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0049] The term "pharmaceutical composition" means a compound of formula (I) described herein or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formulas (IA), (IB), (IC), (ID), and (IE) or a pharmaceutically acceptable salt or solvate thereof) and a mixture with other chemical constituents (collectively referred to herein as "excipients"), such as carriers, stabilizers, diluents, dispersants, suspending agents, and / or fillers, etc. Pharmaceutical compositions facilitate the administration of the compound to an organism. Many techniques for administering the compound exist, including, but not limited to, techniques for rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0050] In the context of treating a disease, disorder, or illness, the terms "treat", "treating", and "treatment" include reducing or suppressing a disorder, disease, or illness, or one or more symptoms associated with said disorder, disease, or illness; or delaying the progression, spread, or worsening of a disease, disorder, or illness, or one or more of its symptoms.

[0051] As used herein, the term "prevent" generally refers to preventing the onset, recurrence, or spread of a disease or illness described herein, in whole or in part, or its symptoms.

[0052] As used herein, the terms "subject", "patient", or "individual" are used interchangeably and mean any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In certain embodiments, the term means a mammalian subject for which a diagnosis, prognosis, or treatment is desired or required. In certain embodiments, the patient is a human. In certain embodiments, the subject is experiencing and / or exhibiting at least one symptom of a disease, disorder, or illness to be treated and / or prevented.

[0053] The terms "treatment plan" and "dosage regimen" are used interchangeably herein to mean the dosage and administration timing of each therapeutic agent in the combinations of the invention.

[0054] 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 and non-fixed combinations of active ingredients. As used herein, the term "combination therapy" means the dosage regimen 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 regulatory authorities, as defined herein.

[0055] As used herein, the term "modulate" means to regulate or adjust (e.g., increase or decrease) and can include, for example, receptor activation, partial receptor activation, or antagonism.

[0056] Compound In one embodiment, formula (I):

Chemical formula

Chem.

Chem.

Chemical formula

Chemical formula

Chemical formula

[0057] In certain embodiments, formula (I):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0058] Embodiments may include one or more of the features shown in the following and / or the claims.

[0059] In one embodiment, Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 are defined by (AA).

[0060] In one embodiment, Q 3 is CR QB . In any of these embodiments, Q 4 is N, CH, or CR QA .

[0061] In one embodiment, Q 4 is CR QB . In any of these embodiments, Q 3 is N, CH, or CR QA .

[0062] In one embodiment, Q 1 is CH or CR QA . In one embodiment, Q 1 is CH.

[0063] In one embodiment, Q 2 is CH or CR QA . In one embodiment, Q 2 is CH.

[0064] In one embodiment, Q5 is CH or CR QA In certain embodiments, Q 5 is CH. In certain other embodiments, Q 5 is CR QA .

[0065] In certain embodiments, Q 3 is CR QB and each of Q 1 , Q 2 , Q 4 , and Q 5 is independently CH or CR QA In any of these embodiments, each of Q 1 , Q 2 , Q 4 , and Q 5 is CH.

[0066] In certain embodiments (where Q 3 is CR QB and each of Q 1 , Q 2 , Q 4 , and Q 5 is independently CH or CR QA ), one of Q 1 , Q 2 , Q 4 , and Q 5 is CR QA and each of the remaining ones of Q 1 , Q 2 , Q 4 , and Q 5 is CH. As a non - limiting example of such embodiments, Q 4 is CR QA ; and Q 1 , Q 2 , and Q 5 are CH.

[0067] In certain embodiments (where Q 3 is CR QB and Q 1 , Q 2 , Q 4 and Q5 each of the remaining ones of which is, independently, CH or CR QA wherein), Q 1 , Q 2 , Q 4 , and Q 5 two of which are, independently selected, CR QA wherein; and Q 1 , Q 2 , Q 4 , and Q 5 each of the remaining ones of which is, independently, CH or CR

[0068] In certain embodiments, Q 3 is CR QB wherein; Q 1 , Q 2 , Q 4 , and Q 5 one of which is N; and Q 1 , Q 2 , Q 4 , and Q 5 each of the remaining ones of which is, independently, CH or CR QA wherein. In any of these embodiments, Q 4 is N. In any of the foregoing embodiments, Q 1 , Q 2 , and Q 5 are CH

[0069] In certain embodiments, Q 3 is CR QB wherein; and said

Chemical formula

Chemical formula

[0070] In certain embodiments, Q 3 is CR QB wherein; and said

Chemical formula

Chem.

[0071] As a non-limiting example, the

Chem.

Chem.

[0072] As another non-limiting example, the

Chem.

Chem.

[0073] In one embodiment, Q 3 is CR QB ; and the

Chem.

Chem.

[0074] As a non-limiting example, the

Chem.

Chem.

[0075] As another non-limiting example, the

Chem.

Chem.

[0076] In one embodiment, Q 4 is CR QB ; and Q 1 、Q 2 、Q 3 、and Q 5 each is, independently, CH or CR QA In any of these embodiments, Q 1 、Q 2 、Q 3 、and Q 5 each is CH.

[0077] In one embodiment (where Q 4 is CR QB ; and Q 1 、Q 2 、Q 3 、and Q 5 each is, independently, CH or CR QA ), one of Q 1 、Q 2 、Q 3 、and Q 5 is CR QA ; and each of the remaining ones of Q 1 、Q 2 、Q 3 、and Q 5 is CH. As a non-limiting example of the above embodiment, Q 5 is CR QA ; and Q 1 、Q 2 、and Q 3 are CH.

[0078] In one embodiment (where Q 4 is CR QB ; and Q 1, Q 2 , Q 3 , and Q 5 each of which is, independently, CH or CR QA in the case where), Q 1 , Q 2 , Q 3 , and Q 5 two of which are, independently selected, CR QA ; and Q 1 , Q 2 , Q 3 , and Q 5 each of which is CH. As a non-limiting example of the embodiment, Q 2 and Q 3 are, independently selected, CR Qa ; and Q 1 and Q 5 are CH.

[0079] In one embodiment, Q 4 is CR QB ; one of Q 1 , Q 2 , Q 3 , and Q 5 is N; and Q 1 , Q 2 , Q 3 , and Q 5 each of which is, independently, CH or CR QA is.

[0080] In one embodiment, Q 4 is CR QB ; and the

Chemical formula

Chemical formula

[0081] In one embodiment, Q 4 is CR QB ; and the [Chemistry] The moiety is [Chemistry] selected from the group consisting of.

[0082] In certain embodiments, the [Chemistry] moiety is [Chemistry] wherein Q 4 and Q 5 are independently selected from the group consisting of N, CH, and CR QA . In any of these embodiments, each of Q 4 and Q 5 is CH. In certain other embodiments, Q 4 is CR QA ; and Q 5 is CH. In certain other embodiments, Q 4 is N; and Q 5 is CR QA or CH. In certain embodiments, Q 5 is CH.

[0083] In certain embodiments, the [Chemistry] moiety is [Chemistry] wherein Q 2 , Q 3 , and Q 5 are independently selected from the group consisting of N, CH, and CR QA . In any of these embodiments, Q 2 , Q 3 , and Q5 Each of them is CH. In certain other embodiments, Q 5 is CR QA ; and each of Q 2 and Q 3 is CH. In certain other embodiments, Q 5 is CH; and Q 2 and Q 3 are independently selected from CR QA .

[0084] In certain embodiments, R QB is P(=O)R a R b , where R a and R b are independently selected from the group consisting of C 1-6 alkyl and C 3-6 cycloalkyl.

[0085] In certain embodiments, R QB is P(=O)R a R b , where R a and R b are each independently C 1-6 alkyl. In certain embodiments, R QB is P(=O)R a R b , where R a and R b are each independently C 1-3 alkyl.

[0086] In certain embodiments, R a and R b are the same.

[0087] In any of these embodiments, R a and R b are each methyl (i.e., R QB is P(=O)Me2).

[0088] In certain embodiments, R a and Rb is ethyl, respectively (i.e., R QB is P(=O)Et2).

[0089] In certain embodiments, R a and R b are each propyl, such as isopropyl. For example, R QB can be P(=O)iPr2.

[0090] In certain embodiments, R QB is P(=O)R a R b ; R a and R b are each independently C 1-6 alkyl; and R a and R b are different. In any of these embodiments, R a is C 1-3 alkyl (such as methyl or ethyl); and R b is C 4-6 alkyl (such as butyl, such as tert-butyl). For example, R a can be methyl; and R b can be tert-butyl (i.e., R QB can be P(=O)(Me)(tBu)). In certain embodiments, R a and R b are independently selected C 1-3 alkyl, provided that R a and R b are different.

[0091] In certain embodiments, R QB is P(=O)R a R b wherein R a and R b are each independently C 3-6 cycloalkyl. In any of these embodiments, R a and R b are the same. For example, Ra and R b can both be cyclopropyl (i.e., R QB is [Chemical formula] can be).

[0092] In one embodiment, R QB is P(=O)R a R b wherein R a and R b together with the phosphorus atom to which each is attached form a ring containing 5 to 8 ring atoms, and 0 to 2 ring atoms (in addition to the phosphorus to which R a and R b are attached) are heteroatoms independently selected from the group consisting of O, S, and N, and the ring may be optionally substituted with 1 to 3 independently selected C 1-6 alkyl.

[0093] In any of these embodiments, R QB is P(=O)R a R b wherein R a and R b together with the phosphorus atom to which each is attached form a ring containing 5 to 6 ring atoms, and 0 to 1 ring atom (in addition to the phosphorus to which R a and R b are attached) is a heteroatom selected from the group consisting of O, S, and N, and the ring may be optionally substituted with 1 to 2 independently selected C 1-6 alkyl.

[0094] As a non-limiting example of the above embodiment, R QB is [Chemical formula] may be, and L Q is a bond, CH2, O, S, NH, or N(C 1-6is (alkyl). For example, R QB is

Chemical formula

[0095] In certain embodiments, each R QA is halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, OH, and NR c R d selected from the group consisting of.

[0096] In certain embodiments, each R QA is halo, cyano, OH, and NR c R d selected from the group consisting of.

[0097] In certain embodiments, one of the R QA is halo. In any of these embodiments, one of the R QA is -F.

[0098] In certain embodiments, one of the R QA is -OH.

[0099] In certain embodiments, one of the R QA is NR c R d is.

[0100] In any of these embodiments, one of the R QA is NH(C 1-3 alkyl) (e.g., NHMe, NHEt, or NHiPr).

[0101] In certain embodiments, one of the R QA is NH2.

[0102] In certain embodiments, one of the R QA is N(C 1-3 alkyl)2 (e.g., NMe2).

[0103] In one embodiment, one of R QA is selected from the group consisting of NHC(=O)(C 1-6 alkyl), NHC(=O)(C 3-6 cycloalkyl), NHC(=O)O(C 1-6 alkyl), NHS(O) 1-2 (C 1-6 alkyl), and NHS(O) 1-2 (C 3-6 cycloalkyl).

[0104] In one embodiment, one of R QA is NHC(=O)(C 1-3 alkyl), NHC(=O)(C 3-6 cycloalkyl) (e.g., NHC(=O)(cyclopropyl)), or NHS(O)2(C 1-3 alkyl) (e.g., NHS(O)2Me).

[0105] In one embodiment, one of R QA is a 5- to 6-membered heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of C 1-6 alkyl and C(=O)(C 1-6 alkyl). In any of these embodiments, one of R QA is morpholinyl.

[0106] In one embodiment, one of R QA is C 1-6 alkoxy optionally substituted with 1 to 6 substituents each independently selected from the group consisting of hydroxy, halo, and C 1-6 alkoxy. In any of these embodiments, one of R QA is C 1-6 alkoxy optionally substituted with 1 to 6 (e.g., 1 to 3) independently selected halo. Non-limiting examples of such embodiments include R QA being -OMe, -OCF3, or -OCHF2. For example, R QAcan be -OMe. For example, R QA can be -OCF3. As another non-limiting example, R QA can be -OCHF2.

[0107] In certain embodiments, R QA is C f alkyl which may be optionally substituted with 1 to 6 independently selected R 1-6 groups. In any of these embodiments, R QA is C 1-3 alkyl. As a non-limiting example of said embodiments, R QA can be methyl.

[0108] In any of these embodiments, one of the R QA groups is C 1-3 alkyl substituted with 1 to 6 independently selected halo groups. For example, R QA can be CF3, CHF2, or CH2F (e.g., CF3 or CHF2).

[0109] In any of these embodiments, one of the R QA groups is C c alkyl substituted with NR d R 1-3 groups. For example, R QA can be CH2NHMe.

[0110] In certain embodiments, each of the remaining R QA groups, if present, is independently selected halo, e.g., -F.

[0111] In certain embodiments, a pair of R QA groups on adjacent carbon atoms together with the atoms to which each is attached form a ring containing 5 to 6 ring atoms, wherein 1 to 2 of the ring atoms are heteroatoms each independently selected from the group consisting of O, N, and S, and said ring may be optionally substituted with 1 to 2 independently selected R h groups.

[0112] In any of these embodiments, a pair of Rs on adjacent carbon atoms QA together with the atoms to which each is attached

Chemical formula

[0113] In one embodiment, a pair of Rs on adjacent carbon atoms QA together with the atoms to which each is attached

Chemical formula

[0114] In one embodiment, each of the remaining Rs QA , when present, is independently halo, cyano, or C 1-3 alkyl.

[0115] In one embodiment, L 2 is

Chemical formula

[0116] In one embodiment, L 2 is

Chemical formula

[0117] is 2 is

Chemical formula

[0118] In certain embodiments, L 2 is

Chemical formula

[0119] In certain embodiments, L 2 is

Chemical formula

[0120] aryl or a 5- to 10-membered heteroaryl, each of which may be optionally substituted with 1 to 4 substituents independently selected from the group consisting of halo, C 6-10 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxy. 1-6 In certain embodiments, ring A is phenyl or pyridyl, each of which may be optionally substituted with 2 to 4 substituents independently selected from the group consisting of C

[0121] alkyl, C 1-6 haloalkyl, and C 1-6 alkoxy. 1-6 In certain embodiments, ring A is phenyl optionally substituted with 2 to 4 substituents independently selected from the group consisting of halo (e.g., -F) and C

[0122] In any of the above embodiments, ring A is phenyl optionally substituted with 2 to 4 substituents independently selected from the group consisting of halo (e.g., -F) and C 1-6 alkyl (e.g., C 1-3 alkyl). As non-limiting examples of the above embodiments, ring A is [Chemical formula] may also be, wherein R AA , R AB , and R AC are independently halo or C 1-6 alkyl. For example, R AA and R AC can independently be C 1-3 alkyl (e.g., methyl); and / or R AB can be halo (e.g., -F).

[0123] In certain embodiments, ring A is pyridyl optionally substituted with 2 - 4 substituents each independently selected from the group consisting of halo and C 1-6 alkyl. For example, ring A can be 4 - pyridyl optionally substituted with 2 - 4 substituents each independently selected from the group consisting of halo and C 1-6 alkyl. As another example, ring A can be 3 - pyridyl optionally substituted with 2 - 4 substituents each independently selected from the group consisting of halo and C 1-6 alkyl. As yet another example, ring A can be 2 - pyridyl optionally substituted with 2 - 4 substituents each independently selected from the group consisting of halo and C 1-6 alkyl.

[0124] In certain embodiments, R 1 is H. In certain embodiments, R 1 is C 1-6 alkyl.

[0125] In certain embodiments, R 2 is H. In certain embodiments, R 2 is C 1-6 alkyl.

[0126] In certain embodiments, R 3 is H. In certain embodiments, R 3 is C 1-6Alkyl (e.g., C 1-3 alkyl, e.g., methyl).

[0127] In certain embodiments, R 1 , R 2 , and R 3 are H. In certain other embodiments, R 1 and R 2 are H; and R 3 is C 1-6 alkyl. In any of these embodiments, R 3 is methyl.

[0128] In certain embodiments, R 1 is H; and R 2 and R 3 are independently selected C 1-6 alkyl.

[0129] In certain embodiments, L 1 is C(=O).

[0130] In certain embodiments, L 1 is -CH2- or -CH(C 1-6 alkyl)-.

[0131] In certain embodiments, L 1 is -S(=O)2.

[0132] In certain embodiments, ring B is

Chemical formula

[0133] In any of these embodiments, R 4 , R 5 , and R 6 are each H or halo. In certain embodiments, R 4 , R 5 , and R 6is each, H or -F. As a non-limiting example of the embodiment, R 4 , R 5 , and R 6 are each, H. As another non-limiting example, R 4 and R 5 are H; and R 6 is -F. In one embodiment, R 7 is H. In another embodiment, R 7 is -F.

[0134] In one embodiment, ring B is

Chemical formula

[0135] In another embodiment, ring B is

Chemical formula

[0136] In one embodiment, ring B is

Chemical formula

Chemical formula

[0137] In any of these embodiments, R 4 , R 5 , R 6 , and R 7Each of them, when present, is independently selected from the group consisting of -H and halo. For example, R 4 , R 5 , R 6 , and R 7 each, when present, can be independently selected from the group consisting of -H and -F.

[0138] In certain embodiments, at least one of L 3 and L 4 is a bond. In any of these embodiments, both L 3 and L 4 are bonds.

[0139] In certain embodiments, L 3 is a bond; and L 4 is C 1-2 alkylene.

[0140] In certain other embodiments, L 4 is a bond; and L 3 is C 1-2 alkylene.

[0141] In certain embodiments, L 3 and L 4 are each independently C 1-2 alkylene.

[0142] In certain embodiments, R 8a and R 8b together with the carbon atoms to which each is attached form a C 1-6 cycloalkyl ring optionally substituted with 1 to 2 independently selected C 3-8 alkyls, wherein said C 1-6 alkyl may be optionally substituted with 1 to 3 independently selected R f .

[0143] In certain embodiments, R 8a and R 8bTogether with the carbon atom to which each is attached, 1 to 2 independently selected C 1-6 Optionally substituted with C 3-5 That forms a cycloalkyl ring, wherein said C 1-6 Alkyl may be optionally substituted with 1 to 3 independently selected R f .

[0144] In certain embodiments, R 8a and R 8b Together with the carbon atom to which each is attached, 1 to 2 independently selected C 1-6 Optionally substituted with C 3-4 Form a cycloalkyl ring.

[0145] As a non-limiting example of said embodiment, R 8a and R 8b Together with the carbon atom to which each is attached,

Chemical formula

Chemical formula

[0146] In certain embodiments, R 8a and R 8b Are each independently selected from the group consisting of H and C 1-6 Alkyl. For example, R 8a and R 8b Can both be H. As another example, R 8a and R 8b Are independently selected C 1-6 Alkyl (e.g., C 1-3 Alkyl). As yet another example, R 8a Can be H; and R 8b Is C 1-6Alkyl (e.g., C 1-3 alkyl) may be.

[0147] In certain embodiments, the L 3 -C(R 8a R 8b )-L 4 -R 9 moiety is

Chemical formula

[0148] In certain embodiments, the L 3 -C(R 8a R 8b )-L 4 -R 9 moiety is

Chemical formula

[0149] In certain embodiments, R 9 is

Chemical formula

[0150] In certain embodiments, R 9 is

Chemical formula

Chemical formula

Chemical formula

[0151] In certain embodiments, R 9 is C(=O)OH

[0152] In certain embodiments, R 9 is C(=O)(OC 1-6 alkyl)

[0153] In certain embodiments, R 9 is C(=O)NR 9a R 9b In any of these embodiments, R 9a is H. In certain embodiments, R 9b is H. In certain embodiments, R 9b is C 1-6 alkyl. In certain embodiments, R 9b is selected from the group consisting of C(=O)(C 1-6 alkyl), S(O) 0-2 (C 1-6 alkyl), and cyano

[0154] In certain embodiments, the

Chemical formula

Chemical formula

Chemical formula

[0155] In certain embodiments (where the

Chemical formula

Chemical formula

Chemical formula

[0156] In certain embodiments, ring C is a 3- to 12-membered heterocyclic ring which may be optionally substituted with 1 to 3 independently selected Rs Ca In certain embodiments, ring C is a 4- to 8-membered heterocyclic ring which may be optionally substituted with 1 to 3 independently selected Rs

[0157] In certain embodiments, ring C is a 5- to 6-membered heterocyclic ring which may be optionally substituted with 1 to 3 independently selected Rs Ca In certain embodiments, ring C is a 5- to 6-membered heterocyclic ring which may be optionally substituted with 1 to 3 independent Rs

[0158] In certain embodiments, ring C is a 5- to 6-membered heterocyclic ring which may be optionally substituted with 1 to 3 independently selected Rs Ca In certain embodiments, ring C is a 5- to 6-membered heterocyclic ring which may be optionally substituted with 1 to 3 independent Rs

[0159] In certain embodiments, ring C is a 5- to 6-membered heterocyclic ring which may be optionally substituted with 1 to 3 independent Rs CaIt is a tetrahydropyranyl that may be appropriately substituted. For example, ring C is

Chemical formula

Chemical formula

[0160] In certain embodiments, ring C is morpholinyl that may be appropriately substituted with 1 to 3 independently selected R Ca For example, ring C is

Chemical formula

[0161] In certain embodiments, ring C is a 5- to 6-membered heteroaryl that may be appropriately substituted with 1 to 3 independently selected R Ca In certain embodiments, ring C is a C

[0162] that may be appropriately substituted with 1 to 3 R Ca In certain embodiments, ring C is a C 3-10 cycloalkyl that may be appropriately substituted with 1 to 3 independently selected R

[0163] In certain embodiments, ring C is a C Ca cycloalkyl that may be appropriately substituted with 1 to 3 independently selected R 3-8 For example, ring C is

Chemical formula

[0164] In certain embodiments, each R Ca is independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkoxy, and NR c R d

[0165] ​ In certain embodiments, each R Ca is independently selected from the group consisting of halo and C 1-6 alkyl.

[0166] In certain embodiments, each R Ca is independently C 1-6 alkyl. For example, each R Ca can be methyl.

[0167] In certain embodiments, each R Ca is independently selected halo. For example, each R Ca can be -F.

[0168] In certain embodiments, a pair of R's on the same or different ring atoms together with the ring atom to which each is attached form a carbocyclic ring containing 3 to 6 ring atoms. In certain embodiments, a pair of R's on the same ring atom together with the ring atom to which each is attached form a carbocyclic ring containing 3 to 5 ring atoms. Ca is attached to the ring atom to which each is attached to form a carbocyclic ring containing 3 to 6 ring atoms. In certain embodiments, a pair of R's on the same ring atom together with the ring atom to which each is attached form a carbocyclic ring containing 3 to 5 ring atoms. Ca is attached to the ring atom to which each is attached to form a carbocyclic ring containing 3 to 5 ring atoms.

[0169] In certain embodiments, the compound of formula (I) is of formula (IA):

Chemical formula

[0170] In certain embodiments of formula (IA), each of Q 4 and Q 5 is CH.

[0171] In certain embodiments of formula (IA), Q 4 is CR QA ; and Q 5 ​is CH.

[0172] In certain embodiments of formula (IA), Q 4 is CR QA ; and Q 5 is CR QA . In any of these embodiments, Q 4 is CR QA ; and Q 5 is C-halo, for example, CF.

[0173] In certain embodiments of formula (IA), Q 4 is N; and Q 5 is CR QA or CH. In any of these embodiments, Q 5 is CH.

[0174] In certain embodiments, the compound of formula (I) is of formula (IB):

Chemical formula

[0175] In certain embodiments of formula (IB), each of Q 2 , Q 3 , and Q 5 is CH.

[0176] In certain embodiments of formula (IB), Q 5 is CR QA ; and each of Q 2 and Q 3 is CH.

[0177] In certain embodiments of formula (IB), Q 5 ​is CH; and Q 2 and Q 3 is independently selected CR QA is.

[0178] In certain embodiments of formula (IA) or (IB), ring B is

Chemical formula

[0179] In any of these embodiments, L 3 and L 4 at least one of is a bond. As a non-limiting example of said embodiments, both L 3 and L 4 are bonds.

[0180] In certain embodiments of formula (IA) or (IB), R 8a and R 8b each together with the carbon atom to which it is attached form a C 1-6 cycloalkyl ring optionally substituted with 1-2 independently selected C 3-5 alkyl, wherein said C 1-6 alkyl may be optionally substituted with 1-3 independently selected R f is.

[0181] In any of these embodiments, R 8a and R 8b each together with the carbon atom to which it is attached form a C 1-6 cycloalkyl ring optionally substituted with 1-2 independently selected C 3-4 alkyl.

[0182] As a non-limiting example of said embodiments, R 8a and R 8b each together with the carbon atom to which it is attached

Chemical formula

[0183] In certain embodiments of formula (IA) or (IB), ring C is a 3- to 12-membered heterocyclic ring optionally substituted with 1 to 3 independently selected R Ca In certain embodiments, ring C is a 5- to 6-membered heterocyclic ring optionally substituted with 1 to 3 independently selected R Ca In certain embodiments, ring C is a 5- to 6-membered heterocyclic ring optionally substituted with 1 to 3 independent R Ca and is tetrahydropyranyl optionally substituted with. As non-limiting examples of said embodiments, ring C is

Chemical formula

Chemical formula

[0184] In certain embodiments of formula (IA) or (IB), ring C is a C Ca cycloalkyl optionally substituted with 1 to 3 R 3-8 For example, ring C is

Chemical formula

[0185] In certain embodiments of formula (IA) or (IB), each R Ca is independently C 1-6 alkyl. For example, each R Ca may be H. As another non-limiting example, each R Ca is C 1-3 alkyl (e.g., methyl).

[0186] In certain embodiments of formula (IA) or (IB), each R Cais a halo (e.g., -F) independently selected.

[0187] In certain embodiments of formula (IA) or (IB), a pair of R on the same or different ring atoms Ca together with the ring atom to which each is attached forms a carbocyclic ring containing 3 to 6 ring atoms.

[0188] In certain embodiments of formula (IA) or (IB), a pair of R on the same ring atom Ca together with the ring atom to which each is attached forms a carbocyclic ring containing 3 to 5 ring atoms.

[0189] In certain embodiments, the compound of formula (I) is of formula (IC):

Chemical formula

[0190] In certain embodiments of formula (IC), ring D is cyclopropyl.

[0191] In certain embodiments of formula (IC), ring D is cyclobutyl.

[0192] In certain embodiments of formula (IC), R 8c is H.

[0193] In certain embodiments of formula (IC), R​​8c is C 1-3 alkyl. For example, R 8c can be methyl.

[0194] In certain embodiments of formula (IC), each R Cb is H.

[0195] In certain embodiments of formula (IC), each R Cb is independently C 1-6 alkyl (e.g., C 1-3 alkyl (e.g., methyl)).

[0196] In certain embodiments of formula (IC), Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 is defined by (AA).

[0197] In embodiments of formula (IC), the

Chemical formula

Chemical formula

[0198] In any of these embodiments, each of Q 4 and Q 5 is CH.

[0199] In certain other embodiments, Q 4 is CR QA ; and Q 5 is CH.

[0200] In certain embodiments, Q 4 is CR QAand Q 5 is CR QA In any of these embodiments, Q 4 is CR QA and Q 5 is C-halo, for example, CF.

[0201] In certain other embodiments, Q 4 is N; and Q 5 is CR QA or CH. In any of these embodiments, Q 5 is CH.

[0202] In certain embodiments of formula (IC), said

Chemical formula

Chemical formula

[0203] In any of these embodiments, each of Q 2 , Q 3 , and Q 5 is CH.

[0204] In certain other embodiments, Q 5 is CR QA ; and each of Q 2 and Q 3 is CH.

[0205] In certain other embodiments, Q 5 is CH; and each of Q 2 and Q 3 is independently selected CR QA .

[0206] In certain embodiments of formula (IC), L 1 is C(=O).

[0207] In certain embodiments of formula (IA), (IB), or (IC), R a and R b are each independently selected from the group consisting of C 1-6 alkyl and C 3-6 cycloalkyl.

[0208] In certain embodiments of formula (IA), (IB), or (IC), R a and R b are each independently C 1-3 alkyl. For example, R a and R b can each be methyl. As another non-limiting example, R a and R b can each be ethyl. As a further non-limiting example, R a and R b can each be isopropyl.

[0209] In certain embodiments of formula (IA), (IB), or (IC), R a is methyl; and R b is tert-butyl.

[0210] In certain embodiments of formula (IA), (IB), or (IC), R a and R b are independently selected C 3-6 cycloalkyl. For example, R a and R b can both be cyclopropyl.

[0211] In certain embodiments of formula (IA), (IB), or (IC), each R QA is halo; cyano; OH; NR c R d ; C optionally substituted with 1 to 6 independently selected R f ​1-6 Alkyl; hydroxy, halo, and C 1-6 Optionally substituted with 1 to 6 substituents each independently selected from the group consisting of alkoxy, C 1-6 Alkoxy; and C 1-6 Alkyl and C(=O)(C 1-6 Optionally substituted with one or more substituents each independently selected from the group consisting of alkyl) and optionally substituted 3- to 12-membered heterocyclyl. It is selected from the group consisting of

[0212] In any of these embodiments, each R QA is selected from the group consisting of -F, OH, NH2NHMe, NHEt, NHiPr, N(Me)2, NHC(=O)(cyclopropyl), NHS(O)2Me, methyl, CF3, CHF2, OMe, OCF3, OCHF2, and morpholinyl.

[0213] In any of these embodiments, R QA is selected from the group consisting of -F, OH, NH2NHMe, NHEt, NHC(=O)(cyclopropyl), NHS(O)2Me, methyl, OMe, OCF3, and morpholinyl.

[0214] In certain embodiments of formula (IA), (IB), or (IC), each R QA is selected from the group consisting of halo, cyano, OH, and NR c R d from the group consisting of

[0215] In any of these embodiments, each R QA is selected from the group consisting of -F, OH, and NHMe.

[0216] In certain embodiments of formula (IA), (IB), or (IC), a pair of R on adjacent carbon atoms QAwhich, together with the atoms to which each is attached, forms a ring containing 5 to 6 ring atoms, wherein 1 to 2 of the ring atoms are heteroatoms each independently selected from the group consisting of O, N, and S, and the ring is optionally substituted with 1 to 2 independently selected R h groups. For example, a pair of R QA on adjacent carbon atoms, together with the atoms to which each is attached,

Chemical formula

Chemical formula

[0217] In certain embodiments of formula (IA), (IB), or (IC), L 2 is

Chemical formula

[0218] In certain embodiments of formula (IA), (IB), or (IC), ring A is phenyl or pyridyl, each of which is optionally substituted with 2 to 4 substituents each independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxy.

[0219] In certain embodiments of formula (IA), (IB), or (IC), ring A is phenyl optionally substituted with 2 to 4 substituents each independently selected from the group consisting of halo and C 1-6 alkyl.

[0220] As a non-limiting example of the foregoing embodiments, ring A is

Chemical formula

[0221] In certain embodiments of formula (IA), (IB), or (IC), R 1 and R 2 are H.

[0222] In certain embodiments of formula (IA), (IB), or (IC), R 3 is H.

[0223] In certain embodiments of formula (IA), (IB), or (IC), R 3 is C 1-6 alkyl.

[0224] In certain embodiments of formula (IA), (IB), or (IC), R 1 and R 2 are H; and R 3 is C 1-6 alkyl. For example, R 3 can be methyl.

[0225] In certain embodiments of formula (IA), (IB), or (IC), R 4 , R 5 , and R 6 are each H or halo.

[0226] In certain embodiments of formula (IA), (IB), or (IC), R4 , R 5 , and R 6 is each H or -F.

[0227] In certain embodiments of formula (IA), (IB), or (IC), R 4 , R 5 , and R 6 are each H.

[0228] In certain embodiments of formula (IA), (IB), or (IC), R 4 and R 5 are H; and R 6 is -F.

[0229] In certain embodiments of formula (IA), (IB), or (IC), R 7 is H.

[0230] In certain embodiments of formula (IA), (IB), or (IC), R 7 is -F.

[0231] In certain embodiments of formula (IA), (IB), or (IC), R 9 is

Chemical formula

[0232] In certain embodiments, the compound of formula (I) is of formula (ID):

Chemical formula

[0233] In certain embodiments of formula (ID), R 1 and R 2 are H.

[0234] In certain embodiments of formula (ID), R 3 is C 1-3 alkyl. In any of these embodiments, R 3 is methyl.

[0235] In certain embodiments of formula (ID), R 4 , R 5 , R 6 , and R 7 are H.

[0236] In certain embodiments of formula (ID), R 9d is H.

[0237] In certain embodiments of formula (ID), R AA and R AC are independently C 1-6 alkyl. In any of these embodiments, R AA and R AC are methyl.

[0238] In certain embodiments of formula (ID), R AB is halo. In any of these embodiments, R AB is -F.

[0239] In certain embodiments of formula (ID), each R Cb is H. In certain embodiments of formula (ID), each R Cb is C 1-3 ​is alkyl. In any of these embodiments, each R Cb is methyl.

[0240] In certain embodiments of formula (ID), R a and R b are independently C 1-3 alkyl. In any of these embodiments, R a and R b are methyl. In certain embodiments, R a and R b are ethyl. In certain embodiments, R a and R b are isopropyl.

[0241] In certain embodiments of formula (ID), R a is methyl; and R b is tert-butyl.

[0242] In certain embodiments of formula (ID), R a and R b are independently C 3-6 cycloalkyl. For example, R a and R b can both be cyclopropyl.

[0243] In certain embodiments of formula (ID), P(=O)R a R b is

Chemical formula

Chemical formula

[0244] In certain embodiments of formula (ID), R QA is -F.

[0245] In certain embodiments of formula (ID), R QA is -OH.

[0246] In certain embodiments of formula (ID), R QA is NR c R d In certain embodiments, R QA is NH(C 1-3 alkyl) (e.g., NHMe or NHEt). In certain embodiments, R QA is NH2. In certain embodiments, R QA is N(C 1-3 alkyl)2 (e.g., NMe2). In certain embodiments, R QA is NHC(=O)(C 1-3 alkyl), NHC(=O)(C 3-6 cycloalkyl), or NHS(O)2(C 1-3 alkyl).

[0247] In certain embodiments of formula (ID), R QA is a 5- to 6-membered heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of C 1-6 alkyl and C(=O)(C 1-6 alkyl).

[0248] In certain embodiments of formula (ID), R QA is a C 1-6 alkoxy optionally substituted with 1 to 6 independently selected halos. In any of these embodiments, R QA is -OMe, -OCF3, or -OCHF2.

[0249] In certain embodiments of formula (ID), R QA is C 1-3 alkyl. In any of these embodiments, R QAis methyl.

[0250] In certain embodiments of formula (ID), R QA is C 1-3 alkyl, optionally substituted with one to three independently selected halo. In any of these embodiments, R QA is -CF3 or -CHF2.

[0251] In certain embodiments of formula (ID), R QC is H.

[0252] In certain embodiments of formula (ID), R QC is halo. In any of these embodiments, R QC is -F. In certain embodiments, R QC is P(=O)R a R b meta to. In certain embodiments, R QC is P(=O)R a R b meta to and R QA ortho to. In certain embodiments, R QC is -F ortho to R QA . In certain embodiments, R QC is P(=O)R a R b meta to and -F ortho to R QA .

[0253] In certain embodiments of formula (ID), the compound is of formula (S,S,S)-(ID)

Chemical formula

[0254] In one embodiment, the compound of formula (I) is of formula (IE): [Chemical Formula] Formula (IE) [wherein: R AA 、R AB 、and R AC are each independently halo or C 1-3 alkyl; R 3 is H or C 1-3 alkyl; R QC is H or halo; R QD is (a) H; (b) -NH2; (c) -NH(C 1-3 alkyl); (d) halo; (e) C 1-3 alkoxy optionally substituted with 1 to 3 independently selected halo; and (f) C 1-3 alkyl optionally substituted with 1 to 3 independently selected halo, selected from the group consisting of; R a and R b are each independently selected from the group consisting of C 1-4 alkyl and C 3-6 cycloalkyl; or R a and R b together with the phosphorus atom to which each is attached form a ring containing 5 to 8 ring atoms, where 0 to 1 ring atoms (in addition to the phosphorus to which R a and R b are attached) are heteroatoms independently selected from the group consisting of O, S, and N; R 8c is H or C 1-3 alkyl; X B is CH or N; and each R Cb is independently selected from the group consisting of H and C 1-3 alkyl) It is a compound represented by or a pharmaceutically acceptable salt or solvate thereof.

[0255] In certain embodiments of formula (IE), R AA and R AC are each independently C 1-3 alkyl. For example, R AA and R AC can each be methyl.

[0256] In certain embodiments of formula (IE), R AB is halo. For example, R AB can be F.

[0257] In certain embodiments of formula (IE), R AA and R AC are each independently C 1-3 alkyl; and R AB is halo. For example, R AA and R AC can each be methyl; and R AB can be F.

[0258] In certain embodiments of formula (IE), R 3 is C 1-3 alkyl. For example, R 3 can be methyl.

[0259] In certain embodiments of formula (IE), R QD is H.

[0260] In certain embodiments of formula (IE), R QD is selected from the group consisting of -NH2 and -NH(C 1-3 alkyl). For example, R QD can be -NH2. As another non-limiting example, R QD can be -NHMe. As a further non-limiting example, R QD can be -NHEt.

[0261] In certain embodiments of formula (IE), R QD is a halo. For example, R QD can be -F or -Cl.

[0262] In certain embodiments of formula (IE), R QD is C 1-3 alkoxy optionally substituted with 1 to 3 independently selected halos. For example, R QD can be -OMe. As another non-limiting example, R QD can be OCF3. As a further non-limiting example, R QD can be OCHF2.

[0263] In certain embodiments of formula (IE), R QD is C 1-3 alkyl optionally substituted with 1 to 3 independently selected halos. For example, R QD can be methyl. As another non-limiting example, R QD can be CF3. As another non-limiting example, R 3 can be -CHF2.

[0264] In certain embodiments of formula (IE), R a and R b are each independently selected C 1-4 alkyl. For example, R a and R b can each be methyl. As another non-limiting example, R a and R b can each be ethyl. As a further non-limiting example, R a and R b can each be isopropyl. As a further non-limiting example, R a can be methyl; and R b can be tert-butyl.

[0265] In certain embodiments of formula (IE), R a and R b are each independently selected C3-6 is a cycloalkyl. For example, R a and R b can each be cyclopropyl.

[0266] In certain embodiments of formula (IE), R a and R b together with the phosphorus atom to which each is attached form a ring containing 5 to 8 ring atoms, and 0 to 1 of the ring atoms (in addition to the phosphorus to which R a and R b is attached) is a heteroatom independently selected from the group consisting of O, S, and N. For example, R a and R b together with the phosphorus atom to which each is attached,

Chemical formula

[0267] In certain embodiments of formula (IE), R QC is H.

[0268] In certain embodiments of formula (IE), R QC is halo. For example, R QC can be -F. In certain embodiments, R QC is ortho to R QD . In certain embodiments, R QC is para to R QD . In certain embodiments, R QC is meta to R QD .

[0269] In certain embodiments of formula (IE), R 8c is H. In certain embodiments of formula (IE), R 8c is C 1-3 alkyl. For example, R 8c can be methyl.

[0270] In certain embodiments of formula (IE), X Bis CH. In certain embodiments of formula (IE), X B is N.

[0271] In certain embodiments of formula (IE), each R Cb is H. In certain embodiments of formula (IE), each R Cb is independently selected C 1-3 alkyl. For example, each R Cb can be methyl.

[0272] In certain embodiments of formula (IE), X B is CH; and each R Cb is H. In certain embodiments of formula (IE), X B is CH; and each R Cb is independently selected C 1-3 alkyl (e.g., methyl). In certain embodiments of formula (IE), X B is N; and each R Cb is H. In certain embodiments of formula (IE), X B is N; and each R Cb is independently selected C 1-3 alkyl (e.g., methyl).

[0273] In certain embodiments of formula (IE), the compound is of formula (S,S,S)-(IE)

Chemical Formula

[0274] In certain embodiments of formula (IE): R AA and R AC are methyl; R AB is -F; R3 is methyl; R QC is H or -F; R QD is selected from the group consisting of H; -NHMe; -NHEt; -NH2; -OMe; -OCF3; -OCHF2; -Me; -CF3; and -CHF2; R a and R b are independently selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, and cyclopropyl; R 8c is H or methyl; X B is CH; and each R Cb is independently H or methyl.

[0275] In any of these embodiments, the compound is a compound represented by the formula (S,S,S)-(IE).

[0276] In one embodiment, the compound of formula (I) is selected from the group consisting of the compounds of Table C1 or a pharmaceutically acceptable salt or solvate thereof. Table C1

Table 1

[0277] In one embodiment, the compound is selected from the group consisting of the compounds of Table C2 or pharmaceutically acceptable salts or solvates thereof. Table C2

Table 2

[0278] The compounds of formula (I) include their pharmaceutically acceptable salts. Further, the compounds of formula (I) also include other salts of such compounds that are not necessarily pharmaceutically acceptable salts, and may be useful as intermediate compounds for preparing, and / or purifying, 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 salts.

[0279] Furthermore, the compounds of formula (I) or their salts may be isolated in the form of solvates, and thus any such solvates are understood to be included within the scope of the invention of the present invention. For example, the compounds of formula (I) and their salts can exist in unsolvated form, as well as in solvated form with pharmaceutically acceptable solvents such as water, ethanol, etc.

[0280] Pharmaceutical Compositions and Administration When used as a medicament, the 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 art and can be administered by various routes depending on whether local or systemic treatment is desired and on the area to be treated. Administration can be local (including transdermal, epidermal, ocular, and delivery to mucous membranes including intranasal, vaginal and rectal), pulmonary (e.g., inhalation or insufflation of powders or aerosols (including nebulizers); intratracheal or intranasal), oral or parenteral. Oral administration can include formulations formulated for once-daily or twice-daily (BID) dosing. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection or infusion; or intracerebral, e.g., intrathecal or intraventricular administration. Parenteral administration can be in the form of a single bolus dose, or, for example, by means of a sustained perfusion pump. Pharmaceutical compositions and formulations for local administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, fillers, etc. may be required or desired.

[0281] Also provided herein are 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). For example, a pharmaceutical composition prepared using a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In certain embodiments, the composition is suitable for topical administration. In preparing the compositions provided herein, the active ingredient is typically admixed with an excipient, diluted by an excipient, or enclosed within such a carrier in the form of, for example, capsules, sachets, paper, or other containers. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid substance that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, troches, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments (e.g., containing 10% by weight of the active compound), soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In certain embodiments, the composition is formulated for oral administration. In certain embodiments, the composition is a solid oral formulation. In certain embodiments, the composition is formulated as a tablet or a capsule.

[0282] Further provided herein are pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof together with a pharmaceutically acceptable excipient. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as an active ingredient can be prepared by intimately mixing the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can be in a wide variety of forms depending on the desired route of administration (e.g., oral, parenteral). In certain embodiments, the composition is a solid oral composition.

[0283] Suitable 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).

[0284] Methods for formulating pharmaceutical compositions are described in many publications such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al; published by Marcel Dekker, Inc.

[0285] In certain embodiments, the compound or pharmaceutical composition can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical formulations such as Tween, poloxamer or other similar polymeric delivery matrices, serum proteins such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene polyoxypropylene block polymers, and lanolin. Cyclodextrins such as α-, β-, and γ-cyclodextrins, or chemically modified derivatives such as hydroxyalkyl cyclodextrins (including 2- and 3-hydroxypropyl-β-cyclodextrin), or other solubilized derivatives can also be used to enhance the delivery of the compounds described herein. Compositions can be prepared that contain the chemical substances described herein in a balance with non-toxic excipients in the range of 0.005% to 100%. The intended compositions may contain the compounds provided herein in amounts of 0.001% to 100%, in one embodiment 0.1 to 95%, in another embodiment 75 to 85%, and in a further embodiment 20 to 80%. The actual methods for preparing such formulations are known or will be apparent to those skilled in the art, for example, see Remington: The Science and Practice of Pharmacy, 22 nd nd Edition (Pharmaceutical Press, London, UK. 2012).

[0286] In certain embodiments, the compounds and pharmaceutical compositions described herein, or pharmaceutical compositions thereof, can be administered to a patient in need thereof by any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, dermal, intracervical, intranasal, intratracheal, enteral, epidural, interstitial, intraperitoneal, intraarterial, intratracheobronchial, intracapsular, intracerebral, intracisternal, intracoronary, intradermal, intraluminal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intramuscular, intralymphatic, intramedullary, intrathecal, intrasynovial, intratesticular, intrasubarachnoid, intraluminal, intratumoral, intrauterine, intravascular, intravenous, nasal (e.g., intranasal), nasogastric, oral, parenteral, percutaneous, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, and vaginal.

[0287] In certain embodiments, a preferred route of administration is parenteral (e.g., intratumoral). In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (e.g., any one of the compounds of formula (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition thereof, is formulated for parenteral administration and can be formulated, for example, for injection by an intraarterial, intracardiac, intracerebral, intravenous, intramuscular, subcutaneous, or intraperitoneal route. For example, such compositions can be prepared as either injectable liquid solvents or suspensions; solid forms suitable for use in preparing a solvent or suspension by addition of a liquid prior to injection can also be prepared; and the formulation may be emulsified. The preparation of such formulations is known to those skilled in the art in view of the present disclosure. In certain embodiments, a device is used for parenteral administration. For example, such devices can include needle injectors, micro needle injectors, needleless injectors, and infusion techniques.

[0288] In certain embodiments, pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions; formulations (including sesame oil, peanut oil, or propylene glycol solutions); and sterile powders for the immediate preparation of sterile injection solvents or dispersions. In certain embodiments, the form needs to be sterile and have sufficient fluidity to be easily injectable. In certain embodiments, the form needs to be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.

[0289] In certain embodiments, the carrier can also be a solvent or dispersion medium including, for example, water, ethanol, polyols (such as glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. In certain embodiments, proper fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the particle size required upon dispersion, and by the use of surfactants. In certain embodiments, the action of microorganisms can be prevented by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In certain embodiments, isotonic agents such as sugars or sodium chloride are included. In certain embodiments, sustained absorption of the injection composition can be achieved by the use in the composition of agents that delay absorption such as aluminum monostearate and gelatin.

[0290] In one embodiment, the sterile injectable solution is prepared by incorporating the required amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formulas (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof) in a suitable solvent into the various other ingredients listed above, and subsequently, if necessary, by sterile filtration. In one embodiment, the dispersant is prepared by incorporating various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and the other required ingredients from those listed above. In one embodiment, the sterile powder is used for the preparation of the sterile injectable solution. In one embodiment, the preparation method is vacuum drying and lyophilization techniques to obtain a powder of the active ingredient and further desired ingredients from its previously sterile filtered solution.

[0291] In certain embodiments, pharmaceutically acceptable excipients that can be used in a rectal composition as a gel, cream, suppository, or rectal suppository include, but are not limited to, cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (e.g., PEG ointment), glycerin, glycerin gelatin, hydrogenated vegetable oil, poloxamer, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p - hydroxybenzoate, sodium propyl p - hydroxybenzoate, diethylamine, carbomer, carbopol, methyl hydroxybenzoate, macrogol cetostearyl ether, cocooyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy - methyl bisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins such as vitamin A and E, and potassium acetate, any one or more of which may be mentioned.

[0292] In certain embodiments, the suppository can be prepared by mixing a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formulas (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition described herein with a suitable non - irritating excipient or carrier that is solid at ambient temperature but liquid at body temperature and thus melts in the rectum to release the active compound, such as cocoa butter, polyethylene glycol, or suppository wax. In certain embodiments, the composition for rectal administration is in the form of an enema.

[0293] In certain embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formulas (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition thereof is formulated for topical delivery to the gastrointestinal or GI tract by oral administration (e.g., a solid or liquid formulation). In certain embodiments, solid formulations for oral administration include capsules, tablets, pills, powders, and granules.

[0294] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formula (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof) is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) wetting agents, such as glycerol, d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicas, and sodium carbonate, e) solution retarding agents, such as paraffin, f) absorption promoters, such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and glycerol monostearate, h) absorbents, such as kaolin and bentonite clays, and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. For example, in the case of capsules, tablets, and pills, the formulation may also contain buffering agents. In one embodiment, solid compositions of the same type may be used as fillers, such as excipients such as lactose or milk sugar, and high molecular weight polyethylene glycol, etc., in soft and hard gelatin capsules.

[0295] In certain embodiments, the pharmaceutical composition is in the form of a unit dosage form such as a pill or tablet, and thus the composition may include a compound of formula (I) provided herein or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formulas (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof), together with a diluent such as lactose, sucrose, dicalcium phosphate, etc.; a lubricant such as magnesium stearate, etc.; and a binder such as starch, gum arabic, polyvinylpyrrolidinone, gelatin, cellulose, cellulose derivatives, etc. In certain embodiments, another solid formulation, powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124 or triglyceride) is encapsulated in a capsule (gelatin or cellulose-based capsule). In certain embodiments, unit dosage forms in which one or more of the compounds and pharmaceutical compositions provided herein or additional active agents are physically separated, such as each drug of a granule capsule and a granule (or a tablet in a capsule); a bilayer tablet; a two-compartment gel cap, etc. are also included. In certain embodiments, enteric-coated or sustained-release oral formulations are also included.

[0296] In certain embodiments, other physiologically acceptable compounds may include wetting agents, emulsifying agents, dispersing agents, or preservatives that are particularly useful for preventing the growth or action of microorganisms. For example, various preservatives are well known, including, for example, phenol and ascorbic acid.

[0297] In certain 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 certain embodiments for various oral formulation excipients such as tablets and capsules, sterilization is not required. For example, United States Pharmacopeia / National Formulary (USP / NF) standards may be sufficient.

[0298] In certain embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formulas (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition thereof, is formulated for ophthalmic use. In certain embodiments, the ophthalmic composition can include, but is not limited to, the following: viscogens (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., pluronics (triblock copolymers), cyclodextrins); preservatives (e.g., benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxyloiron complex; Allergan, Inc.)) of one or more of any of the foregoing.

[0299] In certain embodiments, a compound of formula (I) described herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formulas (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition thereof, is formulated for topical administration (e.g., dermally or transdermally) to the skin or mucosa. In certain embodiments, the topical composition can include ointments and creams. In certain embodiments, an ointment is typically a semisolid preparation based on petrolatum or other petroleum derivatives. In certain embodiments, a cream containing a selected active agent is typically a viscous liquid or semisolid emulsion, often either an oil-in-water or water-in-oil type. For example, a cream base is typically water-washable and includes an oil phase, an emulsifier, and an aqueous phase. For example, the oil phase, also sometimes referred to as the "internal" phase, generally consists of petrolatum and fatty alcohols, such as cetyl or stearyl alcohol, and the aqueous phase, while not always necessary, is generally in greater volume than the oil phase and typically includes a humectant. In certain embodiments, the emulsifier in a cream formulation is generally a nonionic, anionic, cationic, or amphoteric surfactant. In certain embodiments, like other carriers or vehicles, an ointment base needs to be inert, stable, non-irritating, and non-sensitizing.

[0300] In any of the foregoing embodiments, a pharmaceutical composition described herein can include one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradable poly(D,L-lactic-co-glycolic acid) [PLGA] - based or polyanhydride - based nanoparticles or microparticles, and nanoporous particle - supported lipid bilayers.

[0301] In certain embodiments, the dosage for a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formula (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof) is not limited to the following, but is determined based on many factors including the type, age, weight, gender, 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 certain embodiments, an appropriate dosage for a particular situation can be determined by one of ordinary skill in the pharmaceutical art. In certain embodiments, the total daily dosage may be divided and administered separately throughout the day or administered by a method that provides sustained delivery.

[0302] In certain embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formula (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof) is administered at a dosage of about 0.01 to about 1000 mg. For example, about 0.1 to about 30 mg, about 10 to about 80 mg, about 0.5 to about 15 mg, about 50 mg to about 200 mg, about 100 mg to about 300 mg, about 200 to about 400 mg, about 300 mg to about 500 mg, about 400 mg to about 600 mg, about 500 mg to about 800 mg, about 600 mg to about 900 mg, or about 700 mg to about 1000 mg. In certain embodiments, the dosage is a therapeutically effective amount.

[0303] In certain embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formulas (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof) described herein is administered at a dosage of about 0.0002 mg / Kg to about 100 mg / Kg (e.g., about 0.0002 mg / Kg to about 50 mg / Kg; about 0.0002 mg / Kg to about 25 mg / Kg; about 0.0002 mg / Kg to about 10 mg / Kg; about 0.0002 mg / Kg to about 5 mg / Kg; about 0.0002 mg / Kg to about 1 mg / Kg; about 0.0002 mg / Kg to about 0.5 mg / Kg; about 0.0002 mg / Kg to about 0.1 mg / Kg; about 0.001 mg / Kg to about 50 mg / Kg; about 0.001 mg / Kg to about 25 mg / Kg; about 0.001 mg / Kg to about 10 mg / Kg; about 0.001 mg / Kg to about 5 mg / Kg; about 0.001 mg / Kg to about 1 mg / Kg; about 0.001 mg / Kg to about 0.5 mg / Kg; about 0.001 mg / Kg to about 0.1 mg / Kg; about 0.01 mg / Kg to about 50 mg / Kg; about 0.01 mg / Kg to about 25 mg / Kg; about 0.01 mg / Kg to about 10 mg / Kg; about 0.01 mg / Kg to about 5 mg / Kg; about 0.01 mg / Kg to about 1 mg / Kg; about 0.01 mg / Kg to about 0.5 mg / Kg; about 0.01 mg / Kg to about 0.1 mg / Kg; about 0.1 mg / Kg to about 50 mg / Kg; about 0.1 mg / Kg to about 25 mg / Kg; about 0.1 mg / Kg to about 10 mg / Kg; about 0.1 mg / Kg to about 5 mg / Kg; about 0.1 mg / Kg to about 1 mg / Kg; about 0.1 mg / Kg to about 0.5 mg / Kg). In certain embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formulas (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof) described herein is administered at a dosage of about 100 mg / Kg.

[0304] In certain embodiments, said dosage of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formula (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof) can 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., once every day, once every two days, once every three days, once a week, twice a week, once every two weeks, once a month).

[0305] In certain embodiments, the administration period of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formula (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof) is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more. In certain embodiments, 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 more. In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formula (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof) is administered to a patient for a certain period, followed by a washout period during which the administration of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formula (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof) is discontinued.In certain embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formula (IA), (IB), (IC), (ID), and (IE), 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, and then there is a third period during which administration of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formula (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof) is initiated, and then there is a fourth period after the third period during which administration is discontinued. For example, the administration period of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formula (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof), followed by the period during which administration is stopped, is repeated for a predetermined period or an undefined period. In certain embodiments, the administration period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In certain embodiments, 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 more.

[0306] In certain embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formula (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof) is administered orally to a patient once or more per day (e.g., once daily, twice daily, three times daily, four times daily, or once daily dose). In certain embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formula (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof) is administered parenterally to a patient once or more per day (e.g., 1 to 4 times a day, twice daily, three times daily, four times daily, or once daily dose).

[0307] In certain embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (e.g., any one compound of formula (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof) is administered parenterally to a patient once a week.

[0308] Method of treatment In certain embodiments, the present disclosure features a method of treating a patient (e.g., a human) suffering from a disease, disorder, or illness in which modulation (e.g., inhibition or impairment and / or increase or undesired) of the GLP-1R is beneficial for treating the underlying condition and / or symptoms and / or progression of the disease, disorder, or illness. In certain embodiments, the methods described herein may include, or further include, one or more diseases associated with, co-existing with, or secondary to any one or more of the diseases described herein.

[0309] A method for treating a GLP-1 related disease, disorder, or illness, comprising administering to a patient in need thereof an effective amount of a compound of formula I disclosed herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formulas (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition, is provided herein.

[0310] In certain embodiments, the disease, disorder, or illness includes, but is not limited to, type 1 diabetes, type 2 diabetes, juvenile-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), young-onset atypical diabetes (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes in adults (LADA), obesity (including hypothalamic obesity and monogenic obesity), weight gain due to the use of other agents, 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 arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial disorder, vascular compliance disorder, restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorder, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic kidney disease, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataract, glomerulosclerosis, arthritis, osteoporosis, treatment of poisoning, 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).

[0311] In certain embodiments, the disease, disorder, or illness includes, but is not limited to, type 2 diabetes, juvenile-onset type 2 diabetes, obesity, idiopathic intracranial hypertension, Wolfram syndrome, weight gain due to the use of other drugs, gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, gestational diabetes, kidney disease (e.g., acute kidney injury, tubular dysfunction, pro-inflammatory changes to the proximal tubule), adipocyte dysfunction, sleep apnea, visceral fat accumulation, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic kidney disease, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina, 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 fatty liver disease (NASH), non-alcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS), or any combination thereof.

[0312] In certain embodiments, the disease, disorder, or illness includes, but is not limited to, type 2 diabetes, juvenile-onset type 2 diabetes, obesity, idiopathic intracranial hypertension, Wolfram syndrome, 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 arterial disease, stroke, transient ischemic attack, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, chronic kidney disease, syndrome X, angina, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, skin and connective tissue disorders, foot ulcers, or any combination thereof.

[0313] In certain embodiments, the compounds, pharmaceutical compositions, and methods of treating a patient described herein result in one or more of a decrease in blood glucose level (e.g., a reduction in blood glucose level), a decrease in blood hemoglobin A1c (HbA1c) level, an increase in 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., level). In certain embodiments, the compounds, pharmaceutical compositions, and methods of treating a patient described herein decrease blood glucose level, decrease blood hemoglobin A1c (HbA1c) level, increase insulin synthesis, activate insulin secretion, increase the population of β-cells, regulate gastric acid secretion, regulate gastric emptying, decrease body mass index (BMI), decrease glucagon production (e.g., level), and can result in any combination thereof. In certain embodiments, the compounds, pharmaceutical compositions, and methods of treating a patient described herein 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 in need of regulation, the method 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., a compound of any one of formulas (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition.

[0314] In certain embodiments, a method for reducing the risk of major adverse cardiovascular events (MACE) in a patient in need thereof (e.g., by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%) is provided herein, the method 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., a compound of any one of Formulas (IA), (IB), (IC), (ID), and (IE), 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 (T2D). In certain embodiments, the patient is an adult diagnosed with a heart disease. In certain embodiments, the patient is an adult diagnosed with both type 2 diabetes (T2D) and a heart disease. In certain embodiments, the patient is an adult diagnosed with type 2 diabetes (T2D). In certain embodiments, the patient is an adult diagnosed with a heart disease. In certain embodiments, the patient has type 2 diabetes (T2D) and a heart disease.

[0315] Indications Obesity In certain embodiments, the disease, disorder or condition is obesity and 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 insufficiency), hypothalamic obesity, genetic obesity (e.g., Prader-Willi syndrome, Laurence-Moon-Biedl syndrome), and drug-induced obesity (e.g., steroid, phenothiazine, insulin, sulfonylurea agent, or β-blocker-induced obesity).

[0316] In certain embodiments, the disease, disorder or condition is associated with obesity. Examples of such diseases, disorders or conditions include, but are not limited to, glucose intolerance, diabetes (e.g., type 2 diabetes, obesity-related diabetes), dyslipidemia, hyperlipidemia, hypertension, heart failure, hyperuricemia, gout, fatty liver (including non-alcoholic steatohepatitis (NASH)), coronary heart disease (e.g., myocardial infarction, angina pectoris), cerebral infarction (e.g., cerebral thrombosis, transient ischemic attack), bone or joint diseases (e.g., osteoarthritis, coxarthrosis, spondylosis deformans, low back pain), sleep apnea syndrome, obesity hypoventilation syndrome (Pickwickian syndrome), menstrual disorders (e.g., abnormal menstrual cycle, abnormal menstrual bleeding and cycle, amenorrhea, abnormal menstrual-associated symptoms), visceral obesity syndrome, urinary incontinence, and metabolic syndrome. In certain embodiments, the compounds and pharmaceutical compositions described herein can be used to treat patients presenting symptoms of both obesity and insulin deficiency.

[0317] Diabetes In certain embodiments, the disease, disorder or condition is diabetes. Non-limiting examples of diabetes include type 1 diabetes, type 2 diabetes (e.g., type 2 diabetes treated with diet, type 2 diabetes treated with sulfonylureas, more advanced type 2 diabetes, type 2 diabetes treated with long-term insulin), diabetes (e.g., non-insulin-dependent diabetes, insulin-dependent diabetes), gestational diabetes, obesity-related diabetes, autoimmune diabetes, and borderline diabetes. In certain embodiments, the disease, disorder or condition is type 2 diabetes (e.g., type 2 diabetes treated with diet, type 2 diabetes treated with sulfonylureas, more advanced type 2 diabetes, type 2 diabetes treated with long-term insulin).

[0318] A method for treating diabetes in a patient, 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., a compound of any one of formulas (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition, is provided herein.

[0319] A method for treating type 2 diabetes in a patient, comprising administering to a patient identified or diagnosed as having type 2 diabetes a therapeutically effective amount of a compound of formula I disclosed herein or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formulas (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition, is provided herein.

[0320] A method for treating type 2 diabetes in a patient in need of 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 (e.g., a compound of any one of formulas (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition, is also provided.

[0321] In certain embodiments, the compounds, pharmaceutical compositions, and methods for treating a patient having a disease, disorder, or condition described herein (e.g., type 2 diabetes) decrease fasting blood glucose levels. In certain embodiments, the compounds, pharmaceutical compositions, and methods for treating a patient having a disease, disorder, or condition described herein (e.g., type 2 diabetes) decrease postprandial blood glucose levels. In certain embodiments, the compounds, pharmaceutical compositions, and methods for treating a patient having a disease, disorder, or condition described herein (e.g., type 2 diabetes) decrease HbA1c levels. In certain embodiments, the compounds, pharmaceutical compositions, and methods for treating a patient having a disease, disorder, or condition described herein (e.g., type 2 diabetes) decrease glucagon levels. In certain embodiments, the compounds, pharmaceutical compositions, and methods for treating a patient having a disease, disorder, or condition described herein (e.g., type 2 diabetes) increase insulin levels. In certain embodiments, the compounds, pharmaceutical compositions, and methods for treating a patient having a disease, disorder, or condition described herein (e.g., type 2 diabetes) decrease BMI.

[0322] In certain embodiments, a decrease in fasting blood glucose levels of about 5% to about 95% is demonstrated by treatment of type 2 diabetes. A decrease in fasting blood glucose levels of about 15% to about 80% is demonstrated by treatment of type 2 diabetes. A decrease in fasting blood glucose levels of about 25% to about 60% is demonstrated by treatment of type 2 diabetes. In certain embodiments, a decrease in fasting blood glucose levels to about 126 mg / dL or less, about 110 mg / dL or less, or about 90 mg / dL or less is demonstrated by treatment of type 2 diabetes.

[0323] In certain embodiments, a decrease in non-fasting blood glucose levels of about 5% to about 95% is demonstrated by treatment of type 2 diabetes. A decrease in non-fasting blood glucose levels of about 15% to about 80% is demonstrated by treatment of type 2 diabetes. A decrease in non-fasting blood glucose levels of about 25% to about 60% is demonstrated by treatment of type 2 diabetes. In certain embodiments, a decrease in non-fasting blood glucose levels to about 200 mg / dL or less, about 150 mg / dL or less, or about 130 mg / dL or less is demonstrated by treatment of type 2 diabetes.

[0324] In certain embodiments, a decrease in HbA1c levels of about 5% to about 95% is demonstrated by treatment of type 2 diabetes. A decrease in HbA1c levels of about 15% to about 80% is demonstrated by treatment of type 2 diabetes. A decrease in HbA1c levels of about 25% to about 60% is demonstrated by treatment of type 2 diabetes. In certain embodiments, a decrease in HbA1c levels to about 6.5% or less, about 6.0% or less, or about 5.0% or less is demonstrated by treatment of type 2 diabetes.

[0325] In certain embodiments, a decrease in glucagon levels of about 5% to about 95% is demonstrated by treatment of type 2 diabetes. A decrease in glucagon levels of about 15% to about 80% is demonstrated by treatment of type 2 diabetes. A decrease in glucagon levels of about 25% to about 60% is demonstrated by treatment of type 2 diabetes. An increase in insulin levels of about 5% to about 95% is demonstrated by treatment of type 2 diabetes. An increase in insulin levels of about 15% to about 80% is demonstrated by treatment of type 2 diabetes. An increase in insulin levels of about 25% to about 60% is demonstrated by treatment of type 2 diabetes.

[0326] In some embodiments, a reduction in BMI of about 5% to about 95% is shown by treating type 2 diabetes. A reduction in BMI of about 15% to about 80% is shown by treating type 2 diabetes. A reduction in BMI of about 25% to about 60% is shown by treating type 2 diabetes. In some embodiments, a reduction in BMI of about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% is shown by treating type 2 diabetes. In some embodiments, a reduction in BMI of about 40 or less, about 30 or less, or about 20 or less is shown by treating type 2 diabetes.

[0327] In some embodiments, the disease, disorder or disorder is associated with diabetes (e.g., complications of diabetes).Non-limiting examples of disorders associated with diabetes include obesity, obesity-related disorders, metabolic syndrome, neuropathy, nephropathy (e.g., diabetic nephropathy), retinopathy, diabetic cardiomyopathy, cataract, macroangiopathy, osteopenia, hyperosmolar diabetic coma, infection (e.g., respiratory infection, urinary tract infection, gastrointestinal infection, skin and soft tissue infection, lower limb infection), diabetic gangrene, xerostomia, hearing loss, cerebrovascular disease, diabetic cachexia, delayed wound healing, diabetic dyslipidemia, peripheral blood circulation disorder, cardiovascular risk factors (e.g., coronary artery disease, peripheral artery disease, cerebrovascular disease, hypertension, and risk factors related to uncontrolled cholesterol and / or lipid levels, and / or inflammation), NASH, bone fracture, and cognitive impairment.

[0328] Other non-limiting examples of disorders related to diabetes include prediabetes, hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, hyper-LDL cholesterolemia, hypo-LDL cholesterolemia, postprandial dyslipidemia), metabolic syndrome (e.g., a metabolic disorder in which activation of GLP-1R is beneficial, metabolic syndrome X), hypertension, impaired glucose tolerance (IGT), insulin resistance, and sarcopenia.

[0329] In certain embodiments, the disease, disorder or condition is diabetes and obesity (diabesity). In certain embodiments, the compounds described herein are useful for improving the therapeutic efficacy of metformin.

[0330] Disorders of metabolically important tissues In certain embodiments, the disease, disorder or condition is a disorder of metabolically important tissues. Non-limiting examples of metabolically important tissues include the liver, adipose, pancreas, kidney, and intestine.

[0331] In certain embodiments, the disease, disorder or condition is 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 diseases resulting from hepatitis, fatty liver diseases resulting from obesity, fatty liver diseases resulting from diabetes, fatty liver diseases resulting from insulin resistance, fatty liver diseases resulting from hypertriglyceridemia, abetalipoproteinemia, hyperlipoproteinemia, glycogenosis, Weber-Christian disease, Wolman disease, acute fatty liver of pregnancy, and lipodystrophy.

[0332] Non-alcoholic fatty liver disease (NAFLD) refers to a series of diseases that occur in the absence of alcohol abuse and is typically characterized by the presence of 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. This can cause liver disease in adults and children and ultimately 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 and mainly isolated macrovesicular steatosis (i.e., non-alcoholic fatty liver or NAFL) to non-alcoholic steatohepatitis (NASH) (Angulo et al., J Gastroenterol Hepatol 2002; 17 Suppl:S186-90).

[0333] 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, such as 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 insufficiency or hemodialysis, fractures, bone surgery, aging, pregnancy, protection from fractures, and malnutrition polycystic ovary syndrome; kidney disease (e.g., chronic renal insufficiency, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease); muscular dystrophy, angina, acute or chronic diarrhea, testicular dysfunction, respiratory dysfunction, frailty, sexual dysfunction (e.g., erectile dysfunction), and geriatric syndromes. In certain embodiments, the compounds and pharmaceutical compositions described herein can be used to treat surgical trauma by improving recovery after surgery and / or preventing the catabolic response caused by surgical trauma.

[0334] Cardiovascular and vascular diseases In certain embodiments, 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 disorders (e.g., stroke), vascular insufficiency, myocardial infarction, elevated blood pressure (e.g., 130 / 85 mmHg or higher), and prothrombotic states (e.g., high fibrinogen or plasminogen activator inhibitor in the blood).

[0335] In certain embodiments, the disease, disorder or condition is associated with a vascular disease. Non-limiting examples of vascular diseases include peripheral vascular disease, macrovascular complications (e.g., stroke), vascular insufficiency, peripheral arterial disease, abdominal aortic aneurysm, carotid artery disease, cerebrovascular disorders (e.g., stroke), pulmonary embolism, chronic venous insufficiency, critical limb ischemia, retinopathy, kidney disorders, and neuropathy.

[0336] Neurological diseases In certain embodiments, the disease, disorder or condition is a neuropathy (e.g., neurodegenerative disorder) or a mental disorder. Non-limiting examples of neuropathies include idiopathic intracranial hypertension (IIH), brain 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, Parkinson's disease (Morbus Parkinson), Steele-Richardson-Olszewski syndrome, Down syndrome, myasthenia gravis, nerve injury, brain injury, cerebral amyloidosis, cerebral hemorrhage with amyloidosis, encephalitis, Friedreich's ataxia, acute confusional state, 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 disease). See, e.g., U.S. Publication No. 20060275288A1.

[0337] In certain embodiments, the disease, disorder or condition is idiopathic intracranial hypertension. Idiopathic intracranial hypertension is characterized by increased intracranial pressure and papilledema. See, e.g., Virdee et al. Ophthalmol Ther. 2020; 9(4):767-781. In certain embodiments, the compounds, pharmaceutical compositions and methods described herein reduce cerebrospinal fluid secretion in patients with idiopathic intracranial hypertension. In certain embodiments, the compounds, pharmaceutical compositions and methods described herein reduce intracranial pressure in patients with idiopathic intracranial hypertension. In certain embodiments, the compounds, pharmaceutical compositions and methods described herein reduce one or more symptoms in patients with idiopathic intracranial hypertension. Symptoms of idiopathic intracranial hypertension can include severe headache and visual disturbances. In certain embodiments, the patient with idiopathic intracranial hypertension is female. In certain embodiments, the patient with idiopathic intracranial hypertension is about 20 to about 30 years old. In certain embodiments, the patient with idiopathic intracranial hypertension is obese.

[0338] In certain embodiments, the disease, disorder or condition is Wolfram syndrome. Wolfram syndrome is caused by biallelic mutations in the wolframin endoplasmic reticulum transmembrane glycoprotein (Wfs1) gene. See, e.g., Seppa et al. Sci Rep 9, 15742 (2019). Wolfram syndrome can first present as diabetes, followed by optic atrophy, deafness, and neurodegenerative symptoms. Patients with Wolfram syndrome may exhibit symptoms of ataxia due to brainstem atrophy, sleep apnea, dysphagia, deafness, and ageusia. In certain embodiments, the compounds, pharmaceutical compositions, and methods described herein reduce neuroinflammation in patients with Wolfram syndrome. In certain embodiments, the neuroinflammation is reduced in the inferior olive of the patient. In certain embodiments, the compounds, pharmaceutical compositions, and methods described herein reduce retinal ganglion cell death in patients with Wolfram syndrome. In certain embodiments, the compounds, pharmaceutical compositions, and methods described herein reduce axonal degeneration in patients with Wolfram syndrome. In certain embodiments, 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.

[0339] Non-limiting examples of mental disorders include drug dependence / intoxication (narcotics and amphetamines) and attention deficit hyperactivity disorder (ADHD). The compounds and pharmaceutical compositions described herein may be useful for improving behavioral responses to addictive drugs, reducing drug dependence, preventing relapse of drug abuse, and alleviating anxiety caused by the absence of certain addictive substances. See, e.g., U.S. Publication No. 20120021979A1.

[0340] In certain embodiments, the compounds and pharmaceutical compositions described herein are useful for improving learning and memory by enhancing the promotion of neuroplasticity and cell differentiation, and for maintaining dopaminergic neurons and motor function in Parkinson's disease (Morbus Parkinson).

[0341] Insulin-related In certain embodiments, the disease, disorder or condition is impaired fasting glucose (IFG), impaired fasting glycemia (IFG), hyperglycemia, insulin resistance (glucose homeostasis disorder), hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hypoglycemic conditions, insulin resistance syndrome, abnormal sensations caused by hyperinsulinemia, hyperlipidemia, hypercholesterolemia, poor wound healing, leptin resistance, glucose intolerance, elevated fasting glucose, dyslipidemia (e.g., atherogenic dyslipidemia characterized by hyperlipidemia, high triglycerides and low HDL cholesterol), glucagonoma, hyperuricemia, hypoglycemia (e.g., nocturnal hypoglycemia), and a concomitant comatose endpoint related to insulin.

[0342] In certain embodiments, the compounds and pharmaceutical compositions described herein can reduce or delay the progression to diabetes of borderline impaired fasting glucose or impaired fasting glycemia.

[0343] Autoimmune diseases In certain embodiments, the disease, disorder or condition is an autoimmune disease. Non-limiting examples of autoimmune diseases include multiple sclerosis, experimental autoimmune encephalomyelitis, and autoimmune diseases are associated with immune rejection, graft-versus-host disease, uveitis, 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

[0344] Gastrointestinal-related disorders In certain embodiments, the disease, disorder or condition is a disorder related to the stomach or intestine. Non-limiting examples of these disorders include ulcers of any etiology (e.g., gastric ulcers, Zollinger-Ellison syndrome, drug-induced ulcers, ulcers associated with infection or other pathogens), gastrointestinal diseases, malabsorption disorders, short bowel syndrome, blind loop syndrome, inflammatory bowel diseases (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., gastric mucosal injury caused by aspirin), small intestinal mucosal injury, and cachexia (e.g., cancer cachexia, tuberculous cachexia, cachexia associated with blood diseases, cachexia associated with endocrine diseases, cachexia associated with infectious diseases, and cachexia caused by acquired immunodeficiency syndrome).

[0345] Body weight In certain embodiments, the compounds and pharmaceutical compositions described herein can be used to reduce body weight (e.g., excess body weight), prevent weight gain, cause weight loss, reduce body fat, or reduce food intake in a patient (e.g., a patient in need thereof). In certain embodiments, the weight gain of the patient may be due to excessive food intake or an unbalanced diet, or may be weight gain resulting from concomitant medications (e.g., insulin sensitizers having PPARγ agonist-like effects, such as troglitazone, rosiglitazone, englitazone, ciglitazone, pioglitazone, etc.). In certain embodiments, the weight gain may be weight gain prior to becoming obese, or may be weight gain in an obese patient. In certain embodiments, the weight gain may also be drug-induced weight gain or weight gain after smoking cessation. In certain embodiments, the weight gain is caused by the use of steroids or antipsychotics.

[0346] In certain embodiments, the disease, disorder or condition is an eating disorder, such as overeating, binge eating, bulimia, compulsive overeating, or symptomatic obesity, such as Prader-Willi syndrome and Bardet-Biedl syndrome.

[0347] Inflammatory diseases In certain embodiments, the disease, disorder or condition is an inflammatory disease. Non-limiting examples of inflammatory diseases include rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, low back pain, gout, postoperative or post-traumatic inflammation, abdominal distension, neuralgia, pharyngitis, cystitis, pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including ulcerative colitis), inflammation of metabolically important tissues (including the liver, fat, pancreas, kidney and intestine), and pro-inflammatory states (e.g., elevated levels of pro-inflammatory cytokines or markers such as C-reactive protein-like inflammatory markers in the blood).

[0348] Cancer In one embodiment, the disease, disorder or condition 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 tumor), colorectal cancer (e.g., familial colorectal cancer, hereditary non-polyposis colorectal cancer, gastrointestinal stromal tumor), small intestine cancer (e.g., non-Hodgkin lymphoma, gastrointestinal stromal tumor), esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer (e.g., nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer), salivary gland cancer, brain tumor (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma), schwannoma, liver cancer (e.g., primary liver cancer, extrahepatic bile duct cancer), kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter), bile duct cancer, endometrial cancer, cervical cancer, ovarian cancer (e.g., ovarian epithelial cancer, gonadoblastoma, ovarian germ cell tumor, low malignant potential ovarian tumor), bladder cancer, urethral cancer, skin cancer (e.g., intraocular (uveal) melanoma, Merkel cell carcinoma), hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer (e.g., medullary thyroid cancer), parathyroid cancer, nasal cavity cancer, sinus cancer, bone tumor (e.g., osteosarcoma, Ewing tumor, uterine sarcoma, soft tissue sarcoma), angiofibroma, retinal sarcoma, penile cancer, testicular tumor, pediatric solid tumor (e.g., Wilms tumor, pediatric renal tumor), Kaposi sarcoma, Kaposi sarcoma caused by AIDS, maxillary sinus tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia).

[0349] Hypothalamic-pituitary disorder In certain embodiments, the disease, disorder or condition is related to the hypothalamic-pituitary-gonadal axis. For example, the disease, disorder or condition is related to the hypothalamic-pituitary-ovarian axis. In another example, the disease, disorder or condition is related to the hypothalamic-pituitary-testicular axis. Diseases 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.

[0350] In certain embodiments, the disease, disorder or condition related to diabetes is related to the hypothalamic-pituitary-gonadal axis.

[0351] Lung disease In certain embodiments, the disease, disorder or condition 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 (non-reversible) asthma).

[0352] In certain embodiments, the disease, disorder or condition related to diabetes is a lung disease.

[0353] Combination therapy In certain embodiments, the present disclosure includes both monotherapy regimens and combination therapy regimens.

[0354] In certain embodiments, the methods described herein may further include administering one or more additional therapies (e.g., one or more additional therapeutic agents and / or one or more treatment regimens) in combination with the administration of the compounds described herein.

[0355] In certain embodiments, the methods described herein include administering a compound described herein in combination with one or more of diet therapy (e.g., dietary monitoring, diet therapy for diabetes), exercise therapy (e.g., physical activity), blood glucose monitoring, gastric electrical stimulation (e.g., TANTALUS®), and dietary improvement.

[0356] In certain embodiments, a compound of formula (I) described herein (e.g., any one compound of formula (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutically acceptable salt or solvate thereof, can be administered in combination with one or more additional therapeutic agents.

[0357] Representative additional therapeutic agents include, but are not limited to, anti-obesity agents, therapeutic agents for diabetes, therapeutic agents for diabetic complications, therapeutic agents for hyperlipidemia, antihypertensive agents, diuretics, chemotherapeutic agents, immunotherapeutic agents, anti-inflammatory agents, antithrombotic agents, antioxidants, therapeutic agents for osteoporosis, vitamins, therapeutic agents for dementia, therapeutic agents for erectile dysfunction, therapeutic agents for urinary frequency or urinary incontinence, therapeutic agents for NAFLD, therapeutic agents for NASH, and therapeutic agents for dysuria.

[0358] In one embodiment, the one or more additional therapeutic agents include, for example, those useful as anti-obesity agents. Non-limiting examples include monoamine reuptake inhibitors (e.g., tramadol, phentermine, sibutramine, mazindol, fluoxetine, tesofensine), serotonin 2C receptor agonists (e.g., lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptor modulators, GABA modulators (e.g., topiramate) (including GABA receptor agonists (e.g., gabapentin, pregabalin)), neuropeptide Y antagonists (e.g., berneperit), peptide YY or its analogs, cannabinoid receptor antagonists (e.g., rimonabant, taranabant), ghrelin antagonists, ghrelin receptor antagonists, ghrelin acylation enzyme inhibitors, opioid receptor antagonists (e.g., GSK-1521498, naltrexone), orexin receptor antagonists, melanocortin 4 receptor agonists, 11β-hydroxysteroid dehydrogenase inhibitors (e.g., AZD-4017, BVT-3498, INCB-13739), pancreatic lipase inhibitors (e.g., orlistat, cetilistat), β3 agonists (e.g., N-5984), diacylglycerol acyltransferase 1 (DGAT1) inhibitors, acetyl-CoA carboxylase (ACC) inhibitors (e.g., the compounds described in WO2020 / 234726, WO2020 / 044266, and U.S. Patent No. 8,859,577), stearoyl-CoA desaturase inhibitors, microsomal triglyceride transfer protein inhibitors (e.g., R-256918), sodium-glucose transporter 2 (SGLT-2) inhibitors (e.g., JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, remogliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, or ertugliflozin), SGLT-1 inhibitors, MCR-4 agonists, monoamine reuptake inhibitors, melanocyte-stimulating hormone analogs, 5HT2c agonists, galanin antagonists,Hypoappetite agents (e.g., bombesin agonists), thyromimetic agents, dehydroepiandrosterone or its analogs, human agouti-related protein (AGRP) inhibitors, neuromedin U agonists, NFK inhibitors (e.g., HE-3286), PPAR agonists (e.g., GFT-505, DRF-11605, gemfibrozil, fenofibrate, balaglitazone, ciglitazone, daruglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone, CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767, and SB-219994), phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate, trodusquemine), GPR119 agonists (e.g., PSN-821, MBX-2982, APD597, compounds described in WO2010 / 140092, WO2010 / 128425, WO2010 / 128414, WO2010 / 106457), glucokinase activators (e.g., piragliatin, AZD-1656, AZD6370, TTP-355, TTP-399, TTP547, ARRY403, MK-0599, TAK-329, AZD5658 or GKM-001, compounds described in WO2010 / 103437, WO2010 / 103438, WO2010 / 013161, WO2007 / 122482, WO2006 / 112549, WO2007 / 028135, WO2008 / 047821, WO2008 / 050821, WO2008 / 136428 and WO2008 / 156757), leptin, leptin derivatives (e.g., metreleptin), leptin resistance improving agents, CNTF (ciliary neurotrophic factor), BDNF (brain-derived neurotrophic factor), cholecystokinin agonists, amylin preparations (e.g., pramlintide, AC-2307), neuropeptide Y agonists (e.g., PYY3-36, PYY3-36 derivatives, obineptide, TM-30339, TM-30335), oxyntomodulin (OXM) preparations, anorectic agents (e.g., ephedrine), FGF21 preparations (e.g.,Animal FGF21 preparations extracted from bovine or porcine pancreas; human FGF21 preparations genetically synthesized using Escherichia coli or yeast; fragments or derivatives of FGF21), appetite suppressants (e.g., P-57), human proislet peptide (HIP), melanocortin receptor 4 agonists (e.g., setmelanotide), melanin-concentrating hormone receptor 1 antagonists, serotonin agents (e.g., sibutramine, lorcaserin), farnesoid X receptor (FXR) agonists (e.g., obeticholic acid, tropifexor, cilofexor, LY2562175, Met409, TERN-101, EDP305, compounds described in WO2020 / 234726 and WO2020 / 044266), phentermine, zonisamide, norepinephrine / dopamine reuptake inhibitors (e.g., bupropion), GDF-15 analogs, methionine aminopeptidase 2 (MetAP2) inhibitors (e.g., beloranib or ZGN-1061), diethylpropion, phentermine, benzphetamine, fibroblast growth factor receptor (FGFR) modifiers, biotin, MAS receptor modifiers, glucagon receptor agonists, CCKa agonists (e.g., compounds described in WO2005 / 116034 and US Publication No. 2005 / 0287100), and AMP-activated protein kinase (AMPK) activators are included.

[0359] In one embodiment, the one or more additional therapeutic agents include, for example, agents useful as anti-diabetic drugs. 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 Escherichia coli or yeast; zinc insulin; protamine zinc insulin; fragments or derivatives of insulin (e.g., INS-1), oral insulin preparations, synthetic human insulin), insulin sensitizers (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 described in WO2010 / 011439), agents that antagonize the action of glucagon or decrease the secretion of glucagon, sulfonylurea agents (e.g., chlorpropamide, tolazamide, glimepiride, tolbutamide, glyburide, gliclazide, acetohexamide, glycopyramide, glibuzole, glibridine, glipizide), thiazolidinedione agents (e.g., rosiglitazone, lobeglitazone, troglitazone, balaglitazone, rivoglitazone, lobeglitazone or pioglitazone), glitazars (e.g., aleglitazar, chiglitazar, saroglitazar, muraglitazar, tesaglitazar), SGLT2 inhibitors (e.g., JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, THR1474, TS-071, ISIS388626, LX4211, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate, empagliflozin etabonate, ertugliflozin, compounds described in WO2010 / 023594), GPR40 agonists (e.g., FFAR1 / FFA1 agonists, e.g., fasiglifam), α-glucosidase inhibitors (e.g., adiposin, camiglibose, pradimicin-Q, salbostatin, voglibose, acarbose, miglitol, emiglitate), insulin secretagogues, e.g.,Meal glucose regulators (sometimes also referred to as "short-acting secretagogues"), such as meglitinides (e.g., repaglinide and nateglinide), cholinesterase inhibitors (e.g., donepezil, galantamine, rivastigmine, tacrine), NMDA receptor antagonists, GLP-1 / GIP receptor dual agonists (e.g., LBT-2000, ZPD1-70), GLP-1R agonists (e.g., exenatide, liraglutide, albiglutide, dulaglutide, albiglutide, taspoglutide, lixisenatide, semaglutide, AVE-0010, S4P and Boc5), and dipeptidyl peptidase IV (DPP-4) inhibitors (e.g., vildagliptin, dutogliptin, gemigliptin, alogliptin, saxagliptin, sitagliptin, linagliptin, berberine, adogliptin, anagliptin (SK-0403), teneligliptin, omarigliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, ALS2-0426, TA-6666, TS-021, KRP-104, treagliptin).

[0360] In one embodiment, the one or more additional therapeutic agents include, for example, agents useful for the treatment of NAFL and NASH. Non-limiting examples include FXR agonists (e.g., obeticholic acid), PF-05221304, PPARα / δ agonists (e.g., elafibranor), synthetic fatty acid bile conjugates (e.g., aramchol), anti-lysyl oxidase-like 2 (LOXL2) monoclonal antibodies (e.g., simtuzumab), caspase inhibitors (e.g., emricasan), MAPK5 inhibitors (e.g., GS-4997), galectin-3 inhibitors (e.g., GR-MD-02), fibroblast growth factor 21 (FGF21) (e.g., BMS-986036), niacin analogs (e.g., ARJ3037MO), leukotriene D4 (LTD4) receptor antagonists (e.g., zafirlukast), acetyl-CoA carboxylase (ACC) inhibitors (e.g., NDI010976, and compounds described in WO2009 / 144554, WO2003 / 072197, WO2009 / 144555, and WO2008 / 065508), ketohexokinase (KHK) inhibitors (e.g., compounds described in WO2020 / 234726), apoptosis signal-regulating kinase 1 (ASK1) inhibitors, ileal bile acid transporter (IBAT) inhibitors, dual antagonists of chemokine receptor 2 (CCR2) and CCR5 (e.g., cenicriviroc), diacylglycerol acyltransferase 2 (DGAT2) inhibitors (e.g., compounds described in WO2020 / 234726 and U.S. Publication No. 20180051012), CB1 receptor antagonists, anti-CB1R antibodies, glycyrrhizin, Artemisia, ascorbic acid, glutathione, silymarin, lipoic acid, and d-alpha-tocopherol, ascorbic acid, glutathione, vitamin B complex, glitazone / thiazolidinedione (e.g., troglitazone, rosiglitazone, pioglitazone, balaglitazone, riboglitazone, lobeglitazone), metformin, cysteamine, sulfonylurea, alpha-glucosidase inhibitors, meglitinide, vitamin E, tetrahydrolipstatin, mariazamiprotein, antiviral agents, and antioxidants.

[0361] In one embodiment, the one or more additional therapeutic agents include, for example, drugs useful for treating diabetic complications. Non-limiting examples include aldose reductase inhibitors (e.g., tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat, ridorestat), these neurotrophic and growth factors (e.g., NGF, NT-3, BDNF, neurotrophic generation / secretion promoting agents described in WO01 / 14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxyl)propyl]oxazole), compounds described in WO2004 / 039365), PKC inhibitors (e.g., ruboxistaurin mesylate), AGE inhibitors (e.g., ALT946, N-phenacylthiazolium bromide (ALT766), EXO-226, pyridoline, 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-regulating kinase 1 (ASK-1) inhibitors.

[0362] In one embodiment, the one or more additional therapeutic agents include, for example, agents useful for the treatment of hyperlipidemia. Non-limiting examples include HMG-CoA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or salts thereof (e.g., sodium salt, calcium salt)), squalene synthase inhibitors (e.g., the compounds described in WO97 / 10224, e.g., N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-acetic acid), fibrate compounds (e.g., bezafibrate, clofibrate, cinfibrate, clinofibrate), anion exchange resins (e.g., cholestyramine), nicotinic acid drugs (e.g., nicomol, nicertol, niaspan), phytosterols (e.g., soy sterol, gamma oryzanol (γ-oryzanol)), cholesterol absorption inhibitors (e.g., ezetimibe), CETP inhibitors (e.g., dalcetrapib, anacetrapib), and omega-3 fatty acid preparations (e.g., omega-3 fatty acid ethyl ester 90).

[0363] In one embodiment, the one or more additional therapeutic agents include, for example, drugs useful as antihypertensive agents. Non-limiting examples include angiotensin-converting enzyme inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazapril, delapril, pentopril, quinapril, ramipril, lisinopril), angiotensin II antagonists (e.g., candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil, azilsartan, azilsartan medoxomil), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine, cilnidipine), and β-blockers (e.g., metoprolol, atenolol, propranolol, carvedilol, pindolol). Further non-limiting examples of antihypertensive agents include diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid, tricrynafen, chlorthalidone, torsemide, furosemide, musolimine, bumetanide, musolimine, amiloride, spironolactone), alpha-adrenergic blockers, beta-adrenergic blockers, calcium channel blockers (e.g., diltiazem, verapamil, nifedipine, and amlodipine), vasodilators (e.g., hydralazine), renin inhibitors, AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan), ET receptor antagonists (e.g., sitaxentan, 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 blocker ivabradine, and vasopeptidase inhibitors (NEP-ACE dual inhibitors) (e.g., gemopatrilat and nitrates).

[0364] In one embodiment, the one or more additional therapeutic agents include, for example, drugs useful as diuretics. Non-limiting examples include xanthine derivatives (e.g., sodium theophylline salicylate, calcium theophylline salicylate), thiazide agents (e.g., ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penflutizide, polythiazide, methyclothiazide), anti-aldosterone agents (e.g., spironolactone, triamterene), carbonic anhydrase inhibitors (e.g., acetazolamide), and chlorobenzenesulfonamide agents (e.g., chlorthalidone, mefruside, indapamide).

[0365] In one embodiment, the one or more additional therapeutic agents include, for example, drugs useful as immunotherapeutic agents. Non-limiting examples include microorganisms or bacterial compounds (e.g., muramyl dipeptide derivatives, picibanil), polysaccharides having immunopotentiating activity (e.g., lentinan, schizophyllan, krestin), cytokines obtained by genetic manipulation methods (e.g., interferons, interleukins (IL), such as IL-1, IL-2, IL-12), and colony stimulating factors (e.g., granulocyte colony stimulating factor, erythropoietin).

[0366] In one embodiment, the one or more additional 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, boropeptide, heparin, hirudin, and melagatran), FXa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, YM150, compounds described in WO02 / 06234, WO2004 / 048363, WO2005 / 030740, WO2005 / 058823, and WO2005 / 113504), thrombolytic agents (e.g., anisoylated plasminogen streptokinase activator complex), and platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cilostazol, ethyl eicosapentaenoate, veraprost sodium, and sarpogrelate hydrochloride).

[0367] In one embodiment, the one or more additional therapeutic agents include, for example, agents useful for the treatment of osteoporosis. Non-limiting examples include alfacalcidol, calcitriol, elcatonin, salmon calcitonin, 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 erectile dysfunction therapeutic agents include apomorphine and sildenafil citrate. Suitable examples of therapeutic agents for urinary frequency or urinary incontinence include flavoxate hydrochloride, oxybutynin hydrochloride, and propiverine hydrochloride. Suitable examples of therapeutic agents for micturition disorders include acetylcholinesterase inhibitors (e.g., distigmine). Suitable examples of anti-inflammatory agents include non-steroidal anti-inflammatory agents, such as aspirin, acetaminophen, and indomethacin.

[0368] Other exemplary additional therapeutic agents include agents that regulate hepatic glucose balance (e.g., fructose 1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glycogen synthase kinase inhibitors, glucokinase activators), agents designed to treat complications of persistent hyperglycemia, such as aldose reductase inhibitors (e.g., epalrestat and ranirestat), agents used to treat complications associated with microangiopathy, lipid-lowering agents, such as HMG-COA reductase inhibitors (statins, such as rosuvastatin, pravastatin, pitavastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, itavastatin, ZD-4522), HMG-CoA synthase inhibitors, cholesterol-lowering agents, bile acid sequestrants (e.g., cholestyramine, questran, cholestyramine, and colesevelam), 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-glucosidase hydrolase inhibitors, SIRT-1 activators, c-Jun N-terminal kinase (JNK) inhibitors, VPAC2 receptor agonists, TGR5 receptor modifiers (e.g., compounds described), 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 modifiers), ACAT inhibitors, MTP inhibitors (e.g., dirilotapide, mitotapide, and implitapide), lipoxygenase inhibitors, PCSK9 modifiers (e.g., alirocumab and evolocumab), RXR alpha modifiers, cysteamine, cystamine, RNA antisense constructs for inhibiting protein tyrosine phosphatase PTPRU, vitamin B complex, pentraxin proteins, protein tyrosine phosphatase-1B (PTP-1B) inhibitors (e.g., trodusquemine, hyrtiosal extract, and compounds described in Zhang et al. Drug Discovery Today. 2007, 12(9-10): 373-381), ezitimbe, betaine, pentoxifylline, alpha delta-9 desaturase, BCKDK inhibitors, branched-chain alpha-keto acid dehydrogenase (BCBK) inhibitors, PNPLA3 inhibitors, FGF19 analogs, SCD1 inhibitors, bile acid sequestrants, nicotinic acid (niacin) and its analogs, antioxidants (e.g., probucol), omega-3 fatty acids, antihypertensive agents, 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., alpha2 agonists (e.g., clonidine), angiotensin-converting enzyme (ACE) inhibitors (e.g., lisinopril), calcium channel blockers, e.g., dihydropyridines (e.g., nifedipine), phenylalkylamines (e.g., verapamil), and benzothiazepines (e.g., diltiazem), angiotensin II receptor antagonists (e.g., candesartan), aldosterone receptor antagonists (e.g., eplerenone, spironolactone), centrally acting adrenergic drugs, e.g., central alpha agonists (e.g., clonidine), diuretics (e.g., furosemide, torsemide, bumetanide, ethacrynic acid, thiazide diuretics (e.g., chlorothiazide,Hydrochlorothiazide, benzthiazide, hydroflumethiazide, bendroflumethiazide, methyclothiazide, polythiazide, trichloromethiazide, indapamide), phthalimide diuretics (e.g., chlorthalidone, metolazone), quinazoline diuretics (e.g., kinethazone), potassium-retaining diuretics (e.g., triamterene and amiloride), thyroid receptor agonists (e.g., compounds described in WO2020 / 117987), hemostasis modifiers (including antithrombotic agents (e.g., fibrinolytic activators)), thrombin antagonists, factor VIIa inhibitors, anticoagulants (e.g., vitamin K antagonists, e.g., warfarin), heparin and its low molecular weight analogs, factor Xa inhibitors, and direct thrombin inhibitors (e.g., argatroban), antiplatelet agents (e.g., cyclooxygenase inhibitors (e.g., aspirin), non-steroidal anti-inflammatory drugs (NSAIDs), thromboxane-A2-receptor antagonists (e.g., ifetroban), thromboxane-A2-synthase inhibitors, PDE inhibitors (e.g., pretalol, dipyridamole)), purine receptor antagonists (e.g., P2Y1 and P2Y12), adenosine diphosphate (ADP) receptor inhibitors (e.g., clopidogrel), phosphodiesterase inhibitors (e.g., cilostazol), glycoprotein IIB / IIA inhibitors (e.g., tirofiban, eptifibatide, and abciximab), adenosine reuptake inhibitors (e.g., dipyridamole), noradrenergic agonists (e.g., phentermine), serotonin agents (e.g., sibutramine, lorcaserin), diacylglycerol acyltransferase (DGAT) inhibitors, appetite-improving agents, pyruvate dehydrogenase kinase (PDK) modifiers, serotonin receptor modifiers, monoamine transport modifiers, e.g., selective serotonin reuptake inhibitors (SSRI) (e.g., fluoxetine), norepinephrine reuptake inhibitors (NARI), norepinephrine-serotonin reuptake inhibitors (SNRI), and monoamine oxidase inhibitors (MAOI) (e.g., troxatone and amiflamine), compounds described in WO2007 / 013694, WO2007 / 018314, WO2008 / 093639 and WO2008 / 099794,GPR40 agonists (e.g., fasiglifam 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 (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 for improving lipid metabolism (e.g., eicosapentaenoic acid), growth hormone, IGF-1, antibodies against cachexia-inducing factors TNF-α, LIF, IL-6, and oncostatin M, metabolism-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-promoting agents (e.g., Y-128, VX853, prosaptide), antidepressants (e.g., desipramine, amitriptyline, imipramine), antiepileptic drugs (e.g., lamotrigine, trileptal, keppra, zonisamide, pregabalin, harkoseride, carbamazepine), antiarrhythmic drugs (e.g., K, +Channel openers, mexiletine, propafenone, metoprolol, atenolol, carvadiol, propranolol, sotalol, dofetilide, amiodarone, azimilide, ibutilide, ditiazem, and verapamil), acetylcholine receptor ligands (e.g., ABT-594), endothelin receptor antagonists (e.g., ABT-627), narcotic analgesics (e.g., morphine), α2 receptor agonists (e.g., clonidine), 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 agents (e.g., anti-CD20 antibodies (e.g., rituxan), i-BLyS antibodies), agents that affect T cell migration (e.g., anti-integrin alpha4 / beta1 antibodies (e.g., tysabri), agents that act on immunophilins (e.g., cyclosporine, tacrolimus, sirolimus, rapamycin), interferons (e.g., IFN-β), immunomodulators (e.g., glatiramer), TNF-binding proteins (e.g., circulating receptors), immunosuppressants (e.g., mycophenolic acid), metaglidasen, AMG-131, balaglitazone, MBX-2044, riboglitazone, aleglitazar, chiglitazar, saroglitazar, muraglitazar, tesaglitazar, lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, exenatide, exendin-4, memantine, midazolam, ketoconazole, ethyl eicosapentanoate, clonidine, azosemide, isosorbide, ethacrynic acid, pyritanide, bumetanide, etoposide, piroxicam, NO donors (e.g., nitrates), and NO promoters (e.g., phosphodiesterase inhibitors) are included.

[0369] In certain embodiments, the additional therapeutic agent or regimen is administered to the patient before contact with or administration of the compound and pharmaceutical composition (e.g., about 1 hour before, about 6 hours before, about 12 hours before, about 24 hours before, about 48 hours before, about 1 week before, or about 1 month before).

[0370] In certain embodiments, the additional therapeutic agent or regimen is administered to the patient substantially simultaneously with contact with or administration of the compound and pharmaceutical composition. As an example, the additional therapeutic agent or regimen and the compound and pharmaceutical composition are provided to the patient simultaneously in the same formulation. As another example, the additional therapeutic agent or regimen and the compound and pharmaceutical composition are provided to the patient simultaneously in separate formulations.

[0371] In certain embodiments, the methods described herein further comprise identifying a patient (e.g., a subject) in need of such treatment (e.g., by a blood assay, a body mass index, or other conventional methods known in the art).

[0372] In certain embodiments, the methods described herein further comprise identifying a patient (e.g., a patient) suffering from a disease, disorder, or condition provided herein (e.g., a GLP-1 related disease, disorder, or condition).

[0373] In certain embodiments, the methods described herein further comprise identifying a patient (e.g., a subject) suffering from type 2 diabetes. In certain embodiments, determining a patient suffering from type 2 diabetes includes performing an assay to determine hemoglobin A1c (HbA1c) levels, fasting blood glucose, non-fasting blood glucose, or any combination thereof. In certain embodiments, the HbA1c level is from about 6.5% to about 24.0%. In certain embodiments, the HbA1c level is about 6.5% or greater. In certain embodiments, the HbA1c level is about 8.0% or greater. In certain embodiments, the HbA1c level is about 10.0% or greater. In certain embodiments, the HbA1c level is about 12.0% or greater. In certain embodiments, the HbA1c level is about 14.0% or greater. In certain embodiments, the HbA1c level is about 16.0% or greater. In certain embodiments, the HbA1c level is about 18.0% or greater. In certain embodiments, the HbA1c level is about 20.0% or greater. In certain embodiments, the HbA1c level is about 22.0% or greater. In certain embodiments, the HbA1c level is about 24.0% or greater.

[0374] In certain embodiments, the fasting blood glucose level is from about 120 mg / dL or greater to about 750 mg / dL or greater. In certain embodiments, the fasting blood glucose level is from about 200 mg / dL or greater to about 500 mg / dL or greater. In certain embodiments, the fasting blood glucose level is from about 300 mg / dL or greater to about 700 mg / dL or greater.

[0375] In certain embodiments, the non-fasting blood glucose level is from about 190 mg / dL or more to about 750 mg / dL or more. In certain embodiments, the non-fasting blood glucose level is from about 250 mg / dL or more to about 450 mg / dL or more. In certain embodiments, the non-fasting blood glucose level is from about 400 mg / dL or more to about 700 mg / dL or more.

[0376] In certain embodiments, determining whether a patient has type 2 diabetes further includes determining the patient's BMI. In certain embodiments, the patient's BMI is from about 22 kg / m 2 or more to about 100 kg / m 2 or more. In certain embodiments, the patient's BMI is from about 30 kg / m 2 or more to about 90 kg / m 2 or more. In certain embodiments, the patient's BMI is from about 40 kg / m 2 or more to about 80 kg / m 2 or more. In certain embodiments, the patient's BMI is from about 50 kg / m 2 or more to about 70 kg / m 2 or more.

[0377] In certain embodiments, additional factors (e.g., risk factors) used to determine whether a patient has type 2 diabetes further include the patient's age and ethnicity. In certain embodiments, the age of the patient is about 10 years or older. In certain embodiments, the age of the patient is about 15 years or older. In certain embodiments, the age of the patient is about 20 years or older. In certain embodiments, the age of the patient is about 25 years or older. In certain embodiments, the age of the patient is about 30 years or older. In certain embodiments, the age of the patient is about 35 years or older. In certain embodiments, the age of the patient is about 40 years or older. In certain embodiments, the age of the patient is about 42 years or older. In certain embodiments, the age of the patient is about 44 years or older. In certain embodiments, the age of the patient is about 46 years or older. In certain embodiments, the age of the patient is about 48 years or older. In certain embodiments, the age of the patient is about 50 years or older. In certain embodiments, the age of the patient is about 52 years or older. In certain embodiments, the age of the patient is about 54 years or older. In certain embodiments, the age of the patient is about 56 years or older. In certain embodiments, the age of the patient is about 58 years or older. In certain embodiments, the age of the patient is about 60 years or older. In certain embodiments, the age of the patient is about 62 years or older. In certain embodiments, the age of the patient is about 64 years or older. In certain embodiments, the age of the patient is about 66 years or older. In certain embodiments, the age of the patient is about 68 years or older. In certain embodiments, the age of the patient is about 70 years or older. In certain embodiments, the age of the patient is about 72 years or older. In certain embodiments, the age of the patient is about 74 years or older. In certain embodiments, the age of the patient is about 76 years or older. In certain embodiments, the age of the patient is about 78 years or older.In certain embodiments, the age of the patient is about 80 years or older. In certain embodiments, the age of the patient is about 85 years or older. In certain embodiments, the age of the patient is about 90 years or older. In certain embodiments, the age of the patient is about 95 years or older. In certain embodiments, the ethnicity of the patient may be African American, American Indian or Alaska Native, Asian American, Hispanic or Latino, or Native Hawaiian or Other Pacific Islander.

[0378] In certain embodiments, 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 subsets including neonates (from birth to 1 month of age); infants (from 1 month to 2 years of age); children (from 2 years to 12 years of age); and adolescents (from 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: W.B. Saunders Company, 1996; Rudolph AM, et al. Rudolph’s Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.) In certain embodiments, the pediatric patient is from birth to 28 days of age, from 29 days to 2 years of age, from 2 years to 12 years of age, or from 12 years to 21 years of age (including but not limited to 22 years of age). In certain embodiments, the pediatric patient is from birth to 28 days of age, from 29 days to 1 year of age, from 1 month to 4 months of age, from 3 months to 7 months of age, from 6 months to 1 year of age, from 1 year to 2 years of age, from 2 years to 3 years of age, from 2 years to 7 years of age, from 3 years to 5 years of age, from 5 years to 10 years of age, from 6 years to 13 years of age, from 10 years to 15 years of age, or from 15 years to 22 years of age. In certain embodiments, the patient is an adult patient.

Example

[0379] The present invention is further described in the following examples and is not limited to the scope of the present invention as claimed.

[0380] Schemes 1-3 show exemplary methods for preparing the compounds of formula (I) and intermediates useful in the synthesis of the compounds of formula (I).

[0381] [Chemical formula] Regarding Scheme 1, ester I1 (wherein R 4 is as defined in Formula I; [Chemical formula] is [Chemical formula] [wherein R 5 , R 6 , and R 7 are as defined in Formula I] (selected from the group consisting of) is subjected to a metal-catalyzed cross-coupling reaction (e.g., Suzuki coupling using Pd(dppf)ClCH2Cl2 in the presence of potassium carbonate) with a suitable coupling partner, such as a reagent having the formula (Ring C)-Y (wherein Ring C is as defined in Formula I; and Y is B(OH)2 or a boronic acid ester (e.g., BPin)), to give compound I2. Optionally, when Ring C is a saturated heterocyclyl, compound I1 can be coupled with a reagent of the formula (Ring C’)-Y [wherein Ring C’ is a partially saturated heterocyclyl] and then hydrogenated (e.g., using palladium on carbon) to produce compound I2. As a non-limiting example, when Ring C is tetrahydropyran-4-yl, compound I1 can be coupled with a (Ring C’)-Y of the formula: [Chemical formula] .

[0382] Next, reaction of compound I2 with compound I3 (e.g., in the presence of NaH in DMF) gives compound I4, and the ester group is hydrolyzed under standard conditions (e.g., LiOH in H2O / THF) to produce compound I5. Compound I5 is subjected to amide coupling with NHMePh under standard conditions (e.g., HATU and Hunig's base) to give compound I6. Compound I6 is reacted with reagent I6b (wherein the dashed curve Lx is C 1-6 C which may be optionally substituted with alkyl 2-5 represents alkylene, and the C 1-6 alkyl may be optionally substituted with 1 to 3 independently selected R f is reacted under basic conditions (e.g., KHMDS, DMPU) to give compound I7 (wherein ring D' is C 1-6 C which may be optionally substituted with alkyl 3-6 is cycloalkyl, and the C 1-6 alkyl may be optionally substituted with 1 to 3 independently selected R f is provided. As a non-limiting example, compound I6b is

Chemical formula

Chemical formula

[0383] Compound I7 is treated with a hydroxylamine source (e.g., NH2OH·HCl in EtOH under reflux), and then reacted with a phosgene equivalent (e.g., CDI (e.g., in the presence of DBU and DMSO at 80 °C)) to give compound I8. The amide group of compound I8 is hydrolyzed (e.g., with KOH in CH3OCH2CH2OH at 125 °C) to give compound I9.

[0384]

Chemical formula

Chemical formula

[0385]

Chemical formula

[0386] In the synthetic procedures shown above (see Schemes 1 - 3), it will be apparent to those skilled in the art that reactive groups (e.g., NH2, NH, and OH) can be protected with appropriate protecting groups and subsequently deprotected at the appropriate stage of the synthesis. It is also within the scope of those skilled in the art to consider modifications of said methods for synthesizing other compounds of formula I. For example, by substituting compound I6b with other electrophilic reagents, other compounds having an L 3 -C(R 8a R 8b )-L 4 -R 9 group can be obtained. As another example, by substituting compound I16 with other suitable reagents, other compounds having an L 2 moiety can be obtained.

[0387] General information The full NMR spectra were recorded on a Bruker 400 (400 MHz) spectrometer. 1H chemical shifts are reported as δ values (ppm) using the deuterated solvent as an internal standard. The data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad signal, m = multiplet), coupling constant (Hz), integration. LCMS spectra were obtained using an Agilent series by electrospray ionization, unless otherwise indicated.

[0388] Abbreviations

Table 3

[0389] Example 1: Synthesis of 3 - ((1S,2S)-1-(2-((S)-3-(3-(4-(dimethylphosphoryl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 101a)

Chem.

Chem.

[0390] Step B: Ethyl 5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate

Chemical Structure

[0391] Step C: Ethyl 1-(cyanomethyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate

Chemical Structure

[0392] Step D: 1-(Cyanomethyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid

Chemical formula

[0393] Step E: 1-(Cyanomethyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide

Chemical formula

[0394] Step F: 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide

Chemical Structure

[0395] Step G: N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide

Chemical formula

[0396] Step H: 1-((1S,2S)-2-Methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid

Chem.

[0397]

Chemical Structure

Chemical Structure

[0398] Step J: (S)-tert-butyl (1-cyanopropan-2-yl)carbamate [Chemical formula] A mixture of (S)-tert-butyl (4-amino-4-oxobutan-2-yl)carbamate (10.0 g, 49.5 mmol) was added with TFAA (6.90 mL, 49.5 mmol) and pyridine (8.00 mL, 99.0 mmol). The mixture was stirred at room temperature for 1 hour. The reaction was quenched with H2O (100 mL) and extracted with EtOAc (100 mL * 3). The organic layer was washed with brine (100 mL), dried over Na2SO4, concentrated under reduced pressure, and purified by flash chromatography (PE / EtOAc = 20 / 1) to obtain (S)-tert-butyl (1-cyanopropan-2-yl)carbamate as a white solid (6.00 g, 65% yield). 1 1H NMR (400 MHz, DMSO-d6) δ 7.11 (d, J = 7.2 Hz, 1H), 3.71 - 3.74 (m, 1H), 2.57 - 2.69 (m, 2H), 1.39 (s, 9H), 1.11 (d, J = 6.4 Hz, 3H).

[0399] Step K: (S)-3-aminobutanenitrile

Chemical formula

[0400] Step L: (S)-ethyl 3-((tert-butoxycarbonyl)(1-cyanopropan-2-yl)amino)propanoate [Chemical] To a solution of (s)-3-aminobutanenitrile (2.80 g, 23.1 mmol, 1.0 equiv) in EtOH (20 mL) was added TEA (3.50 g, 34.6 mmol, 1.5 equiv) and ethyl acrylate (2.33 g, 23.1 mmol, 1.0 equiv) at room temperature. The mixture was stirred at 70 °C for 3 h, cooled to room temperature, and (Boc)2O (6.10 mL, 27.8 mmol, 1.2 equiv) was added. The solution was stirred at room temperature overnight and then diluted with H2O (50 mL). The mixture was extracted with EtOAc (50 mL * 3). The organic layer was washed with brine (50 mL), dried over Na2SO4, concentrated, and purified by flash chromatography (PE / EtOAc = 10 / 1) to give (s)-ethyl 3-((tert-butoxycarbonyl)(1-cyanopropan-2-yl)amino)propanoate (4.00 g, 68% yield). 1 H NMR (400 MHz, DMSO-d6) δ 4.09 - 4.18 (m, 3H), 3.40 - 3.52 (m, 2H), 2.51 - 2.78 (m, 4H), 1.48 (s, 9H), 1.34 - 1.36 (m, 3H), 1.25 - 1.29 (m, 3H).

[0401] Step M: tert-butyl (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylate [Chemical] A solution of (s)-ethyl 3-((tert-butoxycarbonyl)(1-cyanopropan-2-yl)amino)propanoate (3.00 g, 10.6 mmol) in THF (100 mL) was added with t-BuOK (1.20 g, 10.6 mmol). The mixture was stirred at room temperature for 1 hour and then quenched with 2N HCl solution. The mixture was diluted with H2O (100 mL) and extracted with EtOAc (100 mL * 3). The organic layer was washed with brine, dried over Na2SO4, concentrated under reduced pressure, and purified by flash chromatography (PE / EtOAc = 8 / 1) to obtain tert-butyl (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylate (2.60 g, yield 100%).

[0402] Step N: tert-butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate [Chemical formula] TFA (18 mL) was added to a solution of di-tert-butyl 1-(4-fluoro-3,5-dimethylphenyl)hydrazine-1,2-dicarboxylate (4.46 g, 12.6 mmol) in DCM (40 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. A solution of Py·HCl (145 mg, 1.26 mmol) and tert-butyl (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylate (2.40 g, 10.1 mmol) in EtOH (40 mL) was added. The reaction mixture was stirred at 85 °C for 2 hours. The reaction mixture was cooled to room temperature, diluted with saturated aqueous NaOH solution (20 mL), and extracted with DCM (20 mL * 3). The combined organic layers were concentrated under reduced pressure, and the residue was purified by flash chromatography (PE / EtOAc = 20 / 1) to obtain tert-butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (2.70 g, yield 57%). 1 1H NMR (400 MHz, DMSO-d6) δ: 7.23 (d, J = 6.4 Hz, 2H), 5.20 (br. s, 2H), 5.01 - 5.12 (m, 1H), 4.02 - 4.16 (m, 1H), 2.98 - 3.07 (m, 1H), 2.42 - 2.46 (m, 2H), 2.25 (d, J = 2.0 Hz, 6H), 1.43 (s, 9H), 1.24 - 1.26 (m, 3H).

[0403] Step O: tert-Butyl (S)-3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

Chem.

[0404] Step P: tert-Butyl (S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

Chem.

[0405] Step Q: tert-Butyl (S)-3-(3-(4-(Dimethylphosphoryl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

Chem.

[0406] Step R: (S)-3-(3-(4-(dimethylphosphoryl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-ium chloride

Chemical formula

[0407] Step S: 3-((1S,2S)-1-(2-((S)-3-(3-(4-(dimethylphosphoryl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

Chem.

[0408] Example 2: Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(4-(Diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 121a) [Chemical Structure Diagram] Step A: (4-Bromo-2-fluorophenyl)diethylphosphine oxide A mixture of 4-bromo-2-fluoro-1-iodobenzene (2.00 g, 6.60 mmol), diethylphosphine oxide (775 mg, 7.30 mmol), Pd2(dba)3 (302 mg, 0.330 mmol), and Xantphos (382 mg, 0.660 mmol) in 40 mL of 1,4-dioxane was sparged with argon. Then, triethylamine (1.30 g, 13.2 mmol) was added. The mixture was heated at 60 °C for 12 h under an argon atmosphere. Completion of the reaction was indicated by LCMS. The mixture was concentrated, and the residue was diluted with ethyl acetate (100 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 / methanol = 1:2:0.1) to afford (4-bromo-2-fluorophenyl)diethylphosphine oxide as a pale white solid (1.50 g, 5.37 mmol, 80.6% yield). LCMS: m / z = 279.0, 281.0 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 7.63 - 7.73 (m, 3 H), 1.95 - 2.08 (m, 2 H), 1.80 - 1.92 (m, 2 H), 0.80 - 1.10 (m, 6 H).

[0409] Step B: (4-Bromo-2-(methylamino)phenyl)diethylphosphine oxide To a mixture of (4-bromo-2-fluorophenyl)diethylphosphine oxide (360 mg, 1.29 mmol) in 2 mL of methanol was added methylamine (9.8 M in methanol, 4 mL, 39.2 mmol). The mixture was heated at 80 °C for 3 hours in a microwave reactor. LCMS indicated that most of the starting material had been consumed. The mixture was concentrated, diluted with ethyl acetate (50 mL), and washed with water (30 mL). The organic layer was dried and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EA / methanol = 1:2:0.1) to afford (4-bromo-2-(methylamino)phenyl)diethylphosphine oxide as a white solid (179 mg, 0.617 mmol, 47.9% yield). LCMS: m / z = 290.0, 292.0 (M+H) + . 1 H NMR (600 MHz, DMSO-d6) δ 7.75 - 7.76 (m, 1 H), 7.11 (dd, J = 13.2, 8.4 Hz, 1 H), 6.63 - 6.80 (m, 2 H), 2.71 (d, J = 5.4 Hz, 3 H), 1.88 - 1.94 (m, 4 H), 0.90 - 1.05 (m, 6 H).

[0410] Step C: tert-Butyl (S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (4-Bromo-2-(methylamino)phenyl)diethylphosphine oxide (310 mg, 1.07 mmol), tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (428 mg, 0.970 mmol), CuI (278 mg, 1.46 mmol), potassium carbonate (268 mg, 1.94 mmol), and (1S,2S)-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine (208 mg, 1.46 mmol) in NMP (25 mL) were heated at 130 °C for 3 h under an argon atmosphere. Completion of the reaction was indicated by LCMS. Ethyl acetate (100 mL) was added to the mixture, and it was washed with water (50 mL * 3). The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (PE / EA / methanol = 1:4:0.3) to give tert-butyl (S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate as a pale yellow solid (530 mg, 0.810 mmol, 84.0% yield). LCMS: m / z = 651.3 (M+H) + . 11H NMR (600 MHz, DMSO-d6) δ 7.73 (q, J = 4.8 Hz, 1 H), 7.35 (d, J = 3.0 Hz, 1 H), 7.26 (dd, J = 13.2, 8.4 Hz, 1 H), 7.11 (d, J = 6.6 Hz, 2 H), 6.98 (s, 1 H), 6.89 (d, J = 7.8 Hz, 1 H), 6.86 (s, 1 H), 5.12 (br. s, 1 H), 4.13 - 4.34 (m, 1 H), 3.02 - 3.19 (m, 1 H), 2.69 - 2.74 (m, 4 H), 2.61 - 2.69 (m, 1 H), 2.19 (s, 6 H), 1.89 - 1.95 (m, 4 H), 1.43 (s, 9 H), 1.17 - 1.18 (m, 3 H), 0.95 - 1.05 (m, 6 H).

[0411] Step D: (S)-1-(4-(Diethylphosphoryl)-3-(methylamino)phenyl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride To a mixture of tert-butyl (S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (520 mg, 0.800 mmol) in 1,4-dioxane (6 mL) was added hydrogen chloride (4 M in 1,4-dioxane, 12 mL, 48.0 mmol). The mixture was stirred at room temperature for 3 h. Completion of the reaction was indicated by LCMS. The mixture was concentrated and the residue was dispersed in 40 mL of ethyl ether. The resulting solid was collected and dried under reduced pressure to afford (S)-1-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride as a pale yellow solid (430 mg, 0.730 mmol, 91.7% yield). LCMS: m / z = 551.2 (M + H) + . 11H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1 H), 9.46 - 9.53 (m, 1 H), 7.39 (d, J = 3.2 Hz, 1 H), 7.27 (dd, J = 12.8, 8.4 Hz, 1 H), 7.13 (d, J = 6.4 Hz, 2 H), 6.93 (d, J = 3.2 Hz, 1 H), 6.90 (dt, J = 8.4, 2.0 Hz, 1 H), 6.86 - 6.87 (m, 1 H), 4.55 - 4.59 (m, 2 H), 3.58 - 3.62 (m, 1 H), 3.28 - 3.33 (m, 1 H), 3.03 - 3.10 (m, 1 H), 2.90 - 3.05 (m, 1 H), 2.73 (s, 3 H), 2.20 (d, J = 2.0 Hz, 6 H), 1.88 - 1.97 (m, 4 H), 1.36 (d, J = 6.8 Hz, 3 H), 0.90 - 1.05 (m, 6 H).

[0412] Step E: 3 - ((1S,2S)-1-(2-((S)-3-(3-(4-(Diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one To a mixture of 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (272 mg, 0.710 mmol) and DMF (7 mL) in a 50 mL flask (Flask A) was added HATU (810 mg, 2.13 mmol) and triethylamine (1.45 g, 14.3 mmol). The mixture was stirred at room temperature for 10 minutes. In another 50 mL flask (Flask B), (S)-1-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (420 mg, 0.710 mmol) and triethylamine (2.90 g, 28.7 mmol) in 7 mL of DMF were stirred at room temperature for 10 minutes. Then the mixture in Flask B was added dropwise to Flask A. The resulting mixture was stirred at room temperature for 12 hours. LCMS indicated consumption of most of the starting material. The mixture was diluted with DCM (100 mL) and washed with water (50 mL * 3). The organic layer was dried and concentrated. The residue was purified by preparative HPLC (0.01% hydrochloric acid in water and acetonitrile) to give 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one as a white solid (290 mg). LCMS: m / z = 916.4 (M+H) + . 11H NMR (400 MHz, DMSO-d6, 80 °C) δ 11.58 (br. s, 1 H), 7.66 (br. s, 1 H), 7.52 (s, 1 H), 7.42 (d, J = 8.4 Hz, 1 H), 7.05 - 7.30 (m, 5 H), 6.70 - 6.95 (m, 4 H), 5.56 (br. s, 1 H), 4.45 (br. s, 1 H), 3.95 - 3.99 (m, 2 H), 3.40 - 3.70 (m, 3 H), 2.83 - 2.90 (m, 3 H), 2.60 - 2.80 (m, 3 H), 2.22 (d, J = 1.6 Hz, 6 H), 1.88 - 1.96 (m, 4 H), 1.58 - 1.80 (m, 7 H), 1.43 (br. s, 3 H), 1.17 (br. s, 3 H), 0.95 - 1.10 (m, 6 H).

[0413] The following compound was synthesized using the same method as described in Example 2 for Compound 121a.

[0414] 3-((1S,2S)-1-(2-((S)-3-(3-(3-(Dimethylphosphoryl)-2-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 107a) [Chemical Formula] 11H NMR (400 MHz, DMSO-d6, 80 °C) δ 11.84 (br. s, 1H), 11.60 (br. s, 1H), 7.51 - 7.56 (m, 2H), 7.35 - 7.45 (m, 2H), 7.27 (dd, J = 8.4, 1.2 Hz, 1H), 7.17 (d, J = 6.0 Hz, 2H), 7.02 (br. s, 1H), 6.80 - 6.95 (m, 2H), 6.72 (br. s, 1H), 5.60 (br. s, 1H), 4.44 (br. s, 1H), 3.95 - 4.04 (m, 2H), 3.40 - 3.70 (m, 3H), 2.84 - 2.92 (m, 2H), 2.25 (d, J = 1.6 Hz, 6H), 1.55 - 1.90 (m, 14H), 1.47 (s, 3H), 1.19 (s, 3H). LC-MS: m / z 875.2 (M+H) +

[0415] 3-((1S,2S)-1-(2-((S)-3-(3-(4-(Diethylphosphoryl)-3-methoxyphenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 118a)

Chem.

[0416] 3-((1S,2S)-1-(2-((S)-3-(3-(4-(Diethylphosphoryl)-3-(ethylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 120a)

Chem.

[0417] 3-((1S,2S)-1-(2-((S)-3-(3-(6-(Dimethylphosphoryl)pyridin-2-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 113a)

Chem.

[0418] 3-((1S,2S)-1-(2-((S)-3-(3-(4-(Diethylphosphoryl)-3-(isopropylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 119a)

Chem.

[0419] 3-((1S,2S)-1-(2-((S)-3-(3-(4-(Dimethylphosphoryl)-3-morpholinophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 125a)

Chemical Structure

[0420] 3-((1S,2S)-1-(2-((S)-3-(3-(4-(Dimethylphosphoryl)-3-(trifluoromethoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 123a)

Chem.

[0421] 3-((1S,2S)-1-(2-((S)-3-(3-(6-(Dimethylphosphoryl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 105a)

Chem.

[0422] 3-((1S,2S)-1-(2-((S)-3-(3-(4-(Dimethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 106a) [Chemical Structure] 11H NMR (400 MHz, DMSO-d6, 80 °C) δ: 11.59 (br. s, 1H), 7.53 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.23 - 7.33 (m, 3H), 7.15 (d, J = 6.0 Hz, 2H), 6.86 (br. s, 4H), 5.57 (br. s, 1H), 4.46 (br. s, 1H), 3.97 - 3.99 (m, 2H), 3.49 - 3.58 (m, 3H), 2.85 - 2.94 (m, 3H), 2.74 (br. s, 3H), 2.22 (d, J = 1.6 Hz, 6H), 1.64 - 1.77 (m, 13H), 1.44 (s, 3H), 1.18 (s, 3H). LC-MS: m / z 888.2 (M+H) +

[0423] 3-((1S,2S)-1-(2-((S)-3-(3-(4-(Dimethylphosphoryl)-3-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 108a) [Chemical Structure] 11H NMR (400 MHz, DMSO-d6, 80 °C) δ: 11.58 (br. s, 1H), 7.70 - 7.80 (m, 3H), 7.50 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.35 (br. s, 1H), 7.25 (dd, J = 8.8, 1.6 Hz, 1H), 7.12 (d, J = 6.0 Hz, 2H), 6.93 (s, 1H), 6.86 (s, 1H), 5.55 (br. s, 1H), 4.44 (br. s, 1H), 3.95 - 3.98 (m, 2H), 3.44 - 3.56 (m, 3H), 2.98 - 3.08 (m, 1H), 2.82 - 2.89 (m, 2H), 2.20 (d, J = 2.0 Hz, 6H), 1.59 - 1.78 (m, 13H), 1.41 (s, 3H), 1.15 (s, 3H). LC-MS: m / z 877.2 (M+H) +

[0424] 3-((1S,2S)-1-(2-((S)-3-(3-(3-(Dimethylphosphoryl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 109a)

Chem.

[0425] 3-((1S,2S)-1-(2-((S)-3-(3-(4-(Diethylphosphoryl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 129a)

Chem.

[0426] 3-((1S,2S)-1-(2-((S)-3-(3-(4-(Diisopropylphosphoryl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 128a) [Chemical Structure] 11H NMR (400 MHz, DMSO-d6, 80 °C) δ: 11.57 (br. s, 1H), 7.73 - 7.79 (m, 4H), 7.51 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.28 (s, 1H), 7.25 (dd, J = 8.8, 1.6 Hz, 1H), 7.14 (d, J = 6.0 Hz, 2H), 6.86 (br. s, 2H), 5.56 (br. s, 1H), 4.46 (br. s, 1H), 3.95 - 3.98 (m, 2H), 3.53 - 3.57 (m 1H), 3.47 (td, J = 11.2, 3.2 Hz, 2H), 2.97 - 3.16 (m, 1H), 2.81 - 2.94 (m, 2H), 2.27 - 2.36 (m, 2H), 2.20 (d, J = 1.6 Hz, 6H), 1.70 - 1.76 (m, 6H), 1.63 - 1.65(m, 1H), 1.42 - 1.43(m 3H), 1.07 - 1.15 (m, 9H), 0.85 - 1.00 (m, 6H). LC-MS: m / z 915.3 (M+H) +

[0427] 3-((1S,2S)-1-(2-((S)-3-(3-(4-(Dimethylphosphoryl)-3-methylphenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 124a)

Chem.

[0428] 3-((1S,2S)-1-(2-((S)-3-(3-(4-(Dimethylphosphoryl)-2-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 122a)

Chem.

[0429] 3-((1S,2S)-1-(2-((S)-3-(3-(4-(Diethylphosphoryl)-3-(dimethylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one HCl salt (Compound 117a) [Chemical Structure] 11H NMR (400 MHz, DMSO-d6, 80 °C) δ: 11.58 (br. s, 1H), 7.97 (br. s, 1H), 7.85 (br. s, 2H), 7.50 (s, 1H), 7.40 - 7.42 (m, 2H), 7.25 (dd, J = 8.4, 1.2 Hz, 1H), 7.14 (d, J = 6.4 Hz, 2H), 6.93 (br. s, 1H), 6.86 (br. s, 1H), 5.56 (br. s, 1H), 4.46 (br. s, 1H), 3.95 - 3.97 (m, 2H), 3.55 (br. s, 1H), 3.42 - 3.51 (m, 3H), 2.84 - 2.89 (m, 8H), 2.19 - 2.24 (m, 6H), 2.04 - 2.14 (m, 4H), 1.60 - 1.80 (m, 7H), 1.42 (br. s, 3H), 1.15 (br. s, 3H), 1.04 - 0.95 (m, 6H). LC-MS: m / z 930.4 (M+H) +

[0430] 3-((1S,2S)-1-(2-((S)-3-(3-(4-(Diethylphosphoryl)-3-morpholinophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 114a) [Chemical Structure] 11H NMR (400 MHz, DMSO-d6, 80 °C) δ: 11.56 (br. s, 1H), 7.79 - 7.84 (m, 2H), 7.67 (br. s, 1H), 7.50 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.35 (br. s, 1H), 7.25 (dd, J = 8.4, 1.6 Hz, 1H), 7.14 (d, J = 6.0 Hz, 2H), 6.90 (br. s, 1H), 6.85 (br. s, 1H), 5.52 (br. s, 1H), 4.44 (br. s, 1H), 3.94 - 3.98 (m, 2H), 3.77 - 3.70 (m, 4H), 3.56 (br. s, 1H), 3.47 (td, J = 10.8, 3.2 Hz, 2H), 3.02 - 3.08 (m, 1H), 2.82 - 2.88 (m, 6H), 2.20 (d, J = 2.0 Hz, 6H), 1.95 - 2.12 (m, 4H), 1.60 - 1.75 (m, 7H), 1.42 (br. s, 3H), 1.15 (br. s, 3H), 0.92 - 1.02 (m, 6H). LC-MS: m / z 972.4 (M+H) + .

[0431] 3-((1S,2S)-1-(2-((S)-3-(3-(3-Amino-4-(dimethylphosphoryl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 111a)

Chem.

[0432] 3-((1S,2S)-1-(2-((S)-3-(3-(4-(Dimethylphosphoryl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 102a)

Chem.

[0433] (S)-3-(1-(2-(3-(3-(4-(Diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 135a)

Chem.

[0434] 3-((1S,2S)-1-(2-((S)-3-(3-(4-(Diethylphosphoryl)-3-(difluoromethoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 136a) [Chemical formula] 11H NMR (400 MHz, DMSO-d6, 80 °C) δ 11.57 (s, 1H), 7.92 (br. s, 1H), 7.70 (br. s, 2H), 7.53 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.20 - 7.36 (m, 3H), 7.16 (d, J = 6.4 Hz, 2H), 6.96 (br. s, 1H), 6.88 (br. s, 1H), 5.57 (br. s, 1H), 4.47 (s, 1H), 3.95 - 4.05 (m, 2H), 3.42 - 3.65 (m, 3H), 2.88 - 2.92 (m, 3H), 2.22 (s, 6H), 1.84 - 2.09 (m, 4H), 1.60 - 1.82 (m, 7H), 1.44 (br. s, 3H), 1.18 (br. s, 3H), 0.91 - 1.05 (m, 6H). LC-MS: m / z 952.9 (M+H) + .

[0435] 3-((1S,2S)-1-(2-((S)-3-(3-(3-Amino-4-(diethylphosphoryl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 138a)

Chem.

[0436] 3-((1S,2S)-1-(2-((S)-3-(3-(6-(Diethylphosphoryl)-5-(methylamino)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 139a)

Chem.

[0437] 3-((1S,2S)-1-(2-((S)-3-(3-(4-(Diethylphosphoryl)-3-methyl-5-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 140a)

Chem.

[0438] 3-((1S,2S)-1-(2-((S)-3-(3-(4-(Diisopropylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 141a)

Chem.

[0439] 3-((1S,2S)-1-(2-((S)-3-(3-(4-(Diethylphosphoryl)-3-(difluoromethyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 142a)

Chem.

[0440] 3-((1S,2S)-1-(2-((S)-3-(3-(4-(Diethylphosphoryl)-3-fluoro-5-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 143a)

Chem.

[0441] 3-((1S,2S)-1-(2-((S)-3-(3-(4-(Diethylphosphoryl)-2-fluoro-5-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 144a) [Chemical Structure] 11H NMR (400 MHz, DMSO-d6, 80 °C) δ 11.60 (br. s, 1H), 7.53 (s, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.22 - 7.30 (m, 2H), 7.16 (d, J = 6.4 Hz, 2H), 6.97 (br. s, 1H), 6.88 (br. s, 1H), 6.82 (br. s, 1H), 6.62 (br. s, 1H), 5.57 (br. s, 1H), 4.47 (br. s, 1H), 3.97 - 4.00 (m, 2H), 3.55 (br. s, 1H), 3.46 - 3.53 (m, 2H), 2.98 - 3.03 (m, 1H), 2.88 - 2.91 (m, 2H), 2.72 (br. s, 3H), 2.25 (d, J = 1.6 Hz, 6H), 1.94 - 2.03 (m, 4H), 1.73 - 1.78 (m, 6H), 1.64 (br. s, 1H), 1.47 (s, 3H), 1.12 - 1.30 (m, 3H), 1.00 - 1.10 (m, 6H). LC-MS: m / z 934.3(M+H) + .

[0442] 3-((1S,2S)-1-(2-((S)-3-(3-(4-(Diethylphosphoryl)-2-fluoro-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 145a)

Chem.

[0443] 3 - ((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 146a)

Chem.

[0444] 3 - ((1S,2S)-1-(2-((S)-3-(3-(4-(Diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 146b)

Chem.

[0445] 3 - ((1S,2S)-1-(2-((S)-3-(3-(3-(Dimethylphosphoryl)benzyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 147a) [Chemical Structure] 11H NMR (400 MHz, DMSO-d6, 80 °C) δ 11.56 (br. s, 1H), 7.66 - 7.75 (m, 2H), 7.53 (s, 1H), 7.40 - 7.50 (m, 2H), 7.20 - 7.38 (m, 2H), 7.08 (d, J = 6.0 Hz, 2H), 6.87 (br. s, 1H), 6.77 (br. s, 1H), 6.59 (br. s, 1H), 5.50 (br. s, 1H), 4.82 (br. s, 2H), 4.43 (br. s, 1H), 3.96 - 3.99 (m, 2H), 3.45 - 3.54 (m, 3H), 2.83 - 2.91 (m, 2H), 2.16 (d, J = 0.8 Hz, 6H), 1.72 - 1.77 (m, 6H), 1.61 - 1.65 (m, 8H), 1.36 (br. s, 3H), 1.17 (br. s, 3H). LCMS: m / z = 873.3 (M+H) + .

[0446] Example 3: Synthesis of N-(2-(Diethylphosphoryl)-5-(3-((S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-5-(1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carbonyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)phenyl)cyclopropanecarboxamide (Compound 115a)

Chemical Structure

[0447] Step B: N-(5-bromo-2-(diethylphosphoryl)phenyl)cyclopropanecarboxamide To a solution of (2-amino-4-bromophenyl)diethylphosphine oxide (200 mg, 0.730 mmol) in DCM (5 mL) were added TEA (221 mg, 2.19 mmol) and cyclopropanecarbonyl chloride (114 mg, 1.09 mmol) at room temperature. The resulting mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with water (15 mL). The resulting mixture was extracted with DCM (3 x 15 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 / EA = 1 / 2) to give the title compound N-(5-bromo-2-(diethylphosphoryl)phenyl)cyclopropanecarboxamide as a yellow oil (120 mg, 48% yield). LC-MS: m / z 344.0, 346.0 (M+H) + . 1 1H NMR (400 MHz, CDCl3) δ: 11.85 (s, 1H), 8.94 - 8.96 (m, 1H), 7.20 (dt, J = 8.0, 2.0 Hz, 1H), 6.93 - 6.98 (m, 1H), 1.89 - 2.07 (m, 4H), 1.59 - 1.63 (m, 1H), 1.14 - 1.22 (m, 6H), 1.04 - 1.08 (m, 2H), 0.82 - 0.87 (m, 2H).

[0448] N-(2-(Diethylphosphoryl)-5-(3-((S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-5-(1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carbonyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)phenyl)cyclopropanecarboxamide (Compound 115a) was synthesized according to the method described in Example 2. 1 1H NMR (400 MHz, DMSO-d 6,80 °C) δ 12.01 (s, 1H), 11.59 (br. s, 1H), 8.79 (s, 1H), 7.52 - 7.56 (m, 2H), 7.30 - 7.50 (m, 2H), 7.27 (dd, J = 5.6, 1.6 Hz, 1H), 7.00 - 7.25 (m, 3H), 6.88 (s, 2H), 5.56 (br. s, 1H), 4.47 (br. s, 1H), 3.97 - 3.99 (m, 2H), 3.45 - 3.52 (m, 3H), 3.12 - 3.14 (m, 1H), 2.83 - 2.91 (m, 2H), 2.22 (d, J = 2.0 Hz, 6H), 2.01 - 2.11 (m, 4H), 1.72 - 1.78 (m, 6H), 1.64 - 1.67 (m, 1H), 1.53 - 1.58 (m, 1H), 1.43 (br. s, 3H), 1.17 - 1.27 (m, 3H), 1.02 - 1.10 (m, 6H), 0.84 - 0.91 (m, 4H). LC-MS: m / z 970.4 (M+H) +

[0449] The following compound was synthesized using the same method as described in Example 2 for Compound 115a.

[0450] N-(2-(Diethylphosphoryl)-5-(3-((S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-5-(1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carbonyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)phenyl)methanesulfonamide (Compound 116a) [Chemical formula] 11H NMR (400 MHz, DMSO-d6, 80 °C) δ 11.51 - 11.62 (m, 2H), 7.93 (s, 1H), 7.53 - 7.59 (m, 2H), 7.42 - 7.44 (m, 2H), 7.26 - 7.28 (m, 2H), 7.15 - 7.16 (m, 2H), 6.87 - 6.92 (m, 2H), 5.56 (br. s, 1H), 4.46 (br. s, 1H), 3.97 - 4.00 (m, 2H), 3.46 - 3.52 (m, 3H), 2.99 - 3.20 (m, 2H), 2.87 - 2.91 (m, 2H), 2.22 (d, J = 2.0 Hz, 6H), 2.04 - 2.12 (m, 5H), 1.65 - 1.77 (m, 8H), 1.44 (br. s, 3H), 1.18 (br. s, 3H), 1.00 - 1.10 (m, 6H). LC-MS: m / z 980.3 (M+H) +

[0451] Example 4 3-((1S,2S)-1-(2-((S)-3-(3-(7-(Dimethylphosphoryl)-1H-benzo[d]imidazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 110a)

Chemical Structure

[0452] Step B: 5-Bromo-3-iodobenzen-1,2-diamine To a solution of 4-bromo-2-iodo-6-nitroaniline (3.00 g, 8.70 mmol) in EtOH (30 mL) was added SnCl2 (6.00 g, 43.5 mmol). The resulting mixture was stirred at 80 °C for 3 h. The reaction mixture was quenched with water (10 mL), and a yellow solid appeared. The mixture was filtered, and the filter cake was dried to afford 5-bromo-3-iodobenzen-1,2-diamine as a yellow solid (2.60 g, crude product). The crude product was used directly in the next step without further purification. LC-MS: m / z 312.8, 314.8 (M+H) +

[0453] Step C: 5-Bromo-7-iodo-1H-benzo[d]imidazole A solution of 5-bromo-3-iodobenzene-1,2-diamine (3.50 g, 11.2 mmol) in HCOOH (20 mL) was stirred at 100 °C for 3 h under a N2 atmosphere. The reaction was concentrated to remove the excess HCOOH. Then water was added and the mixture was extracted with EA. The organic layers were combined, washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica column to afford the title compound 5-bromo-7-iodo-1H-benzo[d]imidazole as a yellow solid (2.60 g, 72% yield). LC-MS: m / z 322.8, 324.8 (M+H) +

[0454] 3-((1S,2S)-1-(2-((S)-3-(3-(7-(Dimethylphosphoryl)-1H-benzo[d]imidazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 110a) was synthesized using the method described in Example 2. 11H NMR (400 MHz, DMSO-d6) δ 11.59 (br. s, 1H), 8.10 - 8.46 (m, 1H), 7.74 (br. s, 1H), 7.52 (s, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.16 - 7.21 (m, 4H), 6.85 - 6.88 (m, 3H), 5.59 (br. s, 1H), 4.46 (br. s, 1H), 3.96 - 3.98 (m, 2H), 3.54 - 3.63 (m, 1H), 3.45 - 3.54 (m, 2H), 3.02 - 3.11 (m, 1H), 2.87 - 2.91 (m, 2H), 2.24 (s, 6H), 1.83 - 1.74 (m, 13H), 1.47 (s, 3H), 1.10 - 1.25 (m, 3H). LC-MS: m / z 450.6 (M / 2+H) +

[0455] The following compound was synthesized using the same method as described in Example 4 for Compound 110a.

[0456] 3-((1S,2S)-1-(2-((S)-3-(3-(7-(Dimethylphosphoryl)-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 112a)

Chemical Structure

[0457] Example 5 3-((1S,2S)-1-(2-((S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(4-(1-oxidophospholan-1-yl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 127a)

Chemical formula

[0458] Step B: Diallyl(4-bromophenyl)phosphine oxide To a solution of (4-bromophenyl)phosphonic acid dichloride (3.88 g) in dry THF (10 mL) at -70 °C was added dropwise allylmagnesium chloride (1.0 M in THF, 42.6 mL, 42.6 mmol). The mixture was stirred at -70 °C for 1.5 h. Completion of the reaction was indicated by LCMS. The mixture was quenched at -70 °C with saturated aqueous NH4Cl solution (50 mL). The mixture was then warmed to room temperature and extracted with EtOAc (3 x 30 mL). The organic layer was dried and concentrated. The residue was purified by silica column chromatography (eluting with PE / EtOAc = 1 / 3) to give the title compound diallyl(4-bromophenyl)phosphine oxide as a yellow solid (1.80 g, 46% yield over 2 steps). LC-MS: m / z 285.2, 287.0(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 7.72 - 7.75 (m, 2H), 7.63 - 7.69 (m, 2H), 5.58 - 5.70 (m, 2H), 5.06 - 5.10 (m, 4H), 2.82 - 2.98 (m, 4H).

[0459] Step C: 1-(4-Bromophenyl)-2,5-dihydrophosphol 1-oxide To a solution of diallyl(4-bromophenyl)phosphine oxide (400 mg, 1.58 mmol) in dichloromethane (40 mL) was added Grubbs catalyst (2nd generation, 70.0 mg, 0.08 mmol). The mixture was stirred at 50 °C for 12 h under an Ar atmosphere. Completion of the reaction was indicated by LCMS. The mixture was concentrated and the residue was purified by silica column chromatography (eluting with PE / EA / methanol = 1 / 4 / 0.1) to afford the title compound 1-(4-bromophenyl)-2,5-dihydrophosphol 1-oxide as a pale white solid (154 mg, 38% yield). LC-MS: m / z 257.0, 259.0 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (dd, J = 8.4, 2.0 Hz, 2H), 7.64 (dd, J = 10.8, 8.4 Hz, 2H), 6.03 (d, J = 28.8 Hz, 2H), 2.60 - 2.77 (m, 4H).

[0460] Step D: 1-(4-Bromophenyl)phospholane 1-oxide To a solution of 1-(4-bromophenyl)-2,5-dihydrophosphol 1-oxide (154 mg, 0.600 mmol) in EtOAc (8 mL) was added platinum(IV) oxide (15.0 mg, 0.0660 mmol). The mixture was stirred at room temperature for 4 h under an H2 atmosphere. Completion of the reaction was indicated by LCMS. The solid was filtered off and the filtrate was concentrated. The residue was purified by silica column chromatography (eluting with PE / EA / methanol = 1 / 4 / 0.2) to afford the title compound 1-(4-bromophenyl)phospholane 1-oxide as a pale white solid (107 mg, 69% yield). LC-MS: m / z 259.0, 261.0 (M+H) + . 11H NMR (400 MHz, DMSO-d6) δ: 7.73 - 7.76 (m, 2H), 7.66 - 7.71 (m, 2H), 1.93 - 2.07 (m, 4H), 1.77 - 1.90 (m, 4H).

[0461] 3-((1S,2S)-1-(2-((S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(4-(1-oxidophospholan-1-yl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 127a) was synthesized using the method described in Example 2. 1 1H NMR (400 MHz, DMSO-d6, 80 °C) δ 11.58 (br.s, 1H), 7.81 (br.s, 4H), 7.52 (s, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.26 - 7.28 (m, 2H), 7.15 (d, J = 6.4 Hz, 2H), 6.88 (br.s, 2H), 5.55 (br.s, 1H), 4.48 (br.s, 1H), 3.96 - 3.99 (m, 2H), 3.45 - 3.65 (m, 3H), 3.18 - 3.24 (m, 1H), 2.84 - 2.91 (m, 2H), 2.21 (d, J = 2.0 Hz, 6H), 1.60 - 2.08 (m, 15H), 1.44 (d, J = 4.8 Hz, 3H), 1.17 (s, 3H). LC-MS: m / z 885.3 (M+H) +

[0462] Example 6 3-((1S,2S)-1-(2-((S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(4-(1-methyl-4-oxide-1,4-azaphosphinan-4-yl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one HCl salt (Compound 126a)

Chem.

[0463] 3-((1S,2S)-1-(2-((S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(4-(1-methyl-4-oxide-1,4-azaphosphinan-4-yl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one HCl salt (Compound 126a) was synthesized using the method described in Example 2. 1 H NMR (400 MHz, DMSO-d6, 80℃) δ 11.62 (br. s, 2H), 7.92 (br. s, 4H), 7.52 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.33 (br. s, 1H), 7.28 (dd, J = 8.4, 1.2 Hz, 1H), 7.15 (d, J = 6.0 Hz, 2H), 6.87 - 6.93 (m, 2H), 5.56 (br. s, 1H), 4.46 (br. s, 1H), 3.94 - 3.99 (m, 2H), 3.59 - 3.81 (m, 4H), 3.43 - 3.52 (m, 3H), 3.00 - 3.40 (m, 1H), 2.80 - 2.92 (m, 7H), 2.21 - 2.32 (m, 8H), 1.65 - 1.77 (m, 7H), 1.43 (br. s, 3H), 1.17 (br. s, 3H). LC-MS: m / z 914.4 (M+H) + .

[0464] The following compounds were synthesized using a method similar to the method described in Example 2 for Compound 121a.

[0465] 3-((1S,2S)-1-(2-((S)-3-(3-(4-(Diethylphosphoryl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 130b)

Chem.

[0466] Example 7 3-((1S,2S)-1-(2-((S)-3-(3-(4-(Dicyclopropylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 132a) [Chemical Structure] Step A: Diethyl (4-bromo-2-fluorophenyl)phosphonate A mixture of 4-bromo-2-fluoro-1-iodobenzene (2.02 g, 6.70 mmol), diethyl phosphonate (1.11 g, 8.04 mmol), Pd2(dba)3 (311 mg, 0.34 mmol), Xantphos (388 mg, 0.67 mmol), and triethylamine (1.36 g, 13.4 mmol) in 1,4-dioxane (27 mL) was stirred at 60 °C overnight under an argon atmosphere. Cooled to room temperature, the mixture was concentrated, and the residue was diluted with EtOAc (100 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 = 2 / 1) to give the title compound diethyl (4-bromo-2-fluorophenyl)phosphonate as a yellow oil (1.40 g, yield 67%). LC-MS: m / z 311.0, 313.0 (M+H) + .

[0467] Step B: (4-Bromo-2-fluorophenyl)phosphonic acid dichloride A mixture of diethyl (4-bromo-2-fluorophenyl)phosphonate (1.40 g, 4.50 mmol) in thionyl chloride (49.2 g, 414 mmol) was added dropwise with dry DMF (1.42 g, 19.4 mmol). The mixture was heated to reflux for 72 h. The mixture was concentrated and dried under reduced pressure to give (4-bromo-2-fluorophenyl)phosphonic dichloride as a colorless oil (1.50 g, crude product), which was used directly in the next step without further purification.

[0468] Step C: (4-Bromo-2-fluorophenyl)dicyclopropylphosphine oxide To a mixture of (4-bromo-2-fluorophenyl)phosphonic dichloride (1.50 g, crude product) in dry THF (10 mL) at -70 °C was added dropwise cyclopropylmagnesium bromide (2.0 M in THF, 5.13 mL, 10.3 mmol). The mixture was stirred at -70 °C for 2 h. Completion of the reaction was indicated by LCMS. The mixture was quenched with saturated aqueous NH4Cl solution (50 mL) at -70 °C. The mixture was then warmed to room temperature and extracted with EtOAc (3 x 50 mL). The organic layer was dried and concentrated. The residue was purified by silica column chromatography (eluting with PE / EtOAc = 1 / 2) to give the title compound, (4-bromo-2-fluorophenyl)dicyclopropylphosphine oxide, as a yellow solid (420 mg, 27% yield). 1 1H NMR (400 MHz, CDCl3) δ 7.69 - 7.75 (m, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.31 - 7.35 (m, 1H), 1.15 - 1.24 (m, 2H), 1.01 - 1.12 (m, 2H), 0.71 - 0.97 (m, 6H).

[0469] 3-((1S,2S)-1-(2-((S)-3-(3-(4-(Dicyclopropylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 132a) was synthesized using the method described in Example 2. 1 H NMR (400 MHz, DMSO-d6, 80℃) δ: 10.95 (br. s, 1H), 7.49 (s, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.22 - 7.24 (m, 3H), 7.13 (d, J = 5.6 Hz, 2H), 6.82 - 6.84 (m, 3H), 5.54 (br. s, 1H), 4.41 (br. s, 1H), 3.96 (d, J = 10.8 Hz, 2H), 3.44 - 3.50 (m, 3H), 2.81 - 2.89 (m, 3H), 2.62 - 2.78 (m, 3H), 2.20 (s, 6H), 1.62 - 1.74 (m, 7H), 1.40 (br. s, 3H), 1.17 - 1.25 (m, 5H), 0.71 - 0.93 (m, 6H), 0.57 - 0.70 (m, 2H). LC-MS: m / z 940.4 (M+H) + .

[0470] The following compounds were synthesized using a method similar to the method described in Example 2 for Compound 121a.

[0471] (S)-3-(1-(2-(3-(3-(4-(Dicyclopropylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 148a)

Chem.

[0472] 3-((1S,2S)-1-(2-((4S)-3-(3-(4-(tert-Butyl(methyl)phosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 131a) [Chemical Structure] 1 H NMR (400 MHz, DMSO-d6, 80℃) δ11.57 (br. s, 1H), 7.77 (br. s, 1H), 7.53 (s, 1H), 7.28 (d, J = 1.6 Hz, 1H), 7.14 - 7.26 (m, 5H), 6.87 (br. s, 4H), 5.56 (br,s, 1H), 4.48 (br. s, 1H), 3.97 - 4.00 (m, 2H), 3.46 - 3.57 (m, 3H), 2.83 - 2.91 (m, 3H), 2.72 (br. s, 3H), 2.22 (d, J = 2.0 Hz, 6H), 1.64 - 1.75 (m, 10H), 1.45 (s, 3H), 1.17 (s, 3H), 1.08 (d, J = 14.4Hz, 9H). LCMS: m / z = 930.4 (M+H) + .

[0473] 3-(1-(2-((4S)-3-(3-(4-(tert-Butyl(methyl)phosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 149a) [Chemical formula] 1 HNMR (400 MHz, DMSO-d6, 80 °C) δ 11.76 (br. s, 1H), 7.48 - 7.51 (m, 2H), 7.14 - 7.26 (m, 5H), 6.79 - 6.87 (m, 4H), 5.54 (br. s, 1H), 4.48 (br. s, 1H), 3.97 - 4.00 (m, 2H), 3.46 - 3.53 (m, 3H), 2.83 - 2.91 (m, 3H), 2.72 (s, 3H), 2.22 (d, J = 1.6 Hz, 6H), 1.69 - 1.82 (m, 10H), 1.52 - 1.54 (m, 1H), 1.39 (d, J = 6.4 Hz, 3H), 1.08 (d, J = 11.8 Hz, 9H). LCMS: m / z = 916.4 (M+H) + .

[0474] Example 8 3-((1S,2S)-1-(2-((S)-3-(3-(4-(Diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(4,4-difluorocyclohexyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 133a)

Chem.

[0475] Step B: 5-(4,4-Difluorocyclohexyl)-N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-1H-indole-2-carboxamide To a solution of 5-(4,4-difluorocyclohex-1-en-1-yl)-N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-1H-indole-2-carboxamide (360 mg, 0.71 mmol) in ethyl acetate (10 mL) was added Pd / C (10%, 64 mg) at room temperature under Ar. Subsequently, the resulting solution was stirred at room temperature for 16 h under H2. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by preparative HPLC (HCOOH / CH3CN / H2O) to give 5-(4,4-difluorocyclohexyl)-N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-1H-indole-2-carboxamide as a white solid (50 mg, yield 14%). LC-MS: m / z 507.2 (M+H) + .

[0476] 3-((1S,2S)-1-(2-((S)-3-(3-(4-(Diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(4,4-difluorocyclohexyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 133a) was synthesized using the method described in Example 2. 1 HNMR (400 MHz, DMSO-d6, 80 °C) δ11.57 (br. s, 1H), 7.52 (s, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.12 - 7.25 (m, 5H), 6.84 (br. s, 4H), 5.55 (br. s, 1H), 4.43 (br. s, 1H), 3.54 (br. s, 1H), 3.17 (br. s, 1H), 2.70 - 2.89 (m, 5H), 2.24 - 2.31 (m, 1H), 2.20 (s, 6H), 1.86 - 2.12 (m, 10H), 1.62 - 1.78 (m, 5H), 1.35 - 1.50 (m, 3H), 1.15 - 1.25 (m, 3H), 1.01 (dt, J = 7.6, 16.4 Hz, 6H). LC-MS: m / z 950.4 (M+H) + .

[0477] Example 9 3-((1S,2S)-1-(2-((S)-3-(3-(4-(Diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(2,2-dimethylmorpholino)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 150a) [Chemical] Step A: 5-(2,2-Dimethylmorpholino)-N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-1H-indole-2-carboxamide To a mixture of 5-bromo-N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-1H-indole-2-carboxamide (585 mg, 1.25 mmol), 2,2-dimethylmorpholine (173 mg, 1.50 mmol), Pd2(dba)3 (115 mg, 0.13 mmol) and Davephos (98 mg, 0.25 mmol) in THF (20 mL) was added LiHMDS (2.8 mL, 2.75 mmol) under N2 atmosphere. The mixture was stirred at 100 °C for 4 h by microwave irradiation. 1 M HCl (10 mL) was added to the mixture, and the mixture was extracted with EA (30 mL). The organic layer was washed with saturated aqueous NaHCO3 solution (10 mL) and brine (10 mL), dried over Na2SO4, concentrated and purified by flash chromatography (eluting with DCM / MeOH = 60 / 1) to give the title compound 5-(2,2-dimethylmorpholino)-N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-1H-indole-2-carboxamide as a yellow solid (341 mg, yield 54%). LC-MS: m / z 502.2 (M+H) +

[0478] Step B: 5-(2,2-Dimethylmorpholino)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid A solution of 5-(2,2-dimethylmorpholino)-N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-1H-indole-2-carboxamide (341 mg, 0.68 mmol) in THF (16 mL) was treated with t-BuOK (2.3 g, 20.5 mmol), followed by H2O (116 mg). The mixture was stirred at room temperature overnight. The mixture was concentrated and the pH was adjusted to 4 - 5 using 1N aqueous HCl. The mixture was extracted with DCM (3 x 20 mL), dried over Na2SO4, concentrated and purified by reverse phase to afford the title compound 5-(2,2-dimethylmorpholino)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid as a white solid (225 mg, 80% yield). LC-MS: m / z 411.2 (M-H, negative mode) + .

[0479] Step C: 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(2,2-dimethylmorpholino)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (S)-1-(4-(Diethylphosphoryl)-3-(methylamino)phenyl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (118 mg, 0.210 mmol), 5-(2,2-dimethylmorpholino)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (80 mg, 0.190 mmol), and HATU (221 mg, 0.580 mmol) in DMF (4 mL) were added DIEA (150 mg, 1.16 mmol). The mixture was stirred at room temperature overnight. Water (30 mL) was added to the mixture, and the mixture was extracted with DCM (3 x 20 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated, and purified by preparative HPLC to give 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(2,2-dimethylmorpholino)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one as a white solid (71.0 mg, yield 35%). 1HNMR (400 MHz, DMSO-d6, 80 °C) δ 11.58 (br. s, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.07 - 7.21 (m, 6H), 6.83 (br. s, 3H), 6.77 (br. s, 1H), 5.50 (br. s, 1H), 4.43 (br. s, 1H), 3.74 - 3.82 (m, 2H), 3.54 (br. s, 2H), 2.98 - 3.03 (m, 2H), 2.85 - 2.95 (m, 3H), 2.71 (br. s, 3H), 2.20 (s, 6H), 1.85 - 1.96 (m, 4H), 1.65 - 1.72 (m, 1H), 1.60 (br. s, 1H), 1.42 (br. s, 3H), 1.20 - 1.32 (m, 7H), 1.14 (br. s, 3H), 0.95 - 1.07 (m, 6H). LC-MS: m / z 473.2 (M / 2+H) + .

[0480] Example A: cAMP assay Activation of the GLP-1 receptor is known to activate the production of cyclic AMP (cAMP) in cells that exhibit the initial binding to the G αs subunit of the G protein heterotrimer. It has been suggested that signal transduction by cAMP activation induced by G αs shows a desirable pharmacological response regarding insulin release from pancreatic β-cells.

[0481] Method 1: G αsTo optimize the functional activity related to binding, a CHO-K1 cell line developed by DiscoverX that stably expresses the GLP-1 receptor is used. Cells expressing the GLP-1 receptor are placed in a 384-well microtiter plate and incubated overnight at 37 °C in 5% CO2 to adhere and grow the cells. Then, the medium is aspirated from the cells and replaced with 15 μL of Hank's balanced salt solution (HBSS) / 5 mM Hepes: 0.5 mM IBMX: 0.1% BSA (pH 7.4) [activation buffer]. The plated cells are resuspended in the activation buffer, and 5 microliters (5 μL) of the suspension is added to a previously prepared compound sample at 4x the final concentration in the activation buffer and then added to the cells, and incubated at 37 °C for 30 or 60 minutes.

[0482] After incubation, the assay signal is generated using a europium chelate-labeled cAMP tracer that competes with cAMP for the binding site of a cAMP-specific monoclonal antibody labeled with ULight® dye. The FRET transfer between the europium chelate and the ULight®-labeled antibody when the antibody binds to the Eu-labeled cAMP tracer is detected. The free cAMP generated from the activated cells competes dose-dependently with the Eu-cAMP tracer for binding to ULight-mAb, which results in a decrease in the TR-FRET signal.

[0483] For the method of detecting cAMP using Eu-chelate technology, it is necessary to incubate the Eu-cAMP tracer solution + ULight-anti-cAMP solution at room temperature for 1 hour. The microplate is read after signal generation using a PerkinElmer Envision device that utilizes TR-FRET signal detection. The activity percentage is calculated using the following formula: Activity % = 100% x (Average RLU of test sample - Average RLU of vehicle control) / (Average RLU of MAX control - Average RLU of vehicle control) is used for calculation.

[0484] Method 2: Gαs To optimize the functional activity related to binding, a CHO-K1 cell line developed by DiscoverX that stably expresses the GLP-1 receptor is used. Cells expressing the GLP-1 receptor are plated in 384-well microtiter plates and incubated overnight at 37 °C in 5% CO2 to adhere and grow the cells. Next, the medium is aspirated from the cells and replaced with 15 μL of 2:1 Hank's balanced salt solution (HBSS) / 10 mM Hepes:cAMP XS+Ab reagent. Then, 5 microliters (5 μL) of a previously prepared compound sample at 4x the final concentration in activation buffer is added to the cells and incubated at 37 °C for 30 or 60 minutes.

[0485] After incubation, the assay signal is generated using enzyme fragment complementation (EFC). In EFC, the enzyme β-galactosidase is cleaved into two complementary parts (EA and ED). The fragment ED is fused to cAMP and in this assay method competes with endogenous cAMP for binding to a cAMP-specific antibody. Activated B-Gal is formed when the exogenous EA fragment binds to the free ED-cAMP (which does not bind to the cAMP-specific antibody). The level of activated enzyme is detected by conversion of a B-gal chemiluminescent substrate that generates a detectable luminescence signal and read on a standard microtiter plate.

[0486] The method for detecting cAMP using EFC requires incubation with 20 μL of cAMP XS+ED / CL lysis mixture for 1 hour at room temperature and then incubation with 20 μL of cAMP XS+EA for 3 hours. The microplate is read after signal generation using a PerkinElmer Envision device that utilizes chemiluminescence signal detection. The activity of the compound is analyzed using the CBIS data analysis suite (ChemInnovation, California). The percentage of activity is calculated using the following equation: % Activity = 100% x (Average RLU of test sample - Average RLU of vehicle control) / (Average RLU of MAX control - Average RLU of vehicle control) is calculated using

[0487] Method 3 : Activation of the GLP-1 receptor is known to activate the production of cyclic AMP (cAMP) in cells that indicates the initial binding to the G αs subunit of the G protein heterotrimer. It has been suggested that signal transduction by cAMP activation induced by G αs shows a desirable pharmacological response regarding insulin release from pancreatic β-cells.

[0488] G αs To optimize the functional activity regarding G binding, the HEK293 / CRE-Luc cell line developed by HDB that stably expresses the GLP-1 receptor was used. A 200× concentration compound working solution (Agilent Technologies Bravo) was prepared by serial 1 / 2 log dilution in a 384-well Echo LDV plate (Labcyte, Cat#LP-0200). 50 nL / well of the 200× concentration compound working solution was transferred to a 384-well white low-volume plate (Greiner, Cat#784075) using a Labcyte ECHO550. A HEK293 / GLP1R / CRE-LUC (HD Biosciences) cell suspension at 1×10 5 cells / mL was prepared with assay buffer [DPBS containing 0.5 mM IBMX (Sigma, Cat#I5879) and 0.1% BSA (GENVIEW, Cat#FA016-100g)], and 10 μL of the cell suspension was added to each well of the previously prepared assay plate containing 50 nL of the compound at 200× concentration using a ThermoFisher Multidrop Combi (1000 cells / well). The plate was sealed and incubated at 37 °C for 30 minutes in 5% CO2.

[0489] After incubation, the cAMP assay signal was generated using the cAMP dynamic 2 Kit (Cisbio). 5 μL of the cAMP-d2 working solution was added to each well, followed by addition of 5 μL of the anti-cAMP antibody-cryptate working solution to each well using a ThermoFisher Multidrop Combi. Incubate for 1 hour at room temperature protected from light. The luminescence was read at 665 nm and 615 nm using a Reader PerkinElmer EnVision. % Activity = 100% x (Average RLU of test sample - Average RLU of vehicle control) / (Average RLU of MAX control - Average RLU of vehicle control) Table 1 shows the biological activity of the compounds in the cAMP activation assay (EC 50 ) [nM] of GLP-1R agonists (Method 3)

Table 4

[0490] Example B Rat Pharmacokinetics (PK) Study Pharmacokinetic (PK) studies were conducted using male Sprague-Dawley (SD) rats by two delivery routes: intravenous (IV) and / or forced oral administration (PO). Rats in the IV group (n = 3) had free access to food and water. Rats in the PO group (n = 3) were fasted overnight and given food 4 hours after dosing. The test article was formulated in solution for the IV route and in solution or suspension for the PO route, respectively. On the day of the experiment, the test article was administered by intravenous (e.g., dorsal pedal vein) injection (usually 0.2 - 1 mg / kg and 2 mL / kg) for the IV route or by forced oral administration (usually 5 - 100 mg / kg and 10 mL / kg) for the PO route. Blood samples were collected by serial sampling at approximately 8 time points from 0.083 to 24 hours after dosing. Approximately 150 μL of blood per time point was collected into K2EDTA tubes via the tail vein. The blood samples were placed on wet ice, centrifuged to obtain plasma samples, and the plasma samples were subjected to LC-MS / MS for sample analysis. Pharmacokinetic parameters, including clearance (IV), area under the curve (AUC), and oral bioavailability (F%), were calculated using WinNonlin by non-compartmental modeling.

[0491] Exemplary compounds of formula (I) (e.g., specific compounds of formula (IE)) were tested using the above protocol. The test compounds exhibited plasma clearance (L / hr / kg) in the range of 0.20 - 1.60 (e.g., 0.20 - 0.80 (e.g., 0.30 - 0.50); or 1.00 - 1.60 (e.g., 1.20 - 1.60)); and volume of distribution (L / Kg) in the range of 0.40 - 0.70 (L / Kg).

[0492] Example C Glucose Tolerance Test in Non-Human Primates (NHP) Cynomolgus monkeys (2.5 - 6.0 kg) were each housed in stainless steel cages in a controlled environment maintained at a temperature of 18 - 26 °C and a relative humidity of 30 - 70% during the test period, with a minimum of 10 air exchanges / hour. A time-controlled lighting system was used (lights on from 7:00 AM to 7:00 PM) to provide a regular 12-hour light / 12-hour dark circadian cycle. The monkeys were fed three times a day at 9:00 - 10:00 AM with 100 g of normal diet, at 2:00 - 3:00 PM with 150 g of normal fruit once, and at 4:00 - 5:00 PM with 100 g of normal diet. Drinking water was provided ad libitum. An ivGTT was performed on all animals, and then the selected animals were assigned to predetermined groups based on their baseline ivGTT insulin AUC and their body weights. A general outline of the test is shown in the following table: [Table 5]

[0493] Before the start of the test, the animals were acclimatized for one week. On day 1, all animals were dosed with vehicle by IV injection 5 minutes before IV glucose induction. On day 9, all animals were dosed with vehicle or compound by IV injection 5 minutes before IV glucose induction.

[0494] The ivGTT was performed on day 1 and day 9 respectively. The animals were fasted overnight and anesthetized (Zoletil 50, intramuscular, 5 mg / kg initial dose, then 2.5 - 5 mg / kg maintenance dose as needed).

[0495] 5 minutes after dosing with the compound or vehicle, the animals were injected intravenously with 50% glucose at a dose of 0.5 g / kg (1 mL / kg) for 30 seconds via the saphenous vein or an appropriate peripheral vein. The whole blood samples (1.2 mL) were collected from the saphenous vein into EDTA-K2 tubes at the following time points: -6 (before compound administration) and 1, 3, 5, 10, 20, 40, and 60 minutes (after glucose induction).

[0496] The collected blood samples were stored on wet ice and then centrifuged at 3500 rpm for 10 minutes at 4°C within 60 minutes. The collected plasma samples (0.5 mL each) were stored in a freezer at -80°C while maintaining until the analysis of glucose, insulin and C-peptide.

[0497] For the test compound group, about 1.0 mL of whole blood was collected into EDTA-K2 tubes from the saphenous vein or radial cutaneous vein at each time point of IVGTT on the 9th day. The collected blood samples were maintained on wet ice until centrifugation. Plasma was separated by centrifugation at 3500 rpm for 10 minutes at 4°C within 60 minutes of collection. The statistical analysis of the data was performed by GraphPad Prism (version 9, GraphPad Software Inc, La Jolla, California).

[0498] The exemplary compounds of formula (I) (for example, specific compounds of formula (IE)) were tested using the above protocol. Specifically, the test compound was injected iv into healthy NHP at a dose selected from 0.03 - 0.30 mg / kg (for example, a dose of 0.05 mg / kg). According to the procedure described above, insulin secretion was induced within ivGTT 2.0 - 6.0 times (for example, 3.0 - 5.0 times), and an increase of 10% - 40% (for example, 30% - 40%) in the glucose clearance rate was observed.

[0499] Other embodiments The present invention has been described with its detailed description, but the above description is intended to be illustrative and not to limit the scope of the present invention, and it should be understood that it is defined by the claims. Other aspects, advantages, and modifications are within the scope of the following claims. The present invention includes the following aspects and embodiments. [Item 1] Formula (I): [Chemical formula] Formula (I) [Wherein, Q 1 , Q2 , Q 3 , Q 4 , and Q 5 is defined by the following (AA) or (BB): (AA) Q 1 and Q 5 are independently selected from the group consisting of N, CH, and CR QA ; Q 2 , Q 3 , and Q 4 are independently selected from the group consisting of N, CH, CR QA , and CR QB but provided that at least one of Q 2 , Q 3 , and Q 4 is CR QB ; Each

Chemical formula

Chemical formula

Chemical formula

Claims

1. Formula (I): 【Chemical 1】 Formula (I) [In the formula,[[]]END] Q １ , Q ２ , Q ３ , Q ４ , and Q ５ is defined by the following (AA) or (BB): (AA) Q １ and Q ５ are each independently selected from the group consisting of N, CH, and CR ＱＡ ; Q ２ , Q ３ , and Q ４ are each independently selected from the group consisting of N, CH, CR ＱＡ , and CR ＱＢ , provided that at least one of Q ２ , Q ３ , and Q ４ is CR ＱＢ ; each [Chemical Formula 2] is a single bond or a double bond, provided that Q １ -Q ５ The ring containing is aromatic; (BB) Q １ is a bond; Q ２ 、 Q ３ 、 Q ４ 、 and Q ５ are, independently, selected from the group consisting of O, S, NH, NR ｃ , CH, CR ＱＡ , and CR ＱＢ , provided that at least one of Q ２ , Q ３ , Q ４ , and Q ５ is CR ＱＢ ; each [Chemical Formula 3] is a single bond or a double bond, provided that Q １ -Q ５ the ring containing is aromatic; R ＱＢ is P(=O)R ａ R ｂ wherein, R ａ and R ｂ are each independently selected from the group consisting of C １－６ alkoxy, C ３－６ cycloalkyl, and halo, and may be substituted with 1 to 6 substituents independently selected from the group consisting of C １－６ alkyl; C １－３ alkyl and may be substituted with 1 to 3 substituents independently selected from the group consisting of alkyl and halo C ３－６ cycloalkyl; and 1 to 3 independently selected C １－３ aryl which may be substituted with alkyl C ６－１０ is selected from the group consisting of; or R ａ and R ｂ each together with the phosphorus atom to which it is attached forms a ring containing 5 to 8 ring atoms, and 0 to 2 ring atoms (in addition to the phosphorus to which R ａ and R ｂ is attached) are heteroatoms each independently selected from the group consisting of O, S, and N, and said ring may be substituted with 1 to 3 independently selected C １－６ alkyl; Each R ＱＡ is independently (a) halo; (b) cyano; (c) OH; (d) -NR ｃ R ｄ ; (e) C(=O)NR ｃ R ｄ ; (f) S(=O) ０－２ R ｅ ; (g) C ｆ alkyl which may be substituted with 1 to 6 independently selected R １－６ ; (h) C １－６ alkoxy which may be substituted with 1 to 6 substituents independently selected from the group consisting of hydroxy, halo, and C １－６ alkoxy; (i) a 3- to 12-membered heterocyclyl which may be substituted with one or more substituents independently selected from the group consisting of C １－６ alkyl and C(=O)(C １－６ alkyl); (j) C １－６ aryl which may be substituted with 1 to 3 independently selected C(=O)(C ６－１０ alkyl); and (k) 5- to 10-membered heteroaryl which may be substituted with 1 to 6 independently selected R ｇ ; or is selected from the group consisting of A pair of Rs on adjacent carbon atoms ＱＡ together with the atoms to which each is attached form a ring containing 5 to 8 ring atoms, 0 to 2 of which are heteroatoms each independently selected from the group consisting of O, N, and S, and said ring may be substituted with 1 to 2 independently selected R ｈ groups; L ２ is 【Chemical Formula 4】 is selected from the group consisting of, in the formula,[[]]END] aa represents a bonding point to a ring containing Q １ -Q ５ and indicates; n1 is an integer from 1 to 3; L ２Ａ is a linking or C １－１０ alkylene; R Ｌａ is selected from the group consisting of H, C １－６ alkyl, and C(=O)(C １－６ alkyl); R Ｌｂ and R Ｌｃ each independently is selected from the group consisting of H and C １－６ alkyl; Ring A is C ６－１０ aryl, C ５－７ cycloalkyl, 5- to 7-membered heterocycle, or 5- to 10-membered heteroaryl, each of which may be substituted with 1 to 5 substituents independently selected from the group consisting of halo, C １－６ alkyl, C １－６ haloalkyl, and C １－６ alkoxy; R １ 、R ２ 、and R ３ are each independently selected from the group consisting of H and from 1 to 6 substituents independently selected from the group consisting of halo, -OH, and C １－６ alkoxy, and may be substituted with C １－６ alkyl selected from the group consisting of; L １ is selected from the group consisting of -C(=O)-, -CH ２ -, -CH(C １－６ alkyl)-, and -S(=O) ２ ; Ring B is 【Chemical Formula 5】 is selected from the group consisting of, in the formula,[[]]END] bb indicates the connection point to L １ and indicates; R ４ 、 R ５ 、 R ６ 、 and R ７ are each independently selected from the group consisting of H, halo, and C １－６ alkyl; L ３ is a linking or C １－３ alkylene; L ４ is a linking or C １－５ alkylene; R ８ａ and R ８ｂ are each, independently, C optionally substituted with one or more substituents independently selected from the group consisting of H, halo and C ３－１５ alkyl; or cycloalkyl; or １－６ is selected from the group consisting of alkyl; or R ８ａ and R ８ｂ each, together with the carbon atom to which it is attached, forms a C １－６ cycloalkyl ring which may be substituted with 1 to 3 independently selected C ３－１５ alkyls, said C １－６ alkyls may be substituted with 1 to 6 independently selected R ｆ s; R ９ is C(=O)OH, C(=O)(OC １－６ alkyl), C(=O)NR ９ａ R ９ｂ , (IX-1), (IX-2), (IX-3), and (IX-4): ​ is selected from the group consisting of;[[]]END] R ９ａ is H or C １－６ alkyl; R ９ｂ is H, C １－６ alkyl, C(=O)(C １－６ alkyl), S(O) ０－２ (C １－６ alkyl), or cyano; R ９ｃ , R ９ｄ , R ９ｅ , R ９ｆ , and R ９ｇ are each independently selected from the group consisting of H; 1 to 6 independently selected halo and C １－６ alkyl optionally substituted with alkoxy; and C(=O)(C １－６ alkyl); １－６ and are selected from the group consisting of; Ring C is selected from the group consisting of 3- to 12-membered heterocycles; C ３－１５ cycloalkyl; and 5- to 10-membered heteroaryl, each of which may be substituted with 1 to 3 R Ｃａ ; and may be substituted; Each R Ｃａ is independently selected from the group consisting of halo, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, and NR ｃ R ｄ ; or alternatively A pair of Rs on the same or different ring atoms, together with the ring atoms to which each is attached, form a carbocyclic ring containing 3 to 8 ring atoms; Ｃａ ​ Each R ｃ and R ｄ is selected from the group consisting of H, C １－６ alkyl, C(=O)(C １－６ alkyl), C(=O)(C ３－６ cycloalkyl), C(=O)O(C １－６ alkyl), S(O) １－２ (C １－６ alkyl), and S(O) １－２ (C ３－６ cycloalkyl), and wherein said C １－６ alkyl, C(=O)(C １－６ alkyl), C(=O)(C ３－６ cycloalkyl), C(=O)O(C １－６ alkyl), S(O) １－２ (C １－６ alkyl), and S(O) １－２ (C ３－６ cycloalkyl) may each be substituted with 1 to 6 substituents independently selected from the group consisting of -OH, halo, and C １－６ alkoxy; R ｅ is H, C １－６ alkyl, or C １－６ haloalkyl; Each R ｆ is independently selected from the group consisting of halo, -OH, NR ｃ R ｄ , C １－６ alkoxy, C １－６ haloalkoxy, and -OH, C １－６ alkyl, and a 3- to 12-membered heterocyclyl, each independently selected from the group consisting of 1 to 4 substituents optionally substituted with a 3- to 12-membered heterocyclyl; Each R ｇ is independently selected from the group consisting of C １－６ alkyl, C １－６ alkoxy, NR ｃ R ｄ , and one or more substituents independently selected from the group consisting of C １－６ alkyl and C(=O)C １－６ alkyl, and is optionally substituted with one or more substituents independently selected from the group consisting of 3- to 12-membered heterocyclyl; and Each R ｈ is independently selected from the group consisting of halo, cyano, C １－６ alkyl, C １－６ haloalkyl, -OH, NH ２ , NH(C １－３ alkyl), N(C １－３ alkyl) ２ , C １－３ alkoxy, and C １－３ haloalkoxy]] a compound represented by or a pharmaceutically acceptable salt or solvate.

2. Q １ , Q ２ , Q ３ , Q ４ , and Q ５ is the compound or a pharmaceutically acceptable salt or solvate according to claim 1, as defined by (AA).

3. (i) Q ３ is CR ＱＢ and Q １ , Q ２ , Q ４ , and Q ５ each independently is CH or CR ＱＡ ; or Q １ 、 Q ２ 、 Q ４ 、 and Q ５ each of which is CH; or Q １ , Q ２ , Q ４ , and Q ５ One of them is CR ＱＡ and Q １ , Q ２ , Q ４ , and Q ５ each remaining one of is CH; or Q ４ is CR ＱＡ and Q １ Q ２ and Q ５ is CH; or Q １ , Q ２ , Q ４ , and Q ５ Two of them are independently selected CR ＱＡ , and Q １ , Q ２ , Q ４ , and Q ５ each of the remaining one of them is CH; or (ii) Q ３ is CR ＱＢ and Q １ , Q ２ , Q ４ , and Q ５ of which one is N, and Q １ , Q ２ , Q ４ , and Q ５ each of the remaining ones of which is, independently, CH or CR ＱＡ ; or Q ４ is N, and Q １ , Q ２ , and Q ５ is CH; or (iii) Q ３ is CR ＱＢ and the above-mentioned 【Chemical Formula 7】 The moiety is 【Chemical Formula 8】 selected from the group consisting of; or (iv) Q ４ is CR ＱＢ and Q １ , Q ２ , Q ３ , and Q ５ each one of which is, independently, CH or CR ＱＡ ; or Q １ , Q ２ , Q ３ , and Q ５ Is each one of them CH; or Q １ 、 Q ２ 、 Q ３ 、 and Q ５ of which one is CR ＱＡ and, Q １ 、 Q ２ 、 Q ３ 、 and Q ５ each of the remaining ones of which is CH; or Q ５ is CR ＱＡ and Q １ Q ２ and Q ３ is CH; or Q １ , Q ２ , Q ３ , and Q ５ of which two are independently selected CR ＱＡ , and Q １ , Q ２ , Q ３ , and Q ５ of which each of the remaining one is CH; or Q ２ and Q ３ are CRQA independently selected, and Q １ and Q ５ is CH; or (v) Q ４ is CR ＱＢ and Q １ Q ２ Q ３ and Q ５ one of is N, and Q １ Q ２ Q ３ and Q ５ each of the remaining ones of is independently CH or CR ＱＡ or; alternatively (vi) Q ４ is CR ＱＢ and the above-mentioned 【Chemical Formula 9】 The moiety is 【Chemical Formula 10】 selected from the group consisting of,[[]]END] The compound or pharmaceutically acceptable salt or solvate according to Claim 2.

4. R ＱＢ is P(=O)R ａ R ｂ wherein, (i) R ａ and R ｂ are each independently selected from the group consisting of C １－６ alkyl and C ３－６ cycloalkyl; or (ii) R ａ and R ｂ are each independently C １－３ alkyl, The compound or pharmaceutically acceptable salt or solvate according to any one of Claims 1 to 3.

5. R ＱＢ is P(=O)Me ２ or; alternatively R ＱＢ is P(=O)Et ２ or; alternatively R ＱＢ is P(=O)iPr ２ is The compound or pharmaceutically acceptable salt or solvate according to any one of Claims 1 to 4.

6. R ＱＢ is P(=O)(Me)(tBu), and the compound or pharmaceutically acceptable salt or solvate according to any one of claims 1 to 4.

7. R ＱＢ is P(=O)R ａ R ｂ wherein, R ａ and R ｂ are each independently C ３－６ cycloalkyl; and / or R ＱＢ is 【Chemical 11】 which is The compound or pharmaceutically acceptable salt or solvate according to any one of Claims 1 to 4.

8. (i) R ＱＢ is P(=O)R ａ R ｂ wherein R ａ and R ｂ together with the phosphorus atom to which each is attached form a ring containing 5 to 8 ring atoms, where 0 to 2 ring atoms (in addition to the phosphorus to which R ａ and R ｂ is attached) are heteroatoms each independently selected from the group consisting of O, S, and N, and said ring is optionally substituted with 1 to 3 independently selected C １－６ alkyl; and / or (ii) R ＱＢ is P(=O)R ａ R ｂ wherein R ａ and R ｂ together with the phosphorus atom to which each is attached form a ring containing 5 to 6 ring atoms, where 0 to 1 ring atoms (in addition to the phosphorus to which R ａ and R ｂ are attached) are heteroatoms selected from the group consisting of O, S, and N, and said ring is optionally substituted with 1 to 2 independently selected C １－６ alkyl; and / or (iii) R ＱＢ is 【Chemical Formula 12】 wherein L Ｑ is a bond, CH ２ , O, S, NH, or N(C １－６ alkyl); and / or (iv) R ＱＢ is 【Chemical Formula 13】 which is The compound or pharmaceutically acceptable salt or solvate according to any one of Claims 1 to 3.

9. R ＱＡ One of (i) halo; or (ii) -F; or (iii) -OH; or (iv) NR ｃ R ｄ ; or (v) NH(C １－３ alkyl); or (vi) NH ２ ; or (vii) N(C １－３ alkyl) ２ ; or (viii) NHC(=O)(C １－６ alkyl), NHC(=O)(C ３－６ cycloalkyl), NHC(=O)O(C １－６ alkyl), NHSO １－２ (C １－６ alkyl), and NHSO １－２ (C ３－６ cycloalkyl), selected from the group consisting of; or (ix) NHC(=O)(C １－３ alkyl), NHC(=O)(C ３－６ cycloalkyl) or NHS(O) ２ (C １－３ alkyl); or (x)C １－６ 1 or more substituents each independently selected from the group consisting of alkyl and C(=O)(C １－６ alkyl), optionally substituted 5- to 6-membered heterocyclyl; or (xi) morpholinyl; or (xii) C optionally substituted with 1 to 6 substituents each independently selected from the group consisting of hydroxy, halo and C １－６ alkoxy; or １－６ C alkoxy optionally substituted with 1 to 6 substituents each independently selected from the group consisting of hydroxy, halo and C (xiii) C which may be substituted with 1 to 6 independently selected halos １－６ alkoxy; or (xiv) -OMe, -OCF ３ or -OCHF ２ ; or (xv) 1 to 6 independently selected Rs ｆ which may be substituted with １－６ alkyl; or (xvi) C １－３ alkyl or C substituted with 1 to 6 independently selected halos １－３ alkyl; or (xvii) methyl, -CF ３ or -CHF ２ which is, The compound or pharmaceutically acceptable salt or solvate according to any one of Claims 1 to 8.

10. L ２ is 【Chemical Formula 14】 which is, The compound or pharmaceutically acceptable salt or solvate according to any one of Claims 1 to 9.

11. Ring A is (i) Each is optionally substituted with 1 to 4 substituents each independently selected from the group consisting of halo, C １－６ alkyl, C １－６ haloalkyl and C １－６ aryloxy which is optionally substituted with 1 to 4 substituents each independently selected from the group consisting of halo, C ６－１０ aryl or 5- to 10-membered heteroaryl; or (ii) phenyl or pyridyl, each optionally substituted with 2 to 4 substituents each independently selected from the group consisting of halo, C １－６ alkyl, C １－６ haloalkyl and C １－６ alkoxy; or (iii) phenyl optionally substituted with 2 to 4 substituents each independently selected from the group consisting of halo and C １－６ alkyl; or (iv) Pyridyl optionally substituted with 2 to 4 substituents each independently selected from the group consisting of halo and C １－６ alkyl; or (v) The following structure: 【Chemical Formula 15】 [wherein, R ＡＡ , R ＡＢ , and R ＡＣ are each independently halo or C １－６ alkyl] which is, The compound or pharmaceutically acceptable salt or solvate according to any one of Claims 1 to 10.

12. (i) R １ and R ２ are H, and R ３ is C １－６ alkyl; or R1 and R2 are H, and R ３ is methyl; and / or (ii) L １ is C(=O); and / or (iii) Ring B is 【Chemical 16】 which is; and / or (iv) R ４ , R ５ and R ６ are each H; and / or (v) R ７ is H; and / or (vi) L ３ and L ４ both are bonds The compound or pharmaceutically acceptable salt or solvate according to any one of Claims 1 to 11.

13. R ８ａ and R ８ｂ together with the carbon atoms to which each is attached, (i) One or two independently selected C １－６ Optionally substituted with C ３－８ Forms a cycloalkyl ring, where the C １－６ Alkyl may be substituted with one to three independently selected R ｆ Optionally; or (ii) one or two independently selected C １－６ which may be substituted with C ３－５ cycloalkyl ring, wherein the C １－６ alkyl may be substituted with one to three independently selected R ｆ and / or; (iii) one or two independently selected C １－６ optionally substituted with C ３－４ to form a cycloalkyl ring; or (iv) 【Chemical 17】 forms; or (v) 【Chemical 18】 forms,[[]]END] The compound or pharmaceutically acceptable salt or solvate according to any one of Claims 1 to 12.

14. R ９ is 【Chemical Formula 19】 (IX-2) which is, The compound or pharmaceutically acceptable salt or solvate according to any one of Claims 1 to 13.

15. In claim 1 to 11 or (v) of claim 12, L ３ -C(R ８ａ R ８ｂ )-L ４ -R ９ the part is 【Chemical 20】 ; or 【Chemical 21】 which is, The compound or pharmaceutically acceptable salt or solvate according to any one of Claims 1 to 12.

16. R ９ｄ The compound or pharmaceutically acceptable salt or solvate according to claim 14 or 15, wherein R is H.

17. Ring C is (i) one to three independently selected Rs Ｃａ may be replaced by a 3- to 12-membered heterocycle; or (ii) a 4- to 8-membered heterocycle optionally substituted with 1 to 3 independently selected R Ｃａ or; (iii) a 5- or 6-membered heterocycle optionally substituted with 1 to 3 independently selected Rs Ｃａ optionally substituted with Ｃａ ; or (iv) 1 to 3 independent R Ｃａ which may be substituted with tetrahydropyranyl; or (v) 【Chemical Formula 22】 selected from the group consisting of; or (vi) morpholinyl which may be substituted with 1 to 3 independently selected R Ｃａ or; alternatively (vii) The following structure: 【Chemical 23】 which is; or (viii) 1 to 3 R's Ｃａ C which may be substituted with ３－１０ cycloalkyl; or (ix) 1 to 3 R's Ｃａ C which may be substituted with ３－８ cycloalkyl; or (x) The following structure: 【Chemical 24】 which is,[[]]END] The compound or pharmaceutically acceptable salt or solvate according to any one of claims 1 to 16.

18. Each R Ｃａ is independently selected from the group consisting of halo and C １－６ alkyl, a compound or a pharmaceutically acceptable salt or solvate according to any one of claims 1 to 17.

19. The compound of formula (I) is of formula (IA): 【Chemical 25】 Formula (IA) Wherein, (i) Q ４ and Q ５ are each independently selected from the group consisting of N, CH, and CR ＱＡ or; (ii) Q ４ and Q ５ each is CH; or (iii) Q ４ is CR ＱＡ and Q ５ is CH; or (iv) Q ４ is N, and Q ５ is CR ＱＡ or CH; or (v) Q ５ is CH; or (vi) Q ４ is CR ＱＡ and Q ５ is CR ＱＡ ] The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, which is a compound of.

20. (i) R ａ and R ｂ are each methyl; or (ii) R ａ and R ｂ are each ethyl; or (ii) R ａ and R ｂ are each isopropyl; or (iv) R ａ is methyl and R ｂ is tert-butyl; or (v) R ａ and R ｂ are each independently selected C ３－６ cycloalkyl; or (vi) R ａ and R ｂ both being cyclopropyl, The compound according to claim 19 or a pharmaceutically acceptable salt or solvate thereof.

21. (i) Each R ＱＡ is halo; cyano; OH; NR ｃ R ｄ ; C optionally substituted with 1 to 6 independently selected R ｆ alkyl; C optionally substituted with 1 to 6 substituents each independently selected from the group consisting of hydroxy, halo, and C １－６ alkoxy; and C １－６ alkoxy optionally substituted with 1 to 6 substituents each independently selected from the group consisting of hydroxy, halo, and C １－６ alkoxy; and selected from the group consisting of 3- to 12-membered heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of C １－６ alkyl and C(=O)(C １－６ alkyl); or (ii) each R ＱＡ is selected from the group consisting of -F, OH, NH ２ , NHMe, NHEt, NH iPr, N(Me) ２ , NH C(=O)(cyclopropyl), NH S(O) ２ Me, methyl, CF ３ , CHF ２ , OMe, OCF ３ , OCHF ２ and is selected from the group consisting of morpholinyl; or (iii) A pair of Rs on adjacent carbon atoms ＱＡ together with the atoms to which each is attached form a ring containing 5 to 6 ring atoms, where 1 to 2 ring atoms are heteroatoms each independently selected from the group consisting of O, N, and S, and said ring may be substituted with 1 to 2 independently selected R ｈ groups; or (iv) a pair of Rs on adjacent carbon atoms ＱＡ together with the atoms to which each is attached 【Chemical 26】 To form; or (v) a pair of Rs on adjacent carbon atoms ＱＡ together with the atoms to which each is attached 【Chemical 27】 To form, The compound according to claim 19 or 20 or a pharmaceutically acceptable salt or solvate thereof.

22. The compound of formula (I) is of formula (ID): 【Chemical Formula 28】 Formula (ID) Wherein, R ＡＡ 、R ＡＢ 、and R ＡＣ are, independently, halo or C １－６ alkyl; R ＱＣ is H or halo; and Each R Ｃｂ is independently selected from the group consisting of H and R Ｃａ ; And, (i) R １ and R ２ is H; or R1 and R2 are H, and R ３ is C １－３ alkyl; or R1 and R2 are H, and R ３ is methyl; and / or (ii) R ４ , R ５ , R ６ , and R ７ is H; and / or (iii) R ９ｄ is H; and / or (iv) R ＡＡ and R ＡＣ are each independently C １－６ alkyl; or R ＡＡ and R ＡＣ is methyl; and / or (v) R ＡＢ is a halo; or R ＡＢ is -F; and / or (vi) each R Ｃｂ is H or methyl; or Each R Ｃｂ is H] The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, which is a compound of.

23. (i) R ａ and R ｂ are each independently C １－３ alkyl; or (ii) R ａ and R ｂ is methyl; or (iii) R ａ and R ｂ is ethyl; or (iv) R ａ and R ｂ is isopropyl; or (v) R ａ is methyl and R ｂ is tert-butyl; or (vi) R ａ and R ｂ are each independently C ３－６ cycloalkyl; or (vii) R ａ and R ｂ are each cyclopropyl, The compound according to claim 22 or a pharmaceutically acceptable salt or solvate thereof.

24. (i) R ＱＡ is NR ｃ R ｄ or; alternatively R ＱＡ is NH(C １－３ alkyl); and / or (ii) R ＱＣ is H, The compound according to claim 22 or 23 or a pharmaceutically acceptable salt or solvate thereof.

25. The compound is of formula (S,S,S)-(ID) 【Chemical 29】 Formula (S,S,S)-(ID) [wherein, R ３ is C １－３ alkyl] The compound according to any one of claims 22 to 24 or a pharmaceutically acceptable salt thereof.

26. The compound of formula I is 【Chemical 30】 【Chemical 31】 【Chemical 32】 【Chemical Formula 33】 【Chemical 34】 【Chemical 35】 【Chemical 36】 【Chemical 37】 【Chemical 38】 【Chemical Formula 39】 【Chemical Formula 40】 【Chemical Formula 41】 【Chemical 42】 【Chemical Formula 43】 【Chemical Formula 44】 【Chemical 45】 【Chemical Formula 46】 【Chemical 47】 【Chemical Formula 48】 【Chemical 49】 【Chemical Formula 50】 【Chemical Formula 51】 【Chemical 52】 【Chemical Formula 53】 【Chemical 54】 【Chemical Formula 55】 【Chemical Formula 56】 【Chemical 57】 【Chemical Formula 58】 【Chemical Formula 59】 【Chemical Formula 60】 【Chemical Formula 61】 Or a pharmaceutically acceptable salt or solvate thereof, and is selected from the group consisting of the compound according to any one of claims 1 to 25.

27. The compound is 【Chemical Formula 62】 Or a pharmaceutically acceptable salt thereof, which is the compound according to claim 1.

28. The compound is 【Chemical Formula 63】 Which is the compound according to claim 1.

29. The compound is 【Chemical Formula 64】 Or a pharmaceutically acceptable salt thereof, which is the compound according to claim 1.

30. The compound is 【Chemical Formula 65】 Which is the compound according to claim 1.

31. The compound is 【Chemical Formula 66】 Or a pharmaceutically acceptable salt thereof, which is the compound according to claim 1.

32. The compound is 【Chemical Formula 67】 Which is the compound according to claim 1.

33. The compound is 【Chemical Formula 68】 Or a pharmaceutically acceptable salt thereof, which is the compound according to claim 1.

34. The compound is 【Chemical 69】 Which is the compound according to claim 1.

35. The compound is 【Chemical Formula 70】 Or a pharmaceutically acceptable salt thereof, which is the compound according to claim 1.

36. The compound is 【Chemical Formula 71】 Which is the compound according to claim 1.

37. A pharmaceutical composition comprising the compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

38. A medicament for treating type 2 diabetes, comprising the compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition according to claim 37.

39. The medicament according to claim 38, wherein the compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition according to claim 37 is administered orally.

40. A medicament for regulating insulin level or glucose level, comprising the compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition according to claim 37.

41. A medicament for treating a GLP-1 related disease, disorder, or illness, comprising the compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition according to claim 37, The disease, disorder, or illness is selected from the group consisting of type 1 diabetes, type 2 diabetes, young-onset type 2 diabetes, fulminant type 1 diabetes (type 1b), young-onset atypical diabetes (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes in adults (LADA), obesity, weight gain due to the use of other drugs, 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 disorder, vascular compliance disorder, restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorder, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic kidney disease, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataract, glomerulosclerosis, arthritis, osteoporosis, treatment of poisoning, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcer, 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, or The disease, disorder, or illness is selected from the group consisting of type 2 diabetes, juvenile-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 arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, abnormal glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol intake disorder, chronic renal insufficiency, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina, 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, or The disease, disorder, or illness is type 2 diabetes, juvenile-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 arterial disease, stroke, transient ischemic attack, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, abnormal glucose metabolism, insulin resistance, hepatic insulin resistance, chronic renal insufficiency, syndrome X, angina, 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, a medicament.

42. A medicament for treating obesity, comprising the compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition according to claim 37.

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