Heterocyclic GLP-1 agonists

Abstract

To provide GLP-1 agonists (including pharmaceutically acceptable salts and solvates thereof), pharmaceutical compositions including the same, and methods for treating type 2 diabetes.SOLUTION: Provided herein are compounds represented by Formula (I) or a pharmaceutically acceptable salt or solvate. (Q1, Q2, Q3, Q4 and Q5 are each independently N, CH, or the like; the ring including Q1-Q5 is aromatic; ring A is substituted / unsubstituted C6-10 aryl, C5-7 cycloalkyl, or the like; ring B is a group including an indole ring, or the like; and ring C is substituted / unsubstituted 3-12 membered heterocyclyl, C3-15 cycloalkyl, or the like.)SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of International Patent Application No. PCT / CN2020 / 109304, filed August 14, 2020; and International Patent Application No. PCT / CN2020 / 074537, filed February 7, 2020, each of which is incorporated herein by reference in its entirety.

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

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

[0004] Diabetes refers to a group of metabolic disorders characterized by persistent hyperglycemia. Type 2 diabetes mellitus (T2DM), the most common form, is an acquired disease that accounts for more than 90% of diabetes cases. The disease typically develops in obese or sedentary adults and begins with insulin resistance. While lifestyle changes can be helpful in managing the disease, T2DM patients may need to take antidiabetic medications, including dipeptidyl peptidase-4 inhibitors, SGLT2 inhibitors, and sulfonylureas, among others.

[0005] In healthy individuals, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) regulate the insulin secretory response to glucose digestion. Although this incretin effect is significantly reduced in T2DM (all cases), GLP-1 retains insulinotropic properties even when the endocrine pancreatic response to GIP is effectively shut down. Thus, incretin mimetics and other GLP-1-based therapies can help activate insulin production in T2DM patients. Summary of the Invention

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

[0007] Thus, formula (I): [ka] Formula (I) [In formula: Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 is as follows ( AA )or( BB ) is defined by: (AA) Q 1 and Q 5 are N, CH, and CR QA independently selected from the group consisting of: Q 2 , Q 3 , and Q 4 are N, CH, CR QA , and C.R. QB independently selected from the group consisting of: 2 , Q 3 , and Q 4 At least one of the following is CR QB and; each [ka] is a single or double bond, provided that Q 1 -Q 5 is aromatic; (BB) Q 1 is a bond; Q 2 , Q 3 , Q 4 , and Q 5 are O, S, N, NH, NR c , C.H., C.R. QA , and C.R. QB independently selected from the group consisting of: 2 , Q 3 , Q 4 , and Q 5 At least one of the following is CR QB and; each [ka] is a single or double bond, provided that Q 1 -Q 5 is aromatic; R QB is P(=O)R a R b wherein R a and R b independently, C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents each independently selected from the group consisting of cycloalkyl, and halo 1-6 Alkyl; C 1-3 C optionally substituted with 1 to 3 substituents each independently selected from the group consisting of alkyl and halo 3-6 cycloalkyl; and 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 aryl; or R a and R b are taken together with the phosphorus atom to which they are attached to form a ring containing 5 to 8 ring atoms, and 0 to 2 ring atoms (R a and R b (in addition to the phosphorus bonded to 1-6 optionally substituted with alkyl; Each R QA are 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) 1 to 6 independently selected R f C, which may be optionally substituted with 1-6 alkyl; (h) hydroxy, halo, and C 1-6 C, which may be optionally substituted with 1 to 6 substituents each independently selected from the group consisting of alkoxy 1-6 Alkoxy; (i) C 1-6 Alkyl and C(=O)(C 1-6 (j) a 3- to 12-membered heterocyclyl optionally substituted by one or more substituents, each independently selected from the group consisting of C(=O)(C 1-6 C optionally substituted with alkyl 6-10 aryl; and (k) 1 to 6 independently selected R g or is selected from the group consisting of 5-10 membered heteroaryl optionally substituted with A pair of R on adjacent carbon atoms QA each taken together with the atom to which it is attached forms a ring containing 5 to 8 ring atoms, wherein 0 to 2 ring atoms are heteroatoms each independently selected from the group consisting of O, N, and S, and said ring is joined to 1 to 2 independently selected R h optionally substituted with groups; L2 teeth, [ka] wherein: aa is Q 1 ~Q 5 indicates the point of attachment to the ring containing; n1 is an integer of 1 to 3; L 2A is a bond or C 1-10 is alkylene; R La is H, C 1-6 Alkyl, and C(=O)(C 1-6 alkyl); R Lb and R Lc Each of H and C 1-6 independently selected from the group consisting of alkyl; Ring A is C 6-10 Aryl, C 5-7 cycloalkyl, 5- to 7-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is selected from halo, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 optionally substituted with 1 to 5 substituents each independently selected from the group consisting of alkoxy; R 1 , R 2 , and R 3 are each independently H, and halo, —OH, and C 1-6 C, which may be optionally substituted with 1 to 6 substituents each independently selected from the group consisting of alkoxy 1-6 selected from the group consisting of alkyl; L 1 -C(=O)-, -CH2-, -CH(C 1-6 -S(=O)2; Ring B is [ka] is selected from the group consisting of bb is L 1 indicates the point of attachment to; R 4 , R 5 , R 6 , and R 7 H, halo, and C 1-6 independently selected from the group consisting of alkyl; L 3 is a bond or C 1-3 is alkylene; L 4 is a bond or C 1-5 is alkylene; R 8a and R 8b are independently H, and halo and C 3-15 C optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl 1-6 alkyl; or R 8a and R 8b Each of these, together with the carbon atom to which it is attached, is one to three independently selected C 1-6 C optionally substituted with alkyl 3-15 Forms a cycloalkyl ring, 1-6 Alkyl is 1 to 6 independently selected R f may be optionally substituted with; R 9 are C(=O)OH, C(=O)(OC 1-6 alkyl), C(=O)NR 9a R 9b , (IX-1), (IX-2), (IX-3), and (IX-4): [ka] selected from the group consisting of: R 9a is H or C 1-6 is alkyl; R 9b is H, C 1-6 Alkyl, C(=O)(C 1-6 alkyl), S(O) 0-2 (C1-6 alkyl), or cyano; R 9c , R 9d , R 9e , R 9f , and R 9g are each independently selected from H; 1 to 6 independently selected halo and C 1-6 C optionally substituted with alkoxy 1-6 Alkyl; and C(=O)(C 1-6 alkyl); Ring C is a 3- to 12-membered heterocyclyl; C 3-15 cycloalkyl; and 5- to 10-membered heteroaryl, each of which is selected from the group consisting of 1 to 3 R Ca may be optionally substituted with; Each R Ca Ha, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, and NR c R d or independently selected from the group consisting of A pair of R on the same or different ring atoms Ca each together with the ring atom to which it is attached forms a carbocyclic ring containing 3 to 8 ring atoms; Each R c and R d is 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), 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) is substituted with -OH, halo, and C 1-6 each optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkoxy; R e is H, C 1-6 Alkyl, or C 1-6 is haloalkyl; Each R f are independently halo, -OH, NR c R d , C 1-6 Alkoxy, C 1-6 Haloalkoxy, as well as -OH, C 1-6 selected from the group consisting of alkyl, and 3- to 12-membered heterocyclyl optionally substituted with 1 to 4 substituents each independently selected from the group consisting of 3- to 12-membered heterocyclyl; Each R g independently, C 1-6 Alkyl, C 1-6 Alkoxy, NR c R d , and C 1-6 Alkyl and C(=O)C 1-6 3- to 12-membered heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; and Each R h Halo, Cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, -OH, NH2, NH(C 1-3 alkyl), N(C 1-3 Alkyl)2, C 1-3 Alkoxy, and C 1-3 haloalkoxy] or a pharmaceutically acceptable salt or solvate thereof.

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

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

[0011] Also provided is 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. In some embodiments, 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 some embodiments, the HbA1c level is about 6.5% or higher. In some embodiments, the fasting blood glucose level is about 126 mg / dL or higher. In some embodiments, the non-fasting blood glucose level is about 200 mg / dL or higher.

[0012] In one embodiment, the method further comprises obtaining a sample from the patient. In one embodiment, the sample is a body fluid sample. In one embodiment, the patient is about 40 to about 70 years old and is overweight or obese. In one embodiment, the patient is about 22 kg / m 2 In certain embodiments, the patient has a body mass index (BMI) of about 30 kg / m or greater.2 or have a BMI of 18.5 or higher.

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

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

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

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

[0017] In one embodiment, the method for treating type 2 diabetes comprises reducing BMI. In one embodiment, the BMI is 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 some embodiments, the method for treating type 2 diabetes further comprises administering an additional therapy or therapeutic agent to the patient. In some embodiments, the additional therapy or therapeutic agent is selected from the group consisting of an antidiabetic drug, an antiobesity drug, a GLP-1 receptor agonist, a nonalcoholic steatohepatitis (NASH) drug, gastric electrical stimulation, dietary monitoring, physical activity, or any combination thereof. In some embodiments, the antidiabetic drug is selected from the group consisting of a biguanide, a sulfonylurea, a glitazar, a thiazolidinedione, a dipeptidyl peptidase 4 (DPP-4) inhibitor, a meglitinide, a sodium-dependent glucose transporter 2 (SGLT2) inhibitor, a glitazone, a GRP40 agonist, a glucose-dependent insulinotropic polypeptide (GIP), insulin or an insulin analog, an alpha-glucosidase inhibitor, a sodium-dependent glucose transporter 1 (SGLT1) inhibitor, or any combination thereof. In some embodiments, the biguanide is metformin. In certain embodiments, the antiobesity agent is a neuropeptide Y receptor type 2 (NPYR2) agonist, an NPYR1 or NPYR5 antagonist, human proislet peptide (HIP), or a combination thereof. peptide) (HIP), cannabinoid receptor type 1 (CB1R) antagonist, lipase inhibitor, melanocortin receptor 4 agonist, farnesoid X receptor (FXR) agonist, phentermine, zonisamide, norepinephrine / dopamine reuptake inhibitor, GDF-15 analog, opioid receptor antagonist, cholecystokinin agonist, serotonergic agent, methionine aminopeptidase 2 (MetAP2) inhibitor, diethylpropion, phendimetrazine, benzphetamine, fibroblast growth factor receptor (FGFR) modulator, AMP-activated protein kinase (AMPK) activator, sodium-glucose transporter 1 (SGLT-1) inhibitor, or any combination thereof.In certain embodiments, the GLP-1 receptor agonist is selected from the group consisting of liraglutide, exenatide, dulaglutide, albiglutide, taspoglutide, lixisenatide, semaglutide, or any combination thereof. In some embodiments, the NASH therapeutic agent is selected from the group consisting of FXR agonists, PF-05221304, synthetic fatty acid bile conjugates, anti-lysyl oxidase analog 2 (LOXL2) monoclonal antibodies, caspase inhibitors, MAPK5 inhibitors, galectin 3 inhibitors, fibroblast growth factor 21 (FGF21) agonists, niacin analogs, leukotriene D4 (LTD4) receptor antagonists, acetyl-CoA carboxylase (ACC) inhibitors, ketohexokinase (KHK) inhibitors, ileal bile acid transporter (IBAT) inhibitors, apoptosis signal-regulating kinase 1 (ASK1) inhibitors, peroxisome proliferator-activated receptor (PPAR) agonists, diacylglycerol acyltransferase 2 (DGAT2) inhibitors, or any combination thereof. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvate, or its pharmaceutical composition, and the additional therapeutic agent are administered sequentially in any order as separate preparations.

[0020] Also provided herein is a method for modulating insulin levels in a patient in need thereof, comprising administering to the patient an effective amount of a compound of 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, 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] Also provided herein is a method for treating a GLP-1-associated disease, disorder, or condition, comprising administering to a patient in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In certain embodiments, the disease, disorder, or condition is type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of adults (LADA), obesity, weight gain due to the use of other medications, gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, or kidney disease. Disease, adipocyte dysfunction, sleep apnea, visceral fat accumulation, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, vascular restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial hypertension The indication is selected from the group consisting of: lipemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, alcohol use disorders, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, treatment of addiction, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, psychogenic polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof.In certain embodiments, the disease, disorder, or condition is selected from the group consisting of type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat accumulation, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, and glucose metabolism. abnormalities, insulin resistance, hepatic insulin resistance, alcohol use disorders, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, psychogenic polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS), or any combination thereof. In certain embodiments, the disease, disorder, or condition includes, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat accumulation, myocardial infarction, peripheral arterial disease, stroke, transient ischemic attack, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, chronic renal failure, Syndrome X, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, skin and connective tissue disorders, foot ulcers, or any combination thereof.

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

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

[0025] Detailed Description Provided herein are heterocyclic GLP-1 agonists for use in the treatment of type 2 diabetes mellitus (T2DM) and other conditions in which activation of GLP-1 action is beneficial.

[0026] definition When numerical values ​​are described as ranges, it is understood that all possible subranges within such ranges, as well as the recitation of specific numerical values ​​within such ranges, are included, whether or not a specific numerical value or specific subrange is explicitly stated.

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

[0028] As used herein, the term "alkyl" means a saturated linear or branched monovalent hydrocarbon radical containing the indicated number of carbon atoms. For example, "C 1-6"Alkyl" means a saturated straight or branched chain monovalent hydrocarbon radical of one to six carbon atoms. Non-limiting examples of alkyl include methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, 2-methyl-2-propyl, pentyl, neopentyl, and hexyl.

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

[0031] As used herein, the term "alkynyl" means a straight or branched divalent unsaturated hydrocarbon chain containing the indicated number of carbon atoms. For example, "C 2-6 "Alkynyl" means a straight or branched divalent unsaturated hydrocarbon chain containing 2 to 6 carbon atoms. Non-limiting examples of alkynyl include ethynyl, propynyl, butynyl, or pentynyl.

[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. A cycloalkyl may contain multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyls include bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, and the like. Cycloalkyl also includes spirocycles (e.g., spirocyclic bicycles in which the two rings are joined by only one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like.

[0033] As used herein, the term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic non-aromatic ring group (e.g., a 3- to 8-membered monocyclic, an 8- to 12-membered bicyclic, or an 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., carbon atoms and 1 to 3, 1 to 6, or 1 to 9 heteroatoms (N, O, or S) in the case of a monocyclic, bicyclic, or tricyclic ring, respectively), and 0, 1, 2, or 3 atoms in each ring are optionally substituted. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Heterocyclyls can include multiple fused and bridged rings. Non-limiting examples of fused / bridged heterocyclyls include 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo [3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, etc. Heterocyclyl also includes spirocycles (e.g., spirocyclic bicycles in which the two rings are joined by only one atom).Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[2. 2]pentane, 4-oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane, and the like.

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

[0035] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group having the indicated number of ring atoms (e.g., 5-6 ring atoms; e.g., 5, 6, 9, 10, or 14 ring atoms), in which at least one ring is aromatic (but not necessarily a heteroatom-containing ring, e.g., tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl)) and at least one ring in the group contains one or more heteroatoms independently selected from the group consisting of N, O, and S. Heteroaryl groups can be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolylbenzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, and pyrido[2, 3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chroman, 2,3-dihydrobenzo[b][1,4]dioxone, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]xathiin, isoindoline, and the like.

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

[0037] As used herein, the term "alkoxy" refers to an -O-alkyl group, wherein the group is on an oxygen atom. For example, "C 1-6 "Alkoxy" is -O-(C 1-6 "Alkoxy" refers to an -O-haloalkyl group in which 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" refers to an -O-haloalkyl group in which the group is on the oxygen atom.

[0038] As used herein, " [ka] " indicates any single or double bond, as valence allows. As used herein, " [ka] " indicates the point of attachment to the parent molecule.

[0039] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise indicated.

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

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

[0042] As used herein, the term "GLP-1 associated disease" is intended to include, but is not limited to, any disease, disorder, or condition in which modulation of glucagon-like peptide 1 (GLP-1) receptor signaling can alter the pathology and / or symptoms and / or progression of the disease, disorder, or condition.

[0043] As used herein, the term "GLP-1 agonist" or "GLP-1RA" refers to an agonist of the glucagon-like peptide 1 (GLP-1) receptor. GLP-1RAs enhance glucose-dependent insulin secretion; suppress inappropriately elevated glucagon levels in both fasting and postprandial states; and delay gastric emptying. Karla et al., Glucagon-like peptide-1 receptor agonists in the treatment of type 2 diabetes: Past, present, and future, Indian J Endocrinol Metab. 2016 Mar-Apr; 20(2): 254-267. GLP-1RAs have been shown to treat type 2 diabetes. Examples of GLP-1RAs include, but are not limited to, albiglutide (TANZEMM®), dulaglutide (LY2189265, TRULICITY®), efpeglenatide, exenatide (BYETTA®, BYDUREON®, exendin-4), liraglutide (VICTOZA®, NN2211), lixisenatide (LYXMMIA®), semaglutide (OZEMPIC®), 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 RE453 13; and additional GLP-1 receptor agonists described in International Publication Nos. WO2019 / 239319; WO2019 / 239371; WO2020 / 103815; WO2020 / 207474; WO20202 / 34726; WO2020 / 044266; WO2020117987; and WO2020263695.

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

[0045] As used herein, the term "therapeutic compound" is intended to include, but is not limited to, all compounds of formula (I) or pharmaceutically acceptable salts or solvates 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 all compositions (e.g., pharmaceutical compositions) in which 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) is a component of the composition.

[0046] The term "administration" or "administering" refers to a method for providing a dose of a compound or pharmaceutical composition to a vertebrate or invertebrate, including a mammal, bird, fish, or amphibian. The method of administration can vary depending on various factors, such as the components of the pharmaceutical composition, the site of the disease, and the severity of the disease.

[0047] As used herein, the terms "effective amount," "effective dose," "pharmaceutically effective amount," or "therapeutically effective amount" refer to a sufficient quantity of an administered chemical entity (e.g., a compound of 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)) to relieve to some extent one or more of the symptoms of the disease or condition being treated, and may include curing the disease. "Cure" refers to the elimination of active disease symptoms. Such results include reduction and / or alleviation of the signs, symptoms, or pathogenesis of the disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic applications is the quantity of a composition comprising a compound disclosed herein required to provide a clinically significant reduction in disease symptoms. An appropriate "effective" amount in any individual case may be determined using any suitable technique, such as a dose escalation study. In certain embodiments, a "therapeutically effective amount" of a compound provided herein refers to an amount of the compound that is effective as a monotherapy or 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 filler, diluent, carrier, solvent, or encapsulating material. In certain embodiments, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and suitable for use in contact with the tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problem or complication, commensurate with a reasonable benefit / risk ratio. For example, Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical See Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0049] The term "pharmaceutical composition" refers to a mixture 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) with other chemical components (collectively referred to herein as "excipients"), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or fillers. Pharmaceutical compositions facilitate administration of the compound to an organism. Many techniques exist for administering a compound, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0050] The terms "treat," "treating," and "treatment," in the context of treating a disease, disorder, or condition, include alleviating or arresting the disorder, disease, or condition, or one or more symptoms associated with said disorder, disease, or condition; or slowing the progression, spread, or worsening of the disease, disorder, or condition, or one or more symptoms thereof.

[0051] The term "preventing" as used herein refers to the prevention of the onset, recurrence or spread of a disease or condition described herein in whole or in part, or a symptom thereof.

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

[0053] The terms "treatment plan" and "dosing regimen" are used interchangeably to refer to the dosage and timing of administration of each therapeutic agent in the combination of the present invention.

[0054] As used herein, the term "pharmaceutical combination" refers to a pharmaceutical treatment that involves mixing or combining more than one active ingredient, and includes both fixed and loose combinations of active ingredients. As used herein, the term "combination therapy" refers to a dosing regimen of two different therapeutically active agents (i.e., components or combination partners of the combination), which are administered together or separately as desired by a healthcare professional or in accordance with regulatory authorities, as defined herein.

[0055] As used herein, the term "modulation" means regulation or modulation (eg, increase or decrease) and can include, for example, agonism, partial agonism, or antagonism.

[0056] compound In some embodiments, a compound of formula (I): [ka] Formula (I) [In formula: Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 is as follows ( AA )or( BB ) is defined by: (AA) Q 1 and Q 5 are N, CH, and CR QA independently selected from the group consisting of: Q 2 , Q 3 , and Q 4 are N, CH, CR QA , and C.R. QBindependently selected from the group consisting of: 2 , Q 3 , and Q 4 At least one of the following is CR QB and; each [ka] is a single or double bond, provided that Q 1 -Q 5 is aromatic; (BB) Q 1 is a bond; Q 2 , Q 3 , Q 4 , and Q 5 are O, S, N, NH, NR c , C.H., C.R. QA , and C.R. QB independently selected from the group consisting of: 2 , Q 3 , Q 4 , and Q 5 At least one of the following is CR QB and; each [ka] is a single or double bond, provided that Q 1 -Q 5 is aromatic; R QB is P(=O)R a R b And, R a and R b independently, C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents each independently selected from the group consisting of cycloalkyl, and halo 1-6 Alkyl; C 1-3 C optionally substituted with 1 to 3 substituents each independently selected from the group consisting of alkyl and halo 3-6cycloalkyl; and 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 aryl; or R a and R b are taken together with the phosphorus atom to which they are attached to form a ring containing 5 to 8 ring atoms, and 0 to 2 ring atoms (R a and R b (in addition to the phosphorus bonded to the ring) are heteroatoms each independently selected from the group consisting of O, S, and N, and the ring is 1-6 optionally substituted with alkyl; Each R QA are 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) 1 to 6 independently selected R f C, which may be optionally substituted with 1-6 alkyl; (h) hydroxy, halo, and C 1-6 C, which may be optionally substituted with 1 to 6 substituents each independently selected from the group consisting of alkoxy 1-6 Alkoxy; (i) C 1-6 Alkyl and C(=O)(C 1-6 (j) a 3- to 12-membered heterocyclyl optionally substituted by one or more substituents, each independently selected from the group consisting of C(=O)(C 1-6 C optionally substituted with alkyl 6-10 aryl; and (k) 1 to 6 independently selected R g or A pair of R on adjacent carbon atoms QAeach taken together with the atom to which it is attached forms a ring containing 5 to 8 ring atoms, wherein 0 to 2 ring atoms are heteroatoms each independently selected from the group consisting of O, N, and S, and said ring is joined to 1 to 2 independently selected R h optionally substituted with groups; L 2 teeth, [ka] wherein: aa is Q 1 -Q 5 indicates the point of attachment to the ring containing; n1 is an integer of 1 to 3; L 2A is a bond or C 1-10 is alkylene; R La is H, C 1-6 Alkyl, and C(=O)(C 1-6 alkyl); R Lb and R Lc Each of H and C 1-6 independently selected from the group consisting of alkyl; Ring A is C 6-10 Aryl, C 5-7 cycloalkyl, 5- to 7-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is selected from halo, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 optionally substituted with 1 to 5 substituents each independently selected from the group consisting of alkoxy; R 1 , R 2 , and R 3 are each independently H, and halo, —OH, and C 1-6 C, which may be optionally substituted with 1 to 6 substituents each independently selected from the group consisting of alkoxy 1-6 selected from the group consisting of alkyl; L 1-C(=O)-, -CH2-, -CH(C 1-6 -S(=O)2; Ring B is [ka] is selected from the group consisting of: bb is L 1 indicates the point of attachment to; R 4 , R 5 , R 6 , and R 7 H, halo, and C 1-6 independently selected from the group consisting of alkyl; L 3 is a bond or C 1-3 is alkylene; L 4 is a bond or C 1-5 is alkylene; R 8a and R 8b are independently H, and halo and C 3-15 C optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl 1-6 alkyl; or R 8a and R 8b Each of these, together with the carbon atom to which it is attached, is one to three independently selected C 1-6 C optionally substituted with alkyl 3-15 Forms a cycloalkyl ring, 1-6 Alkyl is 1 to 6 independently selected R f may be optionally substituted with; R 9 are C(=O)OH, C(=O)(OC 1-6 alkyl), C(=O)NR 9a R 9b , (IX-1), (IX-2), (IX-3), and (IX-4): [ka] is selected from the group consisting of: R 9a is H or C 1-6 is 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 H; 1 to 6 independently selected halo and C 1-6 C optionally substituted with alkoxy 1-6 Alkyl; and C(=O)(C 1-6 alkyl); Ring C is a 3- to 12-membered heterocyclyl; C 3-15 cycloalkyl; and 5- to 10-membered heteroaryl, each of which is selected from the group consisting of 1 to 3 R Ca may be optionally substituted with; Each R Ca Ha, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, and NR c R d or independently selected from the group consisting of A pair of R on the same or different ring atoms Ca each together with the ring atom to which it is attached forms a carbocyclic ring containing 3 to 8 ring atoms; Each R c and R d is 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 3-6cycloalkyl), 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) is substituted with -OH, halo, and C 1-6 each optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkoxy; R e is H, C 1-6 Alkyl, or C 1-6 is haloalkyl; Each R f are independently halo, -OH, NR c R d , C 1-6 Alkoxy, C 1-6 Haloalkoxy, as well as -OH, C 1-6 selected from the group consisting of alkyl, and 3- to 12-membered heterocyclyl optionally substituted with 1 to 4 substituents each independently selected from the group consisting of 3- to 12-membered heterocyclyl; Each R g independently, C 1-6 Alkyl, C 1-6 Alkoxy, NR c R d , and C 1-6 Alkyl and C(=O)C 1-6 3- to 12-membered heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; and Each R h Halo, Cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, -OH, NH2, NH(C 1-3 alkyl), N(C 1-3 Alkyl)2, C 1-3 Alkoxy, and C 1-3 haloalkoxy] Provided herein is a compound of the formula: or a pharmaceutically acceptable salt or solvate thereof.

[0057] In some embodiments, a compound of formula (I): [ka] Formula (I) [In formula: Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 is as follows ( AA )or( BB ) is defined by: (AA) Q 1 and Q 5 are N, CH, and CR QA independently selected from the group consisting of: Q 2 , Q 3 , and Q 4 are N, CH, CR QA , and C.R. QB independently selected from the group consisting of: 2 , Q 3 , and Q 4 At least one of the following is CR QB and; each [ka] is a single or double bond, provided that Q 1 -Q 5 is aromatic; (BB) Q 1 is a bond; Q 2 , Q 3 , Q 4 , and Q 5 are O, S, N, NH, NR c , C.H., C.R. QA , and C.R. QBindependently selected from the group consisting of: 2 , Q 3 , Q 4 , and Q 5 At least one of the following is CR QB and; each [ka] is a single or double bond, provided that Q 1 -Q 5 is aromatic; R QB is P(=O)R a R b And, R a and R b independently, C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents each independently selected from the group consisting of cycloalkyl, and halo 1-6 alkyl; and 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 aryl; or R a and R b are taken together with the phosphorus atom to which they are attached to form a ring containing 5 to 8 ring atoms, and 0 to 2 ring atoms (R a and R b (in addition to the phosphorus bonded to the ring) are heteroatoms each independently selected from the group consisting of O, S, and N, and the ring is 1-6 optionally substituted with alkyl; Each R QA are 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) 1 to 6 independently selected R fC, which may be optionally substituted with 1-6 alkyl; (h) hydroxy, halo, and C 1-6 C, which may be optionally substituted with 1 to 6 substituents each independently selected from the group consisting of alkoxy 1-6 Alkoxy; (i) C 1-6 Alkyl and C(=O)(C 1-6 (j) a 3- to 12-membered heterocyclyl optionally substituted by one or more substituents, each independently selected from the group consisting of C(=O)(C 1-6 C optionally substituted with alkyl 6-10 aryl; and (k) 1 to 6 independently selected R g or is selected from the group consisting of 5-10 membered heteroaryl optionally substituted with A pair of R on adjacent carbon atoms QA each taken together with the atom to which it is attached forms a ring containing 5 to 8 ring atoms, wherein 0 to 2 ring atoms are heteroatoms each independently selected from the group consisting of O, N, and S, and said ring is joined to 1 to 2 independently selected R h optionally substituted with groups; L 2 teeth, [ka] wherein: aa is Q 1 -Q 5 indicates the point of attachment to the ring containing; n1 is an integer of 1 to 3; L 2A is a bond or C 1-10 is alkylene; R La is H, C 1-6 Alkyl, and C(=O)(C 1-6 alkyl); R Lb and R Lc Each of H and C 1-6 independently selected from the group consisting of alkyl; Ring A is C 6-10 Aryl, C 5-7 cycloalkyl, 5- to 7-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is selected from halo, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 optionally substituted with 1 to 5 substituents each independently selected from the group consisting of alkoxy; R 1 , R 2 , and R 3 are each independently H, and halo, —OH, and C 1-6 C, which may be optionally substituted with 1 to 6 substituents each independently selected from the group consisting of alkoxy 1-6 selected from the group consisting of alkyl; L 1 -C(=O)-, -CH2-, -CH(C 1-6 -S(=O)2; Ring B is [ka] wherein: bb is L 1 indicates the point of attachment to; R 4 , R 5 , R 6 , and R 7 H, halo, and C 1-6 independently selected from the group consisting of alkyl; L 3 is a bond or C 1-3 is alkylene; L 4 is a bond or C 1-5 is alkylene; R 8a and R 8b are independently H, and halo and C 3-15 C optionally substituted with one or more substituents each independently selected from the group consisting of cycloalkyl 1-6alkyl; or R 8a and R 8b Each of these, together with the carbon atom to which it is attached, is one to three independently selected C 1-6 C optionally substituted with alkyl 3-15 Forms a cycloalkyl ring, 1-6 Alkyl is 1 to 6 independently selected R f may be optionally substituted with; R 9 are C(=O)OH, C(=O)(OC 1-6 alkyl), C(=O)NR 9a R 9b , (IX-1), (IX-2), (IX-3), and (IX-4): [ka] selected from the group consisting of: R 9a is H or C 1-6 is 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 H; 1 to 6 independently selected halo and C 1-6 C optionally substituted with alkoxy 1-6 Alkyl; and C(=O)(C 1-6 alkyl); Ring C is selected from the group consisting of 3- to 12-membered heterocyclyl and 5- to 10-membered heteroaryl, each of which is selected from 1-3 R Ca may be optionally substituted with; Each R Ca Ha, Halo, C 1-6 Alkyl, C 1-6Haloalkyl, C 1-6 Alkoxy, and NR c R d or independently selected from the group consisting of A pair of R on the same or different ring atoms Ca each together with the ring atom to which it is attached forms a carbocyclic ring containing 3 to 8 ring atoms; Each R c and R d is H, C 1-6 Alkyl, and C(=O)(C 1-6 alkyl), wherein said C 1-6 Alkyl and C(=O)(C 1-6 alkyl) are each -OH, halo, and C 1-6 optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkoxy; R e is H, C 1-6 Alkyl, or C 1-6 is haloalkyl; Each R f are independently halo, -OH, NR c R d , C 1-6 Alkoxy, C 1-6 Haloalkoxy, as well as -OH, C 1-6 selected from the group consisting of alkyl, and 3- to 12-membered heterocyclyl optionally substituted with 1 to 4 substituents each independently selected from the group consisting of 3- to 12-membered heterocyclyl; Each R g independently, C 1-6 Alkyl, C 1-6 Alkoxy, NR c R d , and C 1-6 Alkyl and C(=O)C 1-6 3- to 12-membered heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; and Each R h Halo, Cyano, C 1-6 Alkyl, C 1-6Haloalkyl, -OH, NH2, NH(C 1-3 alkyl), N(C 1-3 Alkyl)2, C 1-3 Alkoxy, and C 1-3 haloalkoxy] Provided herein is a compound of the formula: or a pharmaceutically acceptable salt or solvate thereof.

[0058] Implementations may include one or more of the features described below and / or in the claims.

[0059] In one embodiment, Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 is 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 is.

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

[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 one embodiment, Q 5 is CH. In certain other embodiments, Q 5 is CR QA is.

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

[0066] In one embodiment, (Q 3 But, CR QB and Q 1 , Q 2 , Q 4 , and Q 5 each of which is independently CH or CR QA ), 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 and each remaining one of Q is CH. 4 is CR QA and Q 1 , Q 2 , and Q 5 is CH.

[0067] In one embodiment, (Q 3 But, CR QB and Q 1 , Q 2 , Q 4 , and Q5 each of the remainder is independently CH or CR QA ), 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 The remaining one of each is CH.

[0068] In one embodiment, Q 3 is CR QB and;Q 1 , Q 2 , Q 4 , and Q 5 One of the is N; and Q 1 , Q 2 , Q 4 , and Q 5 each remaining one of the groups is independently CH or CR QA In any of these embodiments, Q 4 is N. In any of the above embodiments, Q 1 , Q 2 , and Q 5 is CH.

[0069] In one embodiment, Q 3 is CR QB and [ka] The part is [ka] is selected from the group consisting of:

[0070] In one embodiment, Q 3 is CR QB and [ka] The part is [ka] is selected from the group consisting of:

[0071] As a non-limiting example, [ka] The part is [ka] It could be.

[0072] As another non-limiting example, [ka] The part is [ka] It could be.

[0073] In one embodiment, Q 3 is CR QB and [ka] The part is [ka] is selected from the group consisting of:

[0074] As a non-limiting example, [ka] The part is [ka] It could be.

[0075] As another non-limiting example, [ka] The part is [ka] It could be.

[0076] In one embodiment, 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 any of these embodiments, Q 1 , Q 2 , Q 3 , and Q 5 Each of the is CH.

[0077] In one embodiment, (Q 4 But, CR QB and Q 1 , Q 2 , Q 3 , and Q 5 each of which is independently CH or CR QA ), Q 1 , Q 2 , Q 3 , and Q 5 One of them is CR QA and Q 1 , Q 2 , Q 3 , and Q 5 and each remaining one of Q is CH. 5 is CR QA and Q 1 , Q 2 , and Q 3 is CH.

[0078] In one embodiment, (Q 4 But, CR QB and Q 1, Q 2 , Q 3 , and Q 5 each of which is independently CH or CR QA ), Q 1 , Q 2 , Q 3 , and Q 5 Two of them are independently selected CR QA and Q 1 , Q 2 , Q 3 , and Q 5 Each of Q is CH. As a non-limiting example of the above embodiment, Q 2 and Q 3 are independently selected CRs Qa and Q 1 and Q 5 is CH.

[0079] In one embodiment, 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 which is independently CH or CR QA is.

[0080] In one embodiment, Q 4 is CR QB and [ka] The part is [ka] is selected from the group consisting of:

[0081] In one embodiment, Q 4 is CR QB and [ka] The part is [ka] is selected from the group consisting of:

[0082] In one embodiment, [ka] The part is [ka] wherein Q 4 and Q 5 are N, CH, and CR QA In any of these embodiments, Q is independently selected from the group consisting of 4 and Q 5 Each of Q is CH. 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 some embodiments, Q 5 is CH.

[0083] In one embodiment, [ka] The part is [ka] wherein Q 2 , Q 3 , and Q 5 are N, CH, and CR QA In any of these embodiments, Q is independently selected from the group consisting of 2 , Q 3 , and Q5 Each of Q is CH. 5 is CR QA and Q 2 and Q 3 Each of Q is CH. 5 is CH; and Q 2 and Q 3 is independently QA is selected from.

[0084] In some embodiments, R QB is P(=O)R a R b and R a and R b is C 1-6 Alkyl and C 3-6 cycloalkyl.

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

[0086] In some embodiments, R a and R b are identical.

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

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

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

[0090] In some embodiments, R QB is P(=O)R a R b and;R a and R b are each independently C 1-6 alkyl; and R a and R b In any of these embodiments, R a is C 1-3 alkyl (e.g., methyl or ethyl); and R b is C 4-6 alkyl (e.g., butyl, e.g., 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 some embodiments, R a and R b are independently selected C 1-3 alkyl, provided that R a and R b are considered to be different.

[0091] In some embodiments, R QB is P(=O)R a R b and R a and R b are each independently C 3-6 In any of these embodiments, R a and R b are identical. For example, Ra and R b can both be cyclopropyl (i.e., R QB teeth, [ka] (It may be possible).

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

[0093] In any of these embodiments, R QB is P(=O)R a R b wherein R a and R b are taken together with the phosphorus atom to which they are attached to form a ring containing 5 to 6 ring atoms, and 0 to 1 ring atom (R a and R b (in addition to the phosphorus bonded to 1-6 It may be optionally substituted with alkyl.

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

[0095] In certain embodiments, each R QA Halo, Cyano, C 1-6 Alkyl, C 1-6 Alkoxy, OH, and NR c R d is selected from the group consisting of:

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

[0097] In some embodiments, R QA In any of these embodiments, one of R is halo. QA One of them is -F.

[0098] In some embodiments, R QA One of the groups is -OH.

[0099] In some embodiments, R QA One of the is NR c R d is.

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

[0101] In some embodiments, R QA One of them is NH2.

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

[0103] In some embodiments, R QA One of them is 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 some embodiments, R QA One of them 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)Me).

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

[0106] In some embodiments, R QA One of the groups is hydroxy, halo, and C 1-6 C, which may be optionally substituted with 1 to 6 substituents each independently selected from the group consisting of alkoxy 1-6 In any of these embodiments, R QA one of which is optionally substituted with 1 to 6 (e.g., 1 to 3) independently selected halo; 1-6 As a non-limiting example of this embodiment, R QA can be -OMe, -OCF, or -OCHF. For example, R QAcan be -OMe. For example, R QA As another non-limiting example, R QA can be -OCHF2.

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

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

[0109] In any of these embodiments, R QA One of the is NR c R d C replaced with 1-3 alkyl. For example, R QA can be CHNHMe.

[0110] In some embodiments, each remaining R QA is, if present, an independently selected halo, e.g., —F.

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

[0112] In any of these embodiments, a pair of R on adjacent carbon atoms QA together with the atoms to which they are bonded. [ka] Form.

[0113] In some embodiments, a pair of R on adjacent carbon atoms QA together with the atoms to which they are bonded, [ka] Form.

[0114] In some embodiments, each remaining R QA is, if present, independently halo, cyano, or C 1-3 It is alkyl.

[0115] In one embodiment, L 2 teeth, [ka] In any of these embodiments, L 2A is a bond. 2A is CH2.

[0116] In one embodiment, L 2 teeth, [ka] is.

[0117] In one embodiment, L 2 teeth, [ka] In any of these embodiments, n1 is 1. In certain other embodiments, n1 is 2 or 3. In certain embodiments, L2A is a bond. 2A is C 1-2 It is alkylene.

[0118] In one embodiment, L 2 teeth, [ka] In one embodiment, L 2A is a bond. 2A is C 1-2 It is alkylene.

[0119] In one embodiment, L 2 teeth, [ka] is.

[0120] In some embodiments, the ring is C 6-10 aryl or 5-10 membered heteroaryl, each of which is selected from halo, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 It may be optionally substituted with 1 to 4 substituents each independently selected from the group consisting of alkoxy.

[0121] In certain embodiments, ring A is phenyl or pyridyl, each of which is C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 It may be optionally substituted with 2 to 4 substituents each independently selected from the group consisting of alkoxy.

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

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

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

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

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

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

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

[0129] In one embodiment, L 1 is C(=O).

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

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

[0132] In certain embodiments, ring B is [ka] is.

[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 6are each H or -F. As a non-limiting example of the above embodiment, R 4 , R 5 , and R 6 are each H. As another non-limiting example, R 4 and R 5 is H; and R 6 is -F. In some embodiments, R 7 is H. In certain other embodiments, R 7 is -F.

[0134] In certain embodiments, ring B is [ka] and R 4 , R 5 , R 6 , and R 7 Each of is H.

[0135] In certain other embodiments, ring B is [ka] and;R 4 , R 5 , and R 6 each is H; and R 7 is -F.

[0136] In certain embodiments, ring B is [ka] (For example, ring B is [ka] (It can be) is selected from the group consisting of:

[0137] In any of these embodiments, R 4 , R 5 , R 6 , and R 7Each of, 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 of, when present, may be independently selected from the group consisting of -H and -F.

[0138] In one embodiment, L 3 and L 4 In any of these embodiments, at least one of L 3 and L 4 Both are bonds.

[0139] In one embodiment, L 3 is a bond; and L 4 is C 1-2 It is alkylene.

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

[0141] In one embodiment, L 3 and L 4 are each independently C 1-2 It is alkylene.

[0142] In some embodiments, R 8a and R 8b Each of these, together with the carbon atom to which it is attached, is one to two independently selected C 1-6 C optionally substituted with alkyl 3-8 Forms a cycloalkyl ring, 1-6 Alkyl is one to three independently selected R f may be optionally substituted with

[0143] In some embodiments, R 8a and R 8bEach of these, together with the carbon atom to which it is attached, is one to two independently selected C 1-6 C optionally substituted with alkyl 3-5 Forms a cycloalkyl ring, 1-6 Alkyl is one to three independently selected R f may be optionally substituted with

[0144] In some embodiments, R 8a and R 8b Each of these, together with the carbon atom to which it is attached, is one to two independently selected C 1-6 C optionally substituted with alkyl 3-4 Forms a cycloalkyl ring.

[0145] As a non-limiting example of the above embodiment, R 8a and R 8b together with the carbon atoms to which they are attached, [ka] For example, R 8a and R 8b together with the carbon atoms to which they are attached, [ka] Form.

[0146] In some embodiments, R 8a and R 8b are each independently H and C 1-6 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 As yet another example, R 8a can be H; and R 8b is C 1-6Alkyl (e.g., C 1-3 alkyl).

[0147] In one embodiment, the L 3 -C(R 8a R 8b )-L 4 -R 9 The part is [ka] In any of these embodiments, R 9d is H or C 1-6 alkyl. For example, R 9d can be H.

[0148] In one embodiment, the L 3 -C(R 8a R 8b )-L 4 -R 9 The part is [ka] In any of these embodiments, R 9d is H or C 1-6 alkyl. For example, R 9d can be H.

[0149] In some embodiments, R 9 teeth, [ka] (IX-2) In any of these embodiments, R 9d is H or C 1-6 alkyl. For example, R 9d can be H.

[0150] In some embodiments, R 9 teeth, [ka] (IX-1) In some embodiments, R 9 teeth, [ka] (IX-3) In some embodiments, R 9 teeth, [ka] (IX-4) is.

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

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

[0153] In some 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 In some embodiments, R 9b is C(=O)(C 1-6 alkyl), S(O) 0-2 (C 1-6 alkyl), and cyano.

[0154] In one embodiment, [ka] The part is [ka] wherein ring D is C 3-6 is cycloalkyl; and R8c is H and 1 to 3 independently selected R f C, which may be optionally substituted with 1-6 alkyl. Non-limiting examples include: [ka] Includes:

[0155] In one embodiment (see above) [ka] The part is, [ka] ), R 9 teeth, [ka] (IX-2) In any of these embodiments, R 9d is H or C 1-6 alkyl. For example, R 9d can be H.

[0156] In certain embodiments, ring C is selected from 1 to 3 independently selected R Ca and optionally substituted 3- to 12-membered heterocyclyl.

[0157] In certain embodiments, ring C is selected from 1 to 3 independently selected R Ca and optionally substituted 4- to 8-membered heterocyclyl.

[0158] In certain embodiments, ring C is selected from 1 to 3 independently selected R Ca and optionally substituted 5- or 6-membered heterocyclyl.

[0159] In some embodiments, ring C is selected from 1 to 3 independent R CaFor example, ring C is tetrahydropyranyl optionally substituted by [ka] As another non-limiting example, ring C may be selected from the group consisting of: [ka] It could be.

[0160] In certain embodiments, ring C is selected from 1 to 3 independently selected R Ca For example, Ring C is morpholinyl optionally substituted by [ka] It could be.

[0161] In certain embodiments, ring C is selected from 1 to 3 independently selected R Ca and optionally substituted 5- or 6-membered heteroaryl.

[0162] In certain embodiments, ring C is selected from 1 to 3 R Ca C, which may be optionally substituted with 3-10 It is cycloalkyl.

[0163] In certain embodiments, ring C is selected from 1 to 3 independently selected R Ca C, which may be optionally substituted with 3-8 For example, ring C is: [ka] It could be.

[0164] In certain embodiments, each R Ca Ha, Halo, C 1-6 Alkyl, C 1-6 Alkoxy, and NR c R d are independently selected from the group consisting of:

[0165] In certain embodiments, each R Ca Halo and C 1-6 alkyl.

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

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

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

[0169] In certain embodiments, the compound of Formula (I) has the formula (IA): [ka] Formula (IA) [In the formula, Q 4 and Q 5 are N, CH, and CR QA independently selected from the group consisting of or a pharmaceutically acceptable salt or solvate thereof.

[0170] In certain embodiments of Formula (IA), Q 4 and Q 5 Each of the is CH.

[0171] In certain embodiments of Formula (IA), Q 4 is CR QA and Q 5is 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) has the formula (IB): [ka] Formula (IB) [In the formula, Q 2 , Q 3 , and Q 5 are N, CH, and CR QA independently selected from the group consisting of or a pharmaceutically acceptable salt or solvate thereof.

[0175] In certain embodiments of Formula (IB), Q 2 , Q 3 , and Q 5 Each of the is CH.

[0176] In certain embodiments of Formula (IB), Q 5 is CR QA and Q 2 and Q 3 Each of the is CH.

[0177] In certain embodiments of Formula (IB), Q 5is CH; and Q 2 and Q 3 are independently selected CRs QA is.

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

[0179] In any of these embodiments, L 3 and L 4 At least one of L is a bond. 3 and L 4 are both bonds.

[0180] In certain embodiments of formula (IA) or (IB), R 8a and R 8b Each of these, together with the carbon atom to which it is attached, is one to two independently selected C 1-6 C optionally substituted with alkyl 3-5 Forms a cycloalkyl ring, 1-6 Alkyl is one to three independently selected R f may be optionally substituted with

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

[0182] As a non-limiting example of the above embodiment, R 8a and R 8b together with the carbon atoms to which they are attached, [ka] Form.

[0183] In certain embodiments of formula (IA) or (IB), ring C is selected from 1 to 3 independently selected R Ca In some embodiments, ring C is a 3- to 12-membered heterocyclyl optionally substituted with 1 to 3 independently selected R Ca In some embodiments, ring C is a 5- to 6-membered heterocyclyl optionally substituted with 1 to 3 independent R Ca As a non-limiting example of the above embodiment, Ring C is tetrahydropyranyl optionally substituted by [ka] In some embodiments, ring C can be selected from the group consisting of 1 to 3 independently selected R Ca For example, Ring C is morpholinyl optionally substituted by [ka] It could be.

[0184] In certain embodiments of formula (IA) or (IB), ring C contains 1 to 3 R Ca C, which may be optionally substituted with 3-8 For example, ring C is: [ka] It could be.

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

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

[0187] In certain embodiments of formula (IA) or (IB), pairs of R Ca are taken together with the ring atoms to which they are each attached to form a carbocyclic ring containing 3 to 6 ring atoms.

[0188] In certain embodiments of formula (IA) or (IB), a pair of R Ca are taken together with the ring atoms to which they are each attached to form a carbocyclic ring containing 3 to 5 ring atoms.

[0189] In certain embodiments, the compound of Formula (I) has the formula (IC): [ka] Formula (IC) [In the formula, Ring D is C 3-6 is cycloalkyl; R 8c is H and 1 to 3 independently selected R f C, which may be optionally substituted with 1-6 alkyl; and Each R Cb is H and R Ca independently selected from the group consisting of or a pharmaceutically acceptable salt or solvate thereof. .

[0190] In some embodiments of Formula (IC), ring D is cyclopropyl.

[0191] In some 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), R8c 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 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 an embodiment of formula (IC), [ka] The part is [ka] wherein Q 4 and Q 5 are N, CH, and CR QA are independently selected from the group consisting of:

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

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

[0200] In one embodiment, 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), [ka] The part is [ka] wherein Q 2 , Q 3 , and Q 5 are N, CH, and CR QA are independently selected from the group consisting of:

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

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

[0205] In certain other embodiments, Q 5 is CH; and Q 2 and Q 3 Each of the QA is.

[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 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 and R can each be methyl. a and R b Each of R can be ethyl. a and R b may 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 may both be cyclopropyl.

[0211] In certain embodiments of formula (IA), (IB), or (IC), each R QA is halo;cyano;OH;NR c R d 1 to 6 independently selected R f C, which may be optionally substituted with1-6 Alkyl; Hydroxy, Halo, and C 1-6 C, which may be optionally substituted with 1 to 6 substituents each independently selected from the group consisting of alkoxy 1-6 Alkoxy; and C 1-6 Alkyl and C(=O)(C 1-6 and 3- to 12-membered heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl.

[0212] In any of these embodiments, each R QA is selected from the group consisting of -F, OH, NHNHMe, 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, NHNHMe, NHEt, NHC(=O)(cyclopropyl), NHS(O)Me, methyl, OMe, OCF, and morpholinyl.

[0214] In certain embodiments of formula (IA), (IB), or (IC), each R QA are halo, cyano, OH, and NR c R d is selected 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 some embodiments of formula (IA), (IB), or (IC), a pair of R QAeach taken together with the atom to which it is attached forms a ring containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms each independently selected from the group consisting of O, N, and S, and said ring is joined to 1-2 independently selected R h For example, a pair of R groups on adjacent carbon atoms may be optionally substituted. QA together with the atoms to which they are bonded, [ka] As another non-limiting example, a pair of R on adjacent carbon atoms can be formed. QA together with the atoms to which they are bonded, [ka] (For example, R h is methyl) can be formed.

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

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

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

[0220] As a non-limiting example of the above embodiment, ring A is [ka] wherein R AA , R AB , and R AC are independently halo or C 1-6 alkyl. For example, R AA and R AC Each of the 1-6 Alkyl, e.g., C 1-3 alkyl (e.g., methyl); and / or R AB can be halo (eg, —F).

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

[0224] In certain embodiments of formula (IA), (IB), or (IC), R 1 and R 2 is 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 are each H or -F.

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

[0228] In certain embodiments of formula (IA), (IB), or (IC), R 4 and R 5 is 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 teeth, [ka] (IX-2) In any of these embodiments, R 9d is H.

[0232] In certain embodiments, the compound of Formula (I) has the formula (ID): [ka] Expression (ID) [In formula: R AA , R AB , and R AC are independently halo or C 1-6 is alkyl; R QCis H or halo; and Each R Cb is H and R Ca independently selected from the group consisting of or a pharmaceutically acceptable salt or solvate thereof.

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

[0234] In certain embodiments of Formula (ID), R 3 is C 1-3 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 is H.

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

[0237] In certain embodiments of Formula (ID), R AA and R AC independently, C 1-6 In any of these embodiments, R AA and R AC is 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 1-3In any of these embodiments, each R Cb is methyl.

[0240] In certain embodiments of Formula (ID), R a and R b independently, C 1-3 In any of these embodiments, R a and R b is methyl. In certain embodiments, R a and R b is ethyl. In certain embodiments, R a and R b is 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 independently, C 3-6 Cycloalkyl. For example, R a and R b may both be cyclopropyl.

[0243] In certain embodiments of Formula (ID), P(=O)R a R b teeth, [ka] wherein L Q is a bond, CH2, O, S, NH, or N(C 1-6 In any of these embodiments, P(=O)R a R b teeth, [ka] is.

[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 some embodiments, R QA is NH(C 1-3 alkyl) (e.g., NHMe or NHEt). In some embodiments, R QA is NH. 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 C 1-6 Alkyl and C(=O)(C 1-6 and 5- to 6-membered heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl.

[0248] In certain embodiments of Formula (ID), R QA is optionally substituted with 1 to 6 independently selected halo; 1-6 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 In any of these embodiments, R QAis methyl.

[0250] In certain embodiments of Formula (ID), R QA is optionally substituted with 1 to 3 independently selected halo; 1-3 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 some embodiments, R QC is P(=O)R a R b In one embodiment, R QC is P(=O)R a R b It is meta to R QA In some embodiments, R QC is R QA In some embodiments, R QC is P(=O)R a R b It is meta to R QA It is -F, which is ortho to

[0253] In certain embodiments of Formula (ID), the compound has the formula (S,S,S)-(ID) [ka] Formula (S,S,S)-(ID) [In the formula, R 3 is C 1-3 alkyl] or a pharmaceutically acceptable salt thereof.

[0254] In certain embodiments, the compound of Formula (I) has the formula (IE): [ka] Formula (IE) [In formula: R AA , R AB , and R AC are each independently halo or C 1-3 is alkyl; R 3 is H or C 1-3 is alkyl; R QC is H or halo; R QD are (a) H; (b) -NH; (c) -NH(C 1-3 (d) halo; (e) C optionally substituted with 1 to 3 independently selected halo. 1-3 alkoxy; and (f) C optionally substituted with 1 to 3 independently selected halo. 1-3 selected from the group consisting of alkyl; R a and R b are each independently C 1-4 Alkyl and C 3-6 cycloalkyl; or R a and R b are taken together with the phosphorus atom to which they are attached to form a ring containing 5 to 8 ring atoms, and 0 to 1 ring atom (R a and R b (in addition to the phosphorus bonded to) are heteroatoms independently selected from the group consisting of O, S, and N; R 8c is H or C 1-3 is alkyl; X B is CH or N; and Each R Cb H and C 1-3 alkyl] 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 may each be methyl.

[0256] In certain embodiments of Formula (IE), R AB is a 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 a halo. For example, R AA and R AC may 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 -NH2 and -NH(C 1-3 For example, R QD can be -NH2. As another non-limiting example, R QD 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 optionally substituted with 1 to 3 independently selected halo; 1-3 Alkoxy. For example, R QD As another non-limiting example, R QD can be OCF3. As a further non-limiting example, R QD may be OCHF2.

[0263] In certain embodiments of Formula (IE), R QD is optionally substituted with 1 to 3 independently selected halo; 1-3 alkyl. For example, R QD As another non-limiting example, R QD 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 and R can each be methyl. a and R b Each of R can be ethyl. a and R b and each can 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 Cycloalkyl. For example, R a and R b may each be cyclopropyl.

[0266] In certain embodiments of Formula (IE), R a and R b are taken together with the phosphorus atom to which they are attached to form a ring containing 5 to 8 ring atoms, and 0 to 1 ring atom (R a and R b (in addition to the phosphorus bonded to R) are heteroatoms 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, [ka] can be formed.

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

[0268] In certain embodiments of Formula (IE), R QC is a halo. For example, R QC can be -F. In some embodiments, R QC is R QD In some embodiments, R QC is R QD In some embodiments, R QC is R QD It is meta to that.

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

[0273] In certain embodiments of formula (IE), the compound has the formula (S,S,S)-(IE) [ka] Formula (S,S,S)-(IE) [In the formula, R 3 is C 1-3 alkyl] or a pharmaceutically acceptable salt thereof.

[0274] In certain embodiments of Formula (IE): R AA and R AC is 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 is 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 of the formula (S,S,S)-(IE).

[0276] In certain embodiments, 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] TIFF2025160228000102.tif226128 TIFF2025160228000103.tif237128 TIFF2025160228000104.tif232130 TIFF2025160228000105.tif239129 TIFF2025160228000106.tif238129 TIFF2025160228000107.tif236130 TIFF2025160228000108.tif239130 TIFF2025160228000109.tif246132 TIFF2025160228000110.tif236132 TIFF2025160228000111.tif241133 TIFF2025160228000112.tif245132 TIFF2025160228000113.tif124134

[0277] In certain embodiments, the compound is selected from the group consisting of the compounds of Table C2 or a pharmaceutically acceptable salt or solvate thereof. Table C2 [Table 2] TIFF2025160228000115.tif237118 TIFF2025160228000116.tif249118 TIFF2025160228000117.tif240119 TIFF2025160228000118.tif248118 TIFF2025160228000119.tif243118 TIFF2025160228000120.tif242119 TIFF2025160228000121.tif241118 TIFF2025160228000122.tif244117 TIFF2025160228000123.tif250116 TIFF2025160228000124.tif241114 TIFF2025160228000125.tif239113 TIFF2025160228000126.tif237111

[0278] The compounds of formula (I) include pharmaceutically acceptable salts thereof. In addition, the compounds of formula (I) also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts, and may be useful as intermediate compounds for preparing and / or purifying the compounds of formula (I) and / or separating the enantiomers of the compounds of formula (I). Non-limiting examples of pharmaceutically acceptable salts of the compounds of formula (I) include trifluoroacetic acid salts.

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

[0280] Pharmaceutical Compositions and Administration When used as a pharmaceutical, the compound of formula (I) (including its pharmaceutically acceptable salts or solvates) can be administered in the form of a pharmaceutical composition. 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 the area to be treated. Administration can be topical (including transdermal, epidermal, ocular, and mucosal delivery, including intranasal, vaginal, and rectal), pulmonary (e.g., powder or aerosol inhalation or insufflation (including nebulizer); intratracheal or intranasal), oral, or parenteral. Oral administration can include preparations formulated for once-daily or twice-daily (BID) administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracerebral, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose or, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, fillers and the like may be necessary or desirable.

[0281] Also provided herein is a pharmaceutical composition comprising a compound of formula (I) or its pharmaceutically acceptable salt or solvate as an active ingredient in combination with one or more pharmaceutically acceptable excipients (carriers). For example, a pharmaceutical composition prepared using a compound of formula (I) or its pharmaceutically acceptable salt or solvate. In some embodiments, the composition is suitable for topical administration. When preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed in such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When the excipient is used 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, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), 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 some embodiments, the composition is formulated for oral administration.In some embodiments, the composition is a solid oral formulation.In some embodiments, the composition is formulated as a tablet or capsule.

[0282] Further provided herein is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof together with a pharmaceutically acceptable excipient. Pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as an active ingredient can be prepared by intimately mixing a 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 take a wide variety of forms depending on the desired route of administration (e.g., oral, parenteral). In some embodiments, the composition is a solid oral composition.

[0283] Suitable pharmaceutically acceptable carriers are well known in the art, and descriptions of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients (published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain).

[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 some embodiments, the compound or pharmaceutical composition can be administered in combination with one or more conventional pharmaceutical excipients.Pharmaceutically acceptable excipients include but are not limited to ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery system (SEDDS), such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical preparations, such as Tween, poloxamer or other similar polymer delivery matrices, serum proteins, such as human serum albumin, buffer substances, such as phosphate, Tris, glycine, sorbic acid, potassium sorbate, saturated vegetable fatty acid partial glyceride mixture, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene polyoxypropylene block polymer, and wool fat. Cyclodextrins, e.g., α-, β-, and γ-cyclodextrin, or chemically modified derivatives, e.g., hydroxyalkylcyclodextrins (including 2- and 3-hydroxypropyl-β-cyclodextrin), or other solubilized derivatives, can also be used to enhance delivery of the compounds described herein. Formulations of compositions containing the chemical entities described herein in the range of 0.005% to 100%, with the balance being composed of non-toxic excipients, can be prepared. Contemplated compositions may contain the compounds provided herein in the range of 0.001% to 100%, in one embodiment, 0.1 to 95%, in another embodiment, 75 to 85%, and in a further embodiment, 20 to 80%. Actual methods for preparing such formulations are known or apparent to those skilled in the art, and are described, for example, in Remington: The Science and Practice of Pharmacy, 22 nd Edition (Pharmaceutical Press, London, UK. 2012).

[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, cutaneous, intracervical, intraantral, intratracheal, intraintestinal, epidural, intrainterstitial, intraperitoneal, intra-arterial, intrabronchial, intravesical, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intratracheal, intrathecal, intrasynovial, intratesticular, intrathecal, intraductal, intratumoral, intrauterine, intravascular, intravenous, intranasal (e.g., intranasal), nasogastric, oral, parenteral, transdermal, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and vaginal.

[0287] In some embodiments, the preferred route of administration is parenteral (e.g., intratumoral). In some embodiments, the 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 parenteral administration, and can be formulated for injection, for example, by intraarterial, intrasternal, intracerebral, intravenous, intramuscular, subcutaneous, or intraperitoneal route. For example, such compositions can be prepared as either an injectable liquid solution or suspension; solid forms suitable for preparing a solution or suspension by adding a liquid before injection can also be prepared; and the formulation can be emulsified. The preparation of such formulations is known to those skilled in the art in light of the present disclosure. In some embodiments, a device is used for parenteral administration. For example, such devices can include needle injectors, microneedle injectors, needleless injectors, and infusion techniques.

[0288] In some 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 extemporaneous preparation of sterile injectable solutions or dispersions. In some embodiments, the form must be sterile and fluid to the extent that it can be easily injected. In some embodiments, the form must 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 some embodiments, the carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. In some embodiments, proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in dispersion, and by the use of surfactants. In some embodiments, the action of microorganisms can be prevented by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In some embodiments, isotonic agents, for example, sugars or sodium chloride, are included. In some embodiments, prolonged absorption of the injectable composition can be achieved by using agents that delay absorption, for example, aluminum monostearate and gelatin in the composition.

[0290] In some embodiments, sterile injectable solutions are 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 an appropriate solvent with various other ingredients listed above, followed by sterile filtration, as needed. In some embodiments, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and the required other ingredients listed above. In some embodiments, sterile powders are used to prepare sterile injectable solutions. In some embodiments, the preparation method is vacuum drying and freeze-drying techniques to obtain a powder of the active ingredient and any additional desired ingredient from a previously sterile-filtered solution.

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

[0292] In some embodiments, suppositories 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 pharmaceutical composition described herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository wax, that is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum to release the active compound. In some embodiments, the composition for rectal administration is in the form of an enema.

[0293] In some embodiments, the compound of formula (I) described herein or its pharmaceutically acceptable salt or solvate (e.g., any one compound of formula (IA), (IB), (IC), (ID), and (IE), or its pharmaceutically acceptable salt or solvate) or its pharmaceutical composition is formulated for local delivery to the digestive tract or GI tract by oral administration (e.g., solid or liquid formulation).In some embodiments, the solid formulation for oral administration includes capsules, tablets, pills, powders, and granules.

[0294] In certain embodiments, the 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) 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, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicic acids, and sodium carbonate; e) solution retarders. The composition may be mixed with a soluble or non-soluble filler, such as ...

[0295] In some embodiments, the pharmaceutical composition is in the form of a unit dosage form such as a pill or tablet, and thus the composition may contain a 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, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, etc. In some embodiments, a separate solid formulation, powder, marume, solution, or suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglyceride) is encapsulated in a capsule (gelatin or cellulose-based capsule). In some embodiments, unit formulations in which one or more compounds provided herein and pharmaceutical compositions or additional active agents are physically separated are also included, such as granules, capsules, and granules (or tablets in capsules); bilayer tablets; two-compartment gel capsules, etc. In some embodiments, enteric-coated or sustained-release oral formulations are also included.

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

[0297] In some embodiments, the excipients are sterile and generally free of undesirable substances. For example, these compositions can be sterilized by conventional, well-known sterilization techniques. In some embodiments, for various oral formulation excipients such as tablets and capsules, sterilization is not required. For example, United States Pharmacopoeia / National Standard (USP / NF) standards may be sufficient.

[0298] In some embodiments, the 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 ophthalmic administration. In some embodiments, the ophthalmic composition may include, but is not limited to, one or more of the following: viscogen (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizer (e.g., Pluronic (triblock copolymer), cyclodextrin); preservative (e.g., benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloroisothiazolinone complex; Allergan, Inc.)).

[0299] In some embodiments, the 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 to the skin or mucosa (e.g., cutaneously or transdermally). In some embodiments, topical compositions may include ointments and creams. In some embodiments, ointments are typically semi-solid preparations based on petrolatum or other petroleum derivatives. In some embodiments, creams containing the selected active agent are typically viscous liquids or semi-solid emulsions, often either oil-in-water or water-in-oil. For example, cream bases are typically water-washable and include an oil phase, an emulsifier, and an aqueous phase. For example, the oil phase, also referred to as the "internal" phase, is generally composed of petrolatum and a fatty alcohol, such as cetyl or stearyl alcohol, and the aqueous phase usually, although not necessarily, exceeds the volume of the oil phase and generally contains a humectant. In some embodiments, the emulsifier in a cream formulation is generally a nonionic, anionic, cationic, or amphoteric surfactant. In some embodiments, the ointment base, like other carriers or vehicles, should be inert, stable, non-irritating, and non-sensitizing.

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

[0301] In some embodiments, the dose of the 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) is determined based on many factors, including, but not limited to, the type, age, weight, sex, medical condition, severity of the patient's medical condition, route of administration, and the activity of the compound or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the appropriate dose for a particular situation can be determined by a person skilled in the pharmaceutical arts. In some embodiments, the total daily dose can be divided and administered in portions throughout the day, or administered by a method that provides sustained delivery.

[0302] In certain embodiments, the 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) is administered at a dose of about 0.01 to about 1000 mg. For example, about 0.1 to about 30 mg, about 10 to about 80 mg, about 0.5 to about 15 mg, about 50 mg to about 200 mg, about 100 mg to about 300 mg, about 200 to about 400 mg, about 300 mg to about 500 mg, about 400 mg to about 600 mg, about 500 mg to about 800 mg, about 600 mg to about 900 mg, or about 700 mg to about 1000 mg. In certain embodiments, the dose is a therapeutically effective amount.

[0303] In certain embodiments, the 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) is administered in a dose range of about 0.0002 mg / Kg to about 100 mg / Kg (e.g., about 0.0002 mg / Kg to about 50 mg / Kg; about 0.000 2mg / Kg~about 25mg / Kg;about 0.0002mg / Kg~about 10mg / Kg;about 0.0002mg / Kg~about 5mg / Kg;about 0.0002mg / Kg~about 1mg / Kg;about 0.0002mg / Kg ~ approx. 0.5mg / Kg; approx. 0.0002mg / Kg ~ approx. 0.1mg / Kg; approx. 0.001mg / Kg ~ approx. 50mg / Kg; approx. 0.001mg / Kg ~ approx. 25mg / Kg; approx. 0.001mg / Kg ~Approx. 10mg / Kg; Approx. 0.001mg / Kg ~ Approx. 5mg / Kg; Approx. 0.001mg / Kg ~ Approx. 1mg / Kg; Approx. 0.001mg / Kg ~ Approx. 0.5mg / Kg; Approx. 0.001mg / Kg ~ Approx. 0.1m g / Kg; about 0.01 mg / Kg to about 50 mg / Kg; about 0.01 mg / Kg to about 25 mg / Kg; about 0.01 mg / Kg to about 10 mg / Kg; about 0.01 mg / Kg to about 5 mg / Kg; about 0.01 In some embodiments, the 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 dose of about 100 mg / Kg.

[0304] In certain embodiments, the dose of the 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) can be administered on a daily basis (e.g., as a single dose or two or more divided doses) or off-daily (e.g., every other day, every third day, every third day, once a week, twice a week, once every two weeks, or once a month).

[0305] In certain embodiments, the administration period 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) is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more. In some embodiments, the period of time for which administration is discontinued is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more. 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) is administered to a patient for a period of time, followed by a separation period during which administration of the 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) is discontinued.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) is administered for a first period of time, followed by a second period after the first period of time during which administration is discontinued, then a third period of time during which administration 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) is initiated, followed by a fourth period of time after the third period of time during which administration is discontinued. For example, a period of administration 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), followed by a period during which administration is stopped, can be repeated for a predetermined or indefinite period. In some embodiments, the administration period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In some embodiments, the period of time for which administration is discontinued is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

[0306] In some 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) is orally administered to a patient one or more times daily (e.g., a once-daily, twice-daily, three times-daily, four times-daily, or once-daily dose). In some 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) is parenterally administered to a patient one or more times daily (e.g., one to four times-daily, two times-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., a compound of any one of Formulas (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof) is parenterally administered to a patient once a week.

[0308] Treatment method In some embodiments, the present disclosure features a method for treating a patient (e.g., a human) suffering from a disease, disorder, or condition in which modulation of GLP-1R (e.g., inhibited or impaired and / or increased or undesired GLP-1R) is beneficial for treating the underlying pathology and / or symptoms and / or progression of the disease, disorder, or condition. In some embodiments, the methods described herein may include, or may further include, one or more conditions related to, coexisting with, or secondary to any one or more of the conditions described herein.

[0309] Provided herein is a method for treating a GLP-1-related disease, disorder, or condition, comprising administering to a patient in need thereof an effective amount of a compound of 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.

[0310] In certain embodiments, the disease, disorder, or condition includes, but is not limited to, type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of adults (LADA), obesity (including hypothalamic obesity and monogenic obesity), weight gain due to the use of other medications, idiopathic intracranial hypertension, Wolfram syndrome, Gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat accumulation, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, vascular restenosis, blood Thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, alcohol intake disorders, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, joint inflammation, osteoporosis, treatment of addiction, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, psychogenic polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, and polycystic ovarian syndrome (PCOS).

[0311] In certain embodiments, the disease, disorder, or condition includes, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, idiopathic intracranial hypertension, Wolfram syndrome, weight gain due to the use of other medications, gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, gestational diabetes, kidney disease (e.g., acute kidney injury, renal tubular dysfunction, pro-inflammatory changes to the proximal tubules), 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, hyperlipidemia, and the like. glycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, alcohol use disorders, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, psychogenic polydipsia, nonalcoholic steatohepatitis (NASH), nonalcoholic 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 condition includes, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, idiopathic intracranial hypertension, Wolfram syndrome, weight gain due to the use of other medications, gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat accumulation, myocardial infarction, peripheral arterial disease, stroke, transient ischemic attack, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, chronic renal failure, syndrome X, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, skin and connective tissue disorders, foot ulcers, or any combination thereof.

[0313] In some embodiments, the compounds and pharmaceutical compositions and patient treatment methods described herein can reduce blood glucose levels (e.g., reduce blood glucose levels), reduce blood hemoglobin A1c (HbA1c) levels, promote insulin synthesis, activate insulin secretion, increase β-cell population, regulate gastric acid secretion, regulate gastric emptying, reduce body mass index (BMI), and / or reduce glucagon production (e.g., level).In some embodiments, the compounds and pharmaceutical compositions and patient treatment methods described herein can reduce blood glucose levels, reduce blood hemoglobin A1c (HbA1c) levels, promote insulin synthesis, activate insulin secretion, increase β-cell population, regulate gastric acid secretion, regulate gastric emptying, reduce body mass index (BMI), reduce glucagon production (e.g., level), or any combination thereof.In some embodiments, the compounds and pharmaceutical compositions and patient treatment methods described herein can 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 thereof, 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, provided herein are methods for reducing the risk of major adverse cardiovascular events (MACE) in a patient in need thereof (e.g., by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%), comprising administering to the patient an effective amount of a compound 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 heart disease. In certain embodiments, the patient is an adult diagnosed with type 2 diabetes (T2D) and heart disease. In certain embodiments, the patient is an adult diagnosed with type 2 diabetes (T2D). In certain embodiments, the patient is an adult diagnosed with heart disease. In certain embodiments, the patient has type 2 diabetes (T2D) and cardiovascular disease.

[0315] Indications Obesity In some embodiments, the disease, illness, or disorder is obesity and illness, illness, or disorder associated with or related to obesity.Non-limiting examples of obesity and obesity-related conditions include symptomatic obesity, simple obesity, childhood obesity, morbid obesity, and abdominal obesity (central obesity characterized by abdominal fat accumulation).Non-limiting examples of symptomatic obesity include endocrine obesity (e.g., Cushing's syndrome, hypothyroidism, insulinoma, obesity-related type 2 diabetes, pseudohypoparathyroidism, hypogonadism), hypothalamic obesity, genetic obesity (e.g., Prader-Willi syndrome, Laurence-Moon-Biedl syndrome), and drug-induced obesity (e.g., steroid-, phenothiazine-, insulin-, sulfonylurea-, or beta-blocker-induced obesity).

[0316] In some embodiments, the disease, disorder or disorder is related to obesity.Examples of such disease, disorder or disorder include, but are not limited to, impaired glucose tolerance, 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 disease (e.g., knee osteoarthritis, hip osteoarthritis, spondylitis osteoarthritis, lower back pain), sleep apnea syndrome, obesity-hypoventilation syndrome (Pickwickian syndrome), menstrual disorders (e.g., abnormal menstrual cycle, menstrual bleeding and cycle abnormalities, amenorrhea, abnormal menstrual symptoms), visceral obesity syndrome, urinary incontinence, and metabolic syndrome.In some embodiments, the compounds and pharmaceutical compositions described herein can be used to treat patients who show both symptoms of obesity and insulin deficiency.

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

[0318] Provided herein are methods for treating diabetes in a patient, the methods comprising: (a) determining that the patient has type 2 diabetes; and (b) administering to the patient a therapeutically effective amount of a compound of 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.

[0319] Provided herein is a method for treating type 2 diabetes in a patient, the method comprising administering a therapeutically effective amount of a compound of 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, to a patient identified or diagnosed as having type 2 diabetes.

[0320] Also provided is a method for treating type 2 diabetes in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of 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.

[0321] In certain embodiments, the compounds and pharmaceutical compositions and methods for treating patients with a disease, disorder, or disorder (e.g., type 2 diabetes) described herein reduce fasting blood glucose levels. In certain embodiments, the compounds and pharmaceutical compositions and methods for treating patients with a disease, disorder, or disorder (e.g., type 2 diabetes) described herein reduce non-fasting blood glucose levels. In certain embodiments, the compounds and pharmaceutical compositions and methods for treating patients with a disease, disorder, or disorder (e.g., type 2 diabetes) described herein reduce HbA1c levels. In certain embodiments, the compounds and pharmaceutical compositions and methods for treating patients with a disease, disorder, or disorder (e.g., type 2 diabetes) described herein reduce glucagon levels. In certain embodiments, the compounds and pharmaceutical compositions and methods for treating patients with a disease, disorder, or disorder (e.g., type 2 diabetes) described herein increase insulin levels. In certain embodiments, the compounds and pharmaceutical compositions and methods for treating patients with a disease, disorder, or disorder (e.g., type 2 diabetes) described herein reduce BMI.

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

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

[0324] In certain embodiments, treatment of type 2 diabetes mellitus demonstrates a reduction in HbA1c levels of about 5% to about 95%. Treatment of type 2 diabetes mellitus demonstrates a reduction in HbA1c levels of about 15% to about 80%. Treatment of type 2 diabetes mellitus demonstrates a reduction in HbA1c levels of about 25% to about 60%. In certain embodiments, treatment of type 2 diabetes mellitus demonstrates a reduction in HbA1c levels of about 6.5% or less, about 6.0% or less, or about 5.0% or less.

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

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

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

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

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

[0331] In some embodiments, the disease, condition, or disorder is fatty liver disease, including, but not limited to, non-alcoholic fatty liver disease (NAFLD), steatohepatitis, non-alcoholic steatohepatitis (NASH), fatty liver disease resulting from hepatitis, fatty liver disease resulting from obesity, fatty liver disease resulting from diabetes, fatty liver disease resulting from insulin resistance, fatty liver disease resulting from hypertriglyceridemia, abetalipoproteinemia, hyperlipoproteinemia, glycogen storage disease, Weber-Christian disease, Wolman disease, acute fatty liver of pregnancy, and lipodystrophy.

[0332] Nonalcoholic fatty liver disease (NAFLD) refers to a group of diseases that occur in the absence of alcohol abuse and is typically characterized by the presence of fatty liver (fat in the liver). NAFLD is thought to be associated with various diseases, such as metabolic syndrome (including obesity, diabetes, and hypertriglyceridemia) and insulin resistance. This can cause liver disease in adults and children, ultimately resulting in 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, primarily isolated macrovesicular fatty liver (i.e., nonalcoholic fatty liver or NAFL) to nonalcoholic steatohepatitis (NASH) (Angulo et al., J Gastroenterol Hepatol 2002; 17 Suppl:S186-90).

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

[0334] Cardiovascular and vascular diseases In some embodiments, the disease, disorder, or disorder is a cardiovascular disease.Non-limiting examples of cardiovascular disease include congestive heart failure, atherosclerosis, arteriosclerosis, coronary heart disease, coronary artery disease, congestive heart failure, coronary heart disease, hypertension, heart failure, cerebrovascular disease (e.g., cerebral infarction), vascular insufficiency, myocardial infarction, elevated blood pressure (e.g., 130 / 85 mmHg or higher), and prothrombotic conditions (e.g., elevated blood fibrinogen or plasminogen activator inhibitor levels).

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

[0336] Neurological disorders In certain embodiments, the disease, condition, or disorder is a neurological disorder (eg, a neurodegenerative disorder) or a psychiatric disorder. Non-limiting examples of neurological disorders include idiopathic intracranial hypertension (IIH), cerebral insulin resistance, mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), anxiety, dementia (e.g., senile dementia), traumatic brain injury, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, Morbus Parkinson's disease, Steele-Richard syndrome, Down's syndrome, myasthenia gravis, neurotrauma, brain trauma, vascular amyloidosis, cerebral hemorrhage with amyloidosis, encephalitis, Friedreich's ataxia, acute confusional disorder, amyotrophic lateral sclerosis (ALS), glaucoma, and apoptosis-mediated degenerative diseases of the central nervous system (e.g., Creutzfeldt-Jakob disease, bovine spongiform encephalopathy (mad cow disease), and chronic wasting syndrome). See, for example, US Publication No. 20060275288A1.

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

[0338] In some embodiments, the disease, condition, or disorder is Wolfram syndrome. Wolfram syndrome is caused by biallelic mutations in the Wolframin ER transmembrane glycoprotein (Wfs1) gene. See, for example, Seppa et al. Sci Rep 9, 15742 (2019). Wolfram syndrome may initially manifest as diabetes, followed by symptoms of optic atrophy, hearing loss, and neurodegeneration. Patients with Wolfram syndrome may exhibit symptoms of ataxia due to brainstem atrophy, sleep apnea, dysphagia, hearing loss, and loss of taste. In some embodiments, the compounds, pharmaceutical compositions, and methods described herein reduce neuroinflammation in patients with Wolfram syndrome. In some embodiments, the neuroinflammation is reduced in the inferior olive of the patient. In some embodiments, the compounds, pharmaceutical compositions, and methods described herein reduce retinal ganglion cell death in patients with Wolfram syndrome. In some embodiments, the compounds, pharmaceutical compositions, and methods described herein reduce axonal degeneration in patients with Wolfram syndrome. In certain embodiments, the compounds and pharmaceutical compositions and methods described herein reduce one or more symptoms (e.g., any of the symptoms described herein) in patients with Wolfram Syndrome.

[0339] Non-limiting examples of psychiatric disorders include drug dependence / addiction (narcotics and amphetamine) and attention deficit hyperactivity disorder (ADHD).The compounds and pharmaceutical compositions described herein can be useful for improving the behavioral response to addictive drugs, reducing drug dependence, preventing relapse of drug abuse, and alleviating the anxiety caused by the absence of certain addictive substances.See, for example, US Publication No. 20120021979A1.

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

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

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

[0343] autoimmune disease In some embodiments, the disease, disorder or disorder is an autoimmune disease.Non-limiting examples of autoimmune disease include multiple sclerosis, experimental autoimmune encephalomyelitis, and autoimmune disease is associated with immune rejection, graft-versus-host disease, uveitis, optic neuropathy, optic neuritis, transverse myelitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, myasthenia gravis and Graves' disease.See, for example, US Publication No. 20120148586A1.

[0344] Gastrointestinal disorders In some embodiments, the disease, disorder, or disorder is a stomach or intestinal disorder. Non-limiting examples of these disorders include ulcers of any etiology (e.g., gastric ulcer, Zollinger-Ellison syndrome, drug-induced ulcer, ulcer associated with infection or other pathogens), gastrointestinal disease, malabsorption, short bowel syndrome, blind-tube syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), celiac disease, hypogammaglobulinemia, chemotherapy- and / or radiotherapy-induced mucositis and diarrhea, gastroenteritis, short bowel syndrome, ulcerative colitis, gastric mucosal injury (e.g., aspirin-induced gastric mucosal injury), small intestinal mucosal injury, and cachexia (e.g., cancer cachexia, tuberculosis cachexia, cachexia associated with blood disorders, cachexia associated with endocrine disorders, cachexia associated with infectious diseases, and cachexia caused by acquired immune deficiency syndrome).

[0345] body weight In some embodiments, the compounds and pharmaceutical compositions described herein can be used to reduce weight (e.g., excess weight), prevent weight gain, induce weight loss, reduce body fat, or reduce food intake in a patient (e.g., a patient in need thereof). In some embodiments, the patient's weight gain may be due to excessive food intake or an unbalanced diet, or may be due to concomitant medication (e.g., an insulin sensitizer with PPARγ agonist-like activity, such as troglitazone, rosiglitazone, englitazone, ciglitazone, pioglitazone, etc.). In some embodiments, the weight gain may be pre-obese or may be weight gain in an obese patient. In some embodiments, the weight gain may also be drug-induced weight gain or weight gain after smoking cessation. In some embodiments, the weight gain is caused by the use of steroids or antipsychotics.

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

[0347] Inflammatory diseases In some embodiments, the disease, illness or disorder is inflammatory disease.Non-limiting examples of inflammatory disease include rheumatoid arthritis, spondylitis deformans, osteoarthritis, lower back pain, gout, post-operative or post-traumatic inflammation, abdominal distension, neuralgia, pharyngitis, cystitis, pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory bowel disease), inflammation of metabolically important tissues (including liver, fat, pancreas, kidney and intestine), and pro-inflammatory condition (for example, elevated level of pro-inflammatory cytokine or marker of inflammation-like C-reactive protein in blood).

[0348] cancer In some embodiments, the disease, disorder, or condition is cancer. Suitable examples of cancer include breast cancer (e.g., invasive ductal carcinoma, ductal carcinoma in situ, inflammatory breast cancer), prostate cancer (e.g., hormone-dependent prostate cancer, hormone-independent prostate cancer), pancreatic cancer (e.g., pancreatic ductal carcinoma), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), lung cancer (e.g., non-small cell lung cancer, small cell lung carcinoma, malignant mesothelioma), colon cancer (e.g., gastrointestinal stromal tumor), rectal cancer (e.g., gastrointestinal stromal tumor), and rectal cancer (e.g., gastrointestinal stromal tumor). stromal tumors), colon cancer (e.g., familial colorectal cancer, hereditary non-polyposis colorectal cancer, gastrointestinal stromal tumors), small intestine cancer (e.g., non-Hodgkin's lymphoma, gastrointestinal stromal tumors), esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer (e.g., nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer), salivary gland cancer, brain tumors (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma), schwannoma, liver cancer (e.g., primary liver cancer, extrahepatic bile duct cancer), kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter), bile duct cancer, uterine cancer, cervical cancer, ovarian cancer (e.g., ovarian epithelial cancer, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian tumor of low malignant potential), bladder cancer, urethral cancer, skin cancer (e.g., intraocular (ocular) melanoma, Merkel cell carcinoma), hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer (e.g., medullary thyroid carcinoma), These include parathyroid cancer, nasal cancer, sinus cancer, bone tumors (e.g., osteosarcoma, Ewing's tumor, uterine sarcoma, soft tissue sarcoma), angiofibroma, retinal sarcoma, penile cancer, testicular tumors, childhood solid tumors (e.g., Wilms' tumor, childhood kidney tumor), Kaposi's sarcoma, Kaposi's sarcoma caused by AIDS, maxillary sinus tumors, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia).

[0349] Hypothalamic-pituitary disorders In one embodiment, the disease, disorder, or condition is associated with the hypothalamic pituitary-gonadal axis. For example, the disease, disorder, or condition is associated with the hypothalamic pituitary-ovarian axis. In another example, the disease, disorder, or condition is associated with the hypothalamic pituitary-testicular axis. Disorders of the hypothalamic pituitary-gonadal axis include, but are not limited to, hypogonadism, polycystic ovary syndrome, hypothyroidism, hypopituitarism, sexual dysfunction, and Cushing's disease.

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

[0351] Pulmonary disease In certain embodiments, the disease, condition, or disorder is associated with a pulmonary disease, including, but not limited to, asthma, idiopathic pulmonary fibrosis, pulmonary hypertension, obstructive sleep apnea, and chronic obstructive pulmonary disease (COPD) (e.g., emphysema, chronic bronchitis, and refractory (irreversible) asthma).

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

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

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

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

[0356] In certain embodiments, a compound of Formula (I) described herein (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, 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, chemotherapy agents, immunotherapeutic agents, anti-inflammatory agents, antithrombotic agents, antioxidant agents, 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 some embodiments, the one or more additional therapeutic agents include, for example, those useful as anti-obesity agents. Non-limiting examples include monoamine reuptake inhibitors (e.g., tramadol, phentermine, sibutramine, mazindol, fluoxetine, tesofensine), serotonin 2C receptor agonists (e.g., lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptor modulators, GABA modulators (e.g., topiramate) (including GABA receptor agonists (e.g., gabapentin, pregabalin)), neuropeptide Y antagonists (e.g., verneperit), peptide YY or analogs thereof, 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., compounds described in WO2020 / 234726, WO2020 / 044266, and U.S. Patent No. 8,859,577), stearate-CoA desaturase inhibitors, microsomal triglyceride transfer protein inhibitors (e.g., R-256918), sodium glucose transporter 2 (SGL T-2) inhibitors (e.g., JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, remogliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, or ertugliflozin), SGLT-1 inhibitors, MCR-4 agonists, monoamine reuptake inhibitors, melanocyte-stimulating hormone analogs, 5HT2c agonists, galanin antagonists,Anorectic drugs (e.g., bombesin agonists), thyromimetic agents, dehydroepiandrosterone or analogs thereof, human agouti-related protein (AGRP) inhibitors, neuromedin U agonists, NFK inhibitors (e.g., HE-3286), PPAR agonists (e.g., GFT-505, DRF-11605, gemfibrozil, fenofibrate, balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone, CLX-0940, GW-1536, GW-1929, GW-2 433, KRP-297, L-796449, LR-90, MK-0767, and SB-219994), phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate, trodasquemine), GPR119 agonists (e.g., PSN-821, MBX-2982, APD597, compounds described in WO2010 / 140092, WO2010 / 128425, WO2010 / 128414, WO2010 / 106457), glucokinase activators (e.g., pyragliatin, AZD-1656, AZD6370, TTP-355, TTP-399, TTP547, ARRY403, MK-0599, TAK-329, AZD5658 or GKM-001, compounds described in WO2010 / 103437, WO2010 / 103438, WO2010 / 013161, WO2007 / 122482, WO2006 / 112549, WO2007 / 028135, WO2008 / 047821, WO2008 / 050821, WO2008 / 136428 and WO2008 / 156757), tin, 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, appetite suppressants (e.g., ephedrine), FGF21 preparations (e.g.,Animal FGF21 preparations extracted from bovine or porcine pancreas; human FGF21 preparations genetically synthesized using E. coli or yeast; fragments or derivatives of FGF21), appetite suppressants (e.g., P-57), human proislet peptides (human proislet peptides), peptide) (HIP), melanocortin receptor 4 agonists (e.g., setomelanotide), melanin-concentrating hormone receptor 1 antagonists, serotonergic agents (e.g., sibutramine, lorcaserin), farnesoid X receptor (FXR) agonists (e.g., obeticholic acid, tropifexor, cilofexor, LY2562175, Met409, TERN-101, EDP305, compounds described in WO2020 / 234726 and WO2020 / 044266), phentermine, zonisamide, norepinephrine / dopamine reuptake inhibitors These include anti-inflammatory drugs (e.g., bupropion), GDF-15 analogs, methionine aminopeptidase 2 (MetAP2) inhibitors (e.g., beloranib or ZGN-1061), diethylpropion, phendimetrazine, benzphetamine, fibroblast growth factor receptor (FGFR) modulators, biotin, MAS receptor modulators, glucagon receptor agonists, CCKa agonists (e.g., compounds described in WO2005 / 116034 and U.S. Publication No. 2005 / 0287100), and AMP-activated protein kinase (AMPK) activators.

[0359] In some embodiments, the one or more additional therapeutic agents include, for example, agents useful as antidiabetic agents. Non-limiting examples include insulin and insulin preparations (e.g., animal insulin preparations extracted from bovine or porcine pancreas; human insulin preparations genetically synthesized using E. coli or yeast; zinc insulin; protamine zinc insulin; insulin fragments or derivatives (e.g., INS-1), oral insulin preparations, synthetic human insulin), insulin sensitizers (e.g., pioglitazone or a salt thereof), biguanides (e.g., metformin, buformin or a salt thereof (e.g., hydrochloride , fumarate, succinate), glucagon analogues (e.g., any of the glucagon analogues described in WO2010 / 011439), agents that antagonise the action of glucagon or reduce glucagon secretion, sulfonylurea drugs (e.g., chlorpropamide, tolazamide, glimepiride, tolbutamide, glibenclamide, gliclazide, acetohexamide, glyclopyramide, glybuzole, glyburide, glipizide), thiazolidinedione drugs (e.g., rosiglitazone, lobeglitazone, troglitazone , balaglitazone, rivoglitazone, lobeglitazone, or pioglitazone), glitazars (e.g., aleglitazar, tiglitazar, saroglitazar, muraglitazar, tesaglitazar), SGLT2 inhibitors (e.g., JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, THR1474, TS-071, ISIS388626, LX4211, remogliflozin, empagliflozin , canagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, ertugliflozin, compounds described in WO2010 / 023594), GPR40 agonists (e.g., FFAR1 / FFA1 agonists, e.g., fasiglifam), α-glucosidase inhibitors (e.g., adiposine, camiglibose, pradimicin-Q, salbostatin, voglibose, acarbose, miglitol, emiglitate), insulin secretagogues, e.g.,prandial glucose regulators (sometimes referred to as "short-acting secretagogues"), 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-001), 0, S4P and Boc5), and dipeptidyl peptidase IV (DPP-4) inhibitors (e.g., vildagliptin, dutogliptin, gemigliptin, alogliptin, saxagliptin, sitagliptin, linagliptin, berberine, adogliptin, anagliptin (SK-0403), teneligliptin, omarigliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, ALS2-0426, TA-6666, TS-021, KRP-104, trelagliptin).

[0360] In some embodiments, the one or more additional therapeutic agents include, for example, drugs useful for treating NAFL and NASH. Non-limiting examples include FXR agonists (e.g., obeticholic acid), PF-05221304, PPARα / δ agonists (e.g., elafibranor), synthetic fatty acid bile conjugates (e.g., aranchol), anti-lysyl oxidase analog 2 (LOXL2) monoclonal antibodies (e.g., simtuzumab), caspase inhibitors (e.g., emricasan), MAPK5 inhibitors (e.g., GS-4997), galectin 3 inhibitors (e.g., GR-MD-02), fibronectins (e.g., EGFR-1, EGFR-2, EGFR-3, EGFR-4, EGFR-5, EGFR-6, EGFR-7, EGFR-8, EGFR-9, EGFR-10, EGFR-11, EGFR-12, EGFR-13, EGFR-14, EGFR-15, EGFR-16, EGFR-17, EGFR-18, EGFR-19, EGFR-20, EGFR-21, EGFR-22, EGFR-23, EGFR-24, EGFR-25, EGFR-26, EGFR-27, EGFR-28, EGFR-29, EGFR-29-20, EGFR-29-30, EGFR-21-40, EGFR-22-30, EGFR-23-50, EGFR-24-40, EGFR-25-50, EGFR-26-50, EGFR-27-50, EGFR-28-50, EGFR-29-30, EGFR- blast growth factor 21 (FGF21) (e.g., BMS-986036), niacin analogs (e.g., ARJ3037MO), leukotriene D4 (LTD4) receptor antagonists (e.g., tipelukast), 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., WO202 No. 20180051012), 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, cinnamon, ascorbic acid, benzoyl peroxide ... These include ascorbic acid, glutathione, silymarin, lipoic acid, and d-alpha-tocopherol, ascorbic acid, glutathione, vitamin B complex, glitazones / thiazolidinediones (e.g., troglitazone, rosiglitazone, pioglitazone, balaglitazone, rivoglitazone, lobeglitazone), metformin, cysteamine, sulfonylureas, alpha-glucosidase inhibitors, meglitinides, vitamin E, tetrahydrolipstatin, milk thistle protein, antivirals, and antioxidants.

[0361] In certain embodiments, the one or more additional therapeutic agents include, for example, agents useful for treating diabetic complications. Non-limiting examples include aldose reductase inhibitors (e.g., tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat, lidrestat), neurotrophic factors and growth factors (e.g., NGF, NT-3, BDNF, neurotrophic production / secretion promoting agents described in 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., rubor These include phenacylthiazolium bromide (ALT766), benzodiazepine (EXO-226), pyridoline, pyridoxamine), serotonin and noradrenaline reuptake inhibitors (e.g., duloxetine), sodium channel inhibitors (e.g., lacosamide), reactive oxygen scavengers (e.g., thioctic acid), cerebral vasodilators (e.g., tiapride, mexiletine), somatostatin receptor agonists (e.g., BIM23190), and apoptosis signal-regulating kinase 1 (ASK-1) inhibitors.

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

[0363] In certain embodiments, the one or more additional therapeutic agents include, for example, agents useful as antihypertensive agents. Non-limiting examples include angiotensin-converting enzyme inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazapril, delapril, pentopril, quinapril, ramipril, lisinopril), angiotensin II antagonists (e.g., candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valproate, valproate), and the like. These include sartans (e.g., telmisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil, azilsartan, azilsartan medoxomil), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine, cilnidipine) and beta-blockers (e.g., metoprolol, atenolol, propranolol, carvedilol, pindolol).Further non-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 thiazide, ... channel blockers (e.g., diltiazem, verapamil, nifedipine, and amlodipine), vasodilators (e.g., hydralazine), renin inhibitors, AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan), ET receptor antagonists (e.g., sitaxsentan, atrasentan, compounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265), ET / AII dual antagonists (e.g., compounds disclosed in WO 2000 / 01389), neutral endopeptidase (NEP) inhibitors, the If channel blocker ivabradine, and vasopeptidase inhibitors (NEP-ACE dual inhibitors) (e.g., gemopatrilat and nitrates).

[0364] In some embodiments, the one or more additional therapeutic agents include, for example, drugs useful as diuretics.Non-limiting examples include xanthine derivatives (e.g., sodium theobromine salicylate, calcium theobromine salicylate), thiazides (e.g., ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penfluthiazide, polythiazide, methyclothiazide), antialdosterone drugs (e.g., spironolactone, triamterene), carbonic anhydrase inhibitors (e.g., acetazolamide), and chlorobenzenesulfonamides (e.g., chlorthalidone, mefruside, indapamide).

[0365] In some embodiments, the one or more additional therapeutic agents include, for example, agents useful as immunotherapeutics. Non-limiting examples include microbial or bacterial compounds (e.g., muramyl dipeptide derivatives, picibanil), polysaccharides with immune-enhancing activity (e.g., lentinan, sizofiran, krestin), cytokines obtained by genetic engineering (e.g., interferons, interleukins (IL), e.g., IL-1, IL-2, IL-12), and colony-stimulating factors (e.g., granulocyte colony-stimulating factor, erythropoietin).

[0366] In certain embodiments, the one or more additional therapeutic agents include, for example, agents useful as antithrombotic agents. Non-limiting examples include heparin (e.g., heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarin (e.g., warfarin potassium); antithrombin drugs (e.g., argatroban, dabigatran, boroarginine derivatives, boropeptides, heparin, hirudin, and melagatran), FXa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, YM150, compounds described in WO02 / 06234, WO2004 / 048363, WO2005 / 030740, WO2005 / 058823, and WO2005 / 113504), thrombolytic agents (e.g., anistreplase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), urokinase, tisokinase, alteplase, nateplase, mogamulizumab, thrombus dissolving agents (e.g., thrombus dissolving agents ... antiplatelet agents (e.g., ceteplase, pamiteplase, factor VIla inhibitors, PAI-1 inhibitors, alpha-2 plasmin inhibitors, and anisoylated plasminogen streptokinase activator complex), and platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cilostazol, ethyl icosapentate, beraprost sodium, and sarpogrelate hydrochloride).

[0367] In some embodiments, the one or more additional therapeutic agents include, for example, drugs useful for treating osteoporosis.Non-limiting examples include alfacalcidol, calcitriol, elcatonin, salmon calcitonin, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium, and risedronate disodium.Suitable examples of vitamins include vitamin B1 and vitamin B12.Suitable examples of drugs for treating erectile dysfunction include apomorphine and sildenafil citrate.Suitable examples of drugs for treating urinary frequency or urinary incontinence include flavoxate hydrochloride, oxybutynin hydrochloride, and propiverine hydrochloride.Suitable examples of drugs for treating urinary disorders include acetylcholinesterase inhibitors (e.g., distigmine).Suitable examples of anti-inflammatory drugs include nonsteroidal anti-inflammatory drugs, such as aspirin, acetaminophen, and indomethacin.

[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, agents for treating dyslipidemia, such as HMG-COA reductase inhibitors (statins, e.g., rosuvastatin, pravastatin, pitavastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, itavastatin, ZD-4522), HMG-CoA synthase inhibitors, cholesterol-lowering drugs, bile acid sequestrants (e.g., cholestyramine, questran, colestipol, 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., AZD7687, LCQ908, compounds described in WO2009 / 016462, WO2010 / 086820), monoacylglycerol O-acyltransferase inhibitors, α-amylase inhibitors (e.g., tendamistat, trestatin, AL-3688), α-glucoside hydrolase inhibitors, SIRT-1 activators, c-Jun N-terminal kinase (JNK) inhibitors, VPAC2 receptor agonists, TGR5 receptor modulators (e.g., the compounds described), GPBAR1 receptor modulators, GPR120 modulators, high affinity nicotinic acid receptor (HM74A) activators, carnitine palmitoyltransferase enzyme inhibitors, mineralocorticoid receptor inhibitors, TORC2 inhibitors, fatty acid synthase inhibitors, serine palmitoyltransferase inhibitors, GPR81 modulators, GPR39 modulators, GPR43 modulators, GPR41 modulators, GPR105 modulators, Kv1.3 modulators, retinol binding protein 4 modulators, somatostatin receptor modulators, PDHK2 modulators, PDHK4 modulators, MAP4K4 inhibitors,IL1 family modulators (e.g., ILI beta modulators), ACAT inhibitors, MTP inhibitors (e.g., diriotapide, mitratapide, and implitapide), lipoxygenase inhibitors, PCSK9 modulators (e.g., alirocumab and evolocumab), RXR alpha modulators, 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., trodasquemine, hyrtiosal extract, and compounds described in Zhang et al. Drug Discovery Today. 2007, 12(9-10): 373-381), ezetimibe, betaine, pentoxifylline, alpha delta-9 desaturase (alpha delta-9 desaturase), BCKDK inhibitors, branched-chain alpha keto acid dehydrogenase (BCBK) inhibitors, PNPLA3 inhibitors, FGF19 analogs, SCD1 inhibitors, bile acid binding resins, nicotinic acid (niacin) and its analogs, antioxidants (e.g., probucol), omega-3 fatty acids, antihypertensive agents, for example, adrenoceptor antagonists, for example, beta-blockers (e.g., atenolol), alpha-blockers (e.g., doxazosin), and mixed alpha / beta-blockers (e.g., labetalol), adrenoceptor agonists, for example, alpha-2 agonists (e.g., clonidine), angiotensin-converting enzyme (AC) inhibitors E) 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, trichlormethiazide, indapamide), phthalimidine diuretics (e.g., chlorthalidone, metolazone), quinazoline diuretics (e.g., quinethazone), potassium-sparing diuretics (e.g., triamterene and amiloride), thyroid receptor agonists (e.g., compounds described in WO2020 / 117987), hemostatic modifiers (including antithrombotic agents (e.g., fibrinolytic activators)), thrombin antagonists, Phase VI Factor Ia inhibitors, anticoagulants (e.g., vitamin K antagonists, e.g., warfarin), heparin and its low molecular weight analogues, factor Xa inhibitors, and direct thrombin inhibitors (e.g., argatroban), antiplatelet agents (e.g., cyclooxygenase inhibitors (e.g., aspirin), nonsteroidal anti-inflammatory drugs (NSAIDS), thromboxane-A2-receptor antagonists (e.g., ifetroban), thromboxane-A2-synthetase inhibitors, PDE inhibitors (e.g., pletal, dipyridamole)), purinergic receptor antagonists (e.g., For example, 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), serotonergic agents (e.g., sibutramine, lorcaserin), diacylglycerol acyltransferase (DGAT) inhibitors, feeding behavior modifiers, pyruvate dehydrogenase kinase (PDK) modulators, serotonin receptor modulators, monoamine transport modulators, such as selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine), noradrenaline reuptake inhibitors (NARIs), noradrenaline-serotonin reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs) (e.g., toloxatone and 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 anti-cachexia agents, for example, cyclooxygenase inhibitors (e.g., indomethacin), progesterone derivatives (e.g., megestrol acetate), glucocorticoids (e.g., dexamethasone), metoclopramide agents, tetrahydrocannabinol agents, drugs for improving fat metabolism (e.g., eicosapentaenoic acid), growth hormone Antibodies against lumon, IGF-1, cachexia-inducing factors TNF-α, LIF, IL-6, and oncostatin M, metabolism-improving proteins or peptides, for example, 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), neuroregeneration promoters (e.g., Y-128, VX853, prosaptide), antidepressants (e.g., desipramine, amitriptyline, imipramine), antiepileptic drugs (e.g., lamotrigine, trileptal, keppra, zonegran, pregabalin, harkoseride, carbamazepine), antiarrhythmic drugs (e.g., K, +channel openers, mexiletine, propafenone, metoprolol, atenolol, carvadiol, propranolol, sotalol, dofetilide, amiodarone, azimilide, ibutilide, diltiazem, and verapamil), acetylcholine receptor ligands (e.g., ABT-594), endothelin receptor antagonists (e.g., ABT-627), narcotic analgesics (e.g., morphine), α2 receptor agonists (e.g., clonidine), local anesthetics (e.g., capsaicin), anxiolytics (e.g., benzothiazepines), phosphodiesterase inhibitors (e.g., sildenafil), dopamine receptor agonists (e.g., apomorphine), cytotoxic antibodies (e.g., T cell receptor and IL-2 receptor specific antibodies), B cell depleting therapy drugs (e.g., anti-CD20 antibodies (e.g., Rituxan), i-BLyS antibodies), drugs affecting T cell migration (e.g., anti-integrin alpha 4 / beta 1 antibodies (e.g., Tysa yellowtail), drugs acting on immunophilins (e.g., cyclosporine, tacrolimus, sirolimus, rapamycin), interferons (e.g., IFN-β), immunomodulators (e.g., glatiramer), TNF-binding proteins (e.g., circulating receptors), immunosuppressants (e.g., mycophenolic acid), metaglidasen, AMG-131, balaglitazone, MBX-2044, rivoglitazone, aleglitazar, tiglitazar, These include saroglitazar, muraglitazar, tesaglitazar, lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, exenatide, exendin-4, memantine, midazolam, ketoconazole, ethyl icosapentate, clonidine, azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, etoposide, piroxicam, NO donors (e.g., nitrates), and NO promoters (e.g., phosphodiesterase inhibitors).

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

[0370] In some embodiments, the additional therapeutic agent or regimen is administered to the patient at approximately the same time as the contact or administration of the compound and pharmaceutical composition. In one example, the additional therapeutic agent or regimen and the compound and pharmaceutical composition are administered to the patient simultaneously in the same formulation. In another example, the additional therapeutic agent or regimen and the compound and pharmaceutical composition are administered to the patient simultaneously in separate formulations.

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

[0372] In certain embodiments, the methods described herein further include a step of identifying a patient (e.g., a subject) 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 include identifying a patient (e.g., a patient) suffering from type 2 diabetes. In certain embodiments, determining whether a patient has type 2 diabetes includes performing an assay to determine hemoglobin A1c (HbA1c) levels, fasting blood glucose, non-fasting blood glucose, or any combination thereof. In certain embodiments, the HbA1c level is about 6.5% to about 24.0%. In certain embodiments, the HbA1c level is about 6.5% or higher. In certain embodiments, the HbA1c level is about 8.0% or higher. In certain embodiments, the HbA1c level is about 10.0% or higher. In certain embodiments, the HbA1c level is about 12.0% or higher. In certain embodiments, the HbA1c level is about 14.0% or higher. In certain embodiments, the HbA1c level is about 16.0% or higher. In some embodiments, the HbA1c level is about 18.0% or higher. In some embodiments, the HbA1c level is about 20.0% or higher. In some embodiments, the HbA1c level is about 22.0% or higher. In some embodiments, the HbA1c level is about 24.0% or higher.

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

[0375] In some embodiments, the non-fasting blood glucose level is from about 190 mg / dL or more to about 750 mg / dL or more. In some embodiments, the non-fasting blood glucose level is from about 250 mg / dL or more to about 450 mg / dL or more. In some 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 comprises determining the patient's BMI. In certain embodiments, the patient's BMI is about 22 kg / m 2 or more to about 100 kg / m 2 In certain embodiments, the patient's BMI is about 30 kg / m or greater. 2 or more to about 90 kg / m 2 In certain embodiments, the patient's BMI is about 40 kg / m or greater. 2 or more to about 80 kg / m 2 In certain embodiments, the patient's BMI is about 50 kg / m or greater. 2 or more to about 70 kg / m 2 Or even 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 patient is about 10 years old or older. In certain embodiments, the patient is about 15 years old or older. In certain embodiments, the patient is about 20 years old or older. In certain embodiments, the patient is about 25 years old or older. In certain embodiments, the patient is about 30 years old or older. In certain embodiments, the patient is about 35 years old or older. In certain embodiments, the patient is about 40 years old or older. In certain embodiments, the patient is about 42 years old or older. In certain embodiments, the patient is about 44 years old or older. In certain embodiments, the patient is about 46 years old or older. In certain embodiments, the patient is about 48 years old or older. In certain embodiments, the patient is about 50 years old or older. In certain embodiments, the patient is about 52 years old or older. In some embodiments, the patient is about 54 years of age or older. In some embodiments, the patient is about 56 years of age or older. In some embodiments, the patient is about 58 years of age or older. In some embodiments, the patient is about 60 years of age or older. In some embodiments, the patient is about 62 years of age or older. In some embodiments, the patient is about 64 years of age or older. In some embodiments, the patient is about 66 years of age or older. In some embodiments, the patient is about 68 years of age or older. In some embodiments, the patient is about 70 years of age or older. In some embodiments, the patient is about 72 years of age or older. In some embodiments, the patient is about 74 years of age or older. In some embodiments, the patient is about 76 years of age or older. In some embodiments, the patient is about 78 years of age or older.In some embodiments, the patient is about 80 years of age or older. In some embodiments, the patient is about 85 years of age or older. In some embodiments, the patient is about 90 years of age or older. In some embodiments, the patient is about 95 years of age or older. In some embodiments, the patient's ethnicity may be African American, American Indian or Alaska Native, Asian American, Hispanic or Latino, or Native Hawaiian or Pacific Islander.

[0378] In some embodiments, the patient is a pediatric patient. As used herein, the term "pediatric patient" refers to a patient who is 21 years of age or younger at the time of diagnosis or treatment. The term "child" can be further divided into various subpopulations, including neonates (birth to 1 month); toddlers (1 month to 2 years); children (2 to 12 years); and adolescents (12 to 21 years, including but not limited to 22 years) (Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WB Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; (1994.) In certain embodiments, the pediatric patient is from birth to 28 days of age, from 29 days to 2 years of age, from 2 to 12 years of age, or from 12 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, which do not limit the scope of the invention as claimed.

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

[0381] [ka] With reference to Scheme 1, ester I1 (wherein R 4 is as defined in formula I; [ka] teeth, [ka] [In the formula, R 5 , R 6 , and R 7 is as defined in Formula I] (Ring C)-Y (wherein Ring C is as defined in Formula I; and Y is B(OH) or a boronic acid ester (e.g., BPin)) is subjected to a metal-catalyzed cross-coupling reaction (e.g., Suzuki coupling using Pd(dppf)ClCHCl 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) or a boronic acid ester (e.g., BPin)) to provide 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 prepared by coupling with a reagent of the formula: [ka] can be coupled with (ring C')-Y of the formula:

[0382] Next, reaction of compound I2 with compound I3 (e.g., in the presence of NaH in DMF) provides compound I4, and the ester group is hydrolyzed under standard conditions (e.g., LiOH in HO / THF) to produce compound I5. Compound I5 is amide-coupled with NHMePh under standard conditions (e.g., HATU and Hunig's base) to provide compound I6. Compound I6 is then converted to compound I6b (wherein the dashed curve Lx is C 1-6 C optionally substituted with alkyl 2-5 represents alkylene, 1-6 Alkyl is one to three independently selected R f and optionally substituted with C 1-6 C optionally substituted with alkyl 3-6 Cycloalkyl, wherein the C 1-6 Alkyl is one to three independently selected R f As a non-limiting example, compound I6b is [ka] and ring D' in the corresponding product can be [ka] is.

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

[0384] [ka] With reference to Scheme 2, carboxylic acid I10 (wherein R 3is as defined for Formula I), is subjected to amidation with an ammonium source (e.g., NH4Cl) under standard conditions for amide bond formation (e.g., using a carboxyl activator (e.g., HATU) in the presence of a base such as Hunig's base) to provide compound I11. Compound I11 is converted to compound I12 under dehydrating conditions (e.g., with TFAA and pyridine at room temperature) and subjected to acidic conditions (e.g., MeSO3H in THF (e.g., at 65°C)) to produce compound I13. Compound I13 can then be converted to compound I13b (R 2 and R 3 is as defined for Formula I) via Michael-type addition (e.g., in the presence of NEt in a polar protic solvent (e.g., EtOH) at an elevated temperature such as 70°C) to provide compound I14, and the amino nitrogen is then protected with a suitable protecting group (i.e., Pg). As a non-limiting example, Pg can be a carbonyl protecting group such as Boc. Compound I14 undergoes an intramolecular Dieckmann-type condensation under basic conditions (e.g., t-BuOK at room temperature) to provide compound I15. Protected hydrazine compound I16b (wherein ring A is as defined for Formula I; and each Pg is a nitrogen protecting group, e.g., a carbonyl protecting group such as Boc) is condensed with compound I15 to provide compound I16 (e.g., by treatment with TFA in DCM at room temperature, followed by treatment with Py-HCl in EtOH under reflux). Compound I16 is reacted with compound I17b (e.g., in the presence of a polar aprotic solvent (e.g., DMA)) to provide compound I17, which is treated under acidic conditions (e.g., MeSO3H, THF, 60°C), followed by reprotection of the second amino group (e.g., Boc2O) to provide compound I18 (wherein Pg is a nitrogen protecting group, e.g., a carbonyl protecting group such as Boc). Compound I18 is then converted to compound I18b (wherein Q 1 -Q 5is as defined for Formula I, and X is halo (e.g., -Br or -I) or pseudohalo (e.g., -OTf)) (e.g., under typical Ullmann coupling conditions known in the art) to provide compound I19. As a non-limiting example, the coupling can be carried out using CuI, KCO in NMP (e.g., at 130° C.), and [ka] The nitrogen protecting group (i.e., Pg) in compound I19 is removed (eg, under acidic conditions, such as HCl in dioxane) to provide compound I20.

[0385] [ka] Referring to Scheme 3, compound I20 is coupled with compound I9 under standard amide bond forming conditions (e.g., in the presence of a carboxyl activating agent such as HATU (e.g., in a polar aprotic solvent such as DMF)) to provide compound I21, a compound of Formula I.

[0386] It will be apparent to one skilled in the art that in the synthetic procedures shown above (see Schemes 1-3), reactive groups (e.g., NH, NH, and OH) can be protected with suitable protecting groups, followed by a deprotection step at an appropriate stage in the synthesis. It is also within the skill of the art to consider modifying the above method to synthesize other compounds of Formula I. For example, by substituting other electrophiles for compound I6b, other L 3 -C(R 8a R 8b )-L 4 -R 9 As another example, compounds bearing other L groups can be obtained by replacing compound I16 with other appropriate reagents. 2 Compounds having the moiety can be obtained.

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

[0388] Abbreviation [Table 3] TIFF2025160228000137.tif242157 TIFF2025160228000138.tif165157

[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) [ka] Step A: Ethyl 5-(3,6-dihydro-2H-pyran-4-yl)-1H-indole-2-carboxylate [ka] To a solution of ethyl 5-bromo-1H-indole-2-carboxylate (10.0 g, 37.3 mmol) in dioxane / HO (240 mL / 60 mL) was added 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.60 g, 41.0 mmol), Pd(dppf)Cl·CHCl (3.00 g, 3.73 mmol), and KCO (15.4 g, 112 mmol). The reaction was evacuated and backfilled with N three times. The reaction mixture was stirred at 80° C. under N atmosphere for 2.5 hours, then it was filtered, diluted with DCM, washed with water, dried over NaSO, concentrated, and purified by silica gel column (PE / EtOAc=10 / 1 to 4 / 1) to give ethyl 5-(3,6-dihydro-2H-pyran-4-yl)-1H-indole-2-carboxylate as a white to yellow solid (7.00 g, yield 69%). LC-MS: m / z 272.0 (M+H) + 1 H NMR (400 MHz, CDCl3) δ: 8.89 (s, 1H), 7.66 (s, 1H), 7.44 (dd, J = 8.8, 1.6 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.21 (dd, J = 2.0, 0.8 Hz, 1H), 6.01 - 6.17 (m, 1H), 4.41 (q, J = 7.2 Hz, 2H), 4.35 (q, J = 2.8 Hz, 2H), 3.97 (t, J = 5.6 Hz, 2H), 2.56 - 2.62 (m, 2H), 1.42 (t, J = 7.2 Hz, 3H).

[0390] Step B: Ethyl 5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate [ka] To a solution of ethyl 5-(3,6-dihydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (7.00 g, 25.8 mmol) in MeOH / THF (50 mL / 150 mL), 10 w / w% Pd / C (700 mg) was added. The mixture was stirred overnight at room temperature under an H atmosphere. The reaction mixture was filtered, concentrated, slurried with MeOH, and filtered to obtain ethyl 5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate as a white solid (6.00 g, 85% yield). LC-MS: m / z 274.0 (M+H) + 1 H NMR (400 MHz, CDCl3) δ: 8.87 (s, 1H), 7.51 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.21 (dd, J = 8.4, 1.6 Hz, 1H), 7.18 - 7.19 (m, 1H), 4.41 (q, J = 7.2 Hz, 2H), 4.11 (dd, J = 10.8, 4.0 Hz, 2H), 3.56 (td, J = 11.6, 2.8 Hz, 2H), 2.80 - 2.88 (m, 1H), 1.80 - 1.90 (m, 4H), 1.42 (t, J = 7.2 Hz, 3H).

[0391] Step C: Ethyl 1-(cyanomethyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate [ka] To a solution of ethyl 5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (6.00 g, 22.0 mmol) in DMF (170 mL) was added NaH (60% in oil) (1.30 g, 33.0 mmol) at 0 ° C. The mixture was stirred at 0 ° C. for 0.5 hours, and then 2-chloroacetonitrile (3.30 g, 43.9 mmol) was added. The mixture was stirred at room temperature overnight. The reaction was quenched with H O (100 mL) at 0 ° C. The suspension was filtered and dried to give ethyl 1-(cyanomethyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate as a cream-white solid (6.30 g, 92% yield). LC-MS: m / z 313.0 (M+H) + 1 H NMR (400 MHz, DMSO-d6) δ: 7.71 (d, J = 8.8 Hz, 1H), 7.59 (s, 1H), 7.39 (dd, J = 8.8, 1.6 Hz, 1H), 7.36 (d, J = 0.8 Hz, 1H), 5.75 (s, 2H), 4.37 (q, J = 7.2 Hz, 2H), 3.95 - 3.98 (m, 2H), 3.42 - 3.48 (m, 2H), 2.82 - 2.90 (m, 1H), 1.70 - 1.75 (m, 4H), 1.36 (t, J = 7.2 Hz, 3H).

[0392] Step D: 1-(cyanomethyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid [ka] To a solution of ethyl 1-(cyanomethyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (4.90 g, 15.7 mmol, 1.0 equiv) in HO / THF (40 mL / 70 mL) was added LiOH (564 mg, 23.6 mmol) at 0° C. The mixture was stirred at room temperature for 3 h. The THF was then removed under reduced pressure, and the pH was adjusted to approximately 4-5 with 1N HCl solution. The suspension was filtered to give 1-(cyanomethyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid as an off-white solid (4.30 g, 97% yield). LC-MS: m / z 285.0 (M+H) + 1 H NMR (400 MHz, DMSO-d6) δ: 13.3 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.58 (s, 1H), 7.37 (dd, J = 8.8, 1.6 Hz, 1H), 7.31 (d, J = 0.4 Hz, 1H), 5.76 (s, 2H), 3.95 - 3.98 (m, 2H), 3.45 - 3.49 (m, 2H), 2.82 - 2.90 (m, 1H), 1.71 - 1.76 (m, 4H).

[0393] Step E: 1-(cyanomethyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide [ka] To a solution of 1-(cyanomethyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (4.70 g, 16.6 mmol) and HATU (9.43 g, 24.8 mmol) in DMF (70 mL) was added DIPEA (8.65 mL, 49.6 mmol) at 0 ° C. The mixture was stirred at 0 ° C. for 1 hour, and then N-methylaniline (2.68 mL, 24.8 mmol) was added. The mixture was stirred at room temperature overnight, after which it was diluted with water (150 mL) and extracted with EtOAc (100 mL * 3). The organic layer was dried over Na2SO4, concentrated, and purified by silica gel column (PE / EA = 6 / 1 to 4 / 1) to obtain the title compound as a yellow solid (4.30 g, yield 70%). LC-MS: m / z 374.0 (M+H) + 1 H NMR (400 MHz, CDCl3) δ: 7.34 - 7.38 (m, 2H), 7.29 - 7.31 (m, 2H), 7.21 - 7.24 (m, 4H), 5.90 (s, 1H), 5.54 (s, 2H), 4.04 - 4.07 (m, 2H), 3.47 - 3.54 (m, 5H), 2.73 - 2.80 (m, 1H), 1.72 - 1.84 (m, 4H)

[0394] Step F: 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide [ka] To a solution of 1-(cyanomethyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide (2.90 g, 7.80 mmol) and (R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (2.70 g, 19.5 mmol) in DMPU (15 mL) was added dropwise KHMDS (1.0 mol / L in THF, 31.2 mL, 31.2 mmol) under a N atmosphere at 0° C. The reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was quenched with HCOOH (10 mL), concentrated in vacuo, and purified by flash chromatography (PE / EtOAc=1 / 1) to give the crude product 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide (3.20 g) as a yellow oil, which was used directly in the next step without further purification. LC-MS: m / z 414.1 (M+H) +

[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 [ka] A solution of crude product 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide (3.20 g, 7.80 mmol), NHOH·HCl (2.70 g, 39.0 mmol), and KCO (5.90 g, 43.0 mmol) in EtOH (50 mL) was stirred at 100 °C for 2 h. The reaction mixture was concentrated and diluted with HO (100 mL). The suspension was filtered and dried under reduced pressure. The solid was dissolved in DMSO (10 mL), followed by the addition of carbonyldiimidazole (2.50 g, 15.6 mmol) and 1,8-diazabicycloundec-7-ene (3.00 g, 19.5 mmol). The resulting mixture was stirred at 80° C. for 1 hour. Formic acid (5 mL) was added, and then the mixture was concentrated and purified by reverse-phase chromatography (acetonitrile / HO=7 / 3, 0.1% formic acid) to give 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 as a white solid (1.00 g, 27% yield). LC-MS: m / z 473.1 (M+H) +

[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 [ka] A solution of 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 (1.00 g, 2.10 mmol) and KOH (1.20 g, 21.0 mmol) in CH3CH2CH2OH (4 mL) was stirred at 130° C. for 1 h. The reaction mixture was acidified to pH=3 with 5 N HCl solution, and a brown precipitate was observed. The solid was collected by filtration, washed with HO (5 mL), and dried under reduced pressure to give 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 as a brown solid (700 mg, 86% yield). LC-MS: m / z 384.1 (M+H) + 1 H NMR (400 MHz, DMSO-d6) δ: 12.88 (s, 1H), 12.29 (s, 0.4H), 12.02 (s, 0.6H), 7.54 (d, J = 4.8 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.29 (td, J = 11.2 Hz, 1.2 Hz, 1H), 7.19 (d, J = 4.4 Hz, 1H), 3.94 - 3.97 (m, 2H), 3.41 - 3.49 (m, 2H), 2.79 - 2.88 (m, 1H), 1.89 - 2.03 (m, 1H), 1.54 - 1.82 (m, 6H), 1.39 (d, J = 6.4 Hz, 1.3 H), 1.27 (d, J = 6.5 Hz, 1.7H).

[0397] [ka] Step I: (S)-tert-butyl(4-amino-4-oxobutan-2-yl)carbamate [ka] To a mixture of methyl (S)-3-((tert-butoxycarbonyl)amino)butanoate (10.0 g, 49.2 mmol) in THF (150 mL) was added HATU (22.5 g, 59.0 mmol), DIPEA (19.0 g, 148 mmol), and NHCl (6.60 g, 123 mmol) at 0° C. The reaction mixture was stirred at room temperature under N overnight, after which it was diluted with EtOAc (150 mL), washed with HO (50 mL*3), dried over NaSO, concentrated in vacuo, and purified by flash chromatography (PE / EtOAc=1 / 1) to give (S)-tert-butyl(4-amino-4-oxobutan-2-yl)carbamate as a yellow solid (12.2 g, 100% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.27 (s, 1H), 6.79 (s, 1H), 6.69 (d, J = 8.0 Hz, 1H), 3.70 - 3.84 (m, 1H), 2.23 (dd, J = 14.0, 5.6 Hz, 1H), 2.06 (dd, J = 14.0, 8.0 Hz, 1H), 1.37 (s, 9H), 1.01 (d, J = 6.4 Hz, 3H).

[0398] Step J: (S)-tert-butyl(1-cyanopropan-2-yl)carbamate [ka] To a mixture of (S)-tert-butyl (4-amino-4-oxobutan-2-yl)carbamate (10.0 g, 49.5 mmol), TFAA (6.90 mL, 49.5 mmol) and pyridine (8.00 mL, 99.0 mmol) were added. 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 H 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 [ka] A solution of (S)-tert-butyl(1-cyanopropan-2-yl)carbamate (2.10 g, 11.4 mmol) in 4 N HCl solution in dioxane (20 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo to give (S)-3-aminobutanenitrile HCl salt as a white solid (1.50 g, 100% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.58 (br. s, 2H), 3.38 - 3.53 (m, 1H), 2.90 - 3.06 (m, 2H), 1.27 - 1.38 (m, 3H).

[0400] Step L: (S)-Ethyl 3-((tert-butoxycarbonyl)(1-cyanopropan-2-yl)amino)propanoate [ka] To a solution of (s)-3-aminobutanenitrile (2.80 g, 23.1 mmol, 1.0 equiv.) in EtOH (20 mL), TEA (3.50 g, 34.6 mmol, 1.5 equiv.) and ethyl acrylate (2.33 g, 23.1 mmol, 1.0 equiv.) were added at room temperature. After stirring at 70 °C for 3 hours, the reaction mixture was cooled to room temperature, and (Boc) O (6.10 mL, 27.8 mmol, 1.2 equiv.) was added. The solution was stirred at room temperature overnight, and then diluted with H O (50 mL). The mixture was extracted with EtOAc (50 mL * 3). The organic layer was washed with brine (50 mL), dried over NaSO, 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 [ka] To 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 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 in vacuo, and purified by flash chromatography (PE / EtOAc = 8 / 1) to give tert-butyl (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylate (2.60 g, 100% yield).

[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 [ka] 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), TFA (18 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. 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 (20 mL), and extracted with DCM (20 mL * 3). The organic layers were combined and concentrated in vacuo, and the residue was purified by flash chromatography (PE / EtOAc=20 / 1) to give 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, 57% yield). 1 H 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 [ka] To a solution of 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 (400 mg, 1.10 mmol) and N-(2,2-dimethoxyethyl)-1H-imidazole-1-carboxamide (426 mg, 2.2 mmol) in DMA (20 mL) was added t-BuOK (358 mg, 3.20 mmol) at room temperature. The reaction mixture was stirred at 80° C. for 48 hours. The reaction mixture was quenched with HO (10 mL), concentrated in vacuo, and then purified by flash chromatography (PE / EtOAc=1 / 1) to give 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 as a yellow solid (181 mg, 33% yield). LC-MS: m / z 506.4 (M+H) +

[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 [ka] 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 (181 mg, 0.360 mmol) was suspended in THF (10 mL). Methanesulfonic acid (35.0 mg, 0.360 mmol) was added at an external temperature of 60 ° C. The mixture was stirred for 2 hours. Water (10 mL) was added to the reaction solution, and then the mixture was extracted with EtOAc (10 mL * 3). The organic layer was washed with brine, dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EtOAc=1 / 1) to give 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 as a yellow solid (139 mg, 88% yield). LC-MS: m / z 442.3 (M+H) +

[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 [ka] To a mixture of 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 (139 mg, 0.320 mmol), (4-bromophenyl)dimethylphosphine oxide (110 mg, 0.470 mmol), (1S,2S)-1-N,2-N-dimethylcyclohexane-1,2-diamine (67.0 mg, 0.470 mmol), and potassium carbonate (88.0 mg, 0.640 mmol) in N-methylpyrrolidone (15 mL) was added copper(I) iodide (90.0 mg, 0.470 mmol) at room temperature. The mixture was degassed and refilled with N three times. Then, the mixture was stirred under N atmosphere at 130 °C for 3 hours. The reaction mixture was purified by silica gel chromatography to give 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 as a yellow solid (76.0 mg, yield 41%). LC-MS: m / z 594.4 (M+H) +

[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 [ka] A mixture of 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 (76.0 mg, 0.130 mmol) and 4N HCl solution in dioxane (50 ml) was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure to give the title compound (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 as a yellow solid (54.0 mg, 34% yield). LC-MS: m / z 494.2 (M+H) +

[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 [ka] (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 in DMF (4 ml) A solution 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 (46.0 mg, 0.120 mmol), HATU (125 mg, 0.320 mmol), and EtN (220 mg, 2.20 mmol) was stirred at room temperature for 16 hours. The mixture was treated with water (30 ml) and extracted with EtOAc (10 mL*3). The organic layer was washed with brine, dried over NaSO, concentrated under reduced pressure and purified by preparative HPLC to give the compound 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 as a yellow solid (29.0 mg, 33% yield). LC-MS: m / z 859.2 (M+H) + 1H NMR (400 MHz, DMSO-d6, 80℃) δ: 7.79 - 7.90 (m, 4H), 7.35 - 7.45 (m, 2H), 7.10 - 7.30 (m, 4H), 6.95 (br, 1H), 6.57 (br, 1H), 5.41 - 5.52 (m, 1H), 4.37 (t, J = 8.4 Hz, 1H), 3.96 (d, J = 10.4 Hz, 2H), 3.85 (dd, J = 9.2, 6.0 Hz, 1H), 3.47 (td, J = 10.8, 3.6 Hz, 2H), 2.98 - 3.01 (m, 1H), 2.75 - 2.83 (m, 2H), 2.65 - 2.75 (m, 1H), 2.18 (d, J = 1.2 Hz, 6H), 1.71 - 1.76 (s, 4H), 1.56 - 1.70 (m, 8H), 1.15 - 1.40 (m, 6H).

[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) [ka] 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), Pd(dba) (302 mg, 0.330 mmol), and Xantphos (382 mg, 0.660 mmol) in 40 mL of 1,4-dioxane was sparged with argon. Triethylamine (1.30 g, 13.2 mmol) was then added. The mixture was heated at 60° C. under an argon atmosphere for 12 hours. LCMS showed the reaction was complete. 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 give (4-bromo-2-fluorophenyl)diethylphosphine oxide as a pale white solid (1.50 g, 5.37 mmol, yield 80.6%). 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 in a microwave reactor at 80 °C for 3 hours. LCMS showed that most of the starting material was 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 provide (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 A mixture of 1,2-dimethylcyclohexane-1,2-diamine (208 mg, 1.46 mmol) and 2,3-dimethylcyclohexane-1,2-diamine was heated at 130 °C for 3 hours under an argon atmosphere. LCMS showed the reaction was complete. Ethyl acetate (100 mL) was added to the mixture and 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, yield 84.0%). LCMS: m / z = 651.3 (M+H) + . 1H 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 hours. LCMS showed the reaction was complete. The mixture was concentrated, and the residue was dispersed in 40 mL of ethyl ether. The resulting solid was collected and dried in vacuo to give (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) + . 1H 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 In a 50 mL flask (flask A), 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) were 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 showed that most of the starting material was consumed. 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) + . 1H NMR (400 MHz, DMSO-d6, 80℃) 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 compounds were synthesized using a method similar to that 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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) 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 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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) δ: 11.58 (br. s, 1H), 7.77 (t, J = 8.8 Hz, 1H), 7.53 (s, 1H), 7.33 - 7.44 (m, 4H), 7.27 (dd, J = 8.8, 1.6 Hz, 1H), 7.16 (d, J = 6.4 Hz, 2H), 6.87 - 6.90 (m, 2H), 5.55 (br. s, 1H), 4.49 (br. s, 1H), 3.97 - 4.00 (m, 2H), 3.84 (s, 3H), 3.43 - 3.65 (m, 3H), 2.98 - 3.16 (m, 1H), 2.81 - 2.97 (m, 2H), 2.23 (d, J = 2.0 Hz, 6H), 1.83 - 2.00 (m, 4H), 1.58 - 1.82 (m, 7H), 1.40 - 1.50 (br. s, 3H), 1.09 - 1.30 (m, 3H), 0.90 - 1.00 (m, 6H). LC-MS: m / z 917.4 (M+H) + .

[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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) δ 11.57 (br. s, 1H), 7.53 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.27 (dd, J = 8.8, 1.6 Hz, 1H), 7.18 - 7.22 (m, 2H), 7.15 (d, J = 6.0 Hz, 2H), 6.84 - 6.89 (m, 4H), 5.56 (br. s, 1H), 4.45 (br. s, 1H), 3.97 - 4.00 (m, 2H), 3.61 - 3.44 (m, 3H), 3.08 - 3.11 (m, 3H), 2.85 - 2.94 (m, 2H), 2.22 (d, J = 2.0 Hz, 6H), 1.88 - 1.97 (m, 4H), 1.71 - 1.81 (m, 6H), 1.64 (br. s, 1H), 1.44 (s, 3H), 1.17 (t, J = 7.0 Hz, 6H), 1.07 (t, J = 7.6 Hz, 3H), 1.01 (t, J = 7.6 Hz, 3H). LCMS: m / z = 466.0 (M / 2+H) + .

[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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) δ 11.62 (br. s, 1H), 8.31 (br. s, 1H), 8.06 (br. s, 1H), 7.82 (t, J = 6.0 Hz, 1H), 7.59 - 7.65 (m, 1H), 7.52 (s, 1H), 7.42 - 7.45 (m, 1H), 7.25 - 7.29 (m, 1H), 7.16 - 7.19 (m, 2H), 6.88 (s, 1H), 6.73 (s, 1H), 5.59 (br. s, 1H), 4.48 (br. s, 1H), 3.97 - 4.00 (m, 2H), 3.46 - 3.59 (m, 3H), 3.01 - 3.11 (m, 1H), 2.84 - 2.92 (m, 2H), 2.21 (d, J = 1.8 Hz, 6H), 1.61 - 1.79 (m, 12H), 1.56 (br. s, 1H), 1.43 (br. s, 3H), 1.17 (br. s, 3H). LC-MS: m / z 860.2 (M+H) +

[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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) δ 11.58 (br. s, 1H), 7.53 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.27 (dd, J = 8.4, 1.6 Hz, 1H), 7.18 - 7.21 (m, 2H), 7.15 (d, J = 8.4 Hz, 2H), 6.80 - 6.93 (m, 4H), 5.55 (br. s, 1H), 4.46 (br. s, 1H), 3.97 - 4.00 (m, 2H), 3.46 - 3.57 (m, 5H), 3.07 (br. s, 1H), 2.84 - 3.91 (m, 2H), 2.22 (d, J = 2.0 Hz, 6H), 1.88 - 1.96 (m, 4H), 1.72 - 1.78 (m, 6H), 1.64 (s, 1H), 1.44 (s, 3H), 1.15 - 1.17 (m, 9H), 1.00 - 1.10 (m, 6H). LC-MS: m / z 944.4 (M+H) +

[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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) δ 11.61 (br. s, 1H), 7.81 - 7.87 (m, 1H), 7.76 (br. s, 1H), 7.62 - 7.66 (m, 1H), 7.52 (s, 1H), 7.43 (d, J = 8.6 Hz, 1H), 7.36 (s, 1H), 7.27 (dd, J = 8.4, 1.6 Hz, 1H), 7.16 (d, J = 6.0 Hz, 2H), 6.88 - 6.91 (m, 2H), 5.56 (br. s, 1H), 4.47 (br. s, 1H), 3.97 - 3.99 (m, 2H), 3.74 - 3.79 (m, 4H), 3.50 (dd, J = 11.2, 3.2 Hz, 4H), 2.80 - 3.10 (m, 6H), 2.22 (d, J = 1.6 Hz, 6H), 1.65 - 1.78 (m, 13H), 1.44 (s, 3H), 1.18 (s, 3H). LC-MS: m / z 944.4 (M+H) +

[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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) δ 7.96 - 8.01 (m, 2H), 7.76 (br. s, 1H), 7.50 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.36 - 7.39 (m, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 6.4 Hz, 2H), 6.99 (s, 1H), 6.80 (br. s, 1H), 5.56 (br. s, 1H), 4.44 (br. s, 1H), 3.97 - 4.00 (m, 2H), 3.46 - 3.52 (m, 3H), 3.12 - 3.14 (m, 2H), 2.83 - 2.91 (m, 1H), 2.21 (d, J = 1.6 Hz, 6H), 1.61 - 1.78 (m, 13H), 1.41 (s, 3H), 1.18 (s, 3H). LC-MS: m / z 943.3 (M+H) + .

[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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) δ: 11.58 (br. s, 1H), 9.06 (s, 1H), 8.22 (br. s, 1H), 8.01 (s, 1H), 7.51 (s, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.37 (s, 1H), 7.25 (dd, J = 8.8, 1.6 Hz, 1H), 7.13 (d, J = 6.4 Hz, 2H), 6.94 (br. s, 1H), 6.86 (br. s, 1H), 5.55 (br. s, 1H), 4.46 (br. s, 1H), 3.93 - 4.02 (m, 2H), 3.44 - 3.61 (m, 3H), 2.97 - 3.16 (m, 1H), 2.82 - 2.90 (m, 2H), 2.20 (d, J = 2.0 Hz, 6H), 1.56 - 1.81(m, 13H), 1.42 -1.43 (m, 3H), 1.16 (s, 3H). LC-MS: m / z 860.2 (M+H) +

[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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) 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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) 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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) δ: 11.58 (br. s, 1H), 7.95 (d, J = 9.6 Hz, 1H), 7.78 (br. s, 1H), 7.62 - 7.69 (m, 1H), 7.58 (br. s, 1H), 7.50 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.20 - 7.30 (m, 2H), 7.14 (d, J = 6.0 Hz, 2H), 6.86 (br. s, 2H), 5.55 (br. s, 1H), 4.46 (br. s, 1H), 3.93 - 4.03 (m, 2H), 3.56 (br. s, 1H), 3.44 - 3.50 (m, 2H), 3.05 (br. s, 1H), 2.81 - 2.89 (m, 2H), 2.20 (d, J = 1.6 Hz, 6H), 1.82 - 1.57 (m, 13H), 1.43 (s, 3H), 1.15 (s, 3H). LC-MS: m / z 859.2 (M+H) +

[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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) δ: 11.56 (br. s, 1H), 7.75 - 7.78 (m, 4H), 7.51 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.24 - 7.26 (m, 2H), 7.13 (d, J = 6.0 Hz, 2H), 6.86 - 6.87 (m, 2H), 5.54 (br. s, 1H), 4.44 (br. s, 1H), 3.95 - 3.98 (m, 2H), 3.55 (br. s, 1H), 3.47 (td, J = 11.2, 3.2 Hz, 2H), 3.11 - 3.15 (m, 1H), 2.82 - 2.89 (m, 2H), 2.20 (d, J = 1.6 Hz, 6H), 1.99 - 1.81 (m, 4H), 1.71 -1.76 (m, 6H), 1.60 - 1.70 (m, 1H), 1.41 (s, 3H), 1.15 (s, 3H), 1.02 - 0.91 (m, 6H). LCMS: m / z = 444.2 (M / 2+H)+.

[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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) 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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) δ: 11.56 (br. s, 1H), 7.64 - 7.69 (m, 1H), 7.57 (br. s, 2H), 7.51 (s, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.22 - 7.28 (m, 2H), 7.12 (d, J = 6.4 Hz, 2H), 6.86 (br. s, 2H), 5.54 (br. s, 1H), 4.44 (br. s, 1H), 3.94 - 3.98 (m, 2H), 3.54 (br. s, 1H), 3.47 (td, J = 11.2, 3.2 Hz, 2H), 3.11 - 3.15 (m, 1H), 2.83 - 2.89 (m, 2H), 2.61 (s, 3H), 2.20 (d, J = 1.6 Hz, 6H), 1.68 - 1.75 (m, 13H), 1.41 - 1.42 (br. s, 3H), 1.15 (br. s, 3H). LC-MS: m / z 873.2 (M+H) +

[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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) δ: 11.57 (br. s, 1H), 7.60 - 7.80 (m, 3H), 7.51 (s, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.25 (dd, J = 8.8, 1.6 Hz, 1H), 7.13 (d, J = 6.4 Hz, 2H), 6.98 (s, 1H), 6.75 - 6.95 (m, 2H), 5.56 (br. s, 1H), 4.43 (br. s, 1H), 3.95 - 3.98 (m, 2H), 3.56 (br. s, 1H), 3.47 (td, J = 11.2, 3.6 Hz, 2H), 3.11 - 3.15 (m, 1H), 2.92 - 2.81 (m, 2H), 2.23 (d, J = 1.6 Hz, 6H), 1.67 - 1.74 (m, 13H), 1.44 - 1.45 (m 3H), 1.17 (s, 3H). LC-MS: m / z 877.2 (M+H) +

[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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) 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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) 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 = 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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) δ: 11.55 (br. s, 1H), 7.51 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.21 - 7.25 (m, 2H), 7.11 (d, J = 6.0 Hz, 2H), 7.05 (d, J = 1.6 Hz, 1H), 6.99 (br. s, 1H), 6.70 - 6.90 (m, 3H), 5.53 (br. s, 1H), 4.44 (br. s, 1H), 3.94 - 3.97 (m, 2H), 3.56 (br. s, 1H), 3.44 - 3.49 (m, 3H), 2.90 - 2.83 (m, 2H), 2.20 (d, J = 1.6 Hz, 6H), 1.69 - 1.80 (m, 6H), 1.67 (br. s, 3H), 1.61 - 1.62 (m, 4H), 1.35 - 1.45 (m, 3H), 1.16 (br. s, 3H). LC-MS: m / z 874.2 (M+H) + .

[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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) δ: 11.58 (s, 1H), 7.80 - 7.81 (m, 4H), 7.50 (s, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.23 - 7.28 (m, 2H), 7.13 (d, J = 6.4 Hz, 2H), 6.86 - 6.88 (m, 2H), 5.57 (br. s, 1H), 4.44 (br. s, 1H), 3.65 - 3.75 (m, 2H), 3.55 (br. s, 1H), 3.00 - 3.03 (m, 2H), 2.80 - 2.95 (m, 1H), 2.20 (d, J = 1.6 Hz, 6H), 1.62 - 1.72 (m, 12H), 1.47 - 1.56 (m, 2H), 1.41 - 1.42 (m, 3H), 1.27 (br. s, 3H), 1.15 - 1.18 (m, 5H). LC-MS: m / z 887.3 (M+H) + .

[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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) δ: 11.81 (br. s, 1H), 7.49 - 7.50 (m, 2H), 7.23 - 7.25 (m, 3H), 7.15 (d, J = 6.0 Hz, 2H), 6.81 - 6.92 (m, 3H), 6.79 (s, 1H), 5.54 (br. s, 1H), 4.49 (br. s, 1H), 3.98 - 4.00 (m, 2H), 3.44 - 3.55 (m, 3H), 2.82 - 2.92 (m, 4H), 2.74 (s, 3H), 2.22 (d, J = 2.0 Hz, 6H), 1.90 - 1.95 (m, 4H), 1.75 - 1.79 (m, 7H), 1.54 (br. s, 1H), 1.39 (d, J = 6.4 Hz, 3H), 0.95 - 1.10 (m, 6H). LC-MS: m / z 901.8 (M+H) + .

[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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) 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, 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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) δ 11.39 (br. s, 1H), 7.50 (s, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.11 - 7.19 (m, 2H), 7.08 (s, 1H), 6.99 (s, 1H), 6.77 - 6.82 (m, 2H), 6.32 (s, 2H), 5.55 (br. s, 1H), 4.42 (br. s, 1H), 3.96 (d, J = 10.8 Hz, 2H), 3.40 - 3.55 (m, 3H), 2.95 - 3.01 (m, 1H), 2.82 - 2.89 (m, 2H), 2.20 (s, 6H), 1.85 - 1.94 (m, 4H), 1.70 - 1.75 (m, 6H), 1.62 (br. s, 1H), 1.39 (br. s, 3H), 1.10 - 1.25 (m, 3H), 1.08 - 0.97 (m, 6H). LC-MS: m / z 452.0 (M / 2+H) + .

[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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) δ 11.55 (s, 1H), 8.24 (s, 1H), 7.52 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.34 (s, 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 6.0 Hz, 2H), 6.88 - 6.95 (m, 2H), 5.57 (br. s, 1H), 4.46 (br. s, 1H), 3.90 - 4.10 (m, 2H), 3.43 - 3.62 (m, 3H), 2.84 - 2.92 (m, 3H), 2.75 (br. s, 3H), 2.22 (s, 6H), 1.88 - 2.01 (m, 5H), 1.56 - 1.80 (m, 7H), 1.44 (s, 3H), 1.10 - 1.30 (m, 3H), 0.90 - 1.09 (m, 6H). LCMS: m / z = 917.4 (M+H) + .

[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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) δ 11.59 (s, 1H), 7.52 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.20 (s, 1H), 7.14 (d, J = 5.6 Hz, 2H), 6.67 - 7.00 (m, 4H), 5.55 (br. s, 1H), 4.46 (br. s, 1H), 3.98 (d, J = 10.8 Hz, 2H), 3.53 - 3.45 (m, 3H), 2.87 - 2.91 (m, 3H), 2.67 (br. s, 3H), 2.27 (br. s, 3H), 2.23 (s, 6H), 1.95 - 2.07 (m, 4H), 1.60 - 1.81 (m, 7H), 1.44 (s, 3H), 1.12 - 1.30 (m, 3H), 1.13 - 0.99 (m, 6H). LC-MS: m / z 466.0 (M / 2+H) + .

[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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) δ 11.56 (br. s, 1H), 7.53 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.27 (dd, J = 8.8, 1.6 Hz, 1H), 7.24 (s, 1H), 7.00 - 7.20 (m, 3H), 6.87 (br. s, 4H), 5.57 (br. s, 1H), 4.47 (br. s, 1H), 3.94 - 4.03 (m, 2H), 3.54 (br. s, 1H), 3.49 (td, J = 11.2, 4.0 Hz, 2H), 2.83 - 2.91 (m, 3H), 2.71 (br. s, 3H), 2.38 - 2.27 (m, 2H), 2.22 (d, J = 2.0 Hz, 6H), 1.72 - 1.77 (m, 6H), 1.64 (br. s, 1H), 1.44 (br. s, 3H), 0.97 - 1.20 (m, 9H), 0.95-1.20 (m, 6H). LC-MS: m / z 473.2 (M / 2+H) + .

[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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) δ 11.60 (br. s, 1H), 7.77 - 8.27(m, 4H), 7.53 (s, 1H), 7.30 - 7.50 (m, 2H), 7.27 (d, J = 8.8 Hz, 1H), 7.16 (d, J = 8.0 Hz, 2H), 6.95 (s, 1H), 6.88 (s, 1H), 5.58 (br. s, 1H), 4.46 (br. s, 1H), 3.96 - 4.03 (m, 2H), 3.46 - 3.60 (m, 3H), 2.84 - 2.91 (m, 3H), 2.22 (d, LC-MS: m / z 937.2 (M+H) + .

[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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) δ: 8.39 (br. s, 1H), 7.52 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.25 - 7.32 (m, 2H), 7.13 (d, J = 6.0 Hz, 2H), 6.86 (s, 2H), 6.71 (s, 2H), 5.54 (br. s, 1H), 4.45 (br. s, 1H), 3.97 (d, J = 10.8 Hz, 2H), 3.45 - 3.51 (m, 3H), 2.85 - 2.95 (m, 3H), 2.71 (s, 3H), 2.21 (s, 6H), 1.85 - 1.99 (m, 4H), 1.60 - 1.79 (m, 7H), 1.42 (m, 3H), 1.15 (br. s, 3H), 1.02 - 1.15 (m,6H). LC-MS: m / z 934.4 (M+H) +

[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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) 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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) δ 11.58 (br. s, 1H), 7.53 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 2H), 7.06 - 7.12 (m, 1H), 6.74 - 6.93 (m, 4H), 5.57 (br. s, 1H), 4.45 (br. s, 1H), 3.98 (d, J = 12.0 Hz, 2H), 3.42 - 3.55 (m, 3H), 2.88 - 2.94 (m, 6H), 2.25 LC-MS: m / z 934.2 (M+H) + .

[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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) δ 11.57 (br. s, 1H), 7.68 (br. s, 1H), 7.52 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.21 - 7.27 (m, 3H), 7.15 (d, J = 6.0 Hz, 2H), 6.86 (br. s, 4H), 5.56 (br. s, 1H), 4.48 (br. s, 1H), 3.74 (d, J = 7.2 Hz, 2H), 3.58 (s, 1H), 2.99 - 3.02 (m, 1H), 2.86 - 2.93 (m, 2H), 2.65 - 2.80 (m, 3H), 2.23 (s, 6H), 1.88 - 1.97 (m, 4H), 1.69 - 1.77 (m, 4H), 1.59 - 1.67 (m, 2H), 1.50 - 1.58 (m, 1H), 1.44 (br. s, 3H), 1.30 (br. s, 3H), 1.27 (br. s, 1H), 1.21 (s, 3H), 1.15 - 1.25 (m, 2H), 0.99 - 1.08 (m, 6H). LC-MS: m / z 473.0 (M / 2+H) + .

[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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) δ 11.59 (br. s, 1H), 7.52 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 8.8 Hz, 1H), 7.18 - 7.24 (m, 2H), 7.15 (d, J = 6.0 Hz, 2H), 6.86 (br. s, 4H), 5.55 (br. s, 1H), 4.45 (br. s, 1H), 3.73 (d, J = 8.0 Hz, 2H), 3.56 (br. s, 1H), 2.95 - 3.05 (m, 2H), 2.85 - 2.95 (m, 1H), 2.72 (br. s, 3H), 2.22 (s, 6H), 1.88 - 1.96 (m, 4H), 1.51 - 1.77 (m, 7H), 1.44 (br. s, 3H), 1.29 (s, 3H), 1.20 (s, 3H), 1.17 (br. s, 3H), 0.95 - 1.10 (m, 6H). LC-MS: m / z 944.4 (M+H) +

[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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) δ 11.56 (br. s, 1H), 7.66 - 7.75 (m, 2H), 7.53 (s, 1 H), 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) [ka] Step A: (2-amino-4-bromophenyl)diethylphosphine oxide To a solution of 5-bromo-2-iodoaniline (1.00 g, 3.36 mmol) in dioxane (10 mL) was added Pd(dba) (154 mg, 0.168 mmol), Xantphos (194 mg, 0.336 mmol), TEA (680 mg, 6.71 mmol), and diethylphosphine oxide (356 mg, 3.36 mmol) at room temperature. The resulting mixture was stirred at 60 °C under a N atmosphere for 12 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by flash chromatography (eluted with DCM / MeOH=10 / 1) to give the title compound (2-amino-4-bromophenyl)diethylphosphine oxide as a brown oil (1.10 g, overnight, 100% yield). LC-MS: m / z 276.0, 278.0 (M+H) + 1 H NMR (400 MHz, CDCl3) δ: 6.75 - 6.81 (m, 3H), 5.63 (br. s, 2H), 1.84 - 2.01 (m, 4H), 1.12 - 1.20 (m, 6H).

[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) was 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 hours. The reaction mixture was quenched with water (15 mL). The resulting mixture was extracted with DCM (3 × 15 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by flash chromatography (eluted 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 H 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 H NMR (400 MHz, DMSO-d 6,80℃) 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, 1 H), 4.47 (br. s, 1 H), 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 compounds were synthesized using methods similar to those 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) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) 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) [ka] Step A: 4-Bromo-2-iodo-6-nitroaniline To a solution of 4-bromo-2-nitroaniline (4.40 g, 20.2 mmol) in AcOH (30 mL) was added NIS (8.80 g, 40.4 mmol). The resulting mixture was stirred at 80 °C under a N atmosphere for 2 hours. The reaction mixture was cooled to room temperature, diluted with water (60 mL), and extracted with DCM (3 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by flash chromatography (eluted with PE / EtOAc = 5 / 1) to give the title compound 4-bromo-2-iodo-6-nitroaniline as a yellow solid (6.00 g, 88% yield). 1 H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 2.4 Hz, 1H), 8.01 (d, J = 2.4 Hz, 1H), 6.67 (s, 2H).

[0452] Step B: 5-Bromo-3-iodobenzene-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 SnCl (6.00 g, 43.5 mmol). The resulting mixture was stirred at 80 ° C for 3 hours. 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 obtain 5-bromo-3-iodobenzene-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 hours under a N atmosphere. The reaction was concentrated to remove excess HCOOH. Water was then added, and the mixture was extracted with EA. The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by silica column to give the crude 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. 1H 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 compounds were synthesized using a method similar to that 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) [ka] 1H NMR (400 MHz, DMSO-d6) δ 11.60 (br. s, 1H), 8.23 ​​(s, 1H), 8.16 (br. s, 1H), 7.81 (d, J = 15.2 Hz, 1H), 7.52 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.26 - 7.28 (m, 2H), 7.17 (d, J = 6.4 Hz, 2H), 6.88 (br. s, 2H), 5.60 - 5.63 (m, 1H), 4.53 (s, 3H), 4.46 - 4.58 (m, 1H), 3.96 - 3.99 (m, 2H), 3.51 - 3.58 (m, 1H), 3.45 - 3.50 (m, 2H), 3.02 - 3.07 (m, 1H), 2.88 - 2.91 (m, 2H), 2.23 (d, J = 1.6 Hz, 6H), 1.62 - 2.00 (m, 13H), 1.47 (br. s, 3H), 1.17 (br. s, 3H). LC-MS: m / z 913.4(M+H) +

[0457] Example 5 3-((1S,2S)-1-(2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(4-(1-oxidophosphoran-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) [ka] Step A: (4-Bromophenyl)phosphonic acid dichloride To a mixture of diethyl (4-bromophenyl)phosphonate (4.00 g, 13.6 mmol) and DMF (948 mg, 13.0 mmol) was added thionyl chloride (49.2 g, 413 mmol). The mixture was heated under reflux for 48 hours. The reaction mixture was concentrated, and the residue was dried under reduced pressure to obtain crude (4-bromophenyl)phosphonic acid dichloride as a yellow oil (3.88 g), which was used directly in the next step.

[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, allylmagnesium chloride (1.0 M in THF, 42.6 mL, 42.6 mmol) was added dropwise. The mixture was stirred at -70 °C for 1.5 hours. LCMS showed the reaction was complete. The mixture was quenched with saturated aqueous NH4Cl (50 mL) at -70 °C. 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 (eluted with PE / EtOAc = 1 / 3) to give the title compound diallyl(4-bromophenyl)phosphine oxide as a yellow solid (1.80 g, 46% yield for two 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-dihydrophosphor 1-oxide To a solution of diallyl(4-bromophenyl)phosphine oxide (400 mg, 1.58 mmol) in dichloromethane (40 mL), Grubbs' catalyst (2nd generation, 70.0 mg, 0.08 mmol) was added. The mixture was stirred under Ar atmosphere at 50 ° C for 12 hours. LCMS showed the reaction was complete. The mixture was concentrated, and the residue was purified by silica column chromatography (eluted with PE / EA / methanol = 1 / 4 / 0.1) to obtain the title compound 1-(4-bromophenyl)-2,5-dihydrophosphor 1-oxide as a pale white solid (154 mg, yield 38%). 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)phosphorane 1-oxide To a solution of 1-(4-bromophenyl)-2,5-dihydrophosphor 1-oxide (154 mg, 0.600 mmol) in EtOAc (8 mL) was added platinum oxide (15.0 mg, 0.0660 mmol). The mixture was stirred at room temperature under an H atmosphere for 4 hours. LCMS showed the reaction was complete. The solid was filtered, and the filtrate was concentrated. The residue was purified by silica column chromatography (eluted with PE / EA / methanol = 1 / 4 / 0.2) to obtain the title compound 1-(4-bromophenyl)phosphorane 1-oxide as a pale white solid (107 mg, yield 69%). LC-MS: m / z 259.0, 261.0 (M+H) + . 1H 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-oxidophosphoran-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 H NMR (400 MHz, DMSO-d6, 80℃) 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-oxido-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) [ka] Step A: 4-(4-Bromophenyl)-1-methyl-1,4-azaphosphinane 4-oxide To a solution of (4-bromophenyl)divinylphosphine oxide (585 mg, 2.28 mmol) in methanol (10 mL), methanamine (0.98 M in methanol, 2.79 mL, 2.74 mmol) was added dropwise. The mixture was stirred at 60° C. for 1 hour. LCMS showed the reaction was complete. The mixture was concentrated, and the residue was purified by silica column chromatography (eluted with DCM / methanol=10 / 1) to obtain the title compound 4-(4-bromophenyl)-1-methyl-1,4-azaazaphosphinane 4-oxide as a yellow solid (278 mg, yield 42%). LC-MS: m / z 288.0, 290.0 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 7.72 - 7.77 (m, 4H), 2.68 - 2.78 (m, 4H), 2.19 - 2.29 (m, 5H), 1.84 - 1.99 (m, 2H).

[0463] 3-((1S,2S)-1-(2-((S)-2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(4-(1-methyl-4-oxido-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 methods similar to those 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) [ka] 1 HNMR (400 MHz, DMSO-d6, 80℃) δ 11.47 (br. s, 1H), 7.79 - 7.80 (br. s, 4H), 7.52 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.29 (s, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 6.4 Hz, 2H), 6.91 (br. s, 1H), 6.85 (br. s, 1H), 5.57 (br. s, 1H), 4.44 (br. s, 1H), 3.73 - 3.75 (m, 2H), 3.56 (br. s, 1H), 2.96 - 3.04 (m, 2H), 2.82 - 2.95 (m, 1H), 2.22 (d, J = 1.6 Hz, 6H), 1.82 - 2.04 (m, 4H), 1.52 - 1.76 (m, 7H), 1.35 - 1.50 (m, 3H), 1.25 - 1.35 (m, 3H), 1.18 - 1.21 (m, 6H), 0.92 - 1.05 (m, 6H). LC-MS: m / z 915.4 (M+H) + .

[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) [ka] 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. After cooling 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 To a mixture of diethyl (4-bromo-2-fluorophenyl)phosphonate (1.40 g, 4.50 mmol) in thionyl chloride (49.2 g, 414 mmol), dry DMF (1.42 g, 19.4 mmol) was added dropwise. The mixture was heated under reflux for 72 hours. The mixture was concentrated and dried under reduced pressure to obtain (4-bromo-2-fluorophenyl)phosphonic acid 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 acid dichloride (1.50 g, crude product) in dry THF (10 mL) at -70 °C, cyclopropylmagnesium bromide (2.0 M in THF, 5.13 mL, 10.3 mmol) was added dropwise. The mixture was stirred at -70 °C for 2 hours. LCMS showed the reaction was complete. The mixture was quenched with saturated aqueous NH4Cl solution (50 mL) at -70 °C. Then, the mixture was 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 (eluted with PE / EtOAc = 1 / 2) to give the title compound (4-bromo-2-fluorophenyl)dicyclopropylphosphine oxide as a yellow solid (420 mg, yield 27%). 1 HNMR (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 that 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) [ka] 1 HNMR (400 MHz, DMSO-d6, 80℃) δ 7.45 - 7.50 (m, 3H), 7.18 - 7.20 (m, 3H), 7.13 (d, J = 6.4 Hz, 2H), 6.81 - 6.88 (m, 2H), 6.71 (s, 1H), 5.51 (br. s, 1H), 4.47 (br. s, 1H), 3.96 (d, J = 10.8 Hz, 2H), 3.43 - 3.51 (m, 3H), 2.90 - 2.85 (m, 2H), 2.77 - 2.81 (m, 1H), 2.70 (s, 3H), 2.20 (s, 6H), 1.65 - 1.73 (m, 6H), 1.40 -1.55 (br. s, 1H), 1.35 (d, J = 6.4 Hz, 3H), 1.15 - 1.30 (m, 3H), 0.72 - 0.92 (m, 6H), 0.58 - 0.69 (m, 2H). LC-MS: m / z 926.4 (M+H) +

[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) [ka] 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) [ka] 1 HNMR (400 MHz, DMSO-d6, 80℃) δ11.76 (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) [ka] Step A: 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 To a solution 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 (400 mg, 0.86 mmol) and 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (629.4 mg, 2.58 mmol) in dioxane / HO = 5 / 1 (20 mL) was added KCO (237 mg, 1.72 mmol) and Pd(dppf)Cl (70.1 mg, 0.0860 mmol) at room temperature. The resulting mixture was stirred at 80 °C under a N atmosphere for 16 h. The reaction solution was concentrated, and the residue was purified by silica gel using PE / EA=3 / 1 to 2 / 1 to give 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 as a yellow sticky substance (360 mg, yield 83%). 1HNMR (400 MHz, CDCl3) δ 11.19 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.32 - 7.36 (m, 5H), 7.15 (s, 2H), 5.89 (s, 1H), 5.78 (s, 1H), 3.56 (s, 3H), 2.64 - 2.71 (m, 3H), 2.10 - 2.20 (m, 2H), 1.92 (t, J = 7.2 Hz, 1H), 1.78 - 1.83 (m, 2H), 1.48 (dd, J = 9.2, 6.8 Hz, 1H), 1.28 (d, J = 6.8 Hz, 3H). LC-MS: m / z 505.2 (M+H) + .

[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. The resulting solution was then stirred at room temperature under H for 16 hours. The reaction was filtered, and the filtrate was concentrated. The crude product was purified by preparative HPLC (HCOOH / CHCN / HO) 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, 14% yield). 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℃) 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) [ka] 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), Pd(dba) (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 a N atmosphere. The mixture was stirred at 100° C. for 4 hours under microwave irradiation. 1M HCl (10 mL) was added to the mixture, which was then extracted with EA (30 mL). The organic layer was washed with saturated aqueous NaHCO (10 mL), brine (10 mL), dried over NaSO, concentrated, and purified by flash chromatography (eluted 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, 54% yield). 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 To 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 added t-BuOK (2.3 g, 20.5 mmol), followed by HO (116 mg). The mixture was stirred at room temperature overnight. The mixture was concentrated, and the pH was adjusted to 4-5 with 1 N aqueous HCl. The mixture was extracted with DCM (3x20 mL), dried over Na2SO4, concentrated and purified by reverse phase to give 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 To a mixture of (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) was added DIEA (150 mg, 1.16 mmol). The mixture was stirred at room temperature overnight, water (30 mL) was added to the mixture, and it was extracted with DCM (3x20 mL). The organic layer was washed with brine, dried over NaSO, 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, 35% yield). 1HNMR (400 MHz, DMSO-d6, 80℃) 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 mediated by the G protein heterotrimer G αs It is known to activate the production of cyclic AMP (cAMP) in cells that exhibit initial binding to the G subunit. αs It has been suggested that signaling via cAMP activation induced by β-glucanase (GlcNAc) mediates the desired pharmacological response for insulin release from pancreatic β-cells.

[0481] Method 1: G αsTo optimize the functional activity of binding, the CHO-K1 cell line developed by DiscoverX is used, which stably expresses GLP-1 receptor.The cells expressing GLP-1 receptor are placed in a 384-well microtiter plate and incubated overnight at 37 ℃ in 5% CO 2 to allow cells to adhere and grow.Then, the medium is aspirated from cells and replaced with 15 μL of Hank's balanced salt solution (HBSS) / 5mM Hepes:0.5mM IBMX:0.1% BSA (pH 7.4) [activation buffer].The plated cells are resuspended in activation buffer, and 5 microliters (5 μL) of this suspension is added to the compound sample prepared previously in activation buffer at 4x final concentration, and then added to the cells and incubated at 37 ℃ for 30 or 60 minutes.

[0482] After incubation, the assay signal is developed using a europium chelate-labeled cAMP tracer that competes with cAMP for the binding sites of a cAMP-specific monoclonal antibody labeled with ULight® dye. FRET transition between the Eu chelate and the ULight®-labeled antibody is detected when the antibody binds to the Eu-labeled cAMP tracer. Free cAMP produced from activated cells competes with the Eu-cAMP tracer in a dose-dependent manner for binding to the ULight-mAb, resulting in a decrease in the TR-FRET signal.

[0483] The method for detecting cAMP using Eu-chelation technology requires incubation with Eu-cAMP tracer solution + ULight-anti-cAMP solution for 1 hour at room temperature. The microplate is read after signal development using a PerkinElmer Envision instrument that utilizes TR-FRET signal detection. The activity percentage is calculated using the following formula: % Activity = 100% x (mean RLU of test sample - mean RLU of vehicle control) / (mean RLU of MAX control - mean RLU of vehicle control) Calculate using:

[0484] Method 2: Gαs To optimize the functional activity of binding, the CHO-K1 cell line developed by DiscoverX, which stably expresses GLP-1 receptor, is used. The cells expressing GLP-1 receptor are plated in a 384-well microtiter plate and incubated overnight at 37°C in 5% CO2 to allow the cells to adhere and grow. The medium is then 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. Five microliters (5 μL) of the compound sample previously prepared in activation buffer at 4x final concentration are then 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 B-galactosidase cleaves the enzyme into two complementary moieties (EA and ED). The ED fragment is fused to cAMP and competes with endogenous cAMP for binding to a cAMP-specific antibody in this assay. Activated B-Gal is formed when the exogenous EA fragment binds to free ED-cAMP (but not the cAMP-specific antibody). Activated enzyme levels are detected by conversion of the B-gal chemiluminescent substrate, which generates a detectable luminescent signal and is read in a standard microtiter plate.

[0486] The cAMP detection method using EFC requires incubation with 20 μL of cAMP XS+ED / CL lysis mixture for 1 hour at room temperature, followed by incubation with 20 μL of cAMP XS+EA for 3 hours. The microplate is read after signal development with a PerkinElmer Envision instrument using chemiluminescence signal detection. Compound activity is analyzed using the CBIS data analysis suite (ChemInnovation, CA). Percent activity is calculated using the following equation: % Activity = 100% x (mean RLU of test sample - mean RLU of vehicle control) / (mean RLU of MAX control - mean RLU of vehicle control) Calculate using:

[0487] Method 3 Activation of the GLP-1 receptor occurs via the G protein heterotrimer G αs It is known to activate the production of cyclic AMP (cAMP) in cells that exhibit initial binding to the G subunit. αs It has been suggested that signaling via cAMP activation induced by β-glucanase (GlcNAc) mediates the desired pharmacological response for insulin release from pancreatic β-cells.

[0488] G αs To optimize functional activity for binding, the HEK293 / CRE-Luc cell line developed by HDB, which stably expresses the GLP-1 receptor, was used. A 200x compound working solution (Agilent Technologies Bravo) was prepared in a 1 / 2 log serial dilution in a 384-well Echo LDV plate (Labcyte, Cat# LP-0200). 50 nL / well of the 200x compound working solution was transferred to a 384-well white low-volume plate (Greiner, Cat# 784075) using a Labcyte ECHO550. 1x10 5 Cells / mL of HEK293 / GLP1R / CRE-LUC (HD Biosciences) cell suspension is prepared in assay buffer [DPBS containing 0.5mM IBMX (Sigma, Cat#I5879) and 0.1% BSA (GENVIEW, Cat#FA016-100g)], and 10 μL of cell suspension is added to each well of the previously prepared assay plate containing 50nL of compound at 200x concentration using ThermoFisher Multidrop Combi (1000 cells / well).The plate is sealed and incubated at 37°C under 5% CO2 for 30 minutes.

[0489] After incubation, the cAMP assay signal was developed using the cAMP Dynamic 2 Kit (Cisbio). Five microliters of cAMP-d2 working solution was added to each well, followed by 5 μL of anti-cAMP antibody-cryptate working solution, using a ThermoFisher Multidrop Combi. The wells were incubated at room temperature for 1 hour, protected from light. The luminescence was read at 665 nm and 615 nm using a PerkinElmer EnVision reader. % Activity = 100% x (mean RLU of test sample - mean RLU of vehicle control) / (mean RLU of MAX control - mean RLU of vehicle control) Table 1 shows the cAMP activation assay (EC 50 ) [nM] (Method 3) [Table 4] TIFF2025160228000207.tif23105 Notes: EC 50 Range: A: 0 <EC 50 ≦0.1; B:0.1 <EC 50 ≦0.2; C:0.2 <EC 50 ≦0.5; D:0.5 <EC 50 <5 pEC 50 Range: A: pEC 50 ≥ 10; B: 9 ≤ pEC 50 <10;C:8≦pEC 50 <9

[0490] Example B: Rat Pharmacokinetic (PK) Study Pharmacokinetic (PK) studies were conducted using male Sprague-Dawley (SD) rats via two delivery routes: intravenous (IV) and / or oral gavage (PO). Rats (n = 3) administered via the IV route had free access to food and water. Rats (n = 3) administered via the PO route were fasted overnight and given food 4 hours after dosing. The test drug was formulated in solution for the IV route and in solution or suspension for the PO route. On the experimental day, the test drug was administered via intravenous (e.g., dorsalis pedis) injection (usually 0.2–1 mg / kg and 2 mL / kg) or via oral gavage (usually 5–100 mg / kg and 10 mL / kg) administration for the PO route. Blood samples were collected serially at 8 time points from 0.083 to 24 hours post-dose. Approximately 150 μL of blood per time point was collected via the tail vein into K2EDTA tubes. The blood samples were placed on wet ice and centrifuged to obtain plasma samples, which were then 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 a non-compartmental model using WinNonlin.

[0491] Exemplary compounds of Formula (I) (e.g., certain compounds of Formula (I-E)) were tested using the above protocol. The test compounds exhibited plasma clearances (L / hr / kg) ranging from 0.20 to 1.60 (e.g., 0.20 to 0.80 (e.g., 0.30 to 0.50); ​​or 1.00 to 1.60 (e.g., 1.20 to 1.60)); and volumes of distribution (L / kg) ranging from 0.40 to 0.70 (L / kg).

[0492] Example C Glucose Tolerance Test in Non-Human Primates (NHP) Cynomolgus monkeys (2.5-6.0 kg) were individually housed in stainless steel cages in a controlled environment maintained at 18-26°C and 30-70% relative humidity with a minimum of 10 air changes per hour throughout the study period. A time-controlled lighting system (lights 7:00 AM - 7:00 PM) provided a regular 12-hour light / 12-hour dark circadian cycle. The monkeys were fed three times per day: 100 g of regular chow from 9:00 AM to 10:00 AM, one regular fruit meal (150 g) from 2:00 PM to 3:00 PM, and another 100 g of regular chow from 4:00 PM to 5:00 PM. Drinking water was provided ad libitum. All animals underwent a baseline ivGTT, and selected animals were then assigned to designated groups based on the baseline ivGTT insulin AUC and their body weight. A general study outline is shown in the table below: [Table 5]

[0493] Animals were acclimated for 1 week before the start of the study. On day 1, all animals were dosed with vehicle by IV injection 5 minutes prior to IV glucose challenge. On day 9, all animals were dosed with vehicle or compound by IV injection 5 minutes prior to IV glucose challenge.

[0494] An ivGTT was performed on each of days 1 and 9. Animals were fasted overnight and anesthetized (Zoletil 50, intramuscular, initial dose of 5 mg / kg, followed by maintenance doses of 2.5-5 mg / kg as needed).

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

[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 until analysis of glucose, insulin, and C-peptide.

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

[0498] Exemplary compounds of Formula (I) (e.g., certain compounds of Formula (I-E)) were tested using the above protocol. Specifically, test compounds were injected intravenously into healthy NHPs at doses selected from 0.03-0.30 mg / kg (e.g., a dose of 0.05 mg / kg). Following the procedures described above, a 2.0- to 6.0-fold (e.g., 3.0- to 5.0-fold) increase in insulin secretion was induced in an iv GTT, and a 10% to 40% (e.g., 30% to 40%) increase in glucose clearance rate was observed.

[0499] Other embodiments While the present invention has been described in conjunction with its detailed description, it is to be understood that the description is intended to be illustrative and not limiting of the scope of the invention, which is defined by the claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

1. Formula (I): 【Chemical 1】 Formula (I) [In the formula, Q １ , Q ２ , Q ３ , Q ４ , and Q ５ is defined by (AA) or (BB) below: (AA) Q １ and Q ５ are independently N, CH, and CR ＱＡ selected from the group consisting of: Q ２ , Q ３ , and Q ４ are independently N, CH, CR ＱＡ , and C.R. ＱＢ with the proviso that Q ２ , Q ３ , and Q ４ At least one of the following is CR ＱＢ and each 【Chemistry 2】 is a single or double bond, provided that Q １ -Q ５ is aromatic; (BB) Q １ is a bond; Q ２ , Q ３ , Q ４ , and Q ５ are independently O, S, N, NH, NR ｃ , C.H., C.R. ＱＡ , and C.R. ＱＢ with the proviso that Q ２ , Q ３ , Q ４ , and Q ５ At least one of the following is CR ＱＢ and each 【Chemistry 3】 is a single or double bond, provided that Q １ -Q ５ is aromatic; R ＱＢ is P(=O)R ａ R ｂ wherein R ａ and R ｂ are independently １－６ Alkoxy, C ３－６ C optionally substituted with 1 to 6 substituents each independently selected from the group consisting of cycloalkyl, and halo １－６ Alkyl; C １－３ C optionally substituted with 1 to 3 substituents each independently selected from the group consisting of alkyl and halo ３－６ cycloalkyl; and 1 to 3 independently selected C １－３ C optionally substituted with alkyl ６－１０ aryl; or R ａ and R ｂ are taken together with the phosphorus atom to which they are attached to form a ring containing 5 to 8 ring atoms, and 0 to 2 ring atoms (R ａ and R ｂ (in addition to the phosphorus bonded to １－６ optionally substituted with alkyl; Each R ＱＡ are 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) 1 to 6 independently selected R ｆ C optionally substituted with １－６ alkyl; (h) hydroxy, halo, and C １－６ C optionally substituted with 1 to 6 substituents each independently selected from the group consisting of alkoxy １－６ Alkoxy; (i) C １－６ Alkyl and C(=O)(C １－６ (j) a 3- to 12-membered heterocyclyl optionally substituted with one or more substituents, each independently selected from the group consisting of C(═O)(C １－６ C optionally substituted with alkyl ６－１０ aryl; and (k) 1 to 6 independently selected R ｇ or is selected from the group consisting of 5-10 membered heteroaryl optionally substituted with A pair of R on adjacent carbon atoms ＱＡ are taken together with the atom to which they are each attached to form a ring containing 5 to 8 ring atoms, wherein 0 to 2 ring atoms are heteroatoms each independently selected from the group consisting of O, N, and S, and said ring is joined to 1 to 2 independently selected R ｈ optionally substituted with groups; L ２ teeth, 【Chemistry 4】 wherein: aa is Q １ -Q ５ indicates the point of attachment to the ring containing n1 is an integer from 1 to 3; L ２Ａ is a bond or C １－１０ alkylene; R Ｌａ is H, C １－６ Alkyl, and C(=O)(C １－６ alkyl); R Ｌｂ and R Ｌｃ each independently represents H and C １－６ selected from the group consisting of alkyl; Ring A is C ６－１０ Aryl, C ５－７ cycloalkyl, 5- to 7-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is selected from halo, C １－６ Alkyl, C １－６ Haloalkyl, and C １－６ optionally substituted with 1 to 5 substituents each independently selected from the group consisting of alkoxy; R １ , R ２ , and R ３ are each independently H, and halo, —OH, and C １－６ C optionally substituted with 1 to 6 substituents each independently selected from the group consisting of alkoxy １－６ selected from the group consisting of alkyl; L １ is -C(=O)-, -CH ２ -, -CH(C １－６ alkyl)-, and -S(=O) ２ selected from the group consisting of: Ring B is 【Chemistry 5】 wherein: bb is L １ indicates the point of attachment to R ４ , R ５ , R ６ , and R ７ are independently H, halo, and C １－６ selected from the group consisting of alkyl; L ３ is a bond or C １－３ alkylene; L ４ is a bond or C １－５ alkylene; R ８ａ and R ８ｂ are independently H, and halo and C ３－１５ C optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl １－６ alkyl; or R ８ａ and R ８ｂ Each, together with the carbon atom to which it is attached, represents 1 to 3 independently selected C １－６ C optionally substituted with alkyl ３－１５ Forms a cycloalkyl ring, １－６ Alkyl is 1 to 6 independently selected R ｆ optionally substituted with; R ９ are C(=O)OH, C(=O)(OC １－６ alkyl), C(=O)NR ９ａ R ９ｂ , (IX-1), (IX-2), (IX-3), and (IX-4): 【Chemistry 6】 selected from the group consisting of: R ９ａ is H or C １－６ is 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 H; 1 to 6 independently selected halo and C １－６ C optionally substituted with alkoxy １－６ alkyl; and C(═O)(C １－６ alkyl); Ring C is a 3- to 12-membered heterocyclyl; ３－１５ cycloalkyl; and 5- to 10-membered heteroaryl, each of which is selected from the group consisting of 1 to 3 R Ｃａ optionally substituted with; Each R Ｃａ are independently halo, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, and NR ｃ R ｄ or is selected from the group consisting of: A pair of R on the same or different ring atoms Ｃａ are taken together with the ring atom to which they are each attached to form a carbocyclic ring containing 3 to 8 ring atoms; Each R ｃ and R ｄ is 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), 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) are each selected from —OH, halo, and C １－６ optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkoxy; R ｅ is H, C １－６ Alkyl, or C １－６ haloalkyl; Each R ｆ are independently halo, —OH, NR ｃ R ｄ , C １－６ Alkoxy, C １－６ Haloalkoxy, as well as —OH, C １－６ selected from the group consisting of alkyl, and 3- to 12-membered heterocyclyl, optionally substituted with 1 to 4 substituents, each independently selected from the group consisting of 3- to 12-membered heterocyclyl; Each R ｇ are independently １－６ Alkyl, C １－６ Alkoxy, NR ｃ R ｄ , and C １－６ Alkyl and C(=O)C １－６ is 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 alkyl; and Each R ｈ are independently 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] or a pharmaceutically acceptable salt or solvate thereof.

2. Q １ , Q ２ , Q ３ , Q ４ , and Q ５ The compound of claim 1 wherein is defined by (AA).

3. Q ３ But, CR ＱＢ 3. The compound of claim 2, wherein:

4. Q ４ is N, CH, or CR ＱＡ 4. The compound of claim 3, wherein:

5. Q ４ But, CR ＱＢ and Q ３ is N, CH, or CR ＱＡ 3. The compound of claim 2, wherein:

6. Q １ The compound according to any one of claims 2 to 5, wherein is CH.

7. Q ２ The compound according to any one of claims 2 to 6, wherein is CH.

8. Q ５ But, CR ＱＡ The compound according to any one of claims 2 to 7,

9. Q ５ The compound according to any one of claims 2 to 7, wherein is CH.

10. Q ３ But, CR ＱＢ and Q １ , Q ２ , Q ４ , and Q ５ each independently represents CH or CR ＱＡ 3. The compound of claim 2, wherein:

11. Q １ , Q ２ , Q ４ , and Q ５ 11. The compound of claim 10, wherein each of is CH.

12. 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 and each remaining one of is CH.

13. Q ４ But, CR ＱＡ and Q １ , Q ２ , and Q ５ The compound of claim 12, wherein is CH.

14. Q １ , Q ２ , Q ４ , and Q ５ Two of the CRs are independently selected. ＱＡ and Q １ , Q ２ , Q ４ , and Q ５ and each remaining one of is CH.

15. Q ３ But, CR ＱＢ and Q １ , Q ２ , Q ４ , and Q ５ is N, and Q １ , Q ２ , Q ４ , and Q ５ each remaining one of ＱＡ 3. The compound of claim 2, wherein:

16. Q ４ The compound of claim 15, wherein is N.

17. Q １ , Q ２ , and Q ５ 17. The compound of claim 15 or 16, wherein is CH.

18. Q ３ But, CR ＱＢ and 【Chemistry 7】 The part is, 【Chemistry 8】 3. The compound of claim 2 selected from the group consisting of:

19. Q ４ But, CR ＱＢ and Q １ , Q ２ , Q ３ , and Q ５ each one of is independently CH or CR ＱＡ 3. The compound of claim 2, wherein:

20. Q １ , Q ２ , Q ３ , and Q ５ 20. The compound of claim 19, wherein each one of is CH.

21. Q １ , Q ２ , Q ３ , and Q ５ One of them is CR ＱＡ and Q １ , Q ２ , Q ３ , and Q ５ 20. The compound of claim 19, wherein each remaining one of is CH.

22. Q ５ But, CR ＱＡ and Q １ , Q ２ , and Q ３ 22. The compound of claim 21 , wherein is CH.

23. Q １ , Q ２ , Q ３ , and Q ５ Two of the CRs are independently selected. ＱＡ and Q １ , Q ２ , Q ３ , and Q ５ 20. The compound of claim 19, wherein each remaining one of is CH.

24. Q ２ and Q ３ are independently selected CR Ｑａ and Q １ and Q ５ 24. The compound of claim 23, wherein is CH.

25. Q ４ But, CR ＱＢ and Q １ , Q ２ , Q ３ , and Q ５ is N, and Q １ , Q ２ , Q ３ , and Q ５ each remaining one of ＱＡ 3. The compound of claim 2, wherein:

26. Q ４ But, CR ＱＢ and 【Chemistry 9】 The part is, 【Chemistry 10】 3. The compound of claim 2 selected from the group consisting of:

27. R ＱＢ But P(=O)R ａ R ｂ wherein R ａ and R ｂ But C １－６ Alkyl and C ３－６ 27. The compound of any one of claims 1 to 26, independently selected from the group consisting of cycloalkyl.

28. R ＱＢ But P(=O)R ａ R ｂ wherein R ａ and R ｂ But independently, C １－３ The compound of any one of claims 1 to 27, which is alkyl.

29. R ａ and R ｂ 29. The compound of claim 28, wherein:

30. R ＱＢ is P(=O)Me ２ The compound according to any one of claims 1 to 29,

31. R ＱＢ P(=O)Et ２ The compound according to any one of claims 1 to 29,

32. R ＱＢ is P(=O)iPr ２ The compound according to any one of claims 1 to 29,

33. R ａ and R ｂ 29. The compound of claim 28, wherein:

34. R ＱＢ The compound of any one of claims 1 to 27 or 33, wherein is P(=O)(Me)(tBu).

35. R ＱＢ But P(=O)R ａ R ｂ wherein R ａ and R ｂ However, each independently, C ３－６ The compound of any one of claims 1 to 27, which is cycloalkyl.

36. R ＱＢ but, 【Chemistry 11】 36. The compound of any one of claims 1 to 27 or 35, wherein

37. R ＱＢ But 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 ａ and R ｂ and wherein each of the rings is a heteroatom (in addition to the phosphorus bonded to １－６ 27. The compound of any one of claims 1 to 26, optionally substituted with alkyl.

38. R ＱＢ But 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 ａ and R ｂ is a heteroatom selected from the group consisting of O, S, and N, and the ring is １－６ 38. The compound of any one of claims 1 to 26 or 37, optionally substituted with alkyl.

39. R ＱＢ but, 【Chemistry 12】 wherein L Ｑ is a bond, CH ２ , O, S, NH, or N(C １－６ The compound of any one of claims 1 to 26 or 37 to 38, wherein the aryl group is aryl, ...

40. R ＱＢ but, 【Chemistry 13】 40. The compound according to any one of claims 1 to 26 or 37 to 39, wherein

41. R ＱＡ The compound of any one of claims 1 to 40, wherein one of is halo.

42. R ＱＡ 42. The compound of claim 41, wherein one of is -F.

43. R ＱＡ The compound of any one of claims 1 to 40, wherein one of is -OH.

44. R ＱＡ One of them is NR ｃ R ｄ The compound according to any one of claims 1 to 40,

45. R ＱＡ One of them is NH(C １－３ 45. The compound of claim 44, wherein:

46. R ＱＡ One of them is NH ２ 45. The compound of claim 44, wherein:

47. R ＱＡ One of them is N(C １－３ alkyl) ２ 45. The compound of claim 44, wherein:

48. R ＱＡ One of them is 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 45. The compound of claim 44, wherein the compound is selected from the group consisting of: cycloalkyl.

49. R ＱＡ One of them is NHC(=O)(C １－３ alkyl), NHC(=O)(C ３－６ cycloalkyl), or NHS(O) ２ (C １－３ 49. The compound of claim 48, wherein:

50. R ＱＡ One of them is C １－６ Alkyl and C(=O)(C １－６ 41. The compound of any one of claims 1 to 40, wherein the heterocyclyl is a 5- to 6-membered heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of: alkyl.

51. R ＱＡ 51. The compound of claim 50, wherein one of is morpholinyl.

52. R ＱＡ One of the groups is hydroxy, halo, and C １－６ C optionally substituted with 1 to 6 substituents each independently selected from the group consisting of alkoxy １－６ The compound of any one of claims 1 to 40, which is alkoxy.

53. R ＱＡ C, one of which is optionally substituted with 1 to 6 independently selected halo. １－６ 53. The compound of any one of claims 1 to 40 or 52, which is alkoxy.

54. R ＱＡ -OMe, -OCF ３ , or -OCHF ２ 54. The compound of claim 53, wherein:

55. R ＱＡ is selected from 1 to 6 independently selected R ｆ C optionally substituted with １－６ The compound of any one of claims 1 to 40, which is alkyl.

56. R ＱＡ One of them is C １－３ C substituted with alkyl or 1 to 6 independently selected halo １－３ alkyl, and optionally R ＱＡ Methyl, -CF ３ , or -CHF ２ 56. The compound of any one of claims 1 to 40 or 55, wherein

57. The remaining R ＱＡ 57. The compound of any one of claims 41 to 56, wherein, if present, is independently selected halo.

58. A pair of R on adjacent carbon atoms ＱＡ each taken together with the atom to which it is attached forms a ring containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms each independently selected from the group consisting of O, N, and S, and said ring is ｈ The compound according to any one of claims 1 to 40, optionally substituted with a group.

59. A pair of R on adjacent carbon atoms ＱＡ together with the atoms to which they are bonded, 【Chemistry 14】 59. The compound of claim 58, wherein

60. A pair of R on adjacent carbon atoms ＱＡ together with the atoms to which they are bonded, 【Chemistry 15】 59. The compound of claim 58, wherein

61. L ２ but, 【Chemistry 16】 The compound according to any one of claims 1 to 60,

62. Ring A is C ６－１０ aryl or 5-10 membered heteroaryl, each of which is selected from halo, C １－６ Alkyl, C １－６ Haloalkyl, and C １－６ 62. The compound of any one of claims 1 to 61, optionally substituted with 1 to 4 substituents each independently selected from the group consisting of alkoxy.

63. Ring A is phenyl or pyridyl, each of which is selected from halo, C １－６ Alkyl, C １－６ Haloalkyl, and C １－６ 63. The compound of any one of claims 1 to 62, optionally substituted with 2 to 4 substituents each independently selected from the group consisting of alkoxy.

64. Ring A is selected from halo and C １－６ 64. The compound of claim 63, which is phenyl optionally substituted with 2 to 4 substituents each independently selected from the group consisting of alkyl.

65. Ring A is selected from halo and C １－６ 64. The compound of claim 63, which is pyridyl optionally substituted with 2 to 4 substituents each independently selected from the group consisting of alkyl.

66. Ring A is 【Chemistry 17】 wherein R ＡＡ , R ＡＢ , and R ＡＣ are independently halo or C １－６ The compound of any one of claims 1 to 64, which is alkyl.

67. R １ , R ２ , and R ３ The compound of any one of claims 1 to 66, wherein is H.

68. R １ and R ２ is H and R ３ But C １－６ 67. The compound of any one of claims 1 to 66, which is alkyl.

69. R ３ 69. The compound of claim 68, wherein is methyl.

70. R １ is H and R ２ and R ３ are independently selected C １－６ 67. The compound of any one of claims 1 to 66, which is alkyl.

71. L １ The compound of any one of claims 1 to 70, wherein is C(=O).

72. Ring B is 【Chemistry 18】 The compound according to any one of claims 1 to 71,

73. R ４ , R ５ , and R ６ The compound of any one of claims 1 to 72, wherein each is H or halo.

74. R ４ , R ５ , and R ６ The compound of any one of claims 1 to 73, wherein each is H or -F.

75. R ４ , R ５ , and R ６ The compound of any one of claims 1 to 74, wherein each is H.

76. R ４ and R ５ is H and R ６ The compound of any one of claims 1 to 74, wherein is -F.

77. R ７ The compound of any one of claims 1 to 76, wherein is H.

78. R ７ The compound of any one of claims 1 to 76, wherein is -F.

79. L ３ and L ４ 79. The compound of any one of claims 1 to 78, wherein at least one of is a bond.

80. L ３ and L ４ The compound of any one of claims 1 to 79, wherein both of are a bond.

81. L ３ is a bond, and L ４ But C １－２ 80. The compound of any one of claims 1 to 79, which is alkylene.

82. L ４ is a bond, and L ３ But C １－２ 80. The compound of any one of claims 1 to 79, which is alkylene.

83. L ３ and L ４ However, each independently, C １－２ 79. The compound of any one of claims 1 to 78, which is alkylene.

84. R ８ａ and R ８ｂ each together with the carbon atom to which it is attached, form 1 to 2 independently selected C １－６ C optionally substituted with alkyl ３－８ Forms a cycloalkyl ring, １－６ alkyl is one to three independently selected R ｆ 84. The compound of any one of claims 1 to 83, optionally substituted with

85. R ８ａ and R ８ｂ each together with the carbon atom to which it is attached, form 1 to 2 independently selected C １－６ C optionally substituted with alkyl ３－５ Forms a cycloalkyl ring, １－６ alkyl is one to three independently selected R ｆ 85. The compound of any one of claims 1 to 84, optionally substituted with

86. R ８ａ and R ８ｂ each together with the carbon atom to which it is attached, form 1 to 2 independently selected C １－６ C optionally substituted with alkyl ３－４ The compound according to any one of claims 1 to 85, which forms a cycloalkyl ring.

87. R ８ａ and R ８ｂ together with the carbon atoms to which they are attached, 【Chemistry 19】 84. The compound according to any one of claims 1 to 83, which forms:

88. R ８ａ and R ８ｂ together with the carbon atoms to which they are attached, 【Chemistry 20】 88. The compound of any one of claims 1 to 83 or 87, which forms:

89. R ９ but, 【Chemical 21】 (IX-2) 89. The compound according to any one of claims 1 to 88, wherein

90. Said L ３ -C(R ８ａ R ８ｂ )-L ４ -R ９ The part is, 【Chemical 22】 80. The compound of any one of claims 1 to 79, wherein

91. Said L ３ -C(R ８ａ R ８ｂ )-L ４ -R ９ The part is, 【Chemical 23】 80. The compound of any one of claims 1 to 79, wherein

92. R ９ｄ is H or C １－６ 92. The compound of any one of claims 89 to 91, which is alkyl.

93. R ９ｄ The compound of any one of claims 89 to 92, wherein is H.

94. Ring C is 1 to 3 independently selected R Ｃａ The compound according to any one of claims 1 to 93, which is a 3- to 12-membered heterocyclyl optionally substituted by

95. Ring C is 1 to 3 independently selected R Ｃａ The compound according to any one of claims 1 to 94, which is an optionally substituted 4- to 8-membered heterocyclyl.

96. Ring C is 1 to 3 independently selected R Ｃａ The compound according to any one of claims 1 to 95, which is a 5- or 6-membered heterocyclyl optionally substituted by

97. Ring C is a ring having 1 to 3 independent R Ｃａ 97. The compound of any one of claims 1 to 96, which is tetrahydropyranyl optionally substituted by:

98. Ring C is 【Chemistry 24】 98. The compound of any one of claims 1 to 97, selected from the group consisting of:

99. Ring C is 1 to 3 independently selected R Ｃａ 97. The compound of any one of claims 1 to 96, which is morpholinyl optionally substituted by:

100. Ring C is 【Chemistry 25】 100. The compound of any one of claims 1 to 96 or 99, wherein

101. Ring C is a ring having 1 to 3 R Ｃａ C optionally substituted with ３－１０ 94. The compound of any one of claims 1 to 93, which is cycloalkyl.

102. Ring C is a ring having 1 to 3 R Ｃａ C optionally substituted with ３－８ 102. The compound of any one of claims 1 to 93 or 101, which is cycloalkyl.

103. Ring C is 【Chemical Formula 26】 The compound according to any one of claims 1 to 93 or 101 to 102,

104. Each R Ｃａ independently halo and C １－６ The compound of any one of claims 1 to 103, wherein the compound is selected from the group consisting of alkyl.

105. Each R Ｃａ But independently, C １－６ The compound of any one of claims 1 to 104, which is alkyl.

106. A pair of R on the same or different ring atoms Ｃａ are taken together with the ring atom to which they are each attached to form a carbocyclic ring containing from 3 to 6 ring atoms.

107. A pair of R on the same ring atom Ｃａ are taken together with the ring atom to which they are each attached to form a carbocyclic ring containing from 3 to 5 ring atoms.

108. The compound of formula (I) may be of formula (IA): 【Chemical 27】 Formula (IA) [In the formula, Q ４ and Q ５ are independently N, CH, and CR ＱＡ selected from the group consisting of 2. The compound of claim 1, which is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

109. Q ４ and Q ５ 109. The compound of claim 108, wherein each of is CH.

110. Q ４ But, CR ＱＡ and Q ５ is CH.

111. Q ４ is N, and Q ５ But, CR ＱＡ or CH, and optionally Q ５ is CH.

112. Q ４ But, CR ＱＡ and Q ５ But, CR ＱＡ 109. The compound of claim 108, wherein:

113. The compound of formula (I) may be of formula (IB): 【Chemical 28】 Formula (IB) [In the formula, Q ２ , Q ３ , and Q ５ are independently N, CH, and CR ＱＡ selected from the group consisting of 2. The compound of claim 1, which is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

114. Q ２ , Q ３ , and Q ５ 114. The compound of claim 113, wherein each of is CH.

115. Q ５ But, CR ＱＡ and Q ２ and Q ３ 114. The compound of claim 113, wherein each of is CH.

116. Q ５ is CH, and Q ２ and Q ３ are independently selected CR ＱＡ 114. The compound of claim 113, wherein:

117. Ring B is 【Chemical 29】 The compound according to any one of claims 108 to 116,

118. L ３ and L ４ The compound according to any one of claims 108 to 117, wherein at least one of is a bond.

119. L ３ and L ４ The compound of any one of claims 108 to 118, wherein both of are a bond.

120. R ８ａ and R ８ｂ each together with the carbon atom to which it is attached, form 1 to 2 independently selected C １－６ C optionally substituted with alkyl ３－５ Forms a cycloalkyl ring, １－６ alkyl is one to three independently selected R ｆ The compound according to any one of claims 108 to 119, optionally substituted with

121. R ８ａ and R ８ｂ each together with the carbon atom to which it is attached, form 1 to 2 independently selected C １－６ C optionally substituted with alkyl ３－４ 121. The compound of claim 120, which forms a cycloalkyl ring.

122. R ８ａ and R ８ｂ together with the carbon atoms to which they are attached, 【Chemistry 30】 The compound according to any one of claims 108 to 121, which forms:

123. The compound of formula (I) has the formula (IC): 【Chemical 31】 Formula (IC) [In the formula, Ring D is C ３－６ is cycloalkyl; R ８ｃ is H and 1 to 3 independently selected R ｆ C optionally substituted with １－６ alkyl; and Each R Ｃｂ are independently H and R Ｃａ selected from the group consisting of 2. The compound of claim 1, which is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

124. 124. The compound of claim 123, wherein Ring D is cyclopropyl.

125. 124. The compound of claim 123, wherein Ring D is cyclobutyl.

126. R ８ｃ The compound of any one of claims 123 to 125, wherein is H.

127. R ８ｃ But C １－３ The compound of any one of claims 123 to 125, which is alkyl.

128. R ８ｃ is methyl.

129. Each R Ｃｂ The compound of any one of claims 123 to 128, wherein is H.

130. Each R Ｃｂ But independently, C １－６ The compound of any one of claims 123 to 128, which is alkyl.

131. The aforementioned 【Chemical 32】 The part is, 【Chemical 33】 wherein Q ４ and Q ５ are independently N, CH, and CR ＱＡ 131. The compound of any one of claims 123 to 130, selected from the group consisting of:

132. Q ４ and Q ５ 132. The compound of claim 131, wherein each of is CH.

133. Q ４ But, CR ＱＡ and Q ５ is CH.

134. Q ４ is N, and Q ５ But, CR ＱＡ or CH, and optionally Q ５ is CH.

135. Q ４ But, CR ＱＡ and Q ５ But, CR ＱＡ 132. The compound of claim 131, wherein:

136. The aforementioned 【Chemical 34】 The part is, 【Chemistry 35】 wherein Q ２ , Q ３ , and Q ５ N, CH, and CR ＱＡ 131. The compound of any one of claims 123 to 130, selected from the group consisting of:

137. Q ２ , Q ３ , and Q ５ 137. The compound of claim 136, wherein each of is CH.

138. Q ５ But, CR ＱＡ and Q ２ and Q ３ 137. The compound of claim 136, wherein each of is CH.

139. Q ５ is CH, and Q ２ and Q ３ are independently selected CR ＱＡ 137. The compound of claim 136, wherein:

140. R ａ and R ｂ However, each independently, C １－６ Alkyl and C ３－６ 139. The compound of any one of claims 108-138, wherein the compound is selected from the group consisting of cycloalkyl.

141. R ａ and R ｂ However, each independently, C １－３ The compound of any one of claims 108 to 140, which is alkyl.

142. R ａ and R ｂ The compound of any one of claims 108 to 141, wherein each is methyl.

143. R ａ and R ｂ The compound of any one of claims 108 to 141, wherein each is ethyl.

144. R ａ and R ｂ The compound of any one of claims 108 to 141, wherein each is isopropyl.

145. R ａ is methyl, and R ｂ The compound of any one of claims 108 to 140, wherein is tert-butyl.

146. R ａ and R ｂ are independently selected C ３－６ The compound of any one of claims 108 to 140, which is cycloalkyl.

147. R ａ and R ｂ and R are both cyclopropyl.

148. Each R ＱＡ halo; cyano; OH; NR ｃ R ｄ 1 to 6 independently selected R ｆ C optionally substituted with １－６ Alkyl; hydroxy, halo, and C １－６ C optionally substituted with 1 to 6 substituents each independently selected from the group consisting of alkoxy １－６ Alkoxy; and C １－６ Alkyl and C(=O)(C １－６ 148. The compound of any one of claims 108-147, wherein the heterocyclic group is 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 alkyl.

149. Each R ＱＡ -F, OH, NH ２ , NHMe, NHEt, NHiPr, N(Me) ２ , NHC(═O)(cyclopropyl), NHS(O) ２ Me, methyl, CF ３ , CHF ２ , OMe, OCF ３ , OCHF ２ 149. The compound of any one of claims 108-148, wherein the compound is selected from the group consisting of:

150. A pair of R on adjacent carbon atoms ＱＡ each taken together with the atom to which it is attached forms a ring containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms each independently selected from the group consisting of O, N, and S, and said ring is ｈ The compound according to any one of claims 108 to 147, optionally substituted with a group.

151. A pair of R on adjacent carbon atoms ＱＡ together with the atoms to which they are bonded, 【Chemical 36】 151. The compound of any one of claims 108 to 147 or 150, which forms:

152. A pair of R on adjacent carbon atoms ＱＡ together with the atoms to which they are bonded, 【Chemical 37】 151. The compound of any one of claims 108 to 147 or 150, which forms:

153. L ２ but, 【Chemical Formula 38】 The compound according to any one of claims 123 to 152,

154. Ring A is phenyl or pyridyl, each of which is selected from halo, C １－６ Alkyl, C １－６ Haloalkyl, and C １－６ The compound according to any one of claims 108 to 153, optionally substituted with 2 to 4 substituents each independently selected from the group consisting of alkoxy.

155. Ring A is selected from halo and C １－６ 155. The compound of any one of claims 108 to 154, which is phenyl optionally substituted with 2 to 4 substituents each independently selected from the group consisting of alkyl.

156. Ring A is 【Chemical Formula 39】 wherein R ＡＡ , R ＡＢ , and R ＡＣ are independently halo or C １－６ The compound of any one of claims 108 to 155, which is alkyl.

157. R １ and R ２ The compound of any one of claims 108 to 156, wherein is H.

158. R ３ The compound of any one of claims 108 to 157, wherein is H.

159. R ３ But C １－６ The compound of any one of claims 108 to 157, which is alkyl.

160. R １ and R ２ is H and R ３ But C １－６ The compound of any one of claims 108 to 156, which is alkyl.

161. R ３ is methyl.

162. L １ The compound according to any one of claims 108 to 161, wherein is C(=O).

163. R ４ , R ５ , and R ６ The compound of any one of claims 108 to 162, wherein each is H or halo.

164. R ４ , R ５ , and R ６ The compound of any one of claims 108 to 163, wherein each is H or -F.

165. R ４ , R ５ , and R ６ The compound of any one of claims 108 to 164, wherein each is H.

166. R ４ and R ５ is H and R ６ The compound of any one of claims 108 to 164, wherein is -F.

167. R ７ The compound of any one of claims 108 to 166, wherein is H.

168. R ７ The compound of any one of claims 108 to 166, wherein is -F.

169. R ９ but, 【Chemistry 40】 (IX-2) The compound according to any one of claims 108 to 168,

170. R ９ｄ is H.

171. Ring C is 1 to 3 independently selected R Ｃａ The compound of any one of claims 108 to 122 or 140 to 170, wherein the heterocyclyl is optionally substituted with 3 to 12 membered heterocyclyl.

172. Ring C is 1 to 3 independently selected R Ｃａ The compound according to any one of claims 108 to 122 or 140 to 171, which is an optionally substituted 5- or 6-membered heterocyclyl.

173. Ring C is 1 to 3 independently selected R Ｃａ The compound of any one of claims 108 to 122 or 140 to 172, which is tetrahydropyranyl optionally substituted by

174. Ring C is 【Chemistry 41】 174. The compound of any one of claims 108-122 or 140-173, selected from the group consisting of:

175. Ring C is 1 to 3 independently selected R Ｃａ The compound of any one of claims 108 to 122 or 140 to 172, wherein the compound is morpholinyl optionally substituted with

176. Ring C is 【Chemistry 42】 176. The compound of any one of claims 108-122, 140-172, or 175, wherein

177. Ring C is a ring having 1 to 3 R Ｃａ C optionally substituted with ３－８ 171. The compound of any one of claims 108-122 or 140-170, which is cycloalkyl.

178. Ring C is 【Chemistry 43】 178. The compound of any one of claims 108-122, 140-170, or 177, wherein

179. Each R Ｃａ But independently, C １－６ The compound of any one of claims 108-122 or 140-178, which is alkyl.

180. Each R Ｃａ The compound of any one of claims 108-122 or 140-178, wherein is -F.

181. A pair of R on the same or different ring atoms Ｃａ are taken together with the ring atom to which they are each attached to form a carbocyclic ring containing from 3 to 6 ring atoms.

182. A pair of R on the same ring atom Ｃａ are taken together with the ring atom to which they are each attached to form a carbocyclic ring containing from 3 to 5 ring atoms.

183. The compound of formula (I) has the formula (ID): 【Chemical 44】 Formula (ID) [In the formula, R ＡＡ , R ＡＢ , and R ＡＣ are independently halo or C １－６ is alkyl; R ＱＣ is H or halo; and Each R Ｃｂ are independently H and R Ｃａ selected from the group consisting of 2. The compound of claim 1, which is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

184. R １ and R ２ The compound of claim 183, wherein is H.

185. R ３ But C １－３ 185. The compound of claim 183 or 184, which is alkyl.

186. R ３ The compound according to any one of claims 183 to 185, wherein is methyl.

187. R ４ , R ５ , R ６ , and R ７ The compound of any one of claims 183 to 186, wherein is H.

188. R ９ｄ The compound according to any one of claims 183 to 187, wherein is H.

189. R ＡＡ and R ＡＣ But independently, C １－６ The compound of any one of claims 183 to 188, which is alkyl.

190. R ＡＡ and R ＡＣ The compound of any one of claims 183 to 189, wherein is methyl.

191. R ＡＢ is halo.

192. R ＡＢ The compound according to any one of claims 183 to 191, wherein is -F.

193. Each R Ｃｂ is H or methyl, and where appropriate, each R Ｃｂ The compound according to any one of claims 183 to 192, wherein is H.

194. R ａ and R ｂ But independently, C １－３ The compound of any one of claims 183 to 193, which is alkyl.

195. R ａ and R ｂ The compound according to any one of claims 183 to 194, wherein is methyl.

196. R ａ and R ｂ The compound according to any one of claims 183 to 194, wherein is ethyl.

197. R ａ and R ｂ The compound of any one of claims 183 to 194, wherein is isopropyl.

198. R ａ is methyl, and R ｂ The compound of any one of claims 183 to 193, wherein is tert-butyl.

199. R ａ and R ｂ But independently, C ３－６ 194. The compound of any one of claims 183 to 193, which is cycloalkyl.

200. R ａ and R ｂ 200. The compound of any one of claims 183-193 or 199, wherein each is cyclopropyl.

201. P(=O)R ａ R ｂ but, 【Chemistry 45】 wherein L Ｑ is a bond, CH ２ , O, S, NH, or N(C １－６ The compound according to any one of claims 183 to 193, wherein the aryl group is aryl, ...

202. P(=O)R ａ R ｂ but, 【Chemistry 46】 The compound of claim 201,

203. R ＱＡ The compound according to any one of claims 183 to 202, wherein is -F.

204. R ＱＡ The compound according to any one of claims 183 to 202, wherein is -OH.

205. R ＱＡ But NR ｃ R ｄ The compound according to any one of claims 183 to 202,

206. R ＱＡ But NH(C １－３ 206. The compound of any one of claims 183 to 202 or 205, wherein:

207. R ＱＡ But NH ２ The compound of any one of claims 183 to 202 or 205,

208. R ＱＡ But N(C １－３ alkyl) ２ The compound of any one of claims 183 to 202 or 205,

209. R ＱＡ NHC(=O)(C １－３ alkyl), NHC(=O)(C ３－６ cycloalkyl), or NHS(O) ２ (C １－３ 206. The compound of any one of claims 183 to 202 or 205, wherein:

210. R ＱＡ But C １－６ Alkyl and C(=O)(C １－６ The compound of any one of claims 183 to 202, which is a 5- to 6-membered heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of: alkyl.

211. R ＱＡ is optionally substituted with 1 to 6 independently selected halo; １－６ The compound of any one of claims 183 to 202, which is alkoxy.

212. R ＱＡ -OMe, -OCF ３ , or -CHF ２ 212. The compound of any one of claims 183 to 202 or 211,

213. R ＱＡ is optionally substituted with 1 to 6 independently selected halo; １－３ The compound of any one of claims 183 to 202, which is alkyl.

214. R ＱＡ Methyl, -CF ３ , or CHF ２ 214. The compound of any one of claims 183 to 202 or 213,

215. R ＱＣ The compound according to any one of claims 183 to 214, wherein is H.

216. R ＱＣ The compound of any one of claims 183 to 214, wherein is -F.

217. R ＱＣ But P(=O)R ａ R ｂ The compound of claim 216, which is meta to

218. R ＱＣ But, R ＱＡ The compound of claim 216 or 217, which is ortho to

219. The compound has the formula (S,S,S)-(ID) 【Chemistry 47】 Formula (S, S, S)-(ID) [In the formula, R ３ is C １－３ alkyl] or a pharmaceutically acceptable salt thereof.

220. 220. The compound of any one of claims 1 to 219, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of formula I is selected from the group consisting of Table C1 and Table C2.

221. 221. A pharmaceutical composition comprising a compound according to any one of claims 1 to 220, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

222. 221. A method of treating type 2 diabetes in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound according to any one of claims 1 to 220, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 221.

223. 221. A method for treating type 2 diabetes in a patient, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 220, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 221, to a patient identified or diagnosed as having type 2 diabetes.

224. 1. A method for treating diabetes in a patient, comprising: a) determining that the patient has type 2 diabetes; and then b) administering to said patient a therapeutically effective amount of a compound according to any one of claims 1 to 220 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 221.

225. 225. The method of any one of claims 222-224, wherein the step of determining that the patient has type 2 diabetes comprises performing an assay to determine the level of an analyte in a sample from the patient, wherein the analyte is selected from the group consisting of hemoglobin A1c (HbA1c), fasting blood glucose, non-fasting blood glucose, or any combination thereof.

226. 226. The method of claim 225, wherein the HbA1c level is about 6.5% or greater.

227. 227. The method of any one of claims 225-226, wherein the fasting blood glucose level is about 126 mg / dL or greater.

228. 228. The method of any one of claims 225-227, wherein the non-fasting blood glucose level is about 200 mg / dL or greater.

229. 229. The method of any one of claims 222 to 228, further comprising obtaining a sample from the patient.

230. 230. The method of claim 229, wherein the sample is a bodily fluid sample.

231. 231. The method of any one of claims 222 to 230, wherein the patient is about 40 to about 70 years old and is overweight or obese.

232. The patient has a weight of about 22 kg / m ２ The method of any one of claims 222 to 231, wherein the body mass index (BMI) is or higher.

233. The patient has a weight of about 30 kg / m ２ The method according to any one of claims 222 to 232, wherein the BMI is equal to or higher than that.

234. 234. The method of any one of claims 222 to 233, wherein the treatment of type 2 diabetes comprises reducing fasting blood glucose levels.

235. 235. The method of claim 234, wherein the fasting blood glucose level is reduced to about 100 mg / dL or less.

236. 236. The method of any one of claims 222 to 235, wherein the treatment of type 2 diabetes comprises a reduction in HbA1c levels.

237. 237. The method of claim 236, wherein the HbA1c level is reduced to about 5.7% or less.

238. 238. The method of any one of claims 222 to 237, wherein the treatment of type 2 diabetes comprises reducing glucagon levels.

239. 239. The method of any one of claims 222 to 238, wherein the treatment of type 2 diabetes comprises increasing insulin levels.

240. 240. The method of any one of claims 222 to 239, wherein the treatment of type 2 diabetes comprises reducing BMI.

241. The BMI is about 25 kg / m ２ or less.

242. The method of any one of claims 222 to 241, wherein the compound of any one of claims 1 to 190 or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of claim 191, is administered orally.

243. 243. The method of any one of claims 222 to 242, further comprising administering to said patient an additional therapy or treatment.

244. 244. The method of claim 243, wherein the additional therapy or therapeutic agent is selected from the group consisting of an antidiabetic agent, an antiobesity agent, a GLP-1 receptor agonist, a nonalcoholic steatohepatitis (NASH) medication, gastric electrical stimulation, dietary monitoring, physical activity, or any combination thereof.

245. The method of claim 244, wherein 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.

246. 246. The method of claim 245, wherein the biguanide is metformin.

247. The anti-obesity drug is selected from the group consisting of a neuropeptide Y receptor type 2 (NPYR2) agonist, an NPYR1 or NPYR5 antagonist, a human proislet peptide (HPP) antagonist, a steroid hormone receptor antagonist, and a steroid hormone receptor antagonist.

245. The method of claim 244, wherein the therapeutic agent is selected from the group consisting of cannabinoid receptor type 1 (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, serotonergic agents, methionine aminopeptidase 2 (MetAP2) inhibitors, diethylpropion, phendimetrazine, benzphetamine, fibroblast growth factor receptor (FGFR) modulators, AMP-activated protein kinase (AMPK) activators, sodium-glucose transporter 1 (SGLT-1) inhibitors, or any combination thereof.

248. 245. The method of claim 244, wherein the GLP-1 receptor agonist is selected from the group consisting of liraglutide, exenatide, dulaglutide, albiglutide, taspoglutide, lixisenatide, semaglutide, or any combination thereof.

249. 245. The method of claim 244, wherein the NASH therapeutic agent is selected from the group consisting of FXR agonists, PF-05221304, synthetic fatty acid bile conjugates, anti-lysyl oxidase analog 2 (LOXL2) monoclonal antibodies, caspase inhibitors, MAPK5 inhibitors, galectin 3 inhibitors, fibroblast growth factor 21 (FGF21) agonists, niacin analogs, leukotriene D4 (LTD4) receptor antagonists, acetyl-CoA carboxylase (ACC) inhibitors, ketohexokinase (KHK) inhibitors, ileal bile acid transporter (IBAT) inhibitors, apoptosis signal-regulating kinase 1 (ASK1) inhibitors, peroxisome proliferator-activated receptor (PPAR) agonists, diacylglycerol acyltransferase 2 (DGAT2) inhibitors, or any combination thereof.

250. The method of any one of claims 243 to 249, wherein the compound of any one of claims 1 to 220 or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of claim 221, and the further therapeutic agent are administered sequentially in any order as separate formulations.

251. 221. A method for regulating insulin levels in a patient in need thereof, comprising administering to said patient an effective amount of a compound according to any one of claims 1 to 220, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 221.

252. The method of claim 251, wherein the modulation results in an increase in insulin levels.

253. 221. A method for modulating glucose levels in a patient in need thereof, comprising administering to said patient an effective amount of a compound according to any one of claims 1 to 220, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 221.

254. 254. The method of claim 253, wherein the modulation results in a decrease in glucose levels.

255. 221. A method for treating a GLP-1 related disease, disorder, or condition, comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 220, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 221.

256. The disease, disorder, or condition is type 1 diabetes, type 2 diabetes, juvenile-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of adults (LADA), obesity, weight gain due to the use of other medications, idiopathic intracranial hypertension, Wolfram syndrome, gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, or 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 dysfunction, impaired vascular compliance, vascular restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial hyperlipidemia 256. The method of claim 255, wherein the disease is selected from the group consisting of: diabetes mellitus, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, alcohol use disorders, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, treatment of addiction, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, psychogenic polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof.

257. The disease, disorder, or illness is selected from the group consisting of type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat accumulation, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, and alopecia.

257. The method of claim 256, wherein the condition is selected from the group consisting of choline intake disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, psychogenic polydipsia, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS), idiopathic intracranial hypertension, Wolfram syndrome, or any combination thereof.

258. The method of claim 257, wherein the disease, disorder, or condition includes, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat accumulation, myocardial infarction, peripheral arterial disease, stroke, transient ischemic attack, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, chronic renal failure, syndrome X, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, skin and connective tissue disorders, foot ulcers, idiopathic intracranial hypertension, Wolfram syndrome, or any combination thereof.

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