Heterocyclic GLP-1 agonists

Abstract

The present disclosure relates to GLP-1 agonists of formula (I), pharmaceutically acceptable salts and solvates comprising the same, and pharmaceutical compositions, # imgabs0 # comprising the same

Description

This application is a divisional application of the Chinese patent application with application number 202180013186.2 (application date: February 5, 2021, invention name: Heterocyclic GLP-1 agonist). [Cross-reference to related applications]

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

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

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

[0004] Diabetes refers to a group of metabolic disorders characterized by persistent high blood sugar. The most common form of type 2 diabetes (T2DM) is an acquired condition that accounts for more than 90% of diabetes cases. Typical onset occurs in obese or sedentary adults and begins to develop insulin resistance. Although lifestyle changes can effectively control the disease, patients with T2DM may need to take antidiabetic drugs, including drugs such as dipeptidyl peptidase 4 inhibitors, SGLT2 inhibitors, and sulfonylureas.

[0005] In healthy individuals, the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) act in tandem to regulate insulin secretion in response to glucose intake. Although the incretin effect is significantly diminished (if present at all) in cases of T2DM, GLP-1 retains insulinotropic properties even when the endocrine pancreatic response to GIP is effectively abrogated. Therefore, incretin mimetics and other GLP-1-based therapies may help stimulate insulin production in patients with T2DM. [Summary of the invention]

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

[0007] Thus, provided herein are compounds of formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0008] Q 1 , Q 2 , Q 3 , Q 4 and Q 5 Is defined according to (AA) or (BB):

[0009] (AA) Q 1 and Q 5 are independently selected from N, CH and CR QA The group composed of Q 2 , Q 3 and Q 4 are independently selected from N, CH, CR QA and CR QB The group is composed of Q 2 , Q 3 and Q 4 At least one of them is CR QB ; each is a single bond or a double bond, with the restriction that it contains Q 1 To Q 5 The ring is aromatic;

[0010] (BB) Q 1 is the key; Q 2 , Q 3 , Q 4 and Q 5 are independently selected from the group consisting of: O, S, N, NH, NR c , CH, CR QA and CR QB , whose restriction condition is Q 2 , Q 3 , Q 4 and Q 5 At least one of them is CR QB ; each is a single bond or a double bond, with the restriction that it contains Q 1 To Q 5 The ring is aromatic;

[0011] R QB P(=O)R a R b , where R a and R bare independently selected from the group consisting of: optionally 1 to 6 each independently selected from C 1-6 Alkoxy, C 3-6 The C-substituted substituent group is a cycloalkyl group or a halogen group. 1-6 Alkyl; optionally 1 to 3 each independently selected from C 1-3 C substituted with a substituent consisting of an alkyl group and a halogen group 3-6 Cycloalkyl; and optionally 1 to 3 independently selected C 1-3 Alkyl substituted C 6-10 aryl; or

[0012] R a and R b Together with the phosphorus atoms to which they are attached, they form a ring containing 5 to 8 ring atoms, of which 0 to 2 ring atoms (excluding those with R a and R b The attached phosphorus) is a heteroatom each independently selected from the group consisting of O, S and N, wherein the ring is optionally substituted with 1 to 3 independently selected C 1-6 Alkyl substitution;

[0013] Each R QA are independently selected from the group consisting of: (a) halide; (b) cyano; (c) OH; (d) -NR c R d ; (e) C(═O) NR c R d ; (f) S(═O) 0-2 R e (g) optionally 1 to 6 independently selected R f Substituted C 1-6 (h) optionally substituted with 1 to 6 groups independently selected from hydroxyl, halogen and C 1-6 The C substituted by the substituent group consisting of alkoxy 1-6 Alkoxy; (i) optionally substituted with one or more independently selected from C 1-6 Alkyl and C(=O)(C 1-6 alkyl) substituted with 1 to 3 independently selected C(═O)(C 1-6 Alkyl) substituted C 6-10 Aryl; and (k) optionally 1 to 6 independently selected R g substituted 5- to 10-membered heteroaryl;

[0014] or R on adjacent carbon atoms QAThe ring is optionally substituted with 1 to 2 independently selected R h group substitution;

[0015] L 2 is selected from the group consisting of: Where aa represents the 1 To Q 5 The connection point of the ring; n1 is an integer from 1 to 3; L 2A For key or C 1-10 Alkylene; R La Is selected from H, C 1-6 Alkyl and C(=O)(C 1-6 alkyl) group; R Lb and R Lc Each of which is independently selected from H and C 1-6 The group consisting of alkyl groups;

[0016] 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 optionally substituted by 1 to 5 groups independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Substitution of the substituents of the group consisting of alkoxy groups;

[0017] R 1 , R 2 and R 3 are each independently selected from the group consisting of: H and optionally 1 to 6 each independently selected from halogen, -OH and C 1-6 The C substituted by the substituent group consisting of alkoxy 1-6 alkyl;

[0018] L 1 is selected from the group consisting of: -C(=O)-, -CH2-, -CH(C 1-6 alkyl)- and -S(=O)2;

[0019] Ring B is selected from the group consisting of: Where bb represents the 1 The connection point; R4 , R 5 , R 6 and R 7 are independently selected from the group consisting of: H, halogen and C 1-6 alkyl; L 3 For key or C 1-3 Alkylene; L 4 For key or C 1-5 Alkylene; R 8a and R 8b are independently selected from the group consisting of: H and optionally substituted by one or more independently selected from halogen and C 3-15 The substituents of the group consisting of cycloalkyl groups are substituted with C 1-6 Alkyl; or R 8a and R 8b Together with the carbon atoms to which they are attached, they form optionally 1 to 3 independently selected C 1-6 Alkyl substituted C 3-15 Cycloalkyl ring, wherein the C 1-6 The alkyl group is optionally substituted with 1 to 6 independently selected R f replace; R 9 is selected from the group consisting of: C(=O)OH, C(=O)(OC 1-6 alkyl), C(=O)NR 9a R 9b , (IX-1), (IX-2), (IX-3) and (IX-4): R 9a H or C 1-6 alkyl; R 9b H, C 1-6 Alkyl, C(=O)(C 1-6 Alkyl), S(O) 0-2 (C 1-6 alkyl) or cyano; R 9c , R 9d , R 9e , R 9f and R 9g are each independently selected from the group consisting of: H; and optionally 1 to 6 independently selected halogen and C 1-6 Alkoxy substituted C 1-6 Alkyl; and C(=O)(C 1-6 alkyl);

[0020] Ring C is selected from 3- to 12-membered heterocyclic groups; 3-15 Cycloalkyl; and a group consisting of 5- to 10-membered heteroaryl, each of which is optionally substituted by 1 to 3 R Ca replace;

[0021] Each R Ca are independently selected from the group consisting of: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and NR c R d ;

[0022] or R on the same or different ring atoms Ca The pair together with the one or more ring atoms to which they are respectively attached form a carbocyclic ring containing 3 to 8 ring atoms;

[0023] Each R c and R d are independently selected from the group consisting of: H, C 1-6 Alkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 Cycloalkyl), C(=O)O(C 1-6 Alkyl), S(O) 1-2 (C 1-6 Alkyl) and S(O) 1-2 (C 3-6 Cycloalkyl), wherein 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 optionally substituted with 1 to 6 groups independently selected from -OH, halogen and C 1-6 Substitution of the substituents of the group consisting of alkoxy groups;

[0024] R e H, C 1-6 Alkyl or C 1-6 Haloalkyl;

[0025] Each R f are independently selected from the group consisting of: halogen, -OH, NR c R d , C 1-6 Alkoxy, C 1-6 haloalkoxy and optionally substituted by 1 to 4 each independently selected from -OH, C 1-6A 3- to 12-membered heterocyclic group substituted with a substituent selected from the group consisting of an alkyl group and a 3- to 12-membered heterocyclic group;

[0026] Each R g are independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Alkoxy, NR c R d and optionally one or more independently selected from C 1-6 Alkyl and C(=O)C 1-6 A 3- to 12-membered heterocyclic group substituted with a substituent selected from the group consisting of an alkyl group; and

[0027] Each R h are independently selected from the group consisting of: halogen, 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 Halogenated alkoxy.

[0028] Also provided herein is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient.

[0029] Also provided herein is a method for treating type 2 diabetes in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0030] Also provided herein is a method for treating type 2 diabetes in a patient, comprising administering to a patient identified or diagnosed as having type 2 diabetes a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0031] Also provided herein is a method for treating diabetes in a patient, the method comprising determining that the patient suffers from type 2 diabetes; and administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In some embodiments, the step of determining that the patient suffers from type 2 diabetes comprises performing an analysis to determine the content of an analyte in a sample from the patient, wherein the analyte is selected from a group consisting of: hemoglobin A1c (HbA1c), fasting plasma glucose, non-fasting plasma glucose, or any combination thereof. In some embodiments, the content of HbA1c is greater than or about 6.5%. In some embodiments, the content of fasting plasma glucose is greater than or about 126 mg / dL. In some embodiments, the content of non-fasting plasma glucose is greater than or about 200 mg / dL.

[0032] In some embodiments, the method further comprises obtaining a sample from the patient. In some embodiments, the sample is a body fluid sample. In some embodiments, the patient is about 40 to about 70 years old and is overweight or obese. In some embodiments, the patient's body mass index (BMI) is greater than or about 22 kg / m 2 In some embodiments, the patient's BMI is greater than or about 30 kg / m 2 .

[0033] In some embodiments, the method for treating type 2 diabetes comprises reducing fasting plasma glucose levels. In some embodiments, fasting plasma glucose levels are reduced to about or below 100 mg / dL.

[0034] In some embodiments, the method for treating type 2 diabetes comprises lowering HbA1c levels. In some embodiments, the HbA1c levels are lowered to about or below 5.7%.

[0035] In some embodiments, methods for treating type 2 diabetes comprise reducing glucagon levels.

[0036] In some embodiments, methods for treating type 2 diabetes comprise increasing insulin levels.

[0037] In some embodiments, the method for treating type 2 diabetes comprises reducing BMI. In some embodiments, the BMI is reduced to about or below 25 kg / m 2 .

[0038] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, is administered orally.

[0039] In some embodiments, the method for treating type 2 diabetes further includes 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: antidiabetic agents, anti-obesity agents, GLP-1 receptor agonists, agents for treating non-alcoholic steatohepatitis (NASH), gastric electrical stimulation, dietary monitoring, physical activity, or any combination thereof. In some embodiments, the antidiabetic agent is selected from the group consisting of: biguanide, sulfonylurea, glitazar, thiazolidinedione, dipeptidyl peptidase 4 (DPP-4) inhibitor, meglitinide, sodium-glucose linked transporter 2 (SGLT2) inhibitor, glitazone, GRP40 agonist, glucose-dependent insulinotropic peptide (GIP), insulin or insulin analogs, alpha glucosidase inhibitors, sodium-glucose linked transporter 1 (SGLT1) inhibitors, or any combination thereof. In some embodiments, the biguanide is metformin. In some embodiments, the anti-obesity agent is selected from the group consisting of a neuropeptide Y receptor type 2 (NPYR2) agonist, an NPYR1 or NPYR5 antagonist, a human proislet peptide (HIP), a lipase inhibitor, a melanocortin receptor 4 agonist, a farnesoid X receptor (FXR) agonist, phentermine, zonisamide, a norepinephrine / dopamine reuptake inhibitor, a GDF-15 analog, a cholecystokinin agonist, a serotonergic agent, a methionine aminopeptidase 2 (MetAP2) inhibitor, diethylpropion, phendimetrazine, benzphetamine, a fibroblast growth factor receptor (FGFR) modulator, an AMP-activated protein kinase (AMPK) activator, or any combination thereof. In some 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 agent for treating NASH is selected from the group consisting of: FXR agonist PF-05221304, synthetic fatty acid bile conjugate, anti-lysyl oxidase homolog 2 (LOXL2) monoclonal antibody, apoptotic protease inhibitor, MAPK5 inhibitor, galectin 3 inhibitor, fibroblast growth factor 21 (FGF21) agonist, nicotinic acid analog, leukotriene D4 (LTD4) receptor antagonist, acetyl-CoA carboxylase (ACC) inhibitor, ketokinase (KHK) inhibitor, ileal bile acid transporter (IBAT) inhibitor, apoptosis signal-regulating kinase 1 (ASK1) inhibitor, or any combination thereof. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof and the additional therapeutic agent are administered sequentially in separate doses in any order.

[0040] Also provided herein are methods for regulating insulin levels in a patient in need of such regulation, comprising administering to the patient an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In some embodiments, regulation results in an increase in insulin levels.

[0041] Also provided herein are methods for regulating glucose levels in a patient in need of such regulation, comprising administering to the patient an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In some embodiments, regulation results in a decrease in glucose levels.

[0042] Also provided herein is a method for treating a GLP-1-related disease, disorder or condition, the method 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 some embodiments, the disease, disorder or condition is selected from the group consisting of type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), atypical diabetes of the youth (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of adults (LADA), obesity, weight gain caused by the use of other agents, idiopathic intracranial hypertension, Wolfram syndrome (Wolfram syndrome), gout, sugar cravings, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient cerebral ischemia, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, vascular restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial lipidosis, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, X syndrome symptoms, smoking cessation, premenstrual syndrome, angina, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depression, skin and connective tissue disorders, foot ulcers, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof.In some embodiments, the disease, disorder or condition is selected from the group consisting of: type 2 diabetes, early onset type 2 diabetes, obesity, weight gain caused by the use of other agents, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient cerebral ischemia, atherosclerotic cardiovascular disease, hyperglycemia, postprandial lipidosis, metabolic acidosis, ketosis, hyperinsulinemia. hyperlipidemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, bipolar disorder / major depression, skin and connective tissue diseases, foot ulcers, psoriasis, primary polydipsia, nonalcoholic steatosis hepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS), idiopathic intracranial hypertension, Wolfram's syndrome, or any combination thereof. In some embodiments, the disease, disorder, or condition includes, but is not limited to, type 2 diabetes, early onset type 2 diabetes, obesity, weight gain due to use of other medications, gout, sugar cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat deposition, myocardial infarction, peripheral arterial disease, stroke, transient cerebral ischemia, hyperglycemia, postprandial lipidosis, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, chronic renal failure, syndrome X, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, skin and connective tissue diseases, foot ulcers, idiopathic intracranial hypertension, Wolfram's syndrome, or any combination thereof.

[0043] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent such incorporated by reference publications and patents or patent applications conflict with the disclosure contained in this specification, this specification is intended to supersede and / or take precedence over any such conflicting material.

[0044] Other features and advantages of the present invention will be apparent from the following detailed description and from the scope of the claims. [Implementation Method]

[0045] Provided herein are heterocyclic GLP-1 agonists for use in the management of type 2 diabetes mellitus (T2DM) and other conditions in which activation of GLP-1 activity is useful.

[0046] definition Where values ​​are described as ranges, it should be understood that such disclosure includes disclosure of all possible sub-ranges within such ranges, as well as specific values ​​falling within such ranges, whether or not a specific value or a specific sub-range is explicitly stated.

[0047] As used herein, the term "halo" or "halogen" refers to -F (sometimes referred to herein as "fluoro" or "fluoros"), -Cl (sometimes referred to herein as "chloro" or "chloros"), -Br (sometimes referred to herein as "bromo" or "bromos"), and -I (sometimes referred to herein as "iodo" or "iodos").

[0048] As used herein, the term "alkyl" refers to a saturated straight or branched chain monovalent hydrocarbon radical containing the indicated number of carbon atoms. For example, "C 1-6 "Alkyl" refers to a saturated straight or branched chain monovalent hydrocarbon radical having one to six carbon atoms. Non-limiting examples of alkyl include methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, 2-methyl-2-propyl, pentyl, neopentyl and hexyl.

[0049] As used herein, the term "alkylene" refers to a divalent alkyl group containing the indicated number of carbon atoms. For example, "C 1-3 "Alkylene" refers to a divalent alkyl group having one to three carbon atoms (e.g., -CH2-, -CH(CH3)-, -CH2CH2-, or -CH2CH2CH2-).

[0050] As used herein, the term "alkenyl" refers to a straight or branched monounsaturated hydrocarbon chain containing the indicated number of carbon atoms. 2-6 "Alkenyl" refers to a straight or branched monounsaturated hydrocarbon chain having two to six carbon atoms. Non-limiting examples of alkenyl include ethenyl, propenyl, butenyl or pentenyl.

[0051] As used herein, the term "alkynyl" refers to a straight or branched diunsaturated hydrocarbon chain containing the indicated number of carbon atoms. 2-6 "Alkynyl" refers to a straight or branched diunsaturated hydrocarbon chain having two to six carbon atoms. Non-limiting examples of alkynyl include ethynyl, propynyl, butynyl or pentynyl.

[0052] As used herein, the term "cycloalkyl" refers to a saturated or partially saturated cyclic hydrocarbon containing the indicated number of carbon atoms. For example, "C 3-6 "Cycloalkyl" refers to a saturated or partially saturated cyclic hydrocarbon having three to six ring carbon atoms. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl may contain multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyl include bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3. [1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane and the like. Cycloalkyl also includes spirocycles (e.g., spirocyclic bicycles in which the two rings are connected via 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[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane and the like.

[0053] As used herein, the term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic or polycyclic non-aromatic ring system containing the indicated number of ring atoms (e.g., a 3- to 8-membered monocyclic, 8- to 12-membered bicyclic or 11- to 14-membered tricyclic ring system), with 1 to 3 heteroatoms if monocyclic, 1 to 6 heteroatoms if bicyclic, or 1 to 9 heteroatoms if tricyclic or polycyclic, the heteroatoms being selected from O, N or S (e.g., carbon atoms and 1 to 3, 1 to 6 or 1 to 9 heteroatoms of N, O or S in the case of a monocyclic, bicyclic or tricyclic ring, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted with substituents. Examples of heterocyclyls include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl and the like. Heterocyclyls may include multiple fused and bridged rings. Non-limiting examples of fused / bridged heterocyclic groups include: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 1 .0]octane, 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane and the like. Heterocyclyl also includes spirocycles (e.g., spirobicycles in which the two rings are connected via 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-oxaspiro[5.5]undecane and the like.

[0054] As used herein, the term "aryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic hydrocarbon radical containing the indicated number of carbon atoms, wherein at least one ring in the system is aromatic (e.g., C6 monocyclic, C 10 Bicyclic or C 14 A tricyclic aromatic ring system). Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

[0055] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic radical having the indicated number of ring atoms (e.g., 5 to 6 ring atoms; e.g., 5, 6, 9, 10, or 14 ring atoms); wherein at least one ring in the system is aromatic (but not necessarily a heteroatom-containing ring, e.g., tetrahydroisoquinolyl, e.g., tetrahydroquinolyl), and at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S. Heteroaryl groups may be unsubstituted or substituted with one or more substituents. Examples of heteroaryl groups include thiophenyl, pyridyl, furanyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiadiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolylbenzothiophenyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b] Pyridyl, quinazolinyl, quinolyl, thieno[2,3-c]pyridyl, pyrazolo[3,4-b]pyridyl, pyrazolo[3,4-c]pyridyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridyl, tetrazolyl, chromane, 2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]oxathiin, isoindoline, etc.

[0056] As used herein, the term "haloalkyl" refers to an alkyl group as defined herein in which one or more hydrogen atoms are replaced by one or more halogen atoms. Non-limiting examples include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, chloromethyl, dichloromethyl, chloroethyl, trichloroethyl, bromomethyl and iodomethyl.

[0057] As used herein, the term "alkoxy" refers to an -O-alkyl group, wherein the group is located on the oxygen atom. For example, "C 1-6 "Alkoxy" refers to -O-(C 1-6 The term "haloalkoxy" as used herein refers to an -O-haloalkyl group, wherein the group is on the oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy. Thus, as used herein, the term "haloalkoxy" refers to an -O-haloalkyl group, wherein the group is on the oxygen atom.

[0058] As used herein, Indicates the optional presence of single or double bonds where valency permits. As used herein, The point of attachment to the parent molecule is indicated.

[0059] As used herein, the term "compound" is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structure. Unless otherwise stated, a compound identified herein as one particular tautomeric form by name or structure is intended to encompass the other tautomeric forms.

[0060] As used herein, the term "tautomer" refers to compounds whose structures differ significantly by arrangement of atoms, but which readily and rapidly equilibrate, and it is understood that the compounds provided herein may be depicted as different tautomers, and when a compound has tautomeric forms, all tautomeric forms are intended to be within the scope of the invention, and the naming of the compound does not exclude any tautomer.

[0061] As used herein, the term "GLP-1R" or "GLP-1R 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.

[0062] As used herein, the term "GLP-1 related disease" is intended to include, but is not limited to, all those diseases, disorders, or conditions in which modulation of glucagon-like peptide-1 (GLP-1) receptor signaling can alter the pathology and / or symptoms, and / or progression of the disease, disorder, or condition.

[0063] As used herein, the term "GLP-1 agonist or "GLP-1RA" refers to an agonist of the glucagon-like peptide-1 (GLP-1) receptor. GLP-1RA enhances glucose-dependent insulin secretion; inhibits inappropriate rises in glucagon levels in the fasting and postprandial states; and slows gastric emptying. Karla et al., Glucagon-like peptide-1 receptor agonists in the treatment of type 2 diabetes: Past, present, and future, Indian J Endocrinol Metab. 2016 Mar-Apr;20(2):254-267. GLP-1RA has been shown to treat type 2 diabetes. Examples of GLP-1RA include, but are not limited to, albiglutide. Dulaglutide (LY2189265, )、efpeglenatide、exenatide( Exendin-4), liraglutide ( NN2211), lixisenatide Semaglutide Tirzepatide, ZP2929, NNC0113-0987, BPI-3016 and TT401. GLP-1 receptor agonists are also described in, e.g., 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; RE45313; and International Publication Nos. WO 2019 / 239319; WO 2019 / 239371; WO 2020 / 103815; WO 2020 / 207474; WO 20202 / 34726; WO No. 2020 / 044266; No. WO 2020117987; and No. WO 2020263695.

[0064] The term "pharmaceutically acceptable" as used herein indicates that the compound or its salt or composition is chemically and / or toxicologically compatible with the other ingredients making up the formulation and / or the patient being treated therewith.

[0065] The term "therapeutic compound" as used herein is intended to include, but is not limited to, all compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof (e.g., compounds of any one of Formulas (IA), (IB), (IC), (ID) and (IE), or pharmaceutically acceptable salts or solvates thereof), and all compositions (e.g., pharmaceutical compositions) in which a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of Formulas (IA), (IB), (IC), (ID) and (IE), or pharmaceutically acceptable salts or solvates thereof) is a component of the composition.

[0066] The term "administration" or "administering" refers to a method of giving a dose of a compound or pharmaceutical composition to a vertebrate or invertebrate (including mammals, birds, fish or amphibians). The method of administration may vary depending on various factors, such as the components of the pharmaceutical composition, the site of the disease, and the severity of the disease.

[0067] As used herein, the term "effective amount" or "effective dose" or "pharmaceutically effective amount" or "therapeutically effective amount" refers to a sufficient amount of a chemical entity (e.g., a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any of formulas (IA), (IB), (IC), (ID) and (IE), or a pharmaceutically acceptable salt or solvate thereof) to relieve to some extent one or more symptoms of the disease or condition being treated, and may include curing the disease. "Cure" means eliminating symptoms of active disease. Results include alleviation and / or alleviation of signs, symptoms or causes of disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition including a compound as disclosed herein required to achieve a clinically significant reduction in disease symptoms. The appropriate "effective" amount in any individual case is determined using any suitable technique, such as a dose escalation study. In some embodiments, a "therapeutically effective amount" of a compound provided herein refers to an amount of the compound that is effective as a monotherapy or in combination therapy.

[0068] 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 substance. In some embodiments, each component is "pharmaceutically acceptable" in the sense that it is compatible with the other ingredients of the pharmaceutical formulation and suitable for contact with the tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash, eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson, ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0069] The term "pharmaceutical composition" refers to a mixture of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any 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, dispersants, suspending agents, and / or thickening agents. Pharmaceutical compositions facilitate administration of the compound to an organism. There are a variety of techniques for administering a compound in the art, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0070] In the context of treating a disease, disorder or condition, the terms "treat," "treating," or "treatment" are intended to include alleviating or eliminating the disorder, disease or condition, or one or more of the symptoms associated with the disorder, disease or condition; or slowing the progression, spread, or worsening of the disease, disorder or condition, or one or more symptoms thereof.

[0071] The term "preventing" as used herein is the complete or partial prevention of the onset, recurrence or spread of a disease or condition as described herein, or symptoms thereof.

[0072] As used herein, the terms "subject," "patient," or "individual" are used interchangeably and refer to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some embodiments, the terms refer to a subject in need of diagnosis, prognosis, or therapy, particularly a mammalian subject. In some embodiments, the patient is a human. In some embodiments, the subject has experienced and / or exhibits at least one symptom of the disease, disorder, or condition to be treated and / or prevented.

[0073] The terms "therapeutic regimen" and "dosing schedule" are used interchangeably to refer to the dosages and timing of administration of the various therapeutic agents in the combinations of the invention.

[0074] The term "pharmaceutical combination" as used herein refers to a medical therapy obtained by mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.

[0075] The term "combination therapy" as used herein refers to a dosing regimen of two different therapeutically active agents (ie, components of the combination or combination partners) wherein the therapeutically active agents are administered together or separately in a manner prescribed by a healthcare practitioner or according to a regulatory regime as defined herein.

[0076] As used herein, the term "modulate" means to regulate or adjust (eg, increase or decrease), and may include, for example, agonism, partial agonism, or antagonism.

[0077] Compound In one aspect, provided herein is a compound of formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0078] Q 1 , Q 2 , Q 3 , Q 4 and Q 5 Is defined according to (AA) or (BB):

[0079] (AA) Q 1 and Q 5 are independently selected from N, CH and CR QA The group composed of Q 2 , Q 3 and Q 4 are independently selected from N, CH, CR QA and CR QB The group is composed of Q 2 , Q 3 and Q 4 At least one of them is CR QB ; each is a single bond or a double bond, with the restriction that it contains Q 1 To Q 5 The ring is aromatic;

[0080] (BB) Q 1 is the key; Q 2 , Q 3 , Q 4 and Q 5 are independently selected from the group consisting of: O, S, N, NH, NR c , CH, CR QA and CR QB , whose restriction condition is Q 2 , Q 3 , Q 4 and Q 5 At least one of them is CR QB ; each is a single bond or a double bond, with the restriction that it contains Q 1 To Q 5 The ring is aromatic;

[0081] R QB P(=O)R a R b , where R a and R b are independently selected from the group consisting of: optionally 1 to 6 each independently selected from C 1-6 Alkoxy, C 3-6 The C-substituted substituent group is a cycloalkyl group or a halogen group. 1-6 Alkyl; optionally 1 to 3 each independently selected from C 1-3 C substituted with a substituent consisting of an alkyl group and a halogen group 3-6 Cycloalkyl; and optionally 1 to 3 independently selected C1-3 Alkyl substituted C 6-10 aryl; or

[0082] R a and R b Together with the phosphorus atoms to which they are attached, they form a ring containing 5 to 8 ring atoms, of which 0 to 2 ring atoms (excluding those with R a and R b The attached phosphorus) is a heteroatom each independently selected from the group consisting of O, S and N, wherein the ring is optionally substituted with 1 to 3 independently selected C 1-6 Alkyl substitution;

[0083] Each R QA are independently selected from the group consisting of: (a) halide; (b) cyano; (c) OH; (d) -NR c R d ; (e) C(═O) NR c R d ; (f) S(═O) 0-2 R e (g) optionally 1 to 6 independently selected R f Substituted C 1-6 (h) optionally substituted with 1 to 6 groups independently selected from hydroxyl, halogen and C 1-6 The C substituted by the substituent group consisting of alkoxy 1-6 Alkoxy; (i) optionally substituted with one or more independently selected from C 1-6 Alkyl and C(=O)(C 1-6 alkyl) substituted with 1 to 3 independently selected C(═O)(C 1-6 Alkyl) substituted C 6-10 Aryl; and (k) optionally 1 to 6 independently selected R g substituted 5- to 10-membered heteroaryl;

[0084] or R on adjacent carbon atoms QA The ring is optionally substituted with 1 to 2 independently selected R h group substitution;

[0085] L 2 is selected from the group consisting of: Where aa represents the 1 To Q 5 The connection point of the ring; n1 is an integer from 1 to 3; L 2A For key or C 1-10 Alkylene; R La Is selected from H, C 1-6 Alkyl and C(=O)(C 1-6 alkyl) group; R Lb and R Lc Each of which is independently selected from H and C 1-6 The group consisting of alkyl groups;

[0086] 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 optionally substituted by 1 to 5 groups independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Substitution of the substituents of the group consisting of alkoxy groups;

[0087] R 1 , R 2 and R 3 are each independently selected from the group consisting of: H and optionally 1 to 6 each independently selected from halogen, -OH and C 1-6 The substituents consisting of alkoxy groups are substituted with C 1-6 alkyl;

[0088] L 1 is selected from the group consisting of: -C(=O)-, -CH2-, -CH(C 1-6 alkyl)- and -S(=O)2;

[0089] Ring B is selected from the group consisting of: Where bb represents the 1 The connection point; R 4 , R 5 , R 6 and R 7 are independently selected from the group consisting of: H, halogen and C 1-6 alkyl; L 3 For key or C 1-3 Alkylene; L 4 For key or C 1-5 Alkylene; R 8a and R 8bare independently selected from the group consisting of: H and optionally substituted by one or more independently selected from halogen and C 3-15 The substituents of the group consisting of cycloalkyl groups are substituted with C 1-6 Alkyl; or R 8a and R 8b Together with the carbon atoms to which they are attached, they form optionally 1 to 3 independently selected C 1-6 Alkyl substituted C 3-15 Cycloalkyl ring, wherein the C 1-6 The alkyl group is optionally substituted with 1 to 6 independently selected R f replace; R 9 is selected from the group consisting of: C(=O)OH, C(=O)(OC 1-6 alkyl), C(=O)NR 9a R 9b , (IX-1), (IX-2), (IX-3) and (IX-4): R 9a H or C 1-6 alkyl; R 9b H, C 1-6 Alkyl, C(=O)(C 1-6 Alkyl), S(O) 0-2 (C 1-6 alkyl) or cyano; R 9c , R 9d , R 9e , R 9f and R 9g are each independently selected from the group consisting of: H; and optionally 1 to 6 independently selected halogen and C 1-6 Alkoxy substituted C 1-6 Alkyl; and C(=O)(C 1-6 alkyl);

[0090] Ring C is selected from 3- to 12-membered heterocyclic groups; 3-15 Cycloalkyl; and a group consisting of 5- to 10-membered heteroaryl, each of which is optionally substituted by 1 to 3 R Ca replace;

[0091] Each R Ca are independently selected from the group consisting of: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and NR c R d ;

[0092] or R on the same or different ring atoms Ca The pair together with the one or more ring atoms to which they are respectively attached form a carbocyclic ring containing 3 to 8 ring atoms;

[0093] Each R c and R d are independently selected from the group consisting of: H, C 1-6 Alkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 Cycloalkyl), C(=O)O(C 1-6 Alkyl), S(O) 1-2 (C 1-6 Alkyl) and S(O) 1-2 (C 3-6 Cycloalkyl), wherein 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 optionally substituted with 1 to 6 groups independently selected from -OH, halogen and C 1-6 Substitution of the substituents of the group consisting of alkoxy groups;

[0094] R e H, C 1-6 Alkyl or C 1-6 Haloalkyl;

[0095] Each R f are independently selected from the group consisting of: halogen, -OH, NR c R d , C 1-6 Alkoxy, C 1-6 haloalkoxy and optionally substituted by 1 to 4 each independently selected from -OH, C 1-6 A 3- to 12-membered heterocyclic group substituted with a substituent selected from the group consisting of an alkyl group and a 3- to 12-membered heterocyclic group;

[0096] Each R g are independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Alkoxy, NR c R d and optionally one or more independently selected from C 1-6 Alkyl and C(=O)C 1-6 A 3- to 12-membered heterocyclic group substituted with a substituent selected from the group consisting of an alkyl group; and

[0097] Each R h are independently selected from the group consisting of: halogen, 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 Halogenated alkoxy.

[0098] In some embodiments, provided herein are compounds of formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0099] Q 1 , Q 2 , Q 3 , Q 4 and Q 5 Is defined according to (AA) or (BB):

[0100] (AA) Q 1 and Q 5 are independently selected from N, CH and CR QA The group composed of Q 2 , Q 3 and Q 4 are independently selected from N, CH, CR QA and CR QB The group is composed of Q 2 , Q 3 and Q 4 At least one of them is CR QB ; each is a single bond or a double bond, with the restriction that it contains Q 1 To Q 5 The ring is aromatic;

[0101] (BB) Q 1 is the key; Q 2 , Q 3 , Q 4 and Q 5 are independently selected from the group consisting of: O, S, N, NH, NR c , CH, CR QA and CR QB , whose restriction condition is Q 2 , Q3 , Q 4 and Q 5 At least one of them is CR QB ; each is a single bond or a double bond, with the restriction that it contains Q 1 To Q 5 The ring is aromatic;

[0102] R QB P(=O)R a R b , where R a and R b are independently selected from the group consisting of: optionally 1 to 6 each independently selected from C 1-6 Alkoxy, C 3-6 The C-substituted substituent group is a cycloalkyl group or a halogen group. 1-6 Alkyl; and optionally 1 to 3 independently selected C 1-3 Alkyl substituted C 6-10 aryl; or

[0103] R a and R b Together with the phosphorus atoms to which they are attached, they form a ring containing 5 to 8 ring atoms, of which 0 to 2 ring atoms (excluding those with R a and R b The attached phosphorus) is a heteroatom each independently selected from the group consisting of O, S and N, wherein the ring is optionally substituted with 1 to 3 independently selected C 1-6 Alkyl substitution;

[0104] Each R QA are independently selected from the group consisting of: (a) halide; (b) cyano; (c) OH; (d) -NR c R d ; (e) C(═O) NR c R d ; (f) S(═O) 0-2 R e (g) optionally 1 to 6 independently selected R f Substituted C 1-6 (h) optionally substituted with 1 to 6 groups independently selected from hydroxyl, halogen and C 1-6 The C substituted by the substituent group consisting of alkoxy 1-6 Alkoxy; (i) optionally substituted with one or more independently selected from C 1-6 Alkyl and C(=O)(C 1-6 alkyl) substituted with 1 to 3 independently selected C(═O)(C 1-6Alkyl) substituted C 6-10 Aryl; and (k) optionally 1 to 6 independently selected R g substituted 5- to 10-membered heteroaryl;

[0105] or R on adjacent carbon atoms QA The ring is optionally substituted with 1 to 2 independently selected R h group substitution;

[0106] L 2 is selected from the group consisting of: Where aa represents the 1 To Q 5 The connection point of the ring; n1 is an integer from 1 to 3; L 2A For key or C 1-10 Alkylene; R La Is selected from H, C 1-6 Alkyl and C(=O)(C 1-6 alkyl) group; R Lb and R Lc Each of which is independently selected from H and C 1-6 The group consisting of alkyl groups;

[0107] 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 optionally substituted by 1 to 5 groups independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Substitution of the substituents of the group consisting of alkoxy groups;

[0108] R 1 , R 2 and R 3 are each independently selected from the group consisting of: H and optionally 1 to 6 each independently selected from halogen, -OH and C 1-6 The substituents consisting of alkoxy groups are substituted with C 1-6 alkyl;

[0109] L 1 is selected from the group consisting of: -C(=O)-, -CH2-, -CH(C 1-6 alkyl)- and -S(=O)2;

[0110] Ring B is selected from the group consisting of: Where bb represents the 1 The connection point; R 4 , R 5 , R 6 and R 7 are independently selected from the group consisting of: H, halogen and C 1-6 alkyl; L 3 For key or C 1-3 Alkylene; L 4 For key or C 1-5 Alkylene; R 8a and R 8b are independently selected from the group consisting of: H and optionally substituted by one or more independently selected from halogen and C 3-15 The substituents of the group consisting of cycloalkyl groups are substituted with C 1-6 Alkyl; or R 8a and R 8b Together with the carbon atoms to which they are attached, they form optionally 1 to 3 independently selected C 1-6 Alkyl substituted C 3-15 Cycloalkyl ring, wherein the C 1-6 The alkyl group is optionally substituted with 1 to 6 independently selected R f replace; R 9 is selected from the group consisting of: C(=O)OH, C(=O)(OC 1-6 alkyl), C(=O)NR 9a R 9b , (IX-1), (IX-2), (IX-3) and (IX-4): R 9a H or C 1-6 alkyl; R 9b 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 9gare each independently selected from the group consisting of: H; and optionally 1 to 6 independently selected halogen and C 1-6 Alkoxy substituted C 1-6 Alkyl; and C(=O)(C 1-6 alkyl);

[0111] Ring C is selected from the group consisting of 3- to 12-membered heterocyclyl and 5- to 10-membered heteroaryl, each of which is optionally substituted by 1 to 3 R Ca replace;

[0112] Each R Ca are independently selected from the group consisting of: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and NR c R d ;

[0113] or R on the same or different ring atoms Ca The pair together with the one or more ring atoms to which they are respectively attached form a carbocyclic ring containing 3 to 8 ring atoms;

[0114] Each R c and R d are independently selected from the group consisting of: H, C 1-6 Alkyl and C(=O)(C 1-6 Alkyl), where C 1-6 Alkyl and C(=O)(C 1-6 alkyl) are each optionally substituted with 1 to 6 groups independently selected from -OH, halogen and C 1-6 Substitution of the substituents of the group consisting of alkoxy groups;

[0115] R e H, C 1-6 Alkyl or C 1-6 Haloalkyl;

[0116] Each R f are independently selected from the group consisting of: halogen, -OH, NR c R d , C 1-6 Alkoxy, C 1-6 The halogenated alkoxy group is optionally substituted by 1 to 4 groups independently selected from -OH, C 1-6 A 3- to 12-membered heterocyclic group substituted with a substituent selected from the group consisting of an alkyl group and a 3- to 12-membered heterocyclic group;

[0117] Each R g are independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Alkoxy, NR c Rd and optionally one or more independently selected from C 1-6 Alkyl and C(=O)C 1-6 A 3- to 12-membered heterocyclic group substituted with a substituent selected from the group consisting of an alkyl group; and

[0118] Each R h are independently selected from the group consisting of: halogen, 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 Halogenated alkoxy.

[0119] Implementations may include any one or more of the features described below and / or in the claims.

[0120] In some embodiments, Q 1 , Q 2 , Q 3 , Q 4 and Q 5 It is defined according to (AA).

[0121] In certain embodiments, Q 3 CR QB In certain of these embodiments, Q 4 N, CH or CR QA .

[0122] In certain embodiments, Q 4 CR QB In certain of these embodiments, Q 3 N, CH or CR QA .

[0123] In certain embodiments, Q 1 CH or CR QA In certain embodiments, Q 1 For CH.

[0124] In certain embodiments, Q 2 CH or CR QA In certain embodiments, Q 2 For CH.

[0125] In certain embodiments, Q 5 CH or CR QA In certain embodiments, Q 5 In certain other embodiments, Q 5 CRQA .

[0126] In certain embodiments, Q 3 CR QB ; and Q 1 , Q 2 , Q 4 and Q 5 Each of is independently CH or CR QA In certain of these embodiments, Q 1 , Q 2 , Q 4 and Q 5 Each of is CH.

[0127] In certain embodiments (when Q 3 CR QB ; and Q 1 , Q 2 , Q 4 and Q 5 Each of 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 The rest of each is CH. As a non-limiting example of the foregoing embodiment, Q 4 CR QA ; and Q 1 , Q 2 and Q 5 For CH.

[0128] In certain embodiments (when Q 3 CR QB ; and Q 1 , Q 2 , Q 4 and Q 5 Each of is independently CH or CR QA ), Q 1 , Q 2 , Q 4 and Q 5 Two of them are independently selected CRs QA ; and Q 1 , Q 2 , Q 4 and Q 5 The rest of them are CH.

[0129] In certain embodiments, Q3 CR QB ;Q 1 , Q 2 , Q 4 and Q 5 One of them is N; and Q 1 , Q 2 , Q 4 and Q 5 The rest of them are independently CH or CR QA In certain of these embodiments, Q 4 is N. In certain of the foregoing embodiments, Q 1 , Q 2 and Q 5 For CH.

[0130] In certain embodiments, Q 3 CR QB ;and The part is selected from the group consisting of:

[0131] In certain embodiments, Q 3 CR QB ;and The part is selected from the group consisting of:

[0132] As a non-limiting example, Part can be

[0133] As another non-limiting example, Part can be

[0134] In certain embodiments, Q 3 CR QB ;and The part is selected from the group consisting of:

[0135] As a non-limiting example, Part can be

[0136] As another non-limiting example, Part can be

[0137] In certain embodiments, Q 4 CR QB ; and Q 1 , Q 2 , Q 3 and Q5 Each of is independently CH or CR QA In certain of these embodiments, Q 1 , Q 2 , Q 3 and Q 5 Each of is CH.

[0138] In certain embodiments (when Q 4 CR QB ; and Q 1 , Q 2 , Q 3 and Q 5 Each of 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 The rest of each is CH. As a non-limiting example of the foregoing embodiment, Q 5 CR QA ; and Q 1 , Q 2 and Q 3 For CH.

[0139] In certain embodiments (when Q 4 CR QB ; and Q 1 , Q 2 , Q 3 and Q 5 Each of is independently CH or CR QA ), Q 1 , Q 2 , Q 3 and Q 5 Two of them are independently selected CRs QA ; and Q 1 , Q 2 , Q 3 and Q 5 The rest of each is CH. As a non-limiting example of the foregoing embodiment, Q 2 and Q 3 CR for independent selection Qa ; and Q 1 and Q 5 For CH.

[0140] In certain embodiments, Q 4 CR QB;Q 1 , Q 2 , Q 3 and Q 5 One of them is N; and Q 1 , Q 2 , Q 3 and Q 5 The rest of them are independently CH or CR QA .

[0141] In certain embodiments, Q 4 CR QB ;and The part is selected from the group consisting of:

[0142] In certain embodiments, Q 4 CR QB ;and The part is selected from the group consisting of:

[0143] In certain embodiments, Part of Where Q 4 and Q 5 are independently selected from N, CH and CR QA In certain of these embodiments, Q 4 and Q 5 In certain other embodiments, Q 4 CR QA ; and Q 5 In certain other embodiments, Q 4 is N; and Q 5 CR QA Or CH. In certain embodiments, Q 5 For CH.

[0144] In certain embodiments, Part of Where Q 2 , Q 3 and Q 5 are independently selected from N, CH and CR QA In certain of these embodiments, Q 2 , Q 3 and Q 5 In certain other embodiments, Q 5 CR QA ; and Q 2 and Q 3 In certain other embodiments, Q5 is CH; and Q 2 and Q 3 CR for independent selection QA .

[0145] In some embodiments, R QB P(=O)R a R b , where R a and R b is independently selected from C 1-6 Alkyl and C 3-6 The group consisting of cycloalkyl.

[0146] In some embodiments, R QB P(=O)R a R b , where R a and R b Each independently is C 1-6 In some embodiments, R QB P(=O)R a R b , where R a and R b Each independently is C 1-3 alkyl.

[0147] In certain embodiments, R a With R b same.

[0148] In certain of these embodiments, R a and R b Each is a methyl group (ie, R QB is P(=O)Me2).

[0149] In certain embodiments, R a and R b Each is ethyl (ie, R QB is P(=O)Et2).

[0150] In certain embodiments, R a and R b Each is a propyl group, such as an isopropyl group. QB It can be P(=O)iPr2.

[0151] In certain embodiments, R QB P(=O)R a R b ; R a and R b Each independently is C 1-6 alkyl; and R a With Rb In certain of these embodiments, R a C 1-3 alkyl (eg, methyl or ethyl); and R b C 4-6 For example, R a may be methyl; and R b It can be tert-butyl (ie R QB can be P(=O)(Me)(tBu)). In certain embodiments, R a and R b C for independent selection 1-3 Alkyl, with the restriction that R a With R b different.

[0152] In some embodiments, R QB P(=O)R a R b , where R a and R b Each independently is C 3-6 In certain of these embodiments, R a With R b For example, R a and R b can be cyclopropyl (ie R QB Can ).

[0153] In some embodiments, R QB P(=O)R a R b , where R a and R b Together with the phosphorus atoms to which they are attached, they form a ring containing 5 to 8 ring atoms, of which 0 to 2 ring atoms (excluding those with R a and R b The attached phosphorus) is a heteroatom each independently selected from the group consisting of O, S and N, wherein the ring is optionally substituted with 1 to 3 independently selected C 1-6 Alkyl substitution.

[0154] In certain of these embodiments, R QB P(=O)R a R b , where R a and R b Together with the phosphorus atoms to which they are attached, they form a ring containing 5 to 6 ring atoms, of which 0 to 1 ring atoms (excluding those with R a and R bThe attached phosphorus) is a heteroatom selected from the group consisting of O, S and N, wherein the ring is optionally substituted with 1 to 2 independently selected C 1-6 Alkyl substitution.

[0155] As a non-limiting example of the foregoing embodiment, R QB Can Where L Q is a bond, CH2, O, S, NH or N(C 1-6 For example, R QB Can

[0156] In some embodiments, each R QA is selected from the group consisting of: halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, OH and NR c R d ;

[0157] In some embodiments, each R QA is selected from the group consisting of halogen, cyano, OH and NR c R d .

[0158] In some embodiments, R QA In certain of these embodiments, R QA -F in one occurrence.

[0159] In some embodiments, R QA In one occurrence it is -OH.

[0160] In some embodiments, R QA NR if it occurs once c R d .

[0161] In certain of these embodiments, R QA When it appears once, it is NH(C 1-3 alkyl) (e.g., NHMe, NHEt or NHiPr).

[0162] In certain embodiments, R QA In one occurrence it is NH2.

[0163] In certain embodiments, R QA When it appears once, it is N(C 1-3 alkyl)2 (e.g. NMe2).

[0164] In certain embodiments, R QAWhen present once, it is selected from the group consisting of: NHC(=O)(C 1-6 alkyl), NHC(=O)(C 3-6 Cycloalkyl), NHC(=O)O(C 1-6 Alkyl), NHS(O) 1-2 (C 1-6 Alkyl) and NHS(O) 1-2 (C 3-6 cycloalkyl).

[0165] In certain embodiments, R QA When it appears once, it is NHC(=O)(C 1-3 alkyl), NHC(=O)(C 3-6 Cycloalkyl) (e.g. NHC(=O)(cyclopropyl)) or NHS(O)2(C 1-3 alkyl) (e.g. NHS(O)2Me).

[0166] In some embodiments, R QA When present once, it is optionally selected from one or more independently selected from C 1-6 Alkyl and C(=O)(C 1-6 alkyl) substituted with a 5- to 6-membered heterocyclic group. In certain of these embodiments, R QA In one occurrence it is morpholinyl.

[0167] In some embodiments, R QA When present once, it is optionally substituted with 1 to 6 groups each independently selected from hydroxy, halo and C 1-6 The C substituted by the substituent group consisting of alkoxy 1-6 In certain of these embodiments, R QA is, at one occurrence, C optionally substituted with 1 to 6 (e.g., 1 to 3) independently selected halo 1-6 As non-limiting examples of the foregoing embodiments, RQA may be -OMe, -OCF3 or -OCHF2. For example, R QA It can be -OMe. For example, R QA As another non-limiting example, R QA It can be -OCHF2.

[0168] In some embodiments, R QA is any one to six independently selected R f Substituted C 1-6 In certain of these embodiments, R QA C 1-3 As a non-limiting example of the foregoing embodiment, R QAIt may be methyl.

[0169] In certain of these embodiments, R QA is C substituted with 1 to 6 independently selected halo groups at one occurrence 1-3 Alkyl. For example, R QA It may be CF3, CHF2 or CH2F (eg, CF3 or CHF2).

[0170] In certain of these embodiments, R QA When it appears once, it is NR c R d Substituted C 1-3 Alkyl. For example, R QA It may be CH2NHMe.

[0171] In certain embodiments, the remaining R QA When present, is independently selected halo, such as -F.

[0172] In some embodiments, R on adjacent carbon atoms QA The ring is optionally substituted with 1 to 2 independently selected R h Group substitution.

[0173] In certain of these embodiments, R on adjacent carbon atoms QA The pairs, together with the atoms they are attached to, form:

[0174] In certain embodiments, R on adjacent carbon atoms QA The pairs, together with the atoms they are attached to, form:

[0175] In some embodiments, the remaining R QA When present, independently halo, cyano or C 1-3 alkyl.

[0176] In some embodiments, L 2 for In certain of these embodiments, L 2A In certain other embodiments, L 2A For CH2.

[0177] In some embodiments, L 2 for

[0178] In some embodiments, L 2 for In certain of these embodiments, n1 is 1. In certain other embodiments, n1 is 2 or 3. In certain embodiments, L 2A In certain other embodiments, L 2A C 1-2 Alkylene.

[0179] In some embodiments, L 2 for In certain embodiments, L 2A In certain other embodiments, L 2A C 1-2 Alkylene.

[0180] In some embodiments, L 2 for

[0181] In some embodiments, Ring A is C 6-10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by 1 to 4 groups independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 The substituent group consisting of the alkoxy group is substituted.

[0182] In some embodiments, Ring A is phenyl or pyridinyl, each of which is optionally substituted with 2 to 4 groups independently selected from halo, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 The substituent group consisting of the alkoxy group is substituted.

[0183] In certain of the foregoing embodiments, Ring A is phenyl, which is optionally substituted with 2 to 4 groups each independently selected from halo (eg, -F) and C 1-6 Alkyl (e.g. C 1-3 As a non-limiting example of the foregoing embodiment, ring A may be Where R AA , R AB and R AC are independently halogen or C 1-6 Alkyl. For example, R AA and R AC C can be selected independently 1-3 Alkyl (eg methyl); and / or R AB It may be a halogen group (eg, -F).

[0184] In certain embodiments, Ring A is pyridinyl, which is optionally substituted with 2 to 4 groups each independently selected from halo and C 1-6For example, ring A may be 4-pyridyl, which may be substituted with 2 to 4 substituents each independently selected from halogen and C 1-6 As another embodiment, ring A is 3-pyridyl, which is optionally substituted with 2 to 4 substituents each independently selected from halogen and C 1-6 As another embodiment, ring A is 2-pyridyl, which is optionally substituted with 2 to 4 substituents each independently selected from halogen and C 1-6 The alkyl group is substituted by a substituent.

[0185] In some embodiments, R 1 is H. In some embodiments, R 1 It is C 1-6 alkyl.

[0186] In some embodiments, R 2 is H. In some embodiments, R 2 C 1-6 alkyl.

[0187] In some embodiments, R 3 is H. In some embodiments, R 3 C 1-6 Alkyl (e.g. C 1-3 alkyl group, such as methyl).

[0188] In certain embodiments, R 1 , R 2 and R 3 is H. In certain other embodiments, R 1 and R 2 is H; and R 3 C 1-6 In certain of these embodiments, R 3 It is methyl.

[0189] In certain embodiments, R 1 is H; and R 2 and R 3 C for independent selection 1-6 alkyl.

[0190] In some embodiments, L 1 It is C(=O).

[0191] In some embodiments, L 1 is -CH2- or -CH(C 1-6 alkyl)-.

[0192] In some embodiments, L 1 It is -S(=O)2.

[0193] In some embodiments, Ring B is

[0194] In certain of these embodiments, R 4 , R 5 and R 6 Each is H or halo. In certain embodiments, R 4 , R 5 and R 6 Each is H or -F. As a non-limiting example of the foregoing embodiment, R 4 , R 5 and R 6 Each is H. As another non-limiting example, R 4 and R 5 is H; and R 6 In certain embodiments, R 7 is H, in certain other embodiments, R 7 is -F.

[0195] In certain embodiments, Ring B is And R 4 , R 5 , R 6 and R 7 Each of them is H.

[0196] In certain embodiments, Ring B is R 4 , R 5 and R 6 Each of them is H; and R 7 is -F.

[0197] In some embodiments, Ring B is selected from the group consisting of: (For example, Ring B may be ).

[0198] In certain embodiments, R 4 , R 5 , R 6 and R 7 Each of the above, when present, is independently selected from the group consisting of -H and halogen. 4 , R 5 , R 6 and R 7 Each of -H and -F, when present, is independently selected from the group consisting of -H and -F.

[0199] In some embodiments, L 3 and L 4 In certain of these embodiments, at least one of L 3 and L4 All are keys.

[0200] In certain specific embodiments, L 3 is a key; and L 4 C 1-2 Alkylene.

[0201] In certain other embodiments, L 4 is a key; and L 3 C 1-2 Alkylene.

[0202] In certain embodiments, L 3 and L 4 Each independently is C 1-2 Alkylene.

[0203] In some embodiments, R 8a and R 8b Together with the carbon atoms to which they are attached, they form optionally 1 to 2 independently selected C 1-6 Alkyl substituted C 3-8 Cycloalkyl ring, wherein the C 1-6 The alkyl group is optionally substituted with 1 to 3 independently selected R f replace.

[0204] In certain embodiments, R 8a and R 8b Together with the carbon atoms to which they are attached, they form optionally 1 to 2 independently selected C 1-6 Alkyl substituted C 3-5 Cycloalkyl ring, wherein the C 1-6 The alkyl group is optionally substituted with 1 to 3 independently selected R f replace.

[0205] In certain embodiments, R 8a and R 8b Together with the carbon atoms to which they are attached, they form optionally 1 to 2 independently selected C 1-6 Alkyl substituted C 3-4 Cycloalkyl ring.

[0206] As a non-limiting example of the foregoing embodiment, R 8a and R 8b Together with the carbon atoms to which they are attached they form: (For example )or For example, R 8a and R 8b Together with the carbon atoms to which they are attached they form:

[0207] In some embodiments, R8a and R 8b Each independently selected from H and C 1-6 For example, R 8a and R 8b All can be H. As another embodiment, R 8a and R 8b C can be selected independently 1-6 Alkyl (e.g. C 1-3 As another example, R 8a can be H; and R 8b Can be C 1-6 Alkyl (e.g. C 1-3 alkyl).

[0208] In some embodiments, L 3 -C(R 8a R 8b )-L 4 -R 9 Parts are: In certain of these embodiments, R 9d H or C 1-6 Alkyl. For example, R 9d Can be H.

[0209] In some embodiments, L 3 -C(R 8a R 8b )-L 4 -R 9 Parts are: In certain of these embodiments, R 9d H or C 1-6 Alkyl. For example, R 9d Can be H.

[0210] In some embodiments, R 9 for In certain of these embodiments, R 9d H or C 1-6 Alkyl. For example, R 9d Can be H.

[0211] In some embodiments, R 9 for In some embodiments, R 9 for In some embodiments, R 9 for

[0212] In some embodiments, R 9 It is C(=O)OH.

[0213] In some embodiments, R 9 C(=O)(OC 1-6 alkyl).

[0214] In some embodiments, R 9 C(=O)NR 9a R 9b In certain embodiments, R 9a is H. In certain embodiments, R 9b is H. In certain embodiments, R 9b C 1-6 In certain embodiments, R 9b is selected from the group consisting of: C(=O)(C 1-6 Alkyl), S(O) 0-2 (C 1-6 alkyl) and cyano.

[0215] In some embodiments, Part of Where ring D is C 3-6 Cycloalkyl; and R 8c is selected from the group consisting of: H and optionally 1 to 3 independently selected R f Substituted C 1-6 Alkyl. Non-limiting examples include: (For example )or

[0216] In certain embodiments (when Part of ), R 9 for In certain of these embodiments, R 9d H or C 1-6 Alkyl. For example, R 9d Can be H.

[0217] In some embodiments, Ring C is optionally substituted with 1 to 3 independently selected R Ca A substituted 3- to 12-membered heterocyclic group.

[0218] In certain embodiments, Ring C is optionally substituted with 1 to 3 independently selected R Ca A substituted 4- to 8-membered heterocyclic group.

[0219] In certain embodiments, Ring C is optionally substituted with 1 to 3 independently selected R Ca A substituted 5- to 6-membered heterocyclic group.

[0220] In certain embodiments, Ring C is optionally substituted with 1 to 3 independently R CaFor example, ring C can be selected from the group consisting of: (For example As another non-limiting example, ring C may be (For example, ).

[0221] In certain embodiments, Ring C is optionally substituted with 1 to 3 independently selected R Ca For example, ring C may be (For example ).

[0222] In some embodiments, Ring C is optionally substituted with 1 to 3 independently selected R Ca Substituted 5- to 6-membered heteroaryl.

[0223] In some embodiments, Ring C is optionally substituted with 1 to 3 R Ca Substituted C 3-10 In some embodiments, Ring C is optionally substituted with 1 to 3 independently selected R Ca Substituted C 3-8 For example, ring C can be (For example ).

[0224] In some embodiments, each R Ca are independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy and NR c R d Composed of groups.

[0225] In some embodiments, each R Ca are independently selected from halogen and C 1-6 Alkyl group.

[0226] In some embodiments, each R Ca Independently for C 1-6 For example, each R Ca It may be methyl.

[0227] In some embodiments, each R Ca is an independently selected halogen group. Ca Can be -F.

[0228] In some embodiments, R on the same or different ring atoms Ca The R pairs are taken together with the one or more ring atoms to which they are each attached to form a carbocyclic ring containing 3 to 6 ring atoms. CaThe pairs, together with the ring atoms to which they are respectively attached, form a carbocyclic ring containing 3 to 5 ring atoms.

[0229] In some embodiments, the compound of formula (I) is a compound of formula (IA): Where Q 4 and Q 5 are independently selected from the group consisting of: N, CH and CR QA ; or a pharmaceutically acceptable salt or solvate thereof.

[0230] In some embodiments of Formula (IA), Q 4 and Q 5 Each of them is CH.

[0231] In some embodiments of Formula (IA), Q 4 CR QA ; and Q 5 For CH.

[0232] In some embodiments of Formula (IA), Q 4 CR QA ; and Q 5 CR QA In certain other embodiments, Q 4 CR QA ; and Q 5 is a C-halogen group such as CF.

[0233] In some embodiments of Formula (IA), Q 4 is N; and Q 5 CR QA or CH. In certain of these embodiments, Q 5 For CH.

[0234] In some embodiments, the compound of formula (I) is a compound of formula (IB): Where Q 2 , Q 3 and Q 5 are independently selected from the group consisting of: N, CH and CR QA ; or a pharmaceutically acceptable salt or solvate thereof.

[0235] In some embodiments of Formula (IB), Q 2 , Q 3 and Q 5 Each of them is CH.

[0236] In some embodiments of Formula (IB), Q 5 CR QA ; and Q 2 and Q 3 Each of them is CH.

[0237] In some embodiments of Formula (IB), Q 5 is CH; and Q 2 and Q 3 CR for independent selection QA .

[0238] In some embodiments of Formula (IA) or (IB), Ring B is

[0239] In certain of these embodiments, L 3 and L 4 As a non-limiting example of the foregoing embodiment, L 3 and L 4 All are keys.

[0240] In some embodiments of Formula (IA) or (IB), R 8a and R 8b Together with the carbon atoms to which they are attached, they form optionally 1 to 2 independently selected C 1-6 Alkyl substituted C 3-5 Cycloalkyl ring, wherein the C 1-6 The alkyl group is optionally substituted with 1 to 3 independently selected R f replace.

[0241] In certain of these embodiments, R 8a and R 8b Together with the carbon atoms to which they are attached, they form optionally 1 to 2 independently selected C 1-6 Alkyl substituted C 3-4 Cycloalkyl ring.

[0242] As a non-limiting example of the foregoing embodiment, R 8a and R 8b Together with the carbon atoms to which they are attached they form:

[0243] In some embodiments of Formula (IA) or (IB), Ring C is optionally substituted with 1 to 3 independently selected R Ca In certain embodiments, Ring C is optionally substituted with 1 to 3 independently selected R Ca In certain embodiments, ring C is optionally substituted with 1 to 3 independently R CaAs a non-limiting example of the foregoing embodiment, ring C may be selected from the group consisting of In certain embodiments, Ring C is optionally substituted with 1 to 3 independently selected R Ca Substituted morpholinyl. For example, ring C may be

[0244] In some embodiments of Formula (IA) or (IB), Ring C is optionally substituted with 1 to 3 R Ca Substituted C 3-8 For example, ring C can be

[0245] In some embodiments of Formula (IA) or (IB), each R Ca Independently for C 1-6 For example, each RCa Can be H. As another non-limiting example, each R Ca C 1-3 Alkyl (eg, methyl).

[0246] In some embodiments of Formula (IA) or (IB), each R Ca is an independently selected halo group (eg, -F).

[0247] In some embodiments of Formula (IA) or (IB), R on the same or different ring atoms Ca The pair together with the one or more ring atoms to which they are respectively attached form a carbocyclic ring containing 3 to 6 ring atoms;

[0248] In some embodiments of Formula (IA) or (IB), R on the same ring atom Ca The pairs, together with the ring atoms to which they are respectively attached, form a carbocyclic ring containing 3 to 5 ring atoms.

[0249] In some embodiments, the compound of formula (I) is a compound of formula (IC): or a pharmaceutically acceptable salt or solvate thereof, wherein: Ring D is C 3-6 Cycloalkyl; R 8c is selected from H and optionally 1 to 3 independently selected R f Substituted C 1-6 alkyl; and Each R Cb is independently selected from H and R Ca Composed of groups.

[0250] In some embodiments of Formula (IC), Ring D is cyclopropyl.

[0251] In certain embodiments of Formula (IC), Ring D is cyclobutyl.

[0252] In some embodiments of Formula (IC), R 8c For H.

[0253] In some embodiments of Formula (IC), R 8c C 1-3 Alkyl. For example, R 8c It may be methyl.

[0254] In some embodiments of Formula (IC), each R Cb For H.

[0255] In some embodiments of Formula (IC), each R Cb Independently for C 1-6 Alkyl (e.g. C 1-3 Alkyl (eg methyl)).

[0256] In some embodiments of Formula (IC), Q 1 , Q 2 , Q 3 , Q 4 and Q 5 is as defined according to (AA).

[0257] In an embodiment of formula (IC), Part of Where Q 4 and Q 5 are independently selected from N, CH and CR QA Composed of groups.

[0258] In certain of these embodiments, Q 4 and Q 5 Each of them is CH.

[0259] In certain other embodiments, Q 4 CR QA ; and Q 5 For CH.

[0260] In certain embodiments, Q 4 CR QA ; and Q 5 CR QA In certain other embodiments, Q 4 CR QA ; and Q 5 is a C-halogen group such as CF.

[0261] In certain other embodiments, Q 4 is N; and Q 5 CR QA or CH. In certain of these embodiments, Q 5 For CH.

[0262] In an embodiment of formula (IC), Part of Where Q 2 , Q 3 and Q 5 are independently selected from N, CH and CR QA Composed of groups.

[0263] In certain of these embodiments, Q 2 , Q 3 and Q 5 Each of them is CH.

[0264] In certain other embodiments, Q 5 CR QA ; and Q 2 and Q 3 Each of them is CH.

[0265] In certain other embodiments, Q 5 is CH; and Q 2 and Q 3 CR for independent selection QA .

[0266] In some embodiments of Formula (IC), L 1 It is C(=O).

[0267] In some embodiments of Formula (IA), (IB) or (IC), R a and R b are independently selected from C 1-6 Alkyl and C 3-6 The group consisting of cycloalkyl.

[0268] In some embodiments of Formula (IA), (IB) or (IC), R a and R b Each independently is C 1-3 Alkyl. For example, R a and R b As another non-limiting example, R a and R b As other non-limiting examples, R a and R b Each may be isopropyl.

[0269] In some embodiments of Formula (IA), (IB) or (IC), R a is methyl; and R b It is tert-butyl.

[0270] In some embodiments of Formula (IA), (IB) or (IC), R a and R b C for independent selection 3-6 Cycloalkyl. For example, R a and R b All can be cyclopropyl.

[0271] In some embodiments of Formula (IA), (IB) or (IC), each R QA are independently selected from the group consisting of: halide; cyano; OH; NR c R d ; Optionally 1 to 6 independently selected R f Substituted C 1-6 Alkyl; optionally 1 to 6 groups independently selected from hydroxyl, halogen and C 1-6 The substituents consisting of alkoxy groups are substituted with C 1-6 Alkoxy; and optionally substituted by one or more independently selected from C 1-6 Alkyl and C(=O)(C 1-6 A 3- to 12-membered heterocyclic group substituted with a substituent selected from the group consisting of an alkyl group and an alkyl group.

[0272] In certain of these embodiments, each R QA is independently selected from the group consisting of -F, OH, NH2 NHMe, NHEt, NHiPr, N(Me)2, NHC(=O)(cyclopropyl), NHS(O)2Me, methyl, CF3, CHF2, OMe, OCF3, OCHF2 and morpholinyl.

[0273] In certain of these embodiments, R QA is selected from the group consisting of -F, OH, NH2 NHMe, NHEt, NHC(=O)(cyclopropyl), NHS(O)2Me, methyl, OMe, OCF3 and morpholinyl.

[0274] In some embodiments of Formula (IA), (IB) or (IC), each R QA is selected from the group consisting of halogen, cyano, OH and NR c R d .

[0275] In certain of these embodiments, each R QA is selected from the group consisting of -F, OH and NHMe.

[0276] In some embodiments of Formula (IA), (IB) or (IC), R on adjacent carbon atoms QA The ring is optionally substituted with 1 to 2 independently selected R h For example, R QA The pairs, together with the atoms they are attached to, can form: As another limiting example, R on adjacent carbon atoms QA The pairs, together with the atoms they are attached to, can form: (For example, R h is methyl).

[0277] In some embodiments of Formula (IA), (IB) or (IC), L 2 for

[0278] In some embodiments of Formula (IA), (IB) or (IC), Ring A is phenyl or pyridinyl, each of which is optionally substituted with 2 to 4 groups each independently selected from halo, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 The substituent group consisting of the alkoxy group is substituted.

[0279] In some embodiments of Formula (IA), (IB) or (IC), Ring A is phenyl, which is optionally substituted by 2 to 4 groups each independently selected from halo and C 1-6 The alkyl group is substituted by a substituent.

[0280] As a non-limiting example of the foregoing embodiment, Ring A is Where R AA , R AB and R AC are independently halogen or C 1-6 Alkyl. For example, R AA and R AC Each of them can be independently C 1-6 Alkyl groups, such as C 1-3 Alkyl (eg methyl); and / or R AB It may be a halogen group (eg, -F).

[0281] In some embodiments of Formula (IA), (IB) or (IC), R 1 and R 2 For H.

[0282] In some embodiments of Formula (IA), (IB) or (IC), R3 For H.

[0283] In some embodiments of Formula (IA) or (IB), R 3 C 1-6 alkyl.

[0284] In certain embodiments of Formula (IA), (IB) or (IC), R 1 and R 2 is H; and R 3 C 1-6 Alkyl. For example, R 3 It may be methyl.

[0285] In some embodiments of Formula (IA), (IB) or (IC), R 4 , R 5 and R 6 Each is H or halo.

[0286] In some embodiments of Formula (IA), (IB) or (IC), R 4 , R 5 and R 6 Each is H or -F. In certain embodiments of Formula (IA), (IB) or (IC), R 4 , R 5 and R 6 Each is H. In certain embodiments of Formula (IA), (IB) or (IC), R 4 and R 5 is H; and R 6 is -F.

[0287] In some embodiments of Formula (IA), (IB) or (IC), R 7 For H.

[0288] In some embodiments of Formula (IA), (IB) or (IC), R 7 is -F.

[0289] In some embodiments of Formula (IA), (IB) or (IC), R 9 for (IX-2). In certain of these embodiments, R 9d For H.

[0290] In some embodiments, the compound of formula (I) is a compound of formula (ID): or a pharmaceutically acceptable salt or solvate thereof, wherein: R AA , R AB and RAC are independently halogen or C 1-6 alkyl; R QC is H or halo; and Each R Cb is independently selected from H and R Ca Composed of groups.

[0291] In some embodiments of Formula (ID), R 1 and R 2 For H.

[0292] In some embodiments of Formula (ID), R 3 C 1-3 In certain of these embodiments, R 3 It is methyl.

[0293] In some embodiments of Formula (ID), R 4 , R 5 , R 6 , and R 7 For H.

[0294] In some embodiments of Formula (ID), R 9d For H.

[0295] In some embodiments of Formula (ID), R AA and R AC Independently for C 1-6 In certain of these embodiments, R AA and R AC It is methyl.

[0296] In some embodiments of Formula (ID), R AB In certain of these embodiments, R AB is -F.

[0297] In some embodiments of Formula (ID), each R Cb is H. In some embodiments of Formula (ID), each R Cb C 1-3 In certain of these embodiments, each R Cb It is methyl.

[0298] In some embodiments of Formula (ID), R a and R b Independently for C 1-3 In certain of these embodiments, R a and R b In certain embodiments, R a and R bIn certain embodiments, R a and R b It is isopropyl.

[0299] In some embodiments of Formula (ID), R a is methyl; and R b It is tert-butyl.

[0300] In some embodiments of Formula (ID), R a and R b Independently for C 3-6 Cycloalkyl. For example, R a and R b All can be cyclopropyl.

[0301] In some embodiments of Formula (ID), P(=O)R a R b for Where L Q is a bond, CH2, O, S, NH or N(C 1-6 In certain of these embodiments, P(═O)R a R b for

[0302] In some embodiments of Formula (ID), R QA is -F.

[0303] In some embodiments of Formula (ID), R QA It is -OH.

[0304] In certain embodiments of Formula (ID), R QA NR c R d In certain embodiments, R QA NH(C 1-3 In certain embodiments, R QA is NH2. In certain embodiments, R QA N(C 1-3 In certain embodiments, R QA NHC(=O)(C 1-3 alkyl), NHC(=O)(C 3-6 Cycloalkyl) or NHS(O)2(C 1-3 alkyl).

[0305] In some embodiments of Formula (ID), R QA is optionally substituted by one or more independently selected from C 1-6 Alkyl and C(=O)(C1-6 A 5- to 6-membered heterocyclic group substituted with a substituent selected from the group consisting of an alkyl group and an alkyl group.

[0306] In some embodiments of Formula (ID), R QA is C optionally substituted with 1 to 6 independently selected halo groups 1-6 In certain of these embodiments, R QA It is -OMe, -OCF3 or -OCHF2.

[0307] In some embodiments of Formula (ID), R QA C 1-3 In certain of these embodiments, R QA In some embodiments of Formula (ID), R QA is C optionally substituted with 1 to 3 independently selected halo groups 1-3 In certain of these embodiments, R QA It is -CF3 or -CHF2.

[0308] In some embodiments of Formula (ID), R QC For H.

[0309] In some embodiments of Formula (ID), R QC In certain of these embodiments, R QC In certain embodiments, R QC P(=O)R a R b In certain embodiments, R QC P(=O)R a R b The meta position and R QA In certain embodiments, R QC is -F, which is R QA In certain embodiments, R QC is -F, which is P(=O)R a R b The meta position and R QA The adjacent position.

[0310] In some embodiments of formula (ID), the compound is of the formula (S,S,S)-(ID) or a pharmaceutically acceptable salt thereof; wherein R 3 C 1-3 alkyl.

[0311] In some embodiments, the compound of formula (I) is a compound of formula (IE): or a pharmaceutically acceptable salt or solvate thereof, wherein: R AA , R AB and R AC are independently halogen or C 1-3 alkyl; R 3 H or C 1-3 alkyl; R QC is H or halogen; R QD is selected from the group consisting of: (a) H; (b) -NH2; (c) -NH(C 1-3 (d) halo; (e) C optionally substituted with 1 to 3 independently selected halo 1-3 and (f) C optionally substituted with 1 to 3 independently selected halo 1-3 alkyl; R a and R b are each independently selected from the group consisting of: C 1-4 Alkyl and C 3-6 Cycloalkyl; or R a and R b Together with the phosphorus atoms to which they are attached, they form a ring containing 5 to 8 ring atoms, of which 0 to 1 ring atoms (excluding those with R a and R b The attached phosphorus) is a heteroatom independently selected from the group consisting of O, S and N; R 8c H or C 1-3 alkyl; X B is CH or N; and Each R Cb is independently selected from H and C 1-3 Alkyl group.

[0312] In some embodiments of Formula (IE), R AA and R AC Each independently is C 1-3 Alkyl. For example, R AA and R AC Each may be a methyl group.

[0313] In some embodiments of Formula (IE), R AB is a halogen group. For example, R AB Can be F.

[0314] In some embodiments of Formula (IE), R AAand R AC Each independently is C 1-3 alkyl; and R AB is a halogen group. For example, R AA and R AC may each be methyl; and R AB Can be F.

[0315] In some embodiments of Formula (IE), R 3 C 1-3 Alkyl. For example, R 3 It may be methyl.

[0316] In some embodiments of Formula (IE), R QD For H.

[0317] In some embodiments of Formula (IE), R QD is selected from the group consisting of: -NH2 and -NH(C 1-3 For example, R QD As another non-limiting example, R QD As other non-limiting examples, R QD It may be -NHEt.

[0318] In some embodiments of Formula (IE), R QD is a halogen group. For example, R QD It can be -F or -Cl.

[0319] In some embodiments of Formula (IE), R QD is C optionally substituted with 1 to 3 independently selected halo groups 1-3 Alkoxy. For example, R QD As another non-limiting example, R QD It can be OCF3. As other non-limiting examples, R QD It can be OCHF2.

[0320] In some embodiments of Formula (IE), R QD is C optionally substituted with 1 to 3 independently selected halo groups 1-3 Alkyl. For example, R QD As another non-limiting example, R QD As another non-limiting example, R 3 It can be -CHF2.

[0321] In some embodiments of Formula (IE), R a and R b Each is an independent choice of C 1-4 Alkyl. For example, Ra and R b Each may be methyl. As another non-limiting example, R a and R b As other non-limiting examples, R a and R b As other non-limiting examples, R a may be methyl; and R b It may be tert-butyl.

[0322] In some embodiments of Formula (IE), R a and R b Each is an independent choice of C 3-6 Cycloalkyl. For example, R a and R b Each may be a cyclopropyl group.

[0323] In some embodiments of Formula (IE), R a and R b Together with the phosphorus atoms to which they are attached, they form a ring containing 5 to 8 ring atoms, of which 0 to 1 ring atoms (excluding those with R a and R b The attached phosphorus) is a heteroatom independently selected from the group consisting of O, S and N. For example, R a and R b Together with the phosphorus atoms to which they are attached,

[0324] In some embodiments of Formula (IE), R QC For H.

[0325] In some embodiments of Formula (IE), R QC is a halogen group. For example, R QC Can be -F. In some embodiments, R QC For R QD In some embodiments, R QC For R QD In some embodiments, R QC For R QD The interposition.

[0326] In some embodiments of Formula (IE), R 8c is H. In some embodiments of Formula (IE), R 8c C 1-3 Alkyl. For example, R 8c It may be methyl.

[0327] In some embodiments of Formula (IE), X BIn some embodiments of Formula (IE), X B is N.

[0328] In some embodiments of Formula (IE), each R Cb is H. In some embodiments of Formula (IE), each R Cb C for independent selection 1-3 For example, each R Cb It may be methyl.

[0329] In some embodiments of Formula (IE), X B is CH; and each R Cb In some embodiments of Formula (IE), X B is CH; and each R Cb C for independent selection 1-3 In some embodiments of Formula (IE), X B is N; and each R Cb is H. In some embodiments of Formula (IE), X B is N; and each R Cb C for independent selection 1-3 Alkyl (eg, methyl).

[0330] In some embodiments of formula (IE), the compound is a compound of formula (S,S,S)-(IE) or a pharmaceutically acceptable salt thereof; wherein R 3 C 1-3 alkyl.

[0331] In some embodiments of Formula (IE): R AA and R AC is methyl; R AB for -F; R 3 is methyl; R QC is H or -F; R QD is selected from the group consisting of: H; -NHMe; -NHEt; -NH2; -OMe; -OCF3; -OCHF2; -Me; -CF3; and -CHF2; R a and R b are independently selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl and cyclopropyl; R 8c is H or methyl; XB is CH; and Each R Cb is independently H or methyl.

[0332] In certain of these embodiments, the compound is of formula (S,S,S)-(IE).

[0333] In some embodiments, the compound of Formula (I) is selected from the group consisting of a compound in Table C1 or a pharmaceutically acceptable salt or solvate thereof.

[0334] Table C1

[0335] In some embodiments, the compound is selected from the group consisting of a compound in Table C2 or a pharmaceutically acceptable salt or solvate thereof.

[0336] Table C2

[0337] The compound of formula (I) includes its pharmaceutically acceptable salt. In addition, the compound of formula (I) also includes other salts of such compounds, which may not be pharmaceutically acceptable salts and can be used as intermediates for preparing and / or purifying the compound of formula (I) and / or separating the enantiomers of the compound of formula (I). Non-limiting examples of pharmaceutically acceptable salts of the compound of formula (I) include trifluoroacetate.

[0338] It is further understood that the compound of formula (I) or its salt can be isolated in the form of a solvate, and accordingly, any such solvate is included within the scope of the present invention. For example, the compound of formula (I) and its salt can exist in an unsolvated form as well as in a solvated form formed with a pharmaceutically acceptable solvent (such as water, ethanol and the like).

[0339] Pharmaceutical compositions and administration When used as a drug, the compound of formula (I) (including its pharmaceutically acceptable salt or solvate) can be administered in the form of a pharmaceutical composition. These compositions can be prepared in a manner well known in the pharmaceutical technology, and can be administered by a variety of routes, depending on the local or systemic treatment required and the area to be treated. Administration can be topical (including transdermal, epidermal, ocular and mucosal, including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powder or aerosol, including through a nebulizer; intratracheal or intranasal), oral or parenteral. Oral administration may include a dosage form formulated for once-daily or twice-daily (BID) administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or injection or infusion; or intracranial (e.g., intrathecal or intraventricular). Parenteral administration may be in the form of a single bolus dose, or may be, for example, a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

[0340] Also provided herein is a pharmaceutical composition containing a combination of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as an active ingredient and one or more pharmaceutically acceptable excipients (carriers). For example, a pharmaceutical composition prepared using a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the composition is suitable for topical administration. When preparing the composition provided herein, the active ingredient is usually mixed with an excipient, diluted by the excipient or enclosed in this carrier in the form of, for example, a capsule, a sachet, paper or other container. When the excipient acts as a diluent, it may be a solid, semisolid or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Therefore, the composition may be in the following forms: tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in liquid media), ointments containing, for example, up to 10% by weight of an 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 one embodiment, the composition is formulated as a tablet or capsule.

[0341] Further provided herein is a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient. A pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as an active ingredient can be prepared by uniformly 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 be in various forms depending on the desired route of administration (e.g., oral, parenteral). In some embodiments, the composition is a solid oral composition.

[0342] Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

[0343] Methods of formulating pharmaceutical compositions have been described in numerous 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.

[0344] In some embodiments, the compound or pharmaceutical composition can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; self-emulsifying drug delivery systems (SEDDS), such as d-α-tocopheryl polyethylene glycol 1000 succinate; surfactants used in pharmaceutical dosage forms, such as Tweens, poloxamer, or other similar polymer delivery matrices; serum proteins, such as human serum albumin; buffer substances, such as phosphate, tris, glycine, sorbic acid, potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride; zinc salts; colloidal silicon dioxide; magnesium trisilicate; polyvinyl pyrrolidone; cellulosic substances; polyethylene glycol; sodium carboxymethyl cellulose; polyacrylates; waxes; polyethylene-polyoxypropylene block copolymers; and lanolin. Cyclodextrins such as α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2-hydroxypropyl-β-cyclodextrin and 3-hydroxypropyl-β-cyclodextrin, or other dissolved derivatives can also be used to enhance the delivery of the compounds described herein. Dosage forms or compositions containing chemical entities as described herein in the range of 0.005% to 100% and the remainder consisting of non-toxic excipients can be prepared. The contemplated compositions may contain 0.001% to 100% of the chemical entities provided herein, in one embodiment, 0.1% to 95%, in another embodiment, 75% to 85%, in another embodiment, 20% to 80%. The actual methods for preparing such dosage forms are known or obvious to those skilled in the art; for example, see Remington: The Science and Practice of Pharmacy, 22nd edition (Pharmaceutical Press, London, UK. 2012).

[0345] In some embodiments, the compounds and pharmaceutical compositions described herein, or pharmaceutical compositions thereof, may 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, intrasinus, intratracheal, enteral, epidural, interstitial, intraperitoneal, intraarterial, intrabronchial, intracapsular, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinus, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal (e.g., intranasal), nasogastric, oral, parenteral, transdermal, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, tracheal, ureteral, urethral, ​​and vaginal. In some embodiments, the preferred route of administration is parenteral (e.g., intratumoral).

[0346] In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any of Formulas (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof) as described herein, or a pharmaceutical composition thereof, may be formulated for parenteral administration, such as for injection via an intra-arterial, intrasternal, intracranial, intravenous, intramuscular, subcutaneous, or intraperitoneal route. For example, such compositions may be prepared in an injectable form, such as a liquid solution or suspension; may also be prepared in a solid form suitable for preparing a solution or suspension after adding a liquid prior to injection; and the formulation may also be emulsified. The preparation of such formulations will be 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 may include needle injectors, microneedle injectors, needle-free injectors, and infusion techniques.

[0347] In some embodiments, pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In some embodiments, the form must be sterile and must be fluid to the extent that it can be easily injected. In some embodiments, the form should be stable under the conditions of manufacture and storage, and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.

[0348] In some embodiments, carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyols (for example, glycerol, propylene glycol and liquid polyethylene glycol and the like), suitable mixtures thereof and vegetable oils. In some embodiments, coatings such as lecithin can be used, by maintaining the required particle size for dispersions and by using surfactants to maintain appropriate fluidity. In some embodiments, the prevention of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In some embodiments, isotonic agents are included, such as sugar or sodium chloride. In some embodiments, the absorption of injectable compositions can be extended by using delayed absorption agents (for example, aluminum monostearate and gelatin) in the compositions.

[0349] In some embodiments, sterile injectable solutions are prepared by incorporating a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formula (IA), (IB), (IC), (ID) and (IE), or a pharmaceutically acceptable salt or solvate thereof) in the desired amount in an appropriate solvent with various other ingredients listed above, followed by sterilization by filtration. In some embodiments, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and the desired other ingredients from those 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, which yield a powder of the active ingredient plus any other desired ingredients obtained by previously sterile filtering the solution.

[0350] In some embodiments, pharmacologically acceptable excipients that can be used in rectal compositions as gels, creams, enemas, or rectal suppositories include, but are not limited to, any one or more of the following: cocoa butter glycerides, synthetic polymers (such as polyvinyl pyrrolidone), PEG (such as PEG ointment), glycerin, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharin, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosols, parabens in phenoxyethanol, sodium methylparaoxybenzoate, sodium propylparaoxybenzoate, diethylamine, carbomer, carbopol, methyloxybenzoate, polyethylene glycol cetylstearyl ether, cocoyl caprylate caprylocaprate), isopropyl alcohol, propylene glycol, liquid paraffin, tris-gum, carboxy-metabisulfite, sodium EDTA, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins (such as vitamins A and E), and potassium acetate.

[0351] 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 formula (IA), (IB), (IC), (ID) and (IE), or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition as described herein, with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, a suppository wax, and which is solid at room temperature but liquid at body temperature and therefore melts in the rectum and releases the active compound. In some embodiments, compositions for rectal administration are in the form of enemas.

[0352] In some embodiments, a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any of Formulae (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition thereof, may be formulated for local delivery to the digestive or gastrointestinal tract by oral administration (e.g., solid or liquid dosage form).

[0353] In some embodiments, solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. 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 mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and / or each of the following: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethylcellulose, alginates, gelatin, polyethylene glycol, polyvinyl alcohol ... In some embodiments, the present invention provides a kind of preparation method of the present invention, and the preparation method of the present invention comprises the following: a) pyrrolidone, sucrose and acacia; b) humectants such as glycerol; c) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution delay agents such as paraffin; f) absorption promoters such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glyceryl monostearate; h) adsorbents such as kaolin and bentonite; i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof. For example, in the case of capsules, tablets and pills, the dosage form may also include a buffer. In some embodiments, similar types of solid compositions can also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose (lactose / milk sugar) and high molecular weight polyethylene glycols and their analogs.

[0354] In some embodiments, the pharmaceutical composition will be in the form of a unit dosage form such as a pill or tablet, and thus the composition may contain, in addition to 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): a diluent such as lactose, sucrose, dicalcium phosphate, or an analog thereof; a lubricant such as magnesium stearate, or an analog thereof; and a binder such as starch, acacia, polyvinyl pyrrolidone, gelatin, cellulose, a cellulose derivative, or an analog thereof. In some embodiments, in another solid dosage form, a powder, granulation (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, physically separated unit dosage forms of one or more compounds and pharmaceutical compositions or additional active agents as provided herein are also contemplated; for example, capsules (or tablets in capsules) with granules of each drug; two-layer tablets; two-chamber capsule tablets, etc. In some embodiments, enteric-coated or delayed-release oral dosage forms are also contemplated.

[0355] In some embodiments, other physiologically acceptable compounds may include wetting agents, emulsifiers, dispersants or preservatives particularly useful for preventing the growth or activity of microorganisms. For example, various preservatives are well known and include, for example, phenol and ascorbic acid.

[0356] In some embodiments, the excipient is sterile and generally free of unwanted substances. For example, these compositions can be sterilized by conventional, well-known sterilization techniques. In some embodiments, for various oral dosage form excipients, such as tablets and capsules, sterilization is not required. For example, the United States Pharmacopoeia / National Formulary (USP / NF) standards may be sufficient.

[0357] In some embodiments, a compound of Formula (I) as 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 ocular administration. In some embodiments, an ocular composition may include one or more of, but not limited to, any of the following: a viscosifier (e.g., carboxymethylcellulose, glycerol, polyvinylpyrrolidone, polyethylene glycol); a stabilizer (e.g., Pluronic (triblock copolymer), cyclodextrin); a preservative (e.g., Benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloride complex; Allergan, Inc.)).

[0358] In some embodiments, a compound of Formula (I) as 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., transdermal or transdermal). In some embodiments, topical compositions may include ointments and creams. In some embodiments, ointments are semisolid formulations typically based on paraffin or other petroleum derivatives. In some embodiments, creams containing the selected active agent are typically viscous liquids or semisolid emulsions, often oil-in-water or water-in-oil. For example, a cream base is typically water-washable and contains an oil phase, an emulsifier, and an aqueous phase. For example, the oil phase, sometimes referred to as the "internal" phase, generally includes paraffin and a fatty alcohol such as cetyl alcohol or stearyl alcohol; although not required, the volume of the aqueous phase generally exceeds the oil phase and generally contains a humectant. In some embodiments, the emulsifier in the cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. In some embodiments, like other carriers or vehicles, the ointment base should be inert, stable, non-irritating and non-sensitizing.

[0359] In any of the foregoing embodiments, the pharmaceutical composition as described herein may comprise one or more of the following: lipids, inter-bilayer cross-linked multilamellar vesicles, biodegradable poly (D, L-lactic-co-glycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and nanoporous particle-loaded lipid bilayers.

[0360] In some embodiments, the dosage 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 determined based on a variety of factors, including but not limited to type, age, weight, sex, the patient's medical condition, the severity of the patient's medical condition, the route of administration, and the activity of the compound or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the appropriate dosage for a particular situation can be determined by a person skilled in the art of medicine. In some embodiments, the total daily dose can be divided into multiple portions and administered in multiple portions throughout the day or by providing continuous delivery.

[0361] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formula (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof) is used at a dose of about 0.01 mg to about 1000 mg. For example, about 0.1 mg to about 30 mg, about 10 mg to about 80 mg, about 0.5 mg to about 15 mg, about 50 mg to about 200 mg, about 100 mg to about 300 mg, about 200 mg to about 400 mg, about 300 mg to about 500 mg, about 400 mg to about 600 mg, about 500 mg to about 800 mg, about 600 mg to about 900 mg, or about 700 mg to about 1000 mg. In some embodiments, the dose is a therapeutically effective amount.

[0362] 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 formula (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof) is administered at about 0.0002 mg / Kg to about 100 mg / Kg (e.g., about 0.0002 mg / Kg to about 50 mg / Kg; about 0.0002 mg / Kg to about 25 mg / Kg; about 0.0002 mg / Kg to about 10 mg / Kg; about 0.0002 mg / Kg to about 5 mg / Kg; about 0.0002 mg / Kg to about 1 mg / Kg; about 0.0002 mg / Kg to about 0.5 mg / Kg; about 0.0002 mg / Kg to about 0.1 mg / Kg; about 0.001 mg / Kg to about 50 mg / Kg; about 0.001 mg / Kg to about 25 mg / Kg; about 0.001 mg / Kg to about 10 mg / Kg; about 0.0 0.01mg / Kg to about 5mg / Kg; about 0.001mg / Kg to about 1mg / Kg; about 0.001mg / Kg to about 0.5mg / Kg; about 0.001mg / Kg to about 0.1mg / Kg; about 0.01mg / Kg to about 50mg / Kg; about 0.01mg / Kg to about 25mg / Kg; about 0.01mg / Kg to about 10mg / Kg; about 0.01mg / Kg to about 5mg / Kg; about 0.01mg / Kg In some embodiments, a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formula (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof) is administered at a dose of about 100 mg / Kg.

[0363] In some embodiments, the aforementioned doses 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) may be administered daily (e.g., in a single dose or two or more divided doses) or non-daily (e.g., every other day, every two days, every three days, once a week, twice a week, once every two weeks, once a month).

[0364] In some 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 of Formula (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof) is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In some embodiments, the period of discontinuation of administration is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of Formula (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 discontinuation of administration of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of Formula (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof) for a separate period of time. 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 administered for a first period of time, and the first period of time is followed by a second period of time, wherein administration is stopped during the second period of time, and then a third 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) is started, and then a fourth period of time in which administration is stopped is followed by the third period of time. 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) is followed by repeated cessation of administration for a determined or undetermined period of time.In some embodiments, the administration period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer. In some embodiments, the period of cessation of administration is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer.

[0365] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any of Formulae (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof) is orally administered to a patient one or more times per day (e.g., once a day, twice a day, three times a day, four times a day, or a single daily dose).

[0366] In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any of Formulae (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof) is administered to a patient via parenteral administration one or more times per day (e.g., 1 to 4 times per day, once per day, twice per day, three times per day, four times per day, or a single daily dose).

[0367] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of Formulae (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof) is administered to a patient weekly by parenteral administration.

[0368] Treatment In some embodiments, the disclosure features methods for treating a patient (e.g., a human) having a disease, disorder, or condition, wherein modulation of GLP-1R (e.g., inhibition or attenuation and / or elevation or undesired GLP-1R) is beneficial in treating the underlying pathology and / or symptoms and / or progression of the disease, disorder, or condition. In some embodiments, the methods described herein may include or further include treating one or more conditions, complications, or sequelae associated with any one or more of the conditions described herein.

[0369] 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 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 as disclosed herein.

[0370] In some 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 caused by the use of other agents, idiopathic intracranial hypertension, Wolfram syndrome, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient cerebral ischemia, atherosclerotic cardiovascular disease, traumatic brain injury Injury, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, vascular restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial lipidosis, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorders, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataract, glomerulosclerosis, arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depression, skin and connective tissue disorders, foot ulcers, psoriasis, primary polydipsia, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease disease, short bowel syndrome, Parkinson's, Alzheimer's disease, cognitive impairment, schizophrenia, polycystic ovary syndrome (PCOS).

[0371] In some embodiments, the diseases, disorders, or conditions include, but are not limited to, type 2 diabetes, early onset type 2 diabetes, obesity, idiopathic intracranial hypertension, Wolfram's syndrome, weight gain caused by the use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, kidney disease (e.g., acute kidney disease, tubular dysfunction, proinflammatory changes in the proximal tubules), adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient cerebral ischemia, atherosclerotic heart disease. vascular disease, hyperglycemia, postprandial lipidosis, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, bipolar disorder / major depression, skin and connective tissue disorders, foot ulcers, psoriasis, primary polydipsia, nonalcoholic steatosis hepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS), or any combination thereof.

[0372] In some embodiments, the diseases, disorders, or conditions include, but are not limited to, type 2 diabetes, early onset type 2 diabetes, obesity, idiopathic intracranial hypertension, Wolfram's syndrome, weight gain due to use of other medications, gout, sugar cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat deposition, myocardial infarction, peripheral arterial disease, stroke, transient cerebral ischemia, hyperglycemia, postprandial lipidosis, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, chronic renal failure, syndrome X, smoking cessation, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, skin and connective tissue disorders, foot ulcers, or any combination thereof.

[0373] In some embodiments, the compounds and pharmaceutical compositions and methods for treating the patients described herein induce one or more of the following: reduction in blood glucose levels (e.g., reduction in blood glucose levels), reduction in blood hemoglobin A1c (HbA1c) levels, promotion of insulin synthesis, stimulation of insulin secretion, increase in the mass of β cells, regulation of gastric acid secretion, regulation of gastric emptying, reduction in body mass index (BMI), and / or reduction in glucagon production (e.g., levels). In some embodiments, the compounds and pharmaceutical compositions and methods for treating the patients described herein may reduce blood glucose levels, reduce blood hemoglobin A1c (HbA1c) levels, promote insulin synthesis, stimulate insulin secretion, increase β cell mass, regulate gastric acid secretion, regulate gastric emptying, reduce body mass index (BMI), and / or reduce glucagon production (e.g., levels), or any combination thereof. In certain embodiments, the compounds and pharmaceutical compositions and methods for treating the patients described herein stabilize serum glucose and serum insulin levels (e.g., serum glucose and serum insulin concentrations). Also provided herein are methods of regulating glucose or insulin levels in a patient in need of such regulation, comprising administering to the patient an effective amount of a compound of 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 the form of a pharmaceutical composition, or a pharmaceutical composition as disclosed herein.

[0374] In some embodiments, provided herein is a method of reducing the risk of major adverse cardiovascular events (MACE) in a patient in need thereof (e.g., reducing by about at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80%), the method comprising administering to the patient an effective 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) or a pharmaceutical composition as disclosed herein. In some of these embodiments, the patient is an adult diagnosed with type 2 diabetes (T2D). In certain embodiments, the patient is an adult diagnosed with heart disease. In certain embodiments, the patient is an adult diagnosed with type 2 diabetes (T2D) and heart disease. In certain embodiments, the patient is an adult suffering from type 2 diabetes (T2D). In certain embodiments, the patient is an adult suffering from heart disease. In certain embodiments, the patient suffers from type 2 diabetes (T2D) and heart disease.

[0375] Indications Obesity In some embodiments, the condition, disease or disorder is obesity and conditions, diseases or disorders related to or associated with 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 obesity). Non-limiting examples of symptomatic obesity include endocrine obesity (e.g., Cushing syndrome, hypothyroidism, insulinoma, obesity type II diabetes, pseudoparathyroidism, hypogonadism), hypothalamic obesity, genetic obesity (e.g., Prader-Willi syndrome, Laurence-Moon-Biedl syndrome) and drug-induced obesity (e.g., steroids, phenothiazines, insulin, sulfonylurea agents or beta-blocker-induced obesity).

[0376] In some embodiments, the condition, disease or disorder is associated with obesity. Examples of such conditions, diseases or disorders include, but are not limited to, glucose tolerance disorders, diabetes (e.g., type 2 diabetes, obese diabetes), lipid metabolism disorders, hyperlipidemia, hypertension, heart failure, hyperuricemia, gout, fatty liver (including non-alcoholic steatohepatitis (NASH)), coronary heart disease (e.g., myocardial infarction, angina pectoris), cerebral infarction (e.g., cerebral thrombosis, transient cerebral ischemic attack), bone or joint disease (e.g., knee osteoarthritis, hip arthritis, deformed spondylitis, low back pain), sleep apnea syndrome, obesity hypoventilation syndrome (Pickwickian syndrome), menstrual disorders (e.g., abnormal menstrual cycle, abnormal menstrual volume and cycle, amenorrhea, abnormal menstrual symptoms), visceral obesity syndrome, urinary incontinence and metabolic syndrome. In some embodiments, the compounds and pharmaceutical compositions described herein can be used to treat patients who exhibit symptoms of both obesity and insulin deficiency.

[0377] diabetes In some embodiments, the condition, disease or disorder is diabetes. Non-limiting examples of diabetes include type 1 diabetes, type 2 diabetes (e.g., type 2 diabetes treated with diet, type 2 diabetes treated with sulfonylurea, very advanced type 2 diabetes, type 2 diabetes treated with long-term insulin), diabetes (e.g., non-insulin-dependent diabetes, insulin-dependent diabetes), gestational diabetes, obese diabetes, autoimmune diabetes and borderline diabetes. In some embodiments, the condition, disease or disorder is type 2 diabetes (e.g., type 2 diabetes treated with diet, type 2 diabetes treated with sulfonylurea, very advanced type 2 diabetes, type 2 diabetes treated with long-term insulin).

[0378] Provided herein is a method of treating diabetes in a patient, the method comprising (a) determining that the patient has type 2 diabetes, and (b) administering to the patient a therapeutically effective amount of a compound of 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 as disclosed herein.

[0379] Provided herein is a method for treating type 2 diabetes in a patient, the method comprising administering to a patient identified or diagnosed with type 2 diabetes a therapeutically effective 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) or a pharmaceutical composition as disclosed herein.

[0380] Also provided herein is a method of treating type 2 diabetes in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of 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 as disclosed herein.

[0381] In some embodiments, the compounds and pharmaceutical compositions and methods for treating patients with conditions, diseases or disorders described herein (e.g., type 2 diabetes) reduce fasting plasma glucose levels. In some embodiments, the compounds and pharmaceutical compositions and methods for treating patients with conditions, diseases or disorders described herein (e.g., type 2 diabetes) reduce non-fasting plasma glucose levels. In some embodiments, the compounds and pharmaceutical compositions and methods for treating patients with conditions, diseases or disorders described herein (e.g., type 2 diabetes) reduce HbA1c levels. In some embodiments, the compounds and pharmaceutical compositions and methods for treating patients with conditions, diseases or disorders described herein (e.g., type 2 diabetes) reduce glucagon levels. In some embodiments, the compounds and pharmaceutical compositions and methods for treating patients with conditions, diseases or disorders described herein (e.g., type 2 diabetes) increase insulin levels. In some embodiments, the compounds and pharmaceutical compositions and methods for treating patients with conditions, diseases or disorders described herein (e.g., type 2 diabetes) reduce BMI.

[0382] In some embodiments, a decrease in fasting plasma glucose levels of about 5% to about 95% indicates treatment of type 2 diabetes. In some embodiments, a decrease in fasting plasma glucose levels of about 15% to about 80% indicates treatment of type 2 diabetes. In some embodiments, a decrease in fasting plasma glucose levels of about 25% to about 60% indicates treatment of type 2 diabetes. In some embodiments, a decrease in fasting plasma glucose levels to about or below 126 mg / dL, about or below 110 mg / dL, or about or below 90 mg / dL indicates treatment of type 2 diabetes.

[0383] In some embodiments, a decrease in non-fasting plasma glucose levels of about 5% to about 95% indicates treatment of type 2 diabetes. In some embodiments, a decrease in non-fasting plasma glucose levels of about 15% to about 80% indicates treatment of type 2 diabetes. In some embodiments, a decrease in non-fasting plasma glucose levels of about 25% to about 60% indicates treatment of type 2 diabetes. In some embodiments, a decrease in non-fasting plasma glucose levels to about or below 200 mg / dL, about or below 150 mg / dL, or about or below 130 mg / dL indicates treatment of type 2 diabetes.

[0384] In some embodiments, a decrease in HbA1c levels of about 5% to about 95% indicates treatment of type 2 diabetes. In some embodiments, a decrease in HbA1c levels of about 15% to about 80% indicates treatment of type 2 diabetes. In some embodiments, a decrease in HbA1c levels of about 25% to about 60% indicates treatment of type 2 diabetes. In some embodiments, a decrease in HbA1c levels to about or below 6.5%, about or below 6.0%, or about or below 5.0% indicates treatment of type 2 diabetes.

[0385] In some embodiments, a decrease in glucagon levels of about 5% to about 95% indicates treatment of type 2 diabetes. In some embodiments, a decrease in glucagon levels of about 15% to about 80% indicates treatment of type 2 diabetes. In some embodiments, a decrease in glucagon levels of about 25% to about 60% indicates treatment of type 2 diabetes. In some embodiments, an increase in insulin levels of about 5% to about 95% indicates treatment of type 2 diabetes. In some embodiments, an increase in insulin levels of about 15% to about 80% indicates treatment of type 2 diabetes. In some embodiments, an increase in insulin levels of about 25% to about 60% indicates treatment of type 2 diabetes.

[0386] In some embodiments, a decrease in BMI of about 5% to about 95% indicates treatment of type 2 diabetes. In some embodiments, a decrease in BMI of about 15% to about 80% indicates treatment of type 2 diabetes. In some embodiments, a decrease in BMI of about 25% to about 60% indicates treatment of type 2 diabetes. In some embodiments, a decrease in BMI of about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% indicates treatment of type 2 diabetes. In some embodiments, a decrease in BMI to about or below 40, about or below 30, or about or below 20 indicates treatment of type 2 diabetes.

[0387] In some embodiments, the condition, disease or disorder is associated with diabetes (e.g., complications of diabetes). Non-limiting examples of disorders associated with diabetes include obesity, obesity-related disorders, metabolic syndrome, neuropathy, nephropathy (e.g., diabetic nephropathy), retinopathy, diabetic cardiomyopathy, cataracts, macroangiopathy, osteopenia, hyperosmotic diabetic coma, infectious diseases (e.g., respiratory tract infections, urinary tract infections, gastrointestinal infections, skin and soft tissue infections, lower extremity infections), diabetic gangrene, dry mouth, hearing loss, cerebrovascular disorders, diabetic cachexia, slow wound healing, diabetic dyslipidemia, peripheral blood circulation disorders, cardiovascular risk factors (e.g., coronary artery disease, peripheral artery disease, cerebrovascular disease, hypertension and risk factors associated with uncontrolled cholesterol and / or lipid levels, and / or inflammation), NASH, fractures, and cognitive dysfunction.

[0388] Other non-limiting examples of conditions associated with diabetes include prediabetes, hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, hyperLDL-cholesterolemia, hypoHDL-cholesterolemia, postprandial hyperlipidemia), metabolic syndrome (e.g., a metabolic disorder in which activation of GLP-1R is beneficial, metabolic syndrome X), hypertension, impaired glucose tolerance (IGT), insulin resistance, and sarcopenia.

[0389] In some embodiments, the condition, disease or disorder is diabetes and obesity (diabetic obesity). In some embodiments, the compounds described herein are useful for improving the therapeutic effectiveness of metformin.

[0390] Metabolic diseases of important tissues In some embodiments, the condition, disease or disorder is a metabolically important tissue disorder. Non-limiting examples of metabolically important tissues include liver, fat, pancreas, kidney, and intestine.

[0391] In some embodiments, the condition, disease or disorder is fatty liver disease. Fatty liver disease includes but is not limited to non-alcoholic fatty acid liver disease (NAFLD), steatotic hepatitis, non-alcoholic steatotic hepatitis (NASH), fatty liver disease caused by hepatitis, fatty liver disease caused by obesity, fatty liver disease caused by diabetes, fatty liver disease caused by insulin resistance, fatty liver disease caused by hypertriglyceridemia, abetalipoproteinemia, hyperlipoproteinemia, glycogen storage disease, Weber-Christian disease, Wolman disease, acute fatty liver of pregnancy, and lipodystrophy.

[0392] Non-alcoholic fatty liver disease (NAFLD) refers to a series of diseases that occur in the absence of alcohol abuse and is typically characterized by the presence of steatosis (fat in the liver). It is believed that NAFLD is associated with a variety of conditions, such as metabolic syndrome (including obesity, diabetes and hypertriglyceridemia) and insulin resistance. It can lead to liver disease in adults and children and can eventually lead to cirrhosis (Skelly et al., J Hepatol 2001; 35: 195-9; Chitturi et al., Hepatology 2002; 35 (2): 373-9). The severity of NAFLD ranges from relatively benign isolated, mainly macrovesicular steatosis (i.e., non-alcoholic fatty liver or NAFL) to non-alcoholic steatohepatitis (NASH) (Angulo et al., J Gastroenterol Hepatol 2002; 17 Supplement: S186-90).

[0393] Other non-limiting examples of metabolically important tissue disorders include joint disorders (e.g., osteoarthritis, secondary osteoarthritis), steatosis (e.g., in the liver); fibrosis (e.g., in the liver); cirrhosis (e.g., in the liver); cholelithiasis; gallbladder disorders; gastroesophageal reflux; sleep apnea; hepatitis; fatty liver; bone disorders characterized by altered bone metabolism, such as osteoporosis, including postmenopausal osteoporosis, poor bone strength, osteopenia, Paget's disease, cancer Osteolytic metastases in patients with osteopathic diseases, osteodystrophy in liver disease and altered bone metabolism caused by renal failure or hemodialysis, fractures, bone surgery, aging, pregnancy, protective measures for fractures and malnutrition polycystic ovary syndrome; renal disease (e.g., chronic renal failure, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease); muscular dystrophy, angina, acute or chronic diarrhea, testicular dysfunction, respiratory dysfunction, weakness, sexual dysfunction (e.g., erectile dysfunction) and geriatric syndrome. In some embodiments, the compounds and pharmaceutical compositions described herein can be used to treat surgical trauma by improving postoperative recovery and / or by preventing the catabolic response caused by surgical trauma.

[0394] Cardiovascular and vascular diseases In some embodiments, the condition, disease 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 disorders (e.g., cerebral infarction), vascular dysfunction, myocardial infarction, elevated blood pressure (e.g., 130 / 85 mm Hg or higher), and prothrombotic state (exemplified by high fibrinogen or plasminogen activator inhibitor in the blood).

[0395] In some embodiments, the condition, disease or disorder is about vascular disease. Non-limiting examples of vascular disease include peripheral vascular disease, macrovascular complications (e.g., stroke), vascular dysfunction, peripheral arterial disease, abdominal aortic aneurysm, carotid artery disease, cerebrovascular disorders (e.g., cerebral infarction), pulmonary embolism, chronic venous insufficiency, critical limb ischemia, retinopathy, nephropathy and neuropathy.

[0396] Neurological diseases In some embodiments, the condition, disease, or disorder is a neurological disorder (eg, a neurodegenerative disorder) or a psychiatric disorder. Non-limiting examples of neurological disorders include idiopathic intracranial hypertension (IIH), brain insulin resistance, mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), anxiety disorders, dementia (e.g., Alzheimer's disease), traumatic brain injury, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, Parkinson's disease, Steele-Richard syndrome, Down's syndrome, myasthenia gravis, neurotrauma, brain trauma, vascular amyloidosis, intracerebral hemorrhage I with amyloidosis, encephalitis, Friedrich's ataxia, acute confusional disorders, amyotrophic lateral sclerosis (ALS), glaucoma, and apoptosis-mediated degenerative central nervous system diseases (e.g., Creutzfeld-Jakob Disease, bovine spongiform encephalopathy (mad cow disease), and chronic wasting syndrome). See, e.g., U.S. Publication No. 20060275288A1.

[0397] In some embodiments, the condition, disease 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 and pharmaceutical compositions and methods described herein reduce cerebrospinal fluid secretion in patients with idiopathic intracranial hypertension. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce intracranial pressure in patients with idiopathic intracranial hypertension. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce one or more symptoms of patients with idiopathic intracranial hypertension. Symptoms of idiopathic intracranial hypertension may include severe headache and visual disturbances. In some embodiments, the patient with idiopathic intracranial hypertension is female. In some embodiments, the patient with idiopathic intracranial hypertension is about 20 to about 30 years old. In some embodiments, the patient with idiopathic intracranial hypertension is obese.

[0398] In some embodiments, the condition, disease or illness is Wolfram syndrome. Wolfram syndrome is caused by biallelic mutations in the Wolframin ER transmembrane glycoprotein (Wfs1) gene. See, for example, Seppa et al., "Science Report (Sci Rep)", 9, 15742 (2019). Wolfram syndrome may first present as diabetes, followed by symptoms of optic atrophy, deafness and neurodegeneration. Patients with Wolfram syndrome may have symptoms of ataxia, sleep apnea, dysphagia, hearing loss and taste loss due to brainstem atrophy. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce neuroinflammation in patients with Wolfram syndrome. In some embodiments, neuroinflammation in the inferior olive nucleus of the patient is reduced. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce retinal ganglion cell death in patients with Wolfram syndrome. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce axonal degeneration in patients with Wolfram syndrome. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce one or more symptoms (eg, any of the symptoms described herein) in a patient suffering from Wolfram's syndrome.

[0399] Non-limiting examples of psychiatric disorders include drug dependence / addiction (narcotics) and attention deficit / hyperactivity disorder (ADHD). The compounds and pharmaceutical compositions described herein may be useful for improving behavioral responses to addictive drugs, reducing drug dependence, preventing relapse in drug abuse, and alleviating anxiety caused by lack of a given addictive substance. See, e.g., U.S. Publication No. 20120021979A1.

[0400] In some embodiments, the compounds and pharmaceutical compositions described herein are useful for improving learning and memory by enhancing neuronal plasticity and facilitation of cell differentiation, as well as protecting dopamine neurons and motor function in Parkinson's disease.

[0401] Insulin related In some embodiments, the condition, disease, or disorder is impaired fasting glucose (IFG), impaired fasting glucose (IFG), hyperglycemia, insulin resistance (impaired glucose homeostasis), hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hypoglycemic conditions, insulin resistance syndrome, paresthesias caused by hyperinsulinemia, hyperlipidemia, hypercholesterolemia, impaired wound healing, leptin resistance, glucose intolerance, increased fasting glucose, dyslipidemia (e.g., hyperlipidemia, atherogenic dyslipidemia characterized by high triglycerides and low HDL cholesterol), glucagonoma, hyperuricemia, hypoglycemia (e.g., nocturnal hypoglycemia), and concomitant insulin-related coma events.

[0402] In some embodiments, the compounds and pharmaceutical compositions described herein can reduce or slow the progression of borderline, impaired fasting glucose, or impaired fasting glucose to diabetes.

[0403] Autoimmune diseases In some embodiments, the condition, disease or disorder is an autoimmune disorder. Non-limiting examples of autoimmune disorders include multiple sclerosis, experimental autoimmune encephalomyelitis, autoimmune disorders associated with immune rejection, graft-versus-host disease, uveitis, optic neuropathy, optic neuritis, transverse myelitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, myasthenia gravis, and Graves disease. See, e.g., U.S. Publication No. 20120148586A1.

[0404] Stomach and intestinal diseases In some embodiments, the condition, disease or disorder is a stomach or intestinal related disorder. Non-limiting examples of these disorders include ulcers of any etiology (e.g., gastric ulcers, Zollinger-Ellison syndrome, drug-induced ulcers, ulcers associated with infections or other pathogens), digestive disorders, malabsorption, short bowel syndrome, cul-de-sac syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), steatorrhea, hypogammaglobulinemia mouth sores, chemotherapy and / or radiation therapy-induced mucositis and diarrhea, gastrointestinal inflammation, short bowel syndrome, ulcerative colitis, gastric mucosal damage (e.g., gastric mucosal damage caused by aspirin), small intestinal mucosal damage, and cachexia (e.g., cancer cachexia, tuberculous cachexia, cachexia associated with blood diseases, cachexia associated with endocrine diseases, cachexia associated with infectious diseases, and cachexia caused by acquired immune deficiency syndrome).

[0405] weight In some embodiments, the compounds and pharmaceutical compositions described herein can be used to reduce body weight (e.g., excess body weight), prevent weight gain, induce weight loss, reduce body fat, or reduce food intake in patients (e.g., patients in need). In some embodiments, the patient's weight gain can be attributed to excessive food intake or an unbalanced diet, or can be weight gain from concurrent medications (e.g., insulin sensitizers with PPARγ agonist-like effects, such as troglitazone, rosiglitazone, englitazone, ciglitazone, pioglitazone, and the like). In some embodiments, weight gain can be weight gain before obesity is reached, or it can be weight gain in obese patients. In some embodiments, weight gain can also be drug-induced weight gain or weight gain after smoking cessation. In some embodiments, weight gain is induced by the use of steroids or antipsychotics.

[0406] In some embodiments, the condition, disease, or disorder is an eating disorder, such as overeating, binge eating, bulimia, compulsive eating, or syndromic obesity, such as Prader-Willi syndrome and Bard-Bieder syndrome.

[0407] Inflammatory diseases In some embodiments, the condition, disease or disorder is an inflammatory disorder. Non-limiting examples of inflammatory disorders include chronic rheumatoid arthritis, deforming spondylitis, osteoarthritis, low back pain, gout, postoperative or post-traumatic inflammation, abdominal distension, neuralgia, pharyngitis, cystitis, pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory colorectal disease), inflammation in metabolically important tissues including the liver, fat, pancreas, kidneys, and intestines, and pro-inflammatory states (e.g., elevated levels of pro-inflammatory cytokines or markers of inflammation-like C-reactive protein in the blood).

[0408] cancer In some embodiments, the condition, disease or disorder is cancer. Suitable examples of cancer include breast cancer (e.g., invasive ductal carcinoma, non-invasive ductal carcinoma, inflammatory breast cancer), prostate cancer (e.g., hormone-dependent prostate cancer, hormone-independent prostate cancer), pancreatic cancer (e.g., ductal pancreatic cancer), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, malignant mesothelioma), colon cancer (e.g., gastrointestinal stromal tumor), rectal cancer (e.g., gastrointestinal stromal tumor), colorectal cancer (e.g., familial colorectal cancer, hereditary non-polyposis colorectal cancer, gastrointestinal stromal tumor), small intestine cancer (e.g., non-Hodgkin's lymphoma ), gastrointestinal stromal 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, pleomorphic astrocytoma), neurothecoma, liver cancer (e.g., primary liver cancer, extrahepatic bile duct cancer), kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter), bile duct cancer, endometrial cancer, cervical cancer, ovarian cancer (e.g., epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian tumor of low malignant potential), bladder cancer, urethral cancer, skin cancer (e.g., intraocular (eye) melanoma, Merkel cell carcinoma) cell carcinoma), hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer (e.g. medullary thyroid cancer), parathyroid cancer, nasal cancer, paranasal sinus cancer, bone tumors (e.g. osteosarcoma, Ewing tumor, uterine sarcoma, soft tissue sarcoma), angiofibroma, retinosarcoma, penile cancer, testicular tumors, pediatric solid tumors (e.g. Wilms' tumor, childhood kidney tumor), Kaposi's sarcoma, Kaposi's sarcoma caused by AIDS, maxillary sinus tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemia (e.g. acute myeloid leukemia, acute lymphoblastic leukemia).

[0409] Hypothalamic-pituitary disorders In some embodiments, the condition, disease or disorder is about the hypothalamus-pituitary-gonadal axis. For example, the condition, disease or disorder is about the hypothalamus-pituitary-ovarian axis. In another embodiment, the condition, disease or disorder is about the hypothalamus-pituitary-testicular axis. Hypothalamic-pituitary-gonadal axis diseases include but are not limited to hypogonadism, polycystic ovary syndrome, hypothyroidism, hypopituitarism, sexual dysfunction and Cushing's disease.

[0410] In some embodiments, the condition, disease, or disorder associated with diabetes is related to the hypothalamic-pituitary-gonadal axis.

[0411] pulmonary disease In some embodiments, the condition, disease or disorder is related to lung disease. Lung disease includes but is not limited to asthma, idiopathic pulmonary fibrosis, pulmonary hypertension, obstructive sleep apnea syndrome and chronic obstructive pulmonary disease (COPD) (e.g., emphysema, chronic bronchitis and refractory (non-reversible) asthma).

[0412] In some embodiments, the condition, disease, or disorder associated with diabetes is a lung disease.

[0413] Combination therapy In some embodiments, the present disclosure contemplates both monotherapy regimens as well as combination therapy regimens.

[0414] In some embodiments, the methods described herein can further comprise administering one or more additional therapies (eg, one or more additional therapeutic agents and / or one or more treatment regimens) in combination with administering a compound described herein.

[0415] In some embodiments, the methods described herein comprise administering a compound described herein in combination with one or more of the following: dietary therapy (e.g., dietary monitoring, dietary therapy for diabetes), exercise therapy (e.g., physical activity), blood glucose monitoring, gastric electrical stimulation (e.g., ) and dietary changes.

[0416] In some embodiments, a compound of Formula (I) as described herein (e.g., a compound of any of Formulae (IA), (IB), (IC), (ID), and (IE), or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutically acceptable salt or solvate thereof may be administered in combination with one or more additional therapeutic agents.

[0417] Representative additional therapeutic agents include, but are not limited to, weight loss agents, diabetes therapeutics, diabetic complications therapeutics, hyperlipidemia therapeutics, antihypertensive agents, diuretics, chemotherapeutic agents, immunotherapeutic agents, anti-inflammatory agents, antithrombotic agents, antioxidants, osteoporosis therapeutics, vitamins, anti-dementia drugs, erectile dysfunction drugs, therapeutics for frequent urination or urinary incontinence, therapeutics for NAFLD, therapeutics for NASH, and therapeutics for dysuria.

[0418] In some embodiments, the one or more additional therapeutic agents include those therapeutic agents suitable for use, for example, as weight loss agents. Non-limiting examples include monoamine uptake inhibitors (e.g., tramadol, phentermine, mazindol, fluoxetine, tesofensine), serotonin 2C receptor agonists (e.g., lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptor modulators, GABA modulators (e.g., topiramate) including GABA receptor agonists (e.g., gabapentin, pregabalin), neuropeptide Y antagonists (e.g., velneperit), peptide YY or its analogs, rimonabant ( rimonabant), taranabant, ghrelin antagonists, ghrelin receptor antagonists, ghrelin acylase inhibitors, 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. described in WO 2020 / 234726, WO 2020 / 044266 and US8,859,577), stearoyl-CoA desaturase inhibitors, microsomal triglyceride transfer protein inhibitors (e.g., R-256918), sodium-glucose co-transporter 2 (SGLT-2) inhibitors (e.g., JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, remogliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, sergliflozine tabonate, remogliflozinetabonate or ertugliflozin), SGLT-1 inhibitors, MCR-4 agonists, monoamine reuptake inhibitors, melanocyte stimulating hormone analogs, 5HT2c agonists, galanin antagonists, anorectic agents (such as bombesin agonists), thyromimetic agents, dehydroepiandrosterone or its analogs, human hyaluronic acid-related protein (AGRP) inhibitors, neuromedin U agonists, NFK inhibitors (such as HE-3286), PPAR agonists (such as GFT-5 05, DRF-11605, gemfibrozil, fenofibrate, balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone, CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767, and SB-21 9994), phosphotyrosine phosphatase inhibitors (e.g. sodium vanadate, trodusquemin), GPR119 agonists (e.g. PSN-821, MBX-2982, APD597, compounds described in WO 2010 / 140092, WO 2010 / 128425, WO 2010 / 128414, WO 2010 / 106457), glucokinase activators (e.g. piragliatin, AZD-1656, AZD6370, TTP-355, TTP-399, TTP547, ARRY403, MK-0599, TAK-329, AZD5658 or compounds described in WO 2010 / 103437, WO 2010 / 103438, WO 2010 / 013161, WO 2007 / 122482, WO 2006 / 112549, WO 2007 / 028135, WO2008 / 047821, WO 2008 / 050821, WO 2008 / 136428 and WO2008 / 156757), leptin, leptin derivatives (e.g., metreleptin), leptin resistance improving drugs, CNTF (ciliary neurotrophic factor), BDNF (brain-derived neurotrophic factor), cholecystokinin agonists, amylin preparations (e.g., pramlintide, AC-2307), neuropeptide Y agonists (e.g., PYY3-36, derivatives of PYY3-36, obineptide, TM-30339, TM-30335), oxygenotropic (OXM) preparations agents, appetite suppressants (e.g., ephedrine), FGF21 preparations (e.g., animal FGF21 preparations extracted from bovine or porcine pancreas; human FGF21 preparations synthesized using Escherichia coli or yeast genes; fragments or derivatives of FGF21), anorexigenic agents (e.g., P-57), human propancreatic peptide (HIP), melanocortin receptor 4 agonists (e.g., setmelanotide), melanin concentrating hormone receptor 1 antagonists, serotonergic agents (e.g., lorcaserin), farnesoid X receptor (FXR) agonists (e.g., obeticholic acid), acid), tropifexor, cilofexor, LY2562175, Met409, TERN-101, EDP305, compounds described in WO 2020 / 234726 and WO 2020 / 044266), phentermine, zonisamide, norepinephrine / dopamine reuptake inhibitors (e.g., bupropion), GDF-15 analogs, methionine aminopeptidase 2 (MetAP2) inhibitors (e.g., beloranib or ZGN-1061), amfepramone, phendimetrazine, benzphetamine, fibroblast growth factor receptor (FGFR) modulators, biotin, MAS receptor modulators, glucagon receptor agonists, CCKa agonists (e.g., compounds described in WO 2005 / 116034 and U.S. Publication No. 2005 / 0287100) and AMP-activated protein kinase (AMPK) activators.

[0419] In some embodiments, the one or more additional therapeutic agents include those therapeutic agents suitable for use as, for example, antidiabetic agents. Non-limiting examples include insulin and insulin preparations (e.g., animal insulin preparations extracted from the pancreas of cattle or pigs; human insulin preparations synthesized using E. coli or yeast genes; zinc insulin; protamine zinc insulin; insulin fragments or derivatives (e.g., INS-1), oral insulin preparations, synthetic human insulin), insulin sensitizers (e.g., pioglitazone or a salt thereof), biguanides (e.g., metformin, buformin or a salt thereof (e.g., hydrochloride, fumarate, succinate)), glucagon analogs (e.g., WO any glucagon analogue described in 2010 / 011439), agents that antagonize the action of glucagon or reduce the secretion of glucagon, sulfonylurea agents (e.g., chlorpropamide, tolazamide, glimepiride, tolbutamide, glibenclamide, gliclazide, acetohexamide, glyclopyramide, glybuzole, glyburide, glipizide), thiazolidinedione agents (e.g., rosiglitazone, lobeglitazone, glitazone, balaglitazone, rivoglitazone, lobeglitazone or pioglitazone), glitazars (e.g., aleglitazar, chiglitazar, saroglitazar, muraglitazar, tesaglitazar), SGLT2 inhibitors (e.g., JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, THR1474, TS-071, ISIS388626, LX4211, repagliflozin, empagliflozin, canagliflozin, ipagliptin, topagliflozin, sergliflozin edocarbonate, repagliflozin edocarbonate, erpagliflozin, described in WO 2010 / 023594), GPR40 agonists (e.g., FFAR1 / FFA1 agonists,For example, fasiglifam, alpha glucosidase inhibitors (e.g., adiposin, camiglibose, pradimicin-Q, salbostatin, voglibose, acarbose, miglitol, emiglitate), insulin secretagogues such as prandial glucose regulators (often referred to as "short-acting secretagogues", for example, meglitinides (e.g., repaglinide and nateglinide), cholinesterase inhibitors (e.g., donepezil, galantamine, rivastigmine, tacrine), NMDA receptor antagonists, dual GLP-1 / GIP receptor agonists (e.g., LBT-2000, ZPD1 -70), GLP-1R agonists (e.g., exenatide, liraglutide, albiglutide, dulaglutide, albiglutide, tasiglutide, lixisenatide, semaglutide, AVE-0010, S4P, and Boc5), and dipeptidyl peptidase IV (DPP-4) inhibitors (e.g., vildagliptin, dutogliptin, gemigliptin, alogliptin, saxagliptin, sitagliptin, linagliptin Linagliptin, berberine, adogliptin, anagliptin (SK-0403), teneligliptin, omarigliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, ALS2-0426, TA-6666, TS-021, KRP-104, trelagliptin).

[0420] In some embodiments, the one or more additional therapeutic agents include those useful, for example, in treating NAFL and NASH. Non-limiting examples include FXR agonists (e.g., obeticholic acid), PF-05221304, PPARα / δ agonists (e.g., elafibranor), synthetic fat bile binders (e.g., aramchol), anti-lysyl oxidase homolog 2 (LOXL2) monoclonal antibodies (e.g., simtuzumab), apoptotic protease inhibitors (e.g., emricasan), MAPK5 inhibitors (e.g., GS-4997), galectin 3 inhibitors (e.g., GR-MD-02), fibroblast growth factor 21 (FGF21) (e.g., BMS-986036), niacin analogs (e.g., ARJ3037MO), leukotriene D4 (LTD4) receptor antagonists (e.g., tipelukast), acetyl-CoA carboxylase (ACC) inhibitors (e.g., NDI 010976 and those described in WO 2009 / 144554, WO 2003 / 072197, WO 2009 / 144555 and WO 2008 / 065508), ketokinase (KHK) inhibitors (e.g., compounds described in WO 2020 / 234726), apoptosis signal regulating kinase 1 (ASK1) inhibitors, ileal bile acid transporter (IBAT) inhibitors, dual antagonists of chemokine receptor 2 (CCR2) and CCR5 (e.g., cenicriviroc), diacylglycerol acyltransferase 2 (DGAT2) inhibitors (e.g., compounds described in WO 2020 / 234726 and U.S. Publication No. 20180051012), CB1 receptor antagonists, anti-CB1R antibodies, glycyrrhizin, schisandra extract (schisandra chinensis extract), extract), ascorbic acid, glutathione, silymarin, lipoic acid and d-alpha-tocopherol, ascorbic acid, glutathione, vitamin B complex, glitazone / thiazolidinedione (e.g., troglitazone, rosiglitazone, pioglitazone, balaglitazone, rivoglitazone, lobeglitazone), metformin, cysteamine, sulfonylureas, alpha-glucosidase inhibitors, meglitinide, vitamin E, tetrahydrolipstatin, milk thistle protein, antiviral agents, and antioxidants.

[0421] In some embodiments, the one or more additional therapeutic agents include those therapeutic agents suitable for, for example, treating diabetic complications. Non-limiting examples include aldose reductase inhibitors (e.g., tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat, lidorestat), neurotrophic factors and their enhancing agents (e.g., NGF, NT-3, BDNF, neurotrophic production / secretion promoters described in WO01 / 14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-1 imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole), compounds described in WO 2004 / 039365), PKC inhibitors (e.g., ruboxistaurin mesylate), mesylate), AGE inhibitors (e.g. ALT946, N-benzoylthiazolium bromide (ALT766), EXO-226, pyridorin, pyridoxamine), serotonin and norepinephrine reuptake inhibitors (e.g. duloxetine), sodium channel inhibitors (e.g. lacosamide), active deoxygenases (e.g. lipoic acid), cerebral vasodilators (e.g. tiapuride, mexiletine), somatostatin receptor agonists (e.g. BIM23190), and apoptosis signal regulating kinase 1 (ASK-1) inhibitors.

[0422] In some embodiments, the one or more additional therapeutic agents include those therapeutic agents useful, for example, 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 salt, calcium salt)), squalene synthase inhibitors (e.g., compounds described in WO97 / 10224, such as N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(

[0013] In some embodiments, the present invention relates to an agent that is suitable for use in the treatment of a disease or condition. The agent may be a 2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-acetic acid), a fibrate compound (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate), an anion exchange resin (e.g., colestyramine), a nicotinic acid drug (e.g., nicomol, niceritrol, niaspan), a plant sterol (e.g., soy sterol, amma oryzanol / γ-oryzanol), a cholesterol absorption inhibitor (e.g., zechia), a CETP inhibitor (e.g., dalcetrapib, anacetrapib), and an omega-3 fatty acid preparation (e.g., omega-3-fatty acid ethyl ester 90).

[0423] In some embodiments, the one or more additional therapeutic agents include those therapeutic agents suitable for use as, for example, antihypertensive agents. Non-limiting examples include angiotensin converting enzyme inhibitors (e.g., captopril, zofenopril, fbsinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), angiotensin II antagonists (e.g., candesartan cilexetil, candesartan, losartan, losartan potassium), potassium), eprosartan, valsartan, telmisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil, azilsartan, azilsartan medoxomil), calcium antagonists (such as manidipine, nifedipine, amlodipine, efonidipine, nicardipine, cilnidipine), beta blockers (such as metoprolol, atenolol, propranolol, carvedilol, pindolol).Other 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, triamtrenene, amiloride, spironolactone), alpha adrenergic blockers, beta adrenergic blockers, calcium channel blockers (e.g., diltiazem. The invention also includes but is not limited to the following: diltiazem, verapamil, nifedipine and amlodipine), vasodilators (e.g., hydralazine), renin inhibitors, AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan), ET receptor antagonists (e.g., sitaxsentan, atrsentan, compounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265), dual ET / AII antagonists (e.g., compounds disclosed in WO 2000 / 01389), neutral endopeptidase (NEP) inhibitors, the If channel blocker ivabradin, and vasopeptidase inhibitors (dual NEP-ACE inhibitors) (e.g., gemopatrilat and nitrates).

[0424] In some embodiments, the one or more additional therapeutic agents include those useful as diuretics. Non-limiting examples include xanthine derivatives (e.g., theobromine sodium salicylate, theobromine calcium salicylate), thiazide preparations (e.g., ethiazide, cyclopenthiazide, trichlorothiazide, hydrochlorothiazide, hydroflumethiazide, hydrochlorothiazide, benzoyl hydrochlorothiazide, pentoflumethiazide, polythiazide, methylchlorothiazide), anti-aldosterone preparations (e.g., spironolactone, triamterene), carbonic anhydrase inhibitors (e.g., acetazolamide), and chlorobenzenesulfonamide agents (e.g., chlortalidone, mefruside, indapamide).

[0425] In some embodiments, one or more additional therapeutic agents include those suitable for use as, for example, immunotherapeutic agents. Non-limiting examples include microbial or bacterial compounds (e.g., muramyl dipeptide derivatives, picibanil), polysaccharides with immunoenhancing activity (e.g., lentinan, sizofiran, versicolor polysaccharide), cytokines obtained by genetic engineering methods (e.g., interferons, interleukins (IL), such as IL-1, IL-2, IL-12), and colony stimulating factors (e.g., granulocyte colony stimulating factor, erythropoietin).

[0426] In some embodiments, the one or more additional therapeutic agents include those therapeutic agents suitable for use as, for example, anti-thrombotic 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., aragatroban, dabigatran, boroarginine derivatives, boropeptides, heparin, hirudin, and melagatran), FXa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, described in YM150, WO02 / 06234, WO 2004 / 048363, WO 2005 / 030740, WO 2005 / 058823, and WO 2005 / 113504), thrombolytics (e.g., anistreplase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), urokinase, tisokinase, alteplase, nateplase, monteplase, pamiteplase, factor VIla inhibitors, PAI-1 inhibitors, α2-antiplasmin inhibitors, and anisoylated plasminogen streptokinase activator complexes), and platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cilostazol, eicosapentaenoic acid ethyl, beraprost sodium, and sarpogrelate hydrochloride).

[0427] In some embodiments, the one or more additional therapeutic agents include those therapeutic agents suitable for, for example, treating osteoporosis. Non-limiting examples include alfacalcidol, calcitriol, elcatonin, calcitonin salmon, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium, and risedronate isodium. Suitable examples of vitamins include vitamin B1 and vitamin B12. Suitable examples of erectile dysfunction drugs include sildenafil citrate. Suitable examples of agents for treating frequent urination or incontinence include flavorxate hydrochloride, oxybutynin hydrochloride, and propiverine hydrochloride. Suitable examples of therapeutic agents for urinary pain include acetylcholinesterase inhibitors (e.g., distigmine). Suitable examples of anti-inflammatory agents include nonsteroidal anti-inflammatory drugs, such as aspirin, acetamide, and indomethacin.

[0428] Other exemplary additional therapeutic agents include agents that regulate hepatic glucose homeostasis (e.g., fructose 1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glycogen synthase kinase inhibitors, glucokinase activators), agents intended to treat complications of long-term hyperglycemia, such as aldose reductase inhibitors (e.g., epalrestat and ranirestat), drugs used to treat complications associated with microangiopathy, anti-dyslipidemic drugs, such as HMG-CoA reductase inhibitors (statins, e.g., rosuvastatin, pravastatin, pitavastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, ZD-4522), HMG-CoA synthase inhibitors, cholesterol-lowering agents, bile acid sequestrants (e.g. cholestyramine, questran, colestipol and colesevelam), cholesterol absorption inhibitors (e.g. plant sterols such as phytosterols), cholesterol ester transfer protein (CETP) inhibitors, ileal bile acid transport system inhibitors (IBAT inhibitors), diacylglycerol acyltransferase 1 (DGAT1) inhibitors (e.g. AZD7687, LCQ908, described in WO2009 / 016462, WO 2010 / 086820), monoacylglycerol O-acyltransferase inhibitors, α-amylase inhibitors (e.g., tendamistat, trestatin, AL-3688), α-glucosidase inhibitors, SIRT-1 activators, c-Jun N-terminal kinase (JNK) inhibitors, VPAC2 receptor agonists, TGR5 receptor modulators (e.g., compounds in), GPBAR1 receptor modulators, GPR120 modulators, high affinity nicotinic acid receptor (HM74A) activators, carnitine palmitoyl transferase inhibitors, mineralocorticoid receptor inhibitors, TORC2 inhibitors, fatty acid synthase inhibitors, serine palmitoyl transferase inhibitors, GPR81 modulators, GPR39 modulators, GPR43 modulators, GPR41 modulators, GPR105 modulators, Kv1.3 modulators, retinol binding protein 4 modulators, somatostatin receptor modulators, PDHK2 modulators, PDHK4 modulators, MAP4K4 inhibitors, IL1 family modulators (e.g., ILIβ modulators), ACAT inhibitors, MTP inhibitors (e.g., diriotapide, mitratapide, and implitapide), lipoxygenase inhibitors, PCSK9 modulators (e.g., alirocumab and evolocumab), RXRα modulators, cysteamine, cystamine, RNA antisense constructs that inhibit protein tyrosine phosphatase PTPRU, vitamin B complex, Schisandra protein, protein tyrosine phosphatase-1B (PTP-1B) inhibitors (e.g., trodusquemine, hyrtiosal extract, and described in Zhang et al., Current Drug Discovery Today, 2007, 12(9-10):373-381), ezetimibe, betaine, pentoxifylline, αδ-9 desaturase, BCKDK inhibitor, branched-chain α-ketoacid dehydrogenase kinase (BCBK) inhibitor, PNPLA3 inhibitor, FGF1 9 analogs, SCD1 inhibitors, bile acid binding resins, nicotinic acid (niacin) and its analogs, antioxidants (e.g., probucol), omega-3 fatty acids, antihypertensive agents including adrenergic receptor antagonists (such as beta blockers (e.g., atenolol), alpha blockers (e.g., doxazosin) and mixed alpha / beta blockers (e.g., labetalol), adrenergic receptor agonists including alpha-2 agonists (e.g., clonidine), angiotensin converting enzyme (ACE) inhibitors (e.g., lisinopril), calcium channel blockers (such as dihydropyridines (e.g., nifedipine), phenylalkylamines (e.g., verapamil) and benzthiazepines. (e.g. diltiazem )), angiotensin II receptor antagonists (e.g. candesartan), aldosterone receptor antagonists (e.g. eplerenone, spironolactone), centrally acting adrenergic drugs such as central alpha agonists (e.g. clonidine), diuretics (e.g. furosemide, torsemide, bumetanide, ethacrynic acid, thiazide diuretics (e.g. chlorothiazide, hydrochlorothiazide, benzthiazide, hydroflumethiazide, benzflumethiazide, methylchlorothiazide, polythiazide, trichloromethiazide, indapamide), phthalimide diuretics (e.g. chlorthalidone, metolazone), quinazoline diuretics (e.g. quinethazolone), potassium sparing diuretics (e.g. triaminetetracycline and amiloride), thyroid receptor agonists (e.g. described in WO 2020 / 117987), hemostatic modulators (including antithrombotic agents (e.g., fibrinolytic activators), thrombin antagonists, factor VIIa inhibitors, anticoagulants (e.g., vitamin K antagonists such as warfarin), heparin and its low molecular weight analogs, factor Xa inhibitors and direct thrombin inhibitors (e.g., argatroban)), antiplatelet agents (e.g., cyclooxygenase inhibitors (e.g., aspirin), nonsteroidal anti-inflammatory drugs (NSAIDS), thrombin-A2 receptor antagonists (e.g., ifetroban), thrombin-A2-synthetase inhibitors, PDE inhibitors (e.g., Pletal, dipyridamole), purine receptor antagonists (e.g., P2Y1 and P2Y12), adenosine diphosphate (ADP) receptor inhibitors (e.g., clopidogrel), phosphodiesterase inhibitors ( For example, cilostazol), glycoprotein IIB / IIA inhibitors (e.g., tirofiban, eptifibatide, and abciximab), adenosine reuptake inhibitors (e.g., dipyridamole), noradrenergic agents (e.g., phentermine), serotonergic agents (e.g., locastine), diacylglycerol acyltransferase (DGAT) inhibitors, feeding behavior modulating agents, pyruvate dehydrogenase kinase (PDK) modulators, serotonin receptor modulators, monoamine transmission modulators such as selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine), norepinephrine reuptake inhibitors (NARIs), norepinephrine-serotonin reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs) (e.g., toloxatone and amiflamine), described in WO 2007 / 013694, WO 2007 / 018314, WO 2008 / 093639 and WO 2008 / 099794, GPR40 agonists (e.g., farslifang or a hydrate thereof, compounds described in WO 2004 / 041266, WO 2004 / 106276, WO 2005 / 063729, WO 2005 / 063725, WO2005 / 087710, WO 2005 / 095338, WO 2007 / 013689 and WO 2008 / 001931), SGLT1 inhibitors, adiponectin or its agonists, IKK inhibitors (e.g. AS-2868), somatostatin receptor agonists, ACC2 inhibitors, cachexia improving agents (such as cyclooxygenase inhibitors (e.g. indomethacin)), progesterone derivatives (e.g. megestrol acetate), glucocorticoids (e.g. dexamethasone), metoclopramide agents, agents for improving fat metabolism (e.g. eicosapentaenoic acid), growth hormone, IGF-1, antibodies against cachexia-inducing factor TNF-α, LIF, IL-6, and oncostatin M, metabolic modifying proteins or peptides such as glucokinase (GK), glucokinase regulatory protein (GKRP), uncoupling proteins 2 and 3 (UCP2 and UCP3), peroxisome proliferator-activated receptor α (PPARα), MC4r agonists, insulin receptor agonists, PDE 5 inhibitors, glycosylation inhibitors (such as ALT-711), drugs that promote nerve regeneration (such as Y-128, VX853, neurotrophic peptides (prosaptide)), antidepressants (such as desipramine, amitriptyline, imipramine), antiepileptic drugs (such as lamotrigine, trileptal, levetiracetam (keppra), zonisamide (zonegran), pregabalin, harkoseride, carbamazepine)), antiarrhythmic drugs (such as, K + Channel openers, mexiletine, propafenone, metoprolol, atenolol, carvedilol, 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, α2 receptor agonists (e.g. clonidine), local analgesics (e.g. capsaicin), anxiolytics (e.g. benzothiazepines ), phosphodiesterase inhibitors (e.g., sildenafil), dopamine receptor agonists, cytotoxic antibodies (e.g., T-cell receptor and IL-2 receptor specific antibodies), B-cell depleting therapies (e.g., anti-CD20 antibodies (e.g., rituxan), i-BLyS antibodies), drugs that affect T-cell migration (e.g., anti-integrin α4 / β1 antibodies (e.g., tysabri), drugs that act on immunophilins (e.g., cyclosporine, tacrolimus, sirolimus, rapamicin), interferons (e.g., IFN-β), immunomodulators (e.g., glatiramer), TNF binding proteins (e.g., circulating receptors), immunosuppressants (e.g., mycophenolate), meglitazone glidasen), AMG-131, balaglitazone, MBX-2044, riglitazone, aleglitazar, siglitazar, saxaglitazar, moraglitazar, tesaglitazar, lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, exenatide, incretin analog-4, memantine, midazolam, ketoconazole, icosapent ethyl, clonidine, azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, etoposide, piroxicam, NO donors (e.g., organic nitrates) and NO promoters (e.g., phosphodiesterase inhibitors).

[0429] In some embodiments, the additional therapeutic agent or course of treatment is administered to the patient prior to contact with or administration of the compound and pharmaceutical composition (e.g., about an hour before, or about 6 hours before, or about 12 hours before, or about 24 hours before, or about 48 hours before, or about 1 week before, or about 1 month before).

[0430] In some embodiments, the additional therapeutic agent or regimen is administered to the patient at about the same time as the compound and pharmaceutical composition are contacted or administered. For example, the additional therapeutic agent or regimen and the compound and pharmaceutical composition are provided to the patient at the same time in the same dosage form. As another example, the additional therapeutic agent or treatment course and the compound and pharmaceutical composition are provided to the patient at the same time in separate dosage forms.

[0431] In some embodiments, the methods described herein further comprise the step of identifying a patient (e.g., subject) in need of such treatment (e.g., by blood analysis, body mass index, or other conventional methods known in the art).

[0432] In some embodiments, the methods described herein further comprise the step of identifying a subject (eg, a patient) suffering from a disease, disorder, or condition as provided herein (eg, a GLP-1 related disease, disorder, or condition).

[0433] In some embodiments, the methods described herein further comprise the step of identifying a patient (e.g., a patient) with type 2 diabetes. In some embodiments, determining whether a patient has type 2 diabetes comprises performing an analysis to determine the content of hemoglobin A1c (HbA1c), fasting plasma glucose, non-fasting plasma glucose, or any combination thereof. In some embodiments, the content of HbA1c is from about 6.5% to about 24.0%. In some embodiments, the content of HbA1c is greater than or about 6.5%. In some embodiments, the content of HbA1c is greater than or about 8.0%. In some embodiments, the content of HbA1c is greater than or about 10.0%. In some embodiments, the content of HbA1c is greater than or about 12.0%. In some embodiments, the content of HbA1c is greater than or about 14.0%. In some embodiments, the content of HbA1c is greater than or about 16.0%. In some embodiments, the content of HbA1c is greater than or about 18.0%. In some embodiments, the content of HbA1c is greater than or about 20.0%. In some embodiments, the HbA1c level is greater than or about 22.0%. In some embodiments, the HbA1c level is greater than or about 24.0%.

[0434] In some embodiments, the fasting plasma glucose level is greater than or about 120 mg / dL to greater than or about 750 mg / dL. In some embodiments, the fasting plasma glucose level is greater than or about 200 mg / dL to greater than or about 500 mg / dL. In some embodiments, the fasting plasma glucose level is greater than or about 300 mg / dL to greater than or about 700 mg / dL.

[0435] In some embodiments, the non-fasting plasma glucose level is greater than or about 190 mg / dL to greater than or about 750 mg / dL. In some embodiments, the non-fasting plasma glucose level is greater than or about 250 mg / dL to greater than or about 450 mg / dL. In some embodiments, the non-fasting plasma glucose level is greater than or about 400 mg / dL to greater than or about 700 mg / dL.

[0436] In some embodiments, determining whether the patient has type 2 diabetes further comprises determining the patient's BMI. In some embodiments, the patient's BMI is greater than or about 22 kg / m 2 To greater than or about 100kg / m 2 In some embodiments, the patient's BMI is greater than or about 30 kg / m 2 to greater than or about 90kg / m 2 In some embodiments, the patient's BMI is greater than or about 40 kg / m 2 to greater than or about 80kg / m 2 In some embodiments, the patient's BMI is greater than or about 50 kg / m 2 to greater than or about 70kg / m 2 .

[0437] In some embodiments, the additional factors (e.g., risk factors) used to determine whether a patient suffers from type 2 diabetes further include the patient's age and race. In some embodiments, the patient's age is greater than or about 10 years old. In some embodiments, the patient's age is greater than or about 15 years old. In some embodiments, the patient's age is greater than or about 20 years old. In some embodiments, the patient's age is greater than or about 25 years old. In some embodiments, the patient's age is greater than or about 30 years old. In some embodiments, the patient's age is greater than or about 35 years old. In some embodiments, the patient's age is greater than or about 40 years old. In some embodiments, the patient's age is greater than or about 42 years old. In some embodiments, the patient's age is greater than or about 44 years old. In some embodiments, the patient's age is greater than or about 46 years old. In some embodiments, the patient's age is greater than or about 48 years old. In some embodiments, the patient's age is greater than or about 50 years old. In some embodiments, the patient's age is greater than or about 52 years old. In some embodiments, the patient's age is greater than or about 54 years old. In some embodiments, the patient's age is greater than or about 56 years old. In some embodiments, the patient's age is greater than or about 58 years old. In some embodiments, the patient's age is greater than or about 60 years old. In some embodiments, the patient's age is greater than or about 62 years old. In some embodiments, the patient's age is greater than or about 64 years old. In some embodiments, the patient's age is greater than or about 66 years old. In some embodiments, the patient's age is greater than or about 68 years old. In some embodiments, the patient's age is greater than or about 70 years old. In some embodiments, the patient's age is greater than or about 72 years old. In some embodiments, the patient's age is greater than or about 74 years old. In some embodiments, the patient's age is greater than or about 76 years old. In some embodiments, the patient's age is greater than or about 78 years old. In some embodiments, the patient's age is greater than or about 80 years old. In some embodiments, the patient's age is greater than or about 85 years old. In some embodiments, the patient's age is greater than or about 90 years old. In some embodiments, the patient's age is greater than or about 95 years old. In some embodiments, the patient's race may be African American, American Indian or Alaska Native, Asian American, Hispanic or Latino, or Native Hawaiian or Pacific Islander.

[0438] In some embodiments, the patient is a pediatric patient. As used herein, the term "pediatric patient" refers to a patient under the age of 21 at the time of diagnosis or treatment. The term "pediatric" can be further divided into different subgroups, which include: newborns (from birth to the first month of life); infants (1 month to two years old); children (two years old to 12 years old); and adolescents (12 to 21 years old (up to but not including the 22nd birthday)). 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 some embodiments, the pediatric patient is from birth to the first 28 days of life, from 29 days of age to less than two years of age, from two years of age to less than 12 years of age, or from 12 years of age to 21 years of age (up to but not including the twenty-second birthday). In some embodiments, a pediatric patient is from birth to the first 28 days of life, from 29 days of age to less than 1 year of age, from one month of age to less than four months of age, from three months of age to less than seven months of age, from six months of age to less than 1 year of age, from 1 year of age to less than 2 years of age, from 2 years of age to less than 3 years of age, from 2 years of age to less than 7 years of age, from 3 years of age to less than 5 years of age, from 5 years of age to less than 10 years of age, from 6 years of age to less than 13 years of age, from 10 years of age to less than 15 years of age, or from 15 years of age to less than 22 years of age. In some embodiments, the patient is an adult patient. Example

[0439] The present invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

[0440] Schemes 1-3 depict exemplary methods for preparing compounds of formula (I) and intermediates useful in the synthesis of compounds of formula (I).

[0441] Process 1

[0442] Referring to Scheme 1, ester I1 (wherein R 4 As defined for formula I; is selected from the group consisting of: Where R 5 , R 6 and R 7I2 is a 4-[( ... Coincidence.

[0443] Subsequent reaction of I2 with I3 (e.g., in the presence of NaH in DMF) provides compound I4, followed by hydrolysis of the ester group under standard conditions (e.g., with LiOH in H2O / THF) to afford compound I5. Amide coupling of I5 with NHMePh under standard conditions (e.g., HATU and Hunig's base) affords I6. I6 is reacted with reagent I6b (wherein the dashed line Lx indicates the optional reaction with C 1-6 Alkyl substituted C 2-5 Alkylene, wherein the C 1-6 The alkyl group is optionally substituted with 1 to 3 independently selected R f Substitution) under basic conditions (eg KHMDS, DMPU) then provides I7, wherein ring D' is optionally C 1-6 Alkyl C 3-6 Cycloalkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1 to 3 independently selected R f As a non-limiting example, I6b may be The ring D in the corresponding product is

[0444] Treatment of I7 with a hydroxylamine source (e.g., NH2OH.HCl in EtOH at reflux) followed by reaction with a phosgene equivalent (e.g., CDI (e.g., in the presence of DBU and DMSO at 80°C) affords compound I8. Hydrolysis of the amide group in I8 (e.g., with KOH in CH3OCH2CH2OH at, e.g., 125°C) affords compound I9.

[0445] Process 2

[0446] Refer to Scheme 2, where R 3Carboxylic acid I10 as defined for formula I is subjected to amidation under standard conditions for amide bond formation (e.g., with a carboxyl activating agent such as HATU in the presence of a base such as Huning's base) with an ammonium source (e.g., NH4Cl) to afford compound I11. Under dehydrating conditions (e.g., with TFAA and pyridine at room temperature), I11 is converted to compound I12, which is subjected to acidic conditions (e.g., MeSO3H in THF at, e.g., 65°C) to afford compound I13. Compound I13 is then reacted with I13b (where R 2 and R 3 I15 is coupled to compound I16b (wherein ring A is as defined in formula I; and each Pg is a nitrogen protecting group, such as a carbamate protecting group, such as Boc) in a Michael-type addition manner to afford compound I14 (e.g., at an elevated temperature such as 70° C. in the presence of NEt3 in a polar protic solvent such as EtOH), followed by protection of the amino nitrogen using an appropriate protecting group (i.e., Pg). As a non-limiting example, Pg may be a carbamate protecting group, such as Boc. I14 is subjected to an intramolecular Dieckmann-type condensation under basic conditions (e.g., with tBuOK at room temperature) to afford I15. The protected hydrazine compound I16b (wherein ring A is as defined in formula I; and each Pg is a nitrogen protecting group, such as a carbamate protecting group, such as Boc) is condensed with I15 to afford compound I16 (e.g., treated with TFA in DCM at room temperature, followed by treatment with Py-HCl in EtOH at reflux). Reaction between I16 and I17b (e.g., in the presence of a polar aprotic solvent such as DMA) provides compound I17, which is then treated with an acid (e.g., MeSO3H, THF, 60°C), followed by reprotection of the secondary amino group (e.g., with Boc2O) to afford compound I18, wherein Pg is a nitrogen protecting group, such as a carbamate protecting group, such as Boc. Compound I18 is then coupled with compound I18b, wherein Q 1 To Q 5 As defined for Formula I and X is a halide (e.g., -Br or -I) or a pseudohalide (e.g., -OTf) (e.g., under typical Ullman coupling conditions known in the art) to afford compound I19. As a non-limiting example, CuI, K2CO3 and The coupling is carried out in the presence of NMP (eg at 130° C.) Removal of the nitrogen protecting group (ie Pg) on ​​119 (eg under acidic conditions such as HCl in dioxane) then affords compound 120. Process 3

[0447] Referring to Scheme 3, I20 is coupled with I9 under standard amide bond forming conditions (eg, in the presence of a carboxyl activating agent such as HATU (eg, in a polar aprotic solvent such as DMF)) to provide compound I21, which is a compound of Formula I.

[0448] It will be apparent to one of ordinary skill in the art that in the synthetic sequence described above (see Schemes 1-3), reactive groups such as NH2, NH and OH may be protected with appropriate protecting groups, followed by a deprotection step at an appropriate stage in the synthesis. It is also within the ability of one of ordinary skill in the art to envision variations of the foregoing method for synthesizing other compounds of Formula I. For example, by exchanging I6b with other electrophiles, compounds with other L 3 -C(R 8a R 8b )-L 4 -R 9 As another example, by replacing I16 with other appropriate reagents, compounds with other L 2 Part of the compound.

[0449] General Information All NMR spectra were recorded on a Bruker 400 (400 MHz) spectrometer. 1 H chemical shifts are reported as δ values ​​in ppm with deuterated solvents as internal standards. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad signal, m = multiplet), coupling constant (Hz), integration value. Unless otherwise stated, LCMS spectra were obtained on an Agilent series using electrospray ionization.

[0450] abbreviation

[0451] 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)

[0452] Step A: 5-(3,6-Dihydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester To a solution of ethyl 5-bromo-1H-indole-2-carboxylate (10.0 g, 37.3 mmol) in dioxane / H2O (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)Cl2.CH2Cl2 (3.00 g, 3.73 mmol), K2CO3 (15.4 g, 112 mmol). The reaction was evacuated and backfilled with N2 three times. The reaction mixture was stirred at 80 °C under N2 atmosphere for 2.5 hours, then it was filtered, diluted with DCM, washed with water, dried over Na2SO4, 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, 69% yield). LC-MS: m / z 272.0 (M+H) + 1 H NMR(400MHz, CDCl3)δ:8.89(s,1H),7.66(s,1H),7.44(dd,J=8.8,1.6Hz,1H),7.38(d,J=8.8Hz,1H),7.21(dd,J=2.0,0.8Hz,1H), 6.01-6.17(m,1H),4.41(q,J=7.2Hz,2H),4.35(q,J=2.8Hz,2H),3.97(t,J=5.6Hz,2H),2.56-2.62(m,2H),1.42(t,J=7.2Hz,3H).

[0453] Step B: Ethyl 5-(Tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate 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) was added 10% w / w Pd / C (700 mg). The mixture was stirred at room temperature under H2 atmosphere overnight. The reaction mixture was filtered, concentrated, slurried with MeOH, and filtered to give ethyl 5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (6.00 g, 85% yield) as a white solid. LC-MS: m / z 274.0 (M+H) + 1 H NMR (400MHz, CDCl3) δ: 8.87 (s, 1H), 7.51 (s, 1H), 7.37 (d, J = 8.4Hz, 1H), 7.21 (dd, J = 8.4, 1.6Hz, 1H), 7.18-7.19 (m, 1H), 4.41 (q, J = 7 .2Hz,2H),4.11(dd,J=10.8,4.0Hz,2H),3.56(td,J=11.6,2.8Hz,2H),2.80-2.88(m,1H),1.80-1.90(m,4H),1.42(t,J=7.2Hz,3H).

[0454] Step C: 1-(Cyanomethyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester 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) at 0°C was added NaH (60% in oil) (1.30 g, 33.0 mmol). The mixture was stirred at 0°C for 0.5 h, 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 H2O (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 (6.30 g, 92% yield) as a cream solid. LC-MS: m / z 313.0 (M+H) + 1 H NMR(400MHz, DMSO-d6)δ:7.71(d,J=8.8Hz,1H),7.59(s,1H),7.39(dd,J=8.8,1.6Hz,1H),7.36(d,J=0.8Hz,1H),5.75(s,2H ), 4.37(q,J=7.2Hz,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=7.2Hz,3H).

[0455] Step D: 1-(Cyanomethyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid 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 H2O / 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 hours. THF was then removed in vacuo and the pH was adjusted to about 50°C with 1 N HCl solution. The suspension was filtered to give 1-(cyanomethyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (4.30 g, 97% yield) as an off-white solid. LC-MS: m / z 285.0 (M+H) + 1 H NMR(400MHz, DMSO-d6)δ:13.3(s,1H),7.68(d,J=8.4Hz,1H),7.58(s,1H),7.37(dd,J=8.8,1.6Hz,1H),7.31 (d,J=0.4Hz,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).

[0456] Step E: 1-(Cyanomethyl)-N-methyl-N-phenyl 5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide To a solution of 1-(cyanomethyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (4.70 g, 16.6 mmol) in DMF (70 mL) and HATU (9.43 g, 24.8 mmol) at 0°C was added DIPEA (8.65 mL, 49.6 mmol). 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, then 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 give the title compound (4.30 g, 70% yield) as a yellow solid. LC-MS: m / z 374.0 (M+H) + 1H NMR(400MHz, 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)

[0457] Step F: 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-N-methyl-N-phenyl 5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide 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 KHMDS (1.0 mol / L in THF, 31.2 mL, 31.2 mmol) dropwise under N2 atmosphere at 0°C. The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched with HCOOH (10 mL), concentrated in vacuo, and purified by flash chromatography (PE / EtOAc=1 / 1) to give crude 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) +

[0458] 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 A solution of crude 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), NH2OH·HCl (2.70 g, 39.0 mmol) and K2CO3 (5.90 g, 43.0 mmol) in EtOH (50 mL) was stirred at 100° C. for 2 hours. The reaction mixture was concentrated and diluted with H2O (100 mL). The suspension was filtered and dried under vacuum. The solid was dissolved in DMSO (10 mL), and then carbonyldiimidazole (2.50 g, 15.6 mmol) and 1,8-diazabicycloundec-7-ene (3.00 g, 19.5 mmol) were added. The resulting mixture was stirred at 80° C. for 1 hour. Formic acid (5 mL) was added, and the mixture was then concentrated and purified by reverse phase chromatography (acetonitrile / H2O=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 (1.00 g, 27% yield) as a white solid. LC-MS: m / z 473.1 (M+H) +

[0459] 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 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 hour. The reaction mixture was acidified to pH=3 with 5N HCl solution, and a brown precipitate was observed. The solid was collected by filtration, washed with H2O (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 (700 mg, 86% yield) as a brown solid. LC-MS: m / z 384.1 (M+H)+ 1 H NMR(400MHz,DMSO-d6)δ:12.88(s,1H),12.29(s,0.4H),12.02(s,0.6H),7.54( d,J=4.8Hz,1H),7.37(t,J=8.0Hz,1H),7.29(td,J=11.2Hz,1.2Hz,1H),7.19(d, J=4.4Hz,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=6.4Hz,1.3H),1.27(d,J=6.5Hz,1.7H).

[0460]

[0461] Step I: (S)-tert-butyl (4-amino-4-oxobutan-2-yl)carbamate To a mixture of (S)-methyl 3-((tert-butoxycarbonyl)amino)butanoate (10.0 g, 49.2 mmol) in THF (150 mL) at 0° C., HATU (22.5 g, 59.0 mmol), DIPEA (19.0 g, 148 mmol) and NH4Cl (6.60 g, 123 mmol) were added. The reaction mixture was stirred at room temperature under N2 overnight, then it was diluted with EtOAc (150 mL), washed with H2O (50 mL×3), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography (PE / EtOAc=1 / 1) to give tert-butyl (S)-(4-amino-4-oxobutan-2-yl)carbamate (12.2 g, 100% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ7.27(s,1H),6.79(s,1H),6.69(d,J=8.0Hz,1H),3.70-3.84(m,1H),2 .23(dd,J=14.0,5.6Hz,1H),2.06(dd,J=14.0,8.0Hz,1H),1.37(s,9H),1.01(d,J=6.4Hz,3H).

[0462] Step J: (S)-tert-Butyl (1-cyanopropan-2-yl)carbamate To the mixture in (S)-tert-butyl (4-amino-4-oxobutan-2-yl)carbamate (10.0 g, 49.5 mmol) was added TFAA (6.90 mL, 49.5 mmol) and pyridine (8.00 mL, 99.0 mmol). The mixture was stirred at room temperature for 1 hour. The reaction was quenched with H2O (100 mL) and extracted with EtOAc (100 mL×3). The organic layer was washed with brine (100 mL), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography (PE / EtOAc=20 / 1) to give (S)-tert-butyl (1-cyanopropane-2-yl)carbamate (6.00 g, 65% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ7.11 (d, J = 7.2Hz, 1H), 3.71-3.74 (m, 1H), 2.57-2.69 (m, 2H), 1.39 (s, 9H), 1.11 (d, J = 6.4Hz, 3H).

[0463] Step K: (S)-3-Aminobutyronitrile A solution of (S)-tert-butyl(1-cyanopropan-2-yl)carbamate (2.10 g, 11.4 mmol) in 4N HCl in dioxane (20 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo to give (S)-3-aminobutyronitrile hydrochloride (1.50 g, 100% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.58(br.s,2H),3.38-3.53(m,1H),2.90-3.06(m,2H),1.27-1.38(m,3H).

[0464] Step L: (S)-ethyl 3-((tert-butoxycarbonyl)(1-cyanopropan-2-yl)amino)propanoate To a solution of (S)-3-aminobutyronitrile (2.80 g, 23.1 mmol, 1.0 eq) in EtOH (20 mL) was added TEA (3.50 g, 34.6 mmol, 1.5 eq) and ethyl acrylate (2.33 g, 23.1 mmol, 1.0 eq) at room temperature. After stirring at 70 °C for 3 h, the reaction mixture was cooled to room temperature, and (Boc)2O (6.10 mL, 27.8 mmol, 1.2 eq) was added. The solution was stirred at room temperature overnight and diluted with H2O (50 mL). The mixture was extracted with EtOAc (50 mL×3). The organic layer was washed with brine (50 mL), dried over Na2SO4, concentrated and purified by flash chromatography (PE / EtOAc=10 / 1) to give (S)-ethyl 3-((tert-butoxycarbonyl)(1-cyanopropan-2-yl)amino)propanoate (4.00 g, 68% yield). 1 H NMR (400MHz, DMSO-d6) δ4.09-4.18(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).

[0465] Step M: (2S)-tert-butyl 3-cyano-2-methyl-4-oxopiperidine-1-carboxylate 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).

[0466] Step N: (S)-tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate 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) was added TFA (18 mL), 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 solution (20 mL), and extracted with DCM (20 mL×3). The combined organic phases were concentrated in vacuo, and the residue was purified by flash chromatography (PE / EtOAc=20 / 1) to give (S)-tert-butyl 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(400MHz, DMSO-d6)δ:7.23(d,J=6.4Hz,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 = 2.0Hz, 6H), 1.43 (s, 9H), 1.24-1.26 (m, 3H).

[0467] Step O: (S)-tert-butyl 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 To a solution of (S)-tert-butyl 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 H2O (10 mL), concentrated in vacuo, and purified by flash chromatography (PE / EtOAc=1 / 1) to give (S)-tert-butyl 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, 33% yield) as a yellow solid. LC-MS: m / z 506.4 (M+H) +

[0468] Step P: (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-carboxylic acid tert-butyl ester (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-carboxylic acid tert-butyl ester (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 the mixture was then 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 (S)-tert-butyl 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, 88% yield) as a yellow solid. LC-MS: m / z 442.3 (M+H) +

[0469] Step Q: (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-carboxylic acid tert-butyl ester 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) (I) iodide (90.0 mg, 0.470 mmol) at room temperature was formed. The mixture was degassed and refilled with N2 three times. The mixture was stirred at 130° C. under N2 atmosphere for 3 hours. The reaction mixture was purified by silica gel chromatography to give (S)-tert-butyl 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, 41% yield) as a yellow solid. LC-MS: m / z 594.4 (M+H) +

[0470] 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]pyridinium-5-chloride A mixture of (S)-tert-butyl 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 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 (54.0 mg, 34% yield) as a yellow solid. LC-MS: m / z 494.2 (M+H) +

[0471] 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 (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 (54.0 mg, 0.110 mmol), 1-((1S,2S)-2-methyl-1-(5 A solution of 4-(4-(2-(4-(2-(2-(4-nitro-4-nitro-1-yl)-2-nitro-4-yl)-1H-indole-2-carboxylic acid) (46.0 mg, 0.120 mmol), HATU (125 mg, 0.320 mmol) and Et3N (220 mg, 2.20 mmol) in DMF (4 ml) 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 Na2SO4, concentrated under reduced pressure, and purified by preparative HPLC to give 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 (29.0 mg, 33% yield) as a yellow solid. LC-MS: m / z 859.2 (M+H) + 1H NMR (400MHz, DMSO-d6, 80℃) δ:7.79-7.90(m,4H),7.35-7.45(m,2H),7.10-7.30(m,4H),6.95(b r,1H),6.57(br,1H),5.41-5.52(m,1H),4.37(t,J=8.4Hz,1H),3.96(d,J=10.4Hz,2H),3.85(d d,J=9.2,6.0Hz,1H),3.47(td,J=10.8,3.6Hz,2H),2.98-3.01(m,1H),2.75-2.83(m,2H),2.65 -2.75(m,1H),2.18(d,J=1.2Hz,6H),1.71-1.76(s,4H),1.56-1.70(m,8H),1.15-1.40(m,6H).

[0472] Embodiment 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)

[0473] Step A: (4-bromo-2-fluorophenyl)diethylphosphine oxide A mixture of 4-bromo-2-fluoro-1-iodobenzene (2.00 g, 6.60 mmol), diethylphosphine oxide (775 mg, 7.30 mmol), Pd2(dba)3 (302 mg, 0.330 mmol) and XantPhos (382 mg, 0.660 mmol) in 40 mL of 1,4-dioxane was sparged with argon. 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 that 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 (1.50 g, 5.37 mmol, 80.6% yield) as a pale white solid. LCMS: m / z=279.0,281.0(M+H) + . 1 H NMR (400MHz, DMSO-d6) δ7.63-7.73(m,3H),1.95-2.08(m,2H),1.80-1.92(m,2H),0.80-1.10(m,6H).

[0474] Step B: (4-bromo-2-(methylamino)phenyl)diethylphosphine oxide To a mixture of (4-bromo-2-fluorophenyl)diethylphosphine oxide (360 mg, 1.29 mmol) in 2 mL of methanol was added methylamine (9.8 M in methanol, 4 mL, 39.2 mmol). The mixture was heated at 80 ° C in a microwave reactor for 3 hours. LCMS showed that most of the starting material had been consumed. The mixture was concentrated, diluted with ethyl acetate (50 mL) and washed with water (30 mL). The organic layer was dried and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EA / methanol = 1: 2: 0.1) to give (4-bromo-2- (methylamino) phenyl) diethylphosphine oxide (179 mg, 0.617 mmol, 47.9% yield) as a white solid. LCMS: m / z=290.0,292.0(M+H) + . 1 H NMR(600MHz,DMSO-d6)δ7.75-7.76(m,1H),7.11(dd,J=13.2,8.4Hz,1H),6.6 3-6.80(m,2H),2.71(d,J=5.4Hz,3H),1.88-1.94(m,4H),0.90-1.05(m,6H).

[0475] Step C: (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-carboxylic acid tert-butyl ester (4-bromo-2-(methylamino)phenyl)diethylphosphine oxide (310 mg, 1.07 mmol), (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-carboxylic acid tert-butyl ester (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 dimethylcyclohexane-1,2-diamine (208 mg, 1.46 mmol) in NMP (25 mL) was heated at 130 °C under argon atmosphere for 3 hours. LCMS showed that the reaction was complete. Ethyl acetate (100 mL) was added to the mixture and washed with water (50 mL x 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 (S)-tert-butyl 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 (530 mg, 0.810 mmol, 84.0% yield) as a light yellow solid. LCMS: m / z=651.3 (M+H) + . 1 H NMR (600MHz, DMSO-d6) δ7.73(q,J=4.8Hz,1H),7.35(d,J=3.0Hz,1H),7.26(dd,J=13.2 ,8.4Hz,1H),7.11(d,J=6.6Hz,2H),6.98(s,1H),6.89(d,J=7.8Hz,1H),6.86(s,1H),5. 12(br.s,1H),4.13-4.34(m,1H),3.02-3.19(m,1H),2.69-2.74(m,4H),2.61-2.69(m,1 H),2.19(s,6H),1.89-1.95(m,4H),1.43(s,9H),1.17-1.18(m,3H),0.95-1.05(m,6H).

[0476] 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 (S)-tert-butyl 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 diethyl 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 (430 mg, 0.730 mmol, 91.7% yield) as a light yellow solid. LCMS: m / z=551.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.14(s,1H),9.46-9.53(m,1H),7.39(d,J=3.2Hz,1H),7.27(dd,J=12.8, 8.4Hz,1H),7.13(d,J=6.4Hz,2H),6.93(d,J=3.2Hz,1H),6.90(dt,J=8.4,2.0Hz,1H),6.86-6.87(m ,1H),4.55-4.59(m,2H),3.58-3.62(m,1H),3.28-3.33(m,1H),3.03-3.10(m,1H),2.90-3.05(m,1H ), 2.73 (s, 3H), 2.20 (d, J = 2.0Hz, 6H), 1.88-1.97 (m, 4H), 1.36 (d, J = 6.8Hz, 3H), 0.90-1.05 (m, 6H).

[0477] 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), HATU (810 mg, 2.13 mmol) and triethylamine (1.45 g, 14.3 mmol) were added to a mixture of 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (272 mg, 0.710 mmol) and DMF (7 mL). 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) were stirred at room temperature for 10 minutes in 7 mL of DMF. The mixture in flask B was then added dropwise to flask A. The resulting mixture was stirred at room temperature for 12 hours. LCMS showed that most of the starting material had been 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 (400MHz, DMSO-d6, 80℃) δ11.58(br.s,1H),7.66(br.s,1H),7.52(s,1H),7.42(d,J=8. 4Hz,1H),7.05-7.30(m,5H),6.70-6.95(m,4H),5.56(br.s,1H),4.45(br.s,1H),3.95-3.9 9(m,2H),3.40-3.70(m,3H),2.83-2.90(m,3H),2.60-2.80(m,3H),2.22(d,J=1.6Hz,6H), 1.88-1.96(m,4H),1.58-1.80(m,7H),1.43(br.s,3H),1.17(br.s,3H),0.95-1.10(m,6H).

[0478] The following compounds were synthesized using a method similar to that described in Example 2 for compound 121a.

[0479] 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) 1 H NMR (400MHz, DMSO-d6, 80℃) δ11.84(br.s,1H),11.60(br.s,1H),7.51-7.56(m,2H),7.35-7 .45(m,2H),7.27(dd,J=8.4,1.2Hz,1H),7.17(d,J=6.0Hz,2H),7.02(br.s,1H),6.80-6.95( m,2H),6.72(br.s,1H),5.60(br.s,1H),4.44(br.s,1H),3.95-4.04(m,2H),3.40-3.70(m,3 H), 2.84-2.92 (m, 2H), 2.25 (d, J = 1.6Hz, 6H), 1.55-1.90 (m, 14H), 1.47 (s, 3H), 1.19 (s, 3H). LC-MS:m / z 875.2(M+H) +

[0480] 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) 1 H NMR (400MHz, DMSO-d6, 80℃) δ: 11.58 (br.s, 1H), 7.77 (t, J = 8.8Hz, 1H), 7.53 (s, 1H), 7.33-7.44 (m, 4H), 7 .27(dd,J=8.8,1.6Hz,1H),7.16(d,J=6.4Hz,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=2.0Hz ,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) + .

[0481] 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) 1H NMR (400MHz, DMSO-d6, 80℃) δ11.57(br.s,1H),7.53(s,1H),7.43(d,J=8.4Hz,1H),7.27(dd,J=8.8,1.6Hz,1H) ,7.18-7.22(m,2H),7.15(d,J=6.0Hz,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=2.0Hz,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=7.0Hz,6H),1.07(t,J=7.6Hz,3H),1.01(t,J=7.6Hz,3H). LCMS: m / z=466.0(M / 2+H) + .

[0482] 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) 1H NMR (400MHz, DMSO-d6, 80℃) δ11.62(br.s,1H),8.31(br.s,1H),8.06(br.s,1H),7.82(t,J=6.0Hz,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=1.8Hz,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) +

[0483] 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) 1H NMR (400MHz, DMSO-d6, 80℃) δ11.58(br.s,1H),7.53(s,1H),7.43(d,J=8.4Hz,1H),7.27(dd,J=8.4,1 .6Hz,1H),7.18-7.21(m,2H),7.15(d,J=8.4Hz,2H),6.80-6.93(m,4H),5.55(br.s,1H),4.46(br.s,1 H),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=2.0Hz,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) +

[0484] 3-((1S,2S)-1-(2-((S)-3-(3-(4-(dimethylphosphoryl)-3-morpholinylphenyl)-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) 1H NMR (400MHz, DMSO-d6, 80℃) δ11.61(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=8.6Hz,1H),7.36(s,1H),7.27(dd,J=8.4,1.6Hz,1H),7.16(d,J=6.0Hz,2H),6.8 8-6.91(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. 2,3.2Hz,4H),2.80-3.10(m,6H),2.22(d,J=1.6Hz,6H),1.65-1.78(m,13H),1.44(s,3H),1.18(s,3H). LC-MS:m / z 944.4(M+H) +

[0485] 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) 1 H NMR (400MHz, DMSO-d6, 80℃) δ7.96-8.01(m,2H),7.76(br.s,1H),7.50(s,1H),7.42(d,J=8.4H z,1H),7.36-7.39(m,1H),7.25(d,J=8.4Hz,1H),7.15(d,J=6.4Hz,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=1.6Hz,6H),1.61-1.78(m,13H),1.41(s,3H),1.18(s,3H). LC-MS:m / z 943.3(M+H) + .

[0486] 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) 1 H NMR(400MHz,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=8.8Hz,1H),7.37(s,1H),7.25(dd,J=8.8,1.6Hz,1H),7.13(d,J=6.4Hz,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),3.44-3.6 1(m,3H),2.97-3.16(m,1H),2.82-2.90(m,2H),2.20(d,J=2.0Hz,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) +

[0487] 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) 1H NMR (400MHz, DMSO-d6, 80℃) δ: 11.59 (br.s, 1H), 7.53 (s, 1H), 7.43 (d, J = 8.4Hz, 1H),7.23-7.33(m,3H),7.15(d,J=6.0Hz,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=1.6Hz,6H),1.64-1.77(m,13H),1.44(s,3H),1.18(s,3H). LC-MS: m / z 888.2 (M+H) +

[0488] 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) 1 H NMR (400MHz, DMSO-d6, 80℃) δ: 11.58 (br.s, 1H), 7.70-7.80 (m, 3H), 7.50 (s, 1H), 7.41 (d, J = 8. 4Hz,1H),7.35(br.s,1H),7.25(dd,J=8.8,1.6Hz,1H),7.12(d,J=6.0Hz,2H),6.93(s,1H),6.8 6(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=2.0Hz,6H),1.59-1.78(m,13H),1.41(s,3H),1.15(s,3H). LC-MS:m / z 877.2(M+H) +

[0489] 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) 1 H NMR (400MHz, DMSO-d6, 80℃) δ: 11.58 (br.s, 1H), 7.95 (d, J = 9.6Hz, 1H), 7.78 (br.s, 1H), 7.62-7.69 (m, 1 H),7.58(br.s,1H),7.50(s,1H),7.41(d,J=8.4Hz,1H),7.20-7.30(m,2H),7.14(d,J=6.0Hz,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=1.6Hz,6H),1.82-1.57(m,13H),1.43(s,3H),1.15(s,3H). LC-MS:m / z 859.2(M+H) +

[0490] 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) 1H NMR (400MHz, DMSO-d6, 80℃) δ: 11.56 (br.s, 1H), 7.75-7.78 (m, 4H), 7.51 (s, 1H), 7.41 ( d,J=8.4Hz,1H),7.24-7.26(m,2H),7.13(d,J=6.0Hz,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=11.2,3.2Hz,2H ),3.11-3.15(m,1H),2.82-2.89(m,2H),2.20(d,J=1.6Hz,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)+.

[0491] 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) 1H NMR (400MHz, DMSO-d6, 80℃) δ: 11.57 (br.s, 1H), 7.73-7.79 (m, 4H), 7.51 (s, 1H), 7.42 (d, J = 8.4Hz, 1H), 7 .28(s,1H),7.25(dd,J=8.8,1.6Hz,1H),7.14(d,J=6.0Hz,2H),6.86(br.s,2H),5.56(br.s,1H),4.46(b r.s,1H),3.95-3.98(m,2H),3.53-3.57(m1H),3.47(td,J=11.2,3.2Hz,2H),2.97-3.16(m,1H),2.81-2. 94(m,2H),2.27-2.36(m,2H),2.20(d,J=1.6Hz,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) +

[0492] 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) 1H NMR(400MHz,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=8.8Hz,1H),7.22-7.28(m,2H),7.12(d,J=6.4Hz,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=11.2,3.2Hz,2H),3.11-3.15(m,1H),2.83-2.89( m,2H),2.61(s,3H),2.20(d,J=1.6Hz,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) +

[0493] 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) 1 H NMR (400MHz, 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=8.8,1.6Hz,1H),7.13(d,J=6.4Hz,2H),6.98(s,1H),6.75-6.95(m,2H),5.5 6(br.s,1H),4.43(br.s,1H),3.95-3.98(m,2H),3.56(br.s,1H),3.47(td,J=11.2,3.6Hz,2H) ,3.11-3.15(m,1H),2.92-2.81(m,2H),2.23(d,J=1.6Hz,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)+

[0494] 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 hydrochloride (Compound 117a) 1 H NMR(400MHz,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=8.4,1.2Hz,1H),7.14(d,J=6.4Hz,2H),6.93(br.s,1 H),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) +

[0495] 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-morpholinylphenyl)-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) 1H NMR (400MHz, 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 = 8.4Hz, 1H), 7. 35(br.s,1H),7.25(dd,J=8.4,1.6Hz,1H),7.14(d,J=6.0Hz,2H),6.90(br.s,1H),6.85(br.s,1H),5.52(br.s,1H),4.44(b r.s,1H),3.94-3.98(m,2H),3.77-3.70(m,4H),3.56(br.s,1H),3.47(td,J=10.8,3.2Hz,2H),3.02-3.08(m,1H),2.82-2.8 8(m,6H),2.20(d,J=2.0Hz,6H),1.95-2.12(m,4H),1.60-1.75(m,7H),1.42(br.s,3H),1.15(br.s,3H),0.92-1.02(m,6H). LC-MS:m / z 972.4(M+H) + .

[0496] 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) 1H NMR (400MHz, DMSO-d6, 80℃) δ: 11.55 (br.s, 1H), 7.51 (s, 1H), 7.41 (d, J = 8.4Hz, 1H), 7.21-7.25 (m, 2H ),7.11(d,J=6.0Hz,2H),7.05(d,J=1.6Hz,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 .6Hz,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) + .

[0497] 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) 1 H NMR (400MHz, DMSO-d6, 80℃) δ: 11.58 (s, 1H), 7.80-7.81 (m, 4H), 7.50 (s, 1H), 7.40 (d, J=8.4Hz, 1 H),7.23-7.28(m,2H),7.13(d,J=6.4Hz,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=1.6Hz,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) +.

[0498] (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) 1 H NMR (400MHz, 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=6.0Hz,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=2.0Hz,6H),1.90 -1.95(m,4H),1.75-1.79(m,7H),1.54(br.s,1H),1.39(d,J=6.4Hz,3H),0.95-1.10(m,6H). LC-MS:m / z 901.8(M+H) + .

[0499] 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) 1H NMR (400MHz, DMSO-d6, 80℃) δ11.57(s,1H),7.92(br.s,1H),7.70(br.s,2H),7.53(s,1H),7.43 (d,J=8.0Hz,1H),7.20-7.36(m,3H),7.16(d,J=6.4Hz,2H),6.96(br.s,1H),6.88(br.s,1H),5 .57(br.s,1H),4.47(s,1H),3.95-4.05(m,2H),3.42-3.65(m,3H),2.88-2.92(m,3H),2.22(s, 6H),1.84-2.09(m,4H),1.60-1.82(m,7H),1.44(br.s,3H),1.18(br.s,3H),0.91-1.05(m,6H). LC-MS:m / z 952.9(M+H) + .

[0500] 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) 1 H NMR (400MHz, DMSO-d6, 80℃) δ11.39(br.s,1H),7.50(s,1H),7.41(d,J=8.8Hz,1H),7.24(d,J=8.0Hz,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=10.8Hz,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 / z452.0(M / 2+H)+ .

[0501] 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) 1 H NMR (400MHz, DMSO-d6, 80℃) δ11.55(s,1H),8.24(s,1H),7.52(s,1H),7.43(d,J=8.4Hz,1H),7. 34(s,1H),7.26(d,J=8.0Hz,2H),7.15(d,J=6.0Hz,2H),6.88-6.95(m,2H),5.57(br.s,1H),4.4 6(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) + .

[0502] 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) 1H NMR (400MHz, DMSO-d6, 80℃) δ11.59(s,1H),7.52(s,1H),7.42(d,J=8.4Hz,1H),7.27(d,J=8.4Hz, 1H),7.20(s,1H),7.14(d,J=5.6Hz,2H),6.67-7.00(m,4H),5.55(br.s,1H),4.46(br.s,1H),3.9 8(d,J=10.8Hz,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) + .

[0503] 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) 1H NMR (400MHz, DMSO-d6, 80℃) δ11.56(br.s,1H),7.53(s,1H),7.43(d,J=8.4Hz,1H),7.27(dd,J=8.8,1.6Hz, 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=11.2,4.0Hz,2H),2.83-2.91(m,3H),2.71(br.s,3H),2.38-2.27(m,2H),2.22( d,J=2.0Hz,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) + .

[0504] 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) 1H NMR (400MHz, DMSO-d6, 80℃) δ11.60(br.s,1H),7.77-8.27(m,4H),7.53(s,1H),7.30-7.50(m, 2H),7.27(d,J=8.8Hz,1H),7.16(d,J=8.0Hz,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,J=1.6Hz,6H) ,1.99-2.08(m,4H),1.64-1.77(m,7H),1.44(br.s,3H),1.10-1.30(m,3H),0.80-1.05(m,6H). LC-MS:m / z 937.2(M+H) + .

[0505] 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) 1 H NMR (400MHz, DMSO-d6, 80℃) δ: 8.39 (br.s, 1H), 7.52 (s, 1H), 7.42 (d, J = 8.4Hz, 1H), 7.25-7 .32(m,2H),7.13(d,J=6.0Hz,2H),6.86(s,2H),6.71(s,2H),5.54(br.s,1H),4.45(br.s, 1H),3.97(d,J=10.8Hz,2H),3.45-3.51(m,3H),2.85-2.95(m,3H),2.71(s,3H),2.21(s,6 H),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) +

[0506] 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) 1 H NMR (400MHz, DMSO-d6, 80℃) δ11.60(br.s,1H),7.53(s,1H),7.43(d,J=8.8Hz,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. 6Hz,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) + .

[0507] 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) 1H NMR (400MHz, DMSO-d6, 80℃) δ11.58(br.s,1H),7.53(s,1H),7.43(d,J=8.0Hz,1H),7.27(d,J =8.0Hz,1H),7.15(d,J=8.0Hz,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=12.0Hz,2H),3.42-3.55(m,3H),2.88-2.94(m,6H),2.25(s,6H),1 .94-2.00(m,4H),1.64-1.75(m,7H),1.45(br.s,3H),1.15-1.31(m,4H),1.01-1.10(m,6H). LC-MS:m / z 934.2(M+H) + .

[0508] 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) 1H NMR (400MHz, DMSO-d6, 80℃) δ11.57(br.s,1H),7.68(br.s,1H),7.52(s,1H),7.42(d,J=8.4Hz,1H),7.21-7.27(m,3H), 7.15(d,J=6.0Hz,2H),6.86(br.s,4H),5.56(br.s,1H),4.48(br.s,1H),3.74(d,J=7.2Hz,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) + .

[0509] 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) 1H NMR (400MHz, DMSO-d6, 80℃) δ11.59(br.s,1H),7.52(s,1H),7.41(d,J=8.4Hz,1H),7.25(d,J=8.8Hz,1H), 7.18-7.24(m,2H),7.15(d,J=6.0Hz,2H),6.86(br.s,4H),5.55(br.s,1H),4.45(br.s,1H),3.73(d,J=8. 0Hz,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 / z944.4(M+H) +

[0510] 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) 1 H NMR (400MHz, DMSO-d6, 80℃) δ11.56(br.s,1H),7.66-7.75(m,2H),7.53(s,1H),7.40-7.50(m,2H),7.20-7.38(m,2H),7.08(d,J=6 .0Hz,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=0.8Hz,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)+ .

[0511] Embodiment 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)

[0512] 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 Pd2(dba)3 (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 N2 atmosphere for 12 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (eluting with DCM / MeOH=10 / 1) to give the title compound (2-amino-4-bromophenyl)diethylphosphine oxide (1.10 g, overweight, 100% yield) as a brown oil. LC-MS: m / z 276.0, 278.0 (M+H) + 1 H NMR (400MHz, 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).

[0513] 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 phases were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (eluting with PE / EA=1 / 2) to give the title compound N-(5-bromo-2-(diethylphosphoryl)phenyl)cyclopropanecarboxamide (120 mg, 48% yield) as a yellow oil. LC-MS: m / z 344.0,346.0 (M+H) + . 1 H NMR (400MHz, CDCl3) δ: 11.85 (s, 1H), 8.94-8.96 (m, 1H), 7.20 (dt, J = 8.0, 2.0Hz, 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).

[0514] 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 in Example 2. 1 H NMR (400 MHz, DMSO-d 6,80℃)δ12.01(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 .6Hz,1H),7.00-7.25(m,3H),6.88(s,2H),5.56(br.s,1H),4.47(br.s,1H),3.97-3.99(m,2H),3.45-3.52(m ,3H),3.12-3.14(m,1H),2.83-2.91(m,2H),2.22(d,J=2.0Hz,6H),2.01-2.11(m,4H),1.72-1.78(m,6H),1.6 4-1.67(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) + .

[0515] The following compounds were synthesized using a method similar to that described in Example 2 for compound 115a.

[0516] 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) 1H NMR (400MHz, DMSO-d6, 80℃) δ11.51-11.62(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=2.0Hz, 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) +

[0517] 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)

[0518] 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 N2 atmosphere for 2 hours. The reaction mixture was cooled to room temperature, diluted with water (60 mL) and extracted with DCM (3×50 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4 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 (6.00 g, 88% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ8.31 (d, J = 2.4Hz, 1H), 8.01 (d, J = 2.4Hz, 1H), 6.67 (s, 2H).

[0519] Step B: 5-Bromo-3-iodobenzene-1,2-diamine SnCl2 (6.00 g, 43.5 mmol) was added to a solution of 4-bromo-2-iodo-6-nitroaniline (3.00 g, 8.70 mmol) in EtOH (30 mL). 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 give 5-bromo-3-iodobenzene-1,2-diamine (2.60 g, crude) as a yellow solid. The crude product was used directly in the next step without purification. LC-MS: m / z 312.8, 314.8 (M+H) +

[0520] 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 under N2 atmosphere for 3 hours. The reaction was concentrated to remove excess HCOOH. Water was then added and the mixture was extracted with EA. The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified via a silica column to give the crude title compound 5-bromo-7-iodo-1H-benzo[d]imidazole (2.60 g, 72% yield) as a yellow solid. LC-MS: m / z 322.8, 324.8 (M+H) +

[0521] 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(400MHz,DMSO-d6)δ11.59(br.s,1H),8.10-8.46(m,1H),7.74(br.s,1H),7.52(s,1H),7 .42(d,J=8.8Hz,1H),7.29(d,J=7.6Hz,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) +

[0522] The following compounds were synthesized using a method similar to that described in Example 4 for compound 110a.

[0523] 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) 1H NMR (400MHz, DMSO-d6) δ11.60(br.s,1H),8.23(s,1H),8.16(br.s,1H),7.81(d,J=15.2Hz,1H),7.52(s ,1H),7.43(d,J=8.4Hz,1H),7.26-7.28(m,2H),7.17(d,J=6.4Hz,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=1.6Hz,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) +

[0524] Example 5 3-((1S,2S)-1-(2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(4-(1-phosphine oxide-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)

[0525] Step A: (4-bromophenyl)phosphine 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 to reflux for 48 hours. The reaction mixture was concentrated and the residue was dried in vacuo to give the crude product (4-bromophenyl)phosphine dichloride (3.88 g) as a yellow oil, which was used directly in the next step.

[0526] Step B: Diallyl (4-bromophenyl) phosphine oxide At -70 ° C, to a solution of (4-bromophenyl) dichlorophosphine (3.88 g) in dry THF (10 mL), allyl magnesium 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 that the reaction was complete. The mixture was quenched with saturated NH4Cl aqueous solution (50 mL) at -70 ° C. The mixture was then warmed to room temperature and extracted with EtOAc (3 × 30 mL). The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (eluted with PE / EtOAc=1 / 3) to give the title compound diallyl (4-bromophenyl) phosphine oxide (1.80 g, 46% yield for two steps) as a yellow solid. LC-MS: m / z 285.2, 287.0 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ7.72-7.75(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).

[0527] Step C: 1-(4-bromophenyl)-2,5-dihydrophosphane 1-oxide To a solution of diallyl (4-bromophenyl) phosphine oxide (400 mg, 1.58 mmol) in dichloromethane (40 mL) was added Grubbs catalyst (2nd generation, 70.0 mg, 0.08 mmol). The mixture was stirred at 50 ° C under an Ar atmosphere for 12 hours. LCMS showed that the reaction was complete. The mixture was concentrated and the residue was purified by silica gel column chromatography (eluted with PE / EA / methanol=1 / 4 / 0.1) to give the title compound 1-(4-bromophenyl)-2,5-dihydrophospholipid 1-oxide (154 mg, 38% yield) as a light white solid. LC-MS: m / z 257.0, 259.0 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ7.76 (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).

[0528] Step D: 1-(4-bromophenyl)phosphine 1-oxide To a solution of 1-(4-bromophenyl)-2,5-dihydrophosphazolin 1-oxide (154 mg, 0.600 mmol) in EtOAc (8 mL) was added platinum dioxide (15.0 mg, 0.0660 mmol). The mixture was stirred at room temperature under H2 atmosphere for 4 hours. LCMS showed that the reaction was complete. The solid was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluted with PE / EA / methanol=1 / 4 / 0.2) to give the title compound 1-(4-bromophenyl)phosphine 1-oxide (107 mg, 69% yield) as a light white solid. LC-MS: m / z 259.0, 261.0 (M+H) + . 1 H NMR(400MHz, 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).

[0529] 3-((1S,2S)-1-(2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(4-(1-phosphin-1-oxide)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 (400MHz, DMSO-d6, 80℃) δ11.58(br.s,1H),7.81(br.s,4H),7.52(s,1H),7.43(d,J =8.8Hz,1H),7.26-7.28(m,2H),7.15(d,J=6.4Hz,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=2.0Hz,6H),1.60-2.08(m,15H),1.44(d,J=4.8Hz,3H),1.17(s,3H). LC-MS:m / z 885.3(M+H) + .

[0530] Example 6 3-((1S,2S)-1-(2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(4-(1-methyl-4-oxo-1,4-azaphosphin-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 hydrochloride (Compound 126a)

[0531] Step A: 4-(4-bromophenyl)-1-methyl-1,4-azaphosphane 4-oxide To a solution of (4-bromophenyl) divinylphosphine oxide (585 mg, 2.28 mmol) in methanol (10 mL) was added methylamine (0.98 M in methanol, 2.79 mL, 2.74 mmol) dropwise. The mixture was stirred at 60 ° C for 1 hour. LCMS showed that the reaction was complete. The mixture was concentrated and the residue was purified by silica gel column chromatography (eluted with DCM / methanol=10 / 1) to give the title compound 4-(4-bromophenyl)-1-methyl-1,4-azaphosphane 4-oxide (278 mg, 42% yield) as a yellow solid. LC-MS: m / z 288.0, 290.0 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ7.72-7.77(m,4H), 2.68-2.78(m,4H), 2.19-2.29(m,5H), 1.84-1.99(m,2H).

[0532] 3-((1S,2S)-1-(2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(4-(1-methyl-4-oxo-1,4-azaphosphin-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 hydrochloride (Compound 126a) was synthesized using the method described in Example 2. 1H NMR (400MHz, DMSO-d6, 80℃) δ11.62(br.s,2H),7.92(br.s,4H),7.52(s,1H),7.43(d,J=8.4Hz,1H ),7.33(br.s,1H),7.28(dd,J=8.4,1.2Hz,1H),7.15(d,J=6.0Hz,2H),6.87-6.93(m,2H),5.56(b r.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) + .

[0533] The following compounds were synthesized using a method similar to that described in Example 2 for compound 121a.

[0534] 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) 1HNMR (400MHz, DMSO-d6, 80℃) δ11.47(br.s,1H),7.79-7.80(br.s,4H),7.52(s,1H),7.43(d,J=8.4Hz,1H),7.2 9(s,1H),7.26(d,J=8.4Hz,1H),7.16(d,J=6.4Hz,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=1.6Hz,6H),1.8 2-2.04(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) + .

[0535] 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)

[0536] 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. under an argon atmosphere overnight. After cooling to room temperature, the mixture was concentrated and the residue was diluted with EtOAc (100 mL), 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 (4-bromo-2-fluorophenyl)phosphonic acid diethyl ester (1.40 g, 67% yield) as a yellow oil. LC-MS: m / z 311.0, 313.0 (M+H) + .

[0537] Step B: (4-bromo-2-fluorophenyl)phosphine 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) was added anhydrous DMF (1.42 g, 19.4 mmol) dropwise. The mixture was heated to reflux for 72 hours. The mixture was concentrated and dried in vacuo to give (4-bromo-2-fluorophenyl)phosphine dichloride (1.50 g, crude) as a colorless oil, which was used directly in the next step without further purification.

[0538] Step C: (4-bromo-2-fluorophenyl)dicyclopropylphosphine oxide At -70 ° C, to a mixture of (4-bromo-2-fluorophenyl) dichlorophosphine (1.50 g, crude) in anhydrous THF (10 mL), 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 that the reaction was complete. The mixture was quenched with saturated NH4Cl aqueous solution (50 mL) at -70 ° C. The mixture was then warmed to room temperature and extracted with EtOAc (3 × 50 mL). The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (eluted with PE / EtOAc=1 / 2) to give the title compound as a yellow solid (4-bromo-2-fluorophenyl) dicyclopropylphosphine oxide (420 mg, 27% yield). 1HNMR (400MHz, CDCl3) δ7.69-7.75(m,1H),7.44(d,J=8.0Hz,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).

[0539] 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 (400MHz, DMSO-d6, 80℃) δ: 10.95 (br.s, 1H), 7.49 (s, 2H), 7.41 (d, J = 8.4Hz, 1H), 7.22-7 .24(m,3H),7.13(d,J=5.6Hz,2H),6.82-6.84(m,3H),5.54(br.s,1H),4.41(br.s,1H),3.96 (d,J=10.8Hz,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) + .

[0540] The following compounds were synthesized using a method similar to that described in Example 2 for compound 121a.

[0541] (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) 1 HNMR (400MHz, DMSO-d6, 80℃) δ7.45-7.50(m,3H),7.18-7.20(m,3H),7.13(d,J=6.4Hz,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=10.8Hz,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=6.4Hz,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) +

[0542] 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) 1 H NMR (400MHz, DMSO-d6, 80℃) δ11.57(br.s,1H),7.77(br.s,1H),7.53(s,1H),7.28(d ,J=1.6Hz,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=2.0Hz, 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) + .

[0543] 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) 1 HNMR(400MHz,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=1.6Hz,6H),1.69- 1.82(m,10H),1.52-1.54(m,1H),1.39(d,J=6.4Hz,3H),1.08(d,J=11.8Hz,9H). LCMS: m / z=916.4 (M+H) + .

[0544] 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)

[0545] 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-phenyl1H-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 / H2O=5 / 1 (20 mL) was added K2CO3 (237 mg, 1.72 mmol) and Pd(dppf)Cl2 (70.1 mg, 0.0860 mmol) at room temperature. The resulting mixture was stirred at 80°C under N2 atmosphere for 16 hours. The reaction solution was concentrated. The residue was purified on silica gel with 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-phenyl1H-indole-2-carboxamide (360 mg, 83% yield) as a yellow gum. 1 HNMR(400MHz, CDCl3)δ11.19(s,1H),7.54(d,J=8.4Hz,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=7.2Hz,1H),1.78-1.83(m,2H),1.48(dd,J=9.2,6.8Hz,1H),1.28(d,J=6.8Hz,3H). LC-MS:m / z 505.2(M+H) + .

[0546] 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-phenyl1H-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 H2 for 16 hours. The reaction was filtered and the filtrate was concentrated. The crude product was purified by preparative HPLC (HCOOH / CH3CN / H2O) to give 5-(4,4-difluorocyclohexyl)-N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl1H-indole-2-carboxamide (50 mg, 14% yield) as a white solid. LC-MS: m / z 507.2 (M+H) + .

[0547] 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 (400MHz, DMSO-d6, 80℃) δ11.57(br.s,1H),7.52(s,1H),7.40(d,J=8.8Hz,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=7.6,16.4Hz,6H). LC-MS:m / z 950.4(M+H) + .

[0548] 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-dimethylmorpholinyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 150a)

[0549] Step A: 5-(2,2-dimethylmorpholinyl)-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 Under N2 atmosphere, 5-bromo-N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl1H-indole-2-carboxamide (585 mg, 1.25 mmol), 2,2-dimethylmorpholine (173 mg, 1.50 mmol) were added to the mixture. 、 To a mixture of Pd2(dba)3 (115 mg, 0.13 mmol) and Davephos (98 mg, 0.25 mmol) in THF (20 mL) was added LiHMDS (2.8 mL, 2.75 mmol). The mixture was stirred at 100 °C for 4 h via microwave irradiation. 1 M HCl (10 mL) was added to the mixture and extracted with EA (30 mL). The organic layer was washed with saturated aqueous NaHCO3 solution (10 mL), brine (10 mL), dried over Na2SO4, concentrated and purified by flash chromatography (eluted with DCM / MeOH=60 / 1) to give the title compound 5-(2,2-dimethylmorpholinyl)-N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl1H-indole-2-carboxamide (341 mg, 54% yield) as a yellow solid. LC-MS: m / z 502.2 (M+H) +

[0550] Step B: 5-(2,2-dimethylmorpholinyl)-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-dimethylmorpholinyl)-N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl1H-indole-2-carboxamide (341 mg, 0.68 mmol) in THF (16 mL) was added t-BuOK (2.3 g, 20.5 mmol) followed by H2O (116 mg). The mixture was stirred at room temperature overnight. The mixture was concentrated and the pH was adjusted to 5% by weight using 1N aqueous HCl. The mixture was extracted with DCM (3×20 mL), dried over Na 2 SO 4 , concentrated, and purified by reverse phase to give the title compound 5-(2,2-dimethylmorpholinyl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (225 mg, 80% yield) as a white solid. LC-MS: m / z 411.2 (MH, negative mode) + .

[0551] 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-dimethylmorpholinyl)-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-dimethylmorpholinyl)-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. To the mixture was added water (30 mL) and extracted with DCM (3×20 mL). The organic layer was washed with brine, dried over Na 2 SO 4 , 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-dimethylmorpholinyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (71.0 mg, 35% yield) as a white solid. 1 HNMR (400MHz, DMSO-d6, 80℃) δ11.58(br.s,1H),7.35(d,J=8.8Hz,1H),7.07-7.21(m,6H),6.83(b r.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) + .

[0552] Example A: cAMP analysis It is known that activation of the GLP-1 receptor stimulates cyclic AMP (cAMP) production in cells, which is indicative of Gα in a heterotrimeric complex with G proteins. s The main coupling of the subunits. Evidence suggests that Gα s The induced cAMP-stimulated signaling results in the desired pharmacological response regarding insulin release from pancreatic beta cells.

[0553] Method 1: To optimize Gα s Coupled functional activity, using a CHO-K1 cell line generated by DiscoverX stably expressing the GLP-1 receptor. Cells expressing the GLP-1 receptor were plated in 384-well microtiter plates and incubated overnight at 37°C and 5% CO2 to allow cell attachment and growth. The medium was then aspirated from the cells and replaced with 15 μL of Hanks Balanced Salt Solution (HBSS) / 5 mM Hepes: 0.5 mM IBMX 0.1% BSA (pH 7.4) [stimulation buffer]. The plated cells were resuspended in stimulation buffer and five microliters (5 μL) of the suspension was added to the previously generated compound sample stock solution at a final concentration of 4× in stimulation buffer, then subsequently added to the cells and allowed to incubate at 37°C for 30 or 60 minutes.

[0554] After incubation, an analytical signal is generated using a cAMP tracer labeled with a europium chelator, which competes with cAMP for the presence of ULight tm The dye-labeled cAMP-specific monoclonal antibody has a binding site. When the antibody binds to the Eu-labeled cAMP tracer, Eu chelators and ULIght can be detected. tm FRET transfer between labeled antibodies. Free cAMP produced by stimulated cells competes with the Eu-cAMP tracer for binding to the ULight-mAb, resulting in a dose-dependent decrease in the TR-FRET signal.

[0555] The method for detecting cAMP using Eu-chelator technology requires incubation with Eu-cAMP tracer solution + ULight-anti-cAMP solution for one hour at room temperature. After the signal is generated, the microtiter plate is read by the PerkinElmer Envision instrument using TR-FRET signal detection. The activity percentage is calculated using the following formula:

[0556] Activity % = 100% x (average RLU of test sample - average RLU of vehicle control) / (average RLU of maximum control - average RLU of vehicle control))

[0557] Method 2: To optimize Gα sCoupled functional activity, using a CHO-K1 cell line generated by DiscoverX stably expressing the GLP-1 receptor. Cells expressing the GLP-1 receptor were plated in 384-well microtiter plates and incubated overnight at 37°C and 5% CO2 to allow cell attachment and growth. The medium was then aspirated from the cells and replaced with 15 μL of 2:1 Hanks Balanced Salt Solution (HBSS) / 10 mM Hepes:cAMP XS+Ab reagent. Five microliters (5 μL) of previously generated 4× final concentration compound sample stock in assay buffer were then added to the cells and allowed to incubate at 37°C for 30 or 60 minutes.

[0558] After incubation, the analytical signal is generated using enzyme fragment complementation (EFC). In EFC, the enzyme B-galactosidase is divided into two complementary parts (EA and ED). The fragment ED is fused to cAMP and competes with endogenous cAMP for binding to a cAMP-specific antibody in an analytical format. When the exogenous EA fragment binds to free ED-cAMP (not bound to a cAMP-specific antibody), activated B-Gal is formed. The activated enzyme content is detected via conversion of a B-gal chemiluminescent substrate, which produces a detectable luminescent signal and is read on a standard microtiter plate.

[0559] The method of detecting cAMP using EFC requires incubation with 20 μL cAMP XS+ED / CL lysis mixture for one hour, followed by incubation with 20 μL cAMP XS+EA reagent for three hours at room temperature. After the signal is generated, the microplate is read by the PerkinElmer Envision instrument using chemiluminescent signal detection. The activity of the compound is analyzed using the CBIS data analysis suite (ChemInnovation, CA). The percentage of activity is calculated using the following formula:

[0560] Activity % = 100% x (average RLU of test sample - average RLU of vehicle control) / (average RLU of maximum control - average RLU of vehicle control))

[0561] Method 3: It is known that activation of the GLP-1 receptor stimulates cyclic AMP (cAMP) production in cells, which is indicative of Gα in heterotrimeric complex with G proteins s Primary coupling of subunits. Evidence suggests that Gα s The induced cAMP-stimulated signaling results in the desired pharmacological response regarding insulin release from pancreatic beta cells.

[0562] To optimize the Gα sCoupled functional activity, using HEK293 / CRE-Luc cell line generated by HDB stably expressing GLP-1 receptor. Compound working solutions (Agilent Technologies Bravo) were prepared at 200× concentration in 1 / 2 log serial dilutions in 384-well Echo LDV plates (Labcyte, catalog number LP-0200). 50 nL / well of the 200× concentration compound working solutions were transferred to 384-well white low volume plates (Greiner, catalog number 784075) using Labcyte ECHO550. 1×10 5 Cells / mL HEK293 / GLP1R / CRE-LUC (HD Biosciences) cell suspension was prepared in assay buffer [DPBS containing 0.5 mM IBMX (Sigma, catalog number I5879) and 0.1% BSA (GENVIEW, catalog number FA016-100g)], and 10 μL of the cell suspension was added to each well of a previously generated assay plate (1000 cells / well) containing 50 nl of compound at 200× concentration using a ThermoFisher Multidrop Combi. The plate was sealed and incubated at 37°C and 5% CO2 for 30 minutes.

[0563] After incubation, cAMP analysis signals were generated using the cAMP Dynamic 2 Kit (Cisbio). 5 μL 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. Incubate for 1 hour at room temperature in the dark. Fluorescence was read at 665 and 615 nm using a Reader PerkinElmer EnVision.

[0564] Activity % = 100% x (average RLU of test sample - average RLU of vehicle control) / (average RLU of maximum control - average RLU of vehicle control))

[0565] Table 1 shows the biological activities of the compounds in the GLP-1R agonist cAMP stimulation assay (EC 50 )[nM](Method 3)

[0566] Notice:

[0567] 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

[0568] pEC 50 Range: A: pEC 50 ≥10; B: 9≤pEC 50 <10; C: 8≤pEC 50 <9

[0569] Example B Rat Pharmacokinetic (PK) Study Pharmacokinetic (PK) studies were performed on male Sprague Dawley (SD) rats by two delivery routes, intravenous (IV) and / or oral gavage (PO). Rats for the IV route (n=3) had free access to food and water. Rats for the PO route (n=3) were fasted overnight and fed 4 hours after dosing. The test articles were formulated as solutions for the IV route and solutions or suspensions for the PO route, respectively. On the day of the experiment, the test articles were administered by IV route (usually at 0.2 to 1 mg / kg and 2 mL / kg) or by oral gavage (usually at 5 to 100 mg / kg and 10 mL / kg) by the PO route, respectively. Blood samples were collected at approximately 8 time points by continuous bleeding within 0.083 to 24 hours after dosing. Approximately 150 μL of blood / time point was collected into a K2EDTA tube via the tail vein. Blood samples were placed on wet ice and centrifuged to obtain plasma samples, and the plasma samples were provided to LC-MS / MS for sample analysis. Pharmacokinetic parameters including clearance (IV), area under the curve (AUC), and oral bioavailability (F%) were calculated using WinNonlin by a non-compartmental model.

[0570] Exemplary compounds of Formula (I) (e.g., certain compounds of Formula (IE)) were tested using the above protocol. The compounds tested exhibited a plasma clearance (L / hr / kg) in the range of 0.20 to 1.60 (e.g., between 0.20 to 0.80 (e.g., between 0.30 to 0.50); ​​or between 1.00 to 1.60 (e.g., between 1.20 to 1.60); and a distribution volume (L / Kg) in the range of 0.40 to 0.70 (L / Kg).

[0571] Example C Glucose Tolerance Test in Non-Human Primates (NHP) During the study, cynomolgus macaques (2.5-6.0 kg) were housed individually in stainless steel cages in a controlled environment set to maintain a temperature of 18-26° C. and a relative humidity of 30-70% with a minimum of 10 air changes per hour. A time-controlled lighting system (lighting on from 7:00 AM to 7:00 PM) was used to provide a regular 12-hour light / 12-hour dark diurnal cycle. The monkeys were provided with 3 meals per day, wherein the meals consisted of the following: 100 g of an exclusive normal diet at 9:00-10:00 AM, one regular fruit (150 g) at 14:00-15:00 PM, and 100 g of an exclusive normal diet at 16:00-17:00 PM. Drinking water was provided ad libitum. All animals underwent a baseline ivGTT, and selected animals were subsequently divided into pre-determined groups based on the baseline ivGTT insulin AUC and their body weight.

[0572] A general research overview is presented in the table below:

[0573] Animals were acclimated for 1 week prior to the start of the study. On Day 1, all animals were dosed with vehicle via IV injection 5 minutes prior to IV glucose challenge. On Day 9, all animals were dosed with vehicle or compound via IV injection 5 minutes prior to IV glucose challenge.

[0574] ivGTT was performed on days 1 and 9. Overnight fasted animals were anesthetized (Zoletil 50, intramuscular, initial dose 5 mg / kg and then, if necessary, maintenance doses of 2.5-5 mg / kg).

[0575] 5 minutes after compound or vehicle administration, animals were injected intravenously via the saphenous vein or appropriate peripheral vein with a dose of 0.5 g / kg (1 mL / kg) of 50% glucose for 30 seconds. Whole blood samples (1.2 mL) were collected from peripheral veins into EDTA-K2 tubes at the following time points: -6 (before compound administration) and 1, 3, 5, 10, 20, 40 and 60 minutes after glucose challenge.

[0576] Collected blood samples were stored under wet ice and then centrifuged at 3500 rpm for 10 minutes at 4° C. within 60 minutes. Collected plasma samples (0.5 mL each) were stored in a refrigerator set to maintain 80° F. until analyzed for glucose, insulin, and C-peptide.

[0577] For the test compound group, at each time point on day 9, about 1.0 mL of whole blood was collected from the saphenous vein or the cephalic vein into an EDTA-K2 tube. The collected blood samples were maintained on wet ice until centrifugation. Plasma was separated by centrifugation at 3500 rpm for 10 minutes at 4°C within 60 minutes of collection. Statistical analysis of the data was completed using GraphPad Prism (Version 9, UGraphPad Software Inc, La Jolla, CA).

[0578] Exemplary compounds of Formula (I) (e.g., certain compounds of Formula (IE)) were tested using the above protocol. Specifically, the test compound was injected intravenously into healthy NHPs at a dose selected from 0.03 to 0.30 mg / kg (e.g., at a dose of 0.05 mg / kg). Following the above procedure, 2.0 to 6.0-fold (e.g., 3.0 to 5.0-fold) insulin secretion was induced in the ivGTT, and an increase of 10% to 40% (e.g., 30% to 40%) in glucose clearance was observed.

[0579] Other Implementations It should be understood that although the invention has been described in conjunction with its embodiments, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages and modifications are within the scope of the following claims. In summary, the present invention includes but is not limited to the following items: 1. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein: Q 1 , Q 2 , Q 3 , Q 4 and Q 5 is defined as (AA) or (BB) below: (AA) Q 1 and Q 5 are independently selected from N, CH and CR QA The group composed of Q 2 , Q 3 and Q 4 are independently selected from N, CH, CR QA and CR QB The group is composed of Q 2 , Q 3 and Q 4 At least one of them is CR QB ; each is a single bond or a double bond, with the restriction that it contains Q 1 To Q 5 The ring is aromatic; (BB) Q 1 is the key; Q 2 , Q 3 , Q 4 and Q 5 are independently selected from the group consisting of: O, S, N, NH, NR c , CH, CR QA and CR QB , whose restriction condition is Q 2 , Q 3 , Q 4 and Q 5 At least one of them is CR QB ; each is a single bond or a double bond, with the restriction that it contains Q 1 To Q 5 The ring is aromatic; R QB P(=O)R a R b , where R a and R b are independently selected from the group consisting of: optionally 1 to 6 each independently selected from C 1-6 Alkoxy, C 3-6 The C-substituted substituent group is a cycloalkyl group or a halogen group. 1-6 Alkyl; optionally 1 to 3 each independently selected from C 1-3 C substituted with a substituent consisting of an alkyl group and a halogen group 3-6 Cycloalkyl; and optionally 1 to 3 independently selected C 1-3 Alkyl substituted C 6-10 aryl; or R a and R b Together with the phosphorus atoms to which they are attached, they form a ring containing 5 to 8 ring atoms, of which 0 to 2 ring atoms (excluding those with R a and R b The attached phosphorus) is a heteroatom each independently selected from the group consisting of O, S and N, wherein the ring is optionally substituted with 1 to 3 independently selected C 1-6 Alkyl substitution; Each R QA are independently selected from the group consisting of: (a) halide; (b) cyano; (c) OH; (d) -NR c R d; (e) C(═O) NR c R d ; (f) S(═O) 0-2 R e (g) optionally 1 to 6 independently selected R f Substituted C 1-6 (h) optionally substituted with 1 to 6 groups independently selected from hydroxyl, halogen and C 1-6 The C substituted by the substituent group consisting of alkoxy 1-6 Alkoxy; (i) optionally substituted with one or more independently selected from C 1-6 Alkyl and C(=O)(C 1-6 alkyl) substituted with 1 to 3 independently selected C(═O)(C 1-6 Alkyl) substituted C 6-10 Aryl; and (k) optionally 1 to 6 independently selected R g substituted 5- to 10-membered heteroaryl; or R on adjacent carbon atoms QA The ring is optionally substituted with 1 to 2 independently selected R h group substitution; L 2 is selected from the group consisting of: Where aa represents the 1 To Q 5 The connection point of the ring; n1 is an integer from 1 to 3; L 2A For key or C 1-10 Alkylene; R La Is selected from H, C 1-6 Alkyl and C(=O)(C 1-6 alkyl) group; R Lb and R Lc Each of which is independently selected from H and C 1-6 The group consisting of alkyl groups; 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 optionally substituted by 1 to 5 groups independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6Substitution of the substituents of the group consisting of alkoxy groups; R 1 , R 2 and R 3 are each independently selected from the group consisting of: H and optionally 1 to 6 each independently selected from halogen, -OH and C 1-6 The substituents consisting of alkoxy groups are substituted with C 1-6 alkyl; L 1 is selected from the group consisting of: -C(=O)-, -CH2-, -CH(C 1-6 alkyl)- and -S(=O)2; Ring B is selected from the group consisting of: Where bb represents the 1 The connection point; R 4 , R 5 , R 6 and R 7 are independently selected from the group consisting of: H, halogen and C 1-6 alkyl; L 3 For key or C 1-3 Alkylene; L 4 For key or C 1-5 Alkylene; R 8a and R 8b are independently selected from the group consisting of: H and optionally substituted by one or more independently selected from halogen and C 3-15 The substituents of the group consisting of cycloalkyl groups are substituted with C 1-6 Alkyl; or R 8a and R 8b Together with the carbon atoms to which they are attached, they form optionally 1 to 3 independently selected C 1-6 Alkyl substituted C 3-15 Cycloalkyl ring, wherein the C 1-6 The alkyl group is optionally substituted with 1 to 6 independently selected R f replace; R 9 is selected from the group consisting of: C(=O)OH, C(=O)(OC 1-6 alkyl), C(=O)NR 9a R 9b , (IX-1), (IX-2), (IX-3) and (IX-4): R 9a H or C1-6 alkyl; R 9b H, C 1-6 Alkyl, C(=O)(C 1-6 Alkyl), S(O) 0-2 (C 1-6 alkyl) or cyano; R 9c , R 9d , R 9e , R 9f and R 9g are each independently selected from the group consisting of: H; and optionally 1 to 6 independently selected halogen and C 1-6 Alkoxy substituted C 1-6 Alkyl; and C(=O)(C 1-6 alkyl); Ring C is selected from 3- to 12-membered heterocyclic groups; 3-15 Cycloalkyl; and a group consisting of 5- to 10-membered heteroaryl, each of which is optionally substituted by 1 to 3 R Ca replace; Each R Ca are independently selected from the group consisting of: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and NR c R d ; or R on the same or different ring atoms Ca The pair together with the one or more ring atoms to which they are respectively attached form a carbocyclic ring containing 3 to 8 ring atoms; Each R c and R d are independently selected from the group consisting of: H, C 1-6 Alkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 Cycloalkyl), C(=O)O(C 1-6 Alkyl), S(O) 1-2 (C 1-6 Alkyl) and S(O) 1-2 (C 3-6 cycloalkyl), wherein the 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) are each optionally substituted with 1 to 6 groups independently selected from -OH, halogen and C 1-6 Substitution of the substituents of the group consisting of alkoxy groups; R e H, C 1-6 Alkyl or C 1-6 Haloalkyl; Each R f are independently selected from the group consisting of: halogen, -OH, NR c R d , C 1-6 Alkoxy, C 1-6 The halogenated alkoxy group is optionally substituted by 1 to 4 groups independently selected from -OH, C 1-6 A 3- to 12-membered heterocyclic group substituted with a substituent selected from the group consisting of an alkyl group and a 3- to 12-membered heterocyclic group; Each R g are independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Alkoxy, NR c R d and optionally one or more independently selected from C 1-6 Alkyl and C(=O)C 1-6 A 3- to 12-membered heterocyclic group substituted with a substituent selected from the group consisting of an alkyl group; and Each R h are independently selected from the group consisting of: halogen, 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 Halogenated alkoxy. 2. The compound of item 1, wherein Q 1 , Q 2 , Q 3 , Q 4 and Q 5 is as defined according to (AA). 3. The compound of item 2, wherein Q 3 CR QB . 4. The compound of item 3, wherein Q 4 N, CH or CR QA . 5. The compound of item 2, wherein Q 4 CR QB ; and Q 3 N, CH or CR QA . 6. A compound according to any one of items 2 to 5, wherein Q 1 For CH. 7. A compound according to any one of items 2 to 6, wherein Q 2 For CH. 8. A compound according to any one of items 2 to 7, wherein Q 5 CR QA . 9. A compound according to any one of items 2 to 7, wherein Q 5 For CH. 10. The compound of item 2, wherein Q 3 CR QB ; and Q 1 , Q 2 , Q 4 and Q 5 Each of is independently CH or CR QA . 11. The compound of item 10, wherein Q 1 , Q 2 , Q 4 and Q 5 Each of them is CH. 12. The compound of item 10, wherein 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 The rest of them are CH. 13. The compound of item 12, wherein Q 4 CR QA ; and Q 1 , Q 2 and Q 5 For CH. 14. The compound of item 10, Q 1 , Q 2 , Q 4 and Q 5 Two of them are independently selected CRs QA ; and Q 1 , Q 2 , Q 4 and Q 5 The rest of them are CH. 15. The compound of item 2, wherein Q 3 CR QB ;Q 1 , Q 2 , Q 4and Q 5 One of them is N; and Q 1 , Q 2 , Q 4 and Q 5 The rest of them are independently CH or CR QA . 16. The compound of item 15, wherein Q 4 is N. 17. A compound according to claim 15 or 16, wherein Q 1 , Q 2 and Q 5 For CH. 18. The compound of item 2, wherein Q 3 CR QB ; and said The part is selected from the group consisting of: 19. The compound of item 2, wherein Q 4 CR QB ; and Q 1 , Q 2 , Q 3 and Q 5 Each of is independently CH or CR QA . 20. The compound of item 19, wherein Q 1 , Q 2 , Q 3 and Q 5 Each of them is CH. 21. The compound of item 19, wherein 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 The rest of them are CH. 22. The compound of item 21, wherein Q 5 CR QA ; and Q 1 , Q 2 and Q 3 For CH. 23. The compound of item 19, wherein Q 1 , Q 2 , Q 3 and Q 5 Two of them are independently selected CRs QA ; and Q 1 , Q2 , Q 3 and Q 5 The rest of them are CH. 24. The compound of item 23, wherein Q 2 and Q 3 CR for independent selection QA ; and Q 1 and Q 5 For CH. 25. The compound of item 2, wherein Q 4 CR QB ; and Q 1 , Q 2 , Q 3 and Q 5 One of them is N; and Q 1 , Q 2 , Q 3 and Q 5 The rest of them are independently CH or CR QA . 26. The compound of item 2, wherein Q 4 CR QB ; and said The part is selected from the group consisting of: 27. A compound according to any one of items 1 to 26, wherein R QB P(=O)R a R b , where R a and R b is independently selected from C 1-6 Alkyl and C 3-6 The group consisting of cycloalkyl. 28. A compound according to any one of items 1 to 27, wherein R QB P(=O)R a R b , where R a and R b Independently for C 1-3 alkyl. 29. The compound of item 28, wherein R a With R b same. 30. A compound according to any one of items 1 to 29, wherein R QB It is P(=O)Me2. 31. A compound according to any one of items 1 to 29, wherein R QB It is P(=O)Et2. 32. A compound according to any one of items 1 to 29, wherein R QBIt is P(=O)iPr2. 33. The compound of item 28, wherein R a With R b different. 34. A compound according to any one of items 1 to 27 or 33, wherein R QB is P(=O)(Me)(tBu). 35. A compound according to any one of items 1 to 27, wherein R QB P(=O)R a R b , where R a and R b Each independently is C 3-6 Cycloalkyl. 36. A compound according to any one of items 1 to 27 or 35, wherein R QB for 37. A compound according to any one of items 1 to 26, wherein R QB P(=O)R a R b , where R a and R b Together with the phosphorus atoms to which they are attached, they form a ring containing 5 to 8 ring atoms, of which 0 to 2 ring atoms (excluding those with R a and R b The attached phosphorus) is a heteroatom each independently selected from the group consisting of O, S and N, wherein the ring is optionally substituted with 1 to 3 independently selected C 1-6 Alkyl substitution. 38. A compound according to any one of items 1 to 26 or 37, wherein R QB P(=O)R a R b , where R a and R b Together with the phosphorus atoms to which they are attached, they form a ring containing 5 to 6 ring atoms, of which 0 to 1 ring atoms (excluding those with R a and R b The attached phosphorus) is a heteroatom selected from the group consisting of O, S and N, wherein the ring is optionally substituted with 1 to 2 independently selected C 1-6 Alkyl substitution. 39. A compound according to any one of items 1 to 26 or 37 to 38, wherein R QB for Where L Q is a bond, CH2, O, S, NH or N(C 1-6 alkyl). 40. A compound according to any one of items 1 to 26 or 37 to 39, wherein R QB for 41. A compound according to any one of items 1 to 40, wherein R QA When present once it is a halo. 42. The compound of item 41, wherein R QA -F in one occurrence. 43. A compound according to any one of items 1 to 40, wherein R QA In one occurrence it is -OH. 44. A compound according to any one of items 1 to 40, wherein R QA NR if it occurs once c R d . 45. The compound of item 44, wherein R QA When it appears once, it is NH(C 1-3 alkyl). 46. ​​The compound of item 44, wherein R QA In one occurrence it is NH2. 47. The compound of item 44, wherein R QA When it appears once, it is N(C 1-3 Alkyl)2. 48. The compound of item 44, wherein R QA When present once, it is selected from the group consisting of: NHC(=O)(C 1-6 alkyl), NHC(=O)(C 3-6 Cycloalkyl), NHC(=O)O(C 1-6 Alkyl), NHS(O) 1-2 (C 1-6 Alkyl) and NHS(O) 1-2 (C 3-6 cycloalkyl). 49. The compound of item 48, wherein R QA When it appears once, it is NHC(=O)(C 1-3 alkyl), NHC(=O)(C 3-6 Cycloalkyl) or NHS(O)2(C 1-3 alkyl). 50. A compound according to any one of items 1 to 40, wherein R QA When present once, it is optionally selected from one or more independently selected from C 1-6 Alkyl and C(=O)(C 1-6 A 5- to 6-membered heterocyclic group substituted with a substituent selected from the group consisting of an alkyl group and an alkyl group. 51. The compound of item 50, wherein R QA In one occurrence it is morpholinyl. 52. A compound according to any one of items 1 to 40, wherein R QA When present once, it is optionally substituted with 1 to 6 groups each independently selected from hydroxy, halo and C 1-6 The substituents consisting of alkoxy groups are substituted with C 1-6 Alkoxy. 53. A compound according to any one of items 1 to 40 or 52, wherein R QA is, at one occurrence, C optionally substituted with 1 to 6 independently selected halo 1-6 Alkoxy. 54. The compound of item 53, wherein R QA It is -OMe, -OCF3 or -OCHF2. 55. A compound according to any one of items 1 to 40, wherein R QA When present once, any of 1 to 6 independently selected R f Substituted C 1-6 alkyl. 56. A compound according to any one of items 1 to 40 or 55, wherein R QA C when it appears once 1-3 alkyl or C substituted with 1 to 6 independently selected halogen groups 1-3 Alkyl, optionally wherein R QA It is methyl, -CF3 or -CHF2. 57. A compound according to any one of items 41 to 56, wherein the remaining R QA When present, is independently selected halo. 58. A compound according to any one of items 1 to 40, wherein R on adjacent carbon atoms QA The ring is optionally substituted with 1 to 2 independently selected R h Group substitution. 59. The compound of item 58, wherein R on adjacent carbon atoms QA The pairs, together with the atoms they are attached to, form: 60. The compound of item 58, wherein R on adjacent carbon atoms QA The pairs, together with the atoms they are attached to, form: 61. A compound according to any one of items 1 to 60, wherein L 2 for 62. A compound according to any one of items 1 to 61, wherein ring A is C 6-10aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted by 1 to 4 groups independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 The substituent group consisting of the alkoxy group is substituted. 63. A compound according to any one of items 1 to 62, wherein ring A is phenyl or pyridyl, each of which is optionally substituted by 2 to 4 groups independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 The substituent group consisting of the alkoxy group is substituted. 64. The compound of item 63, wherein ring A is phenyl, which is optionally substituted by 2 to 4 groups independently selected from halogen and C 1-6 The alkyl group is substituted by a substituent. 65. The compound of item 63, wherein ring A is pyridyl, which is optionally substituted by 2 to 4 groups independently selected from halogen and C 1-6 The alkyl group is substituted by a substituent. 66. A compound according to any one of items 1 to 64, wherein ring A is Where R AA , R AB and R AC are independently halogen or C 1-6 alkyl. 67. A compound according to any one of items 1 to 66, wher...

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein: Q 1 , Q 2 , Q 3 , Q 4 and Q 5 is defined as (AA) or (BB) below: (AA) Q 1 and Q 5 are independently selected from N, CH and CR QA The group composed of Q 2 , Q 3 and Q 4 are independently selected from N, CH, CR QA and CR QB The group is composed of Q 2 , Q 3 and Q 4 At least one of them is CR QB ; each is a single bond or a double bond, with the restriction that it contains Q 1 To Q 5 The ring is aromatic; (BB) Q 1 is the key; Q 2 , Q 3 , Q 4 and Q 5 are independently selected from the group consisting of: O, S, N, NH, NR c , CH, CR QA and CR QB , whose restriction condition is Q 2 , Q 3 , Q 4 and Q 5 At least one of them is CR QB ; each is a single bond or a double bond, with the restriction that it contains Q 1 To Q 5 The ring is aromatic; R QB P(=O)R a R b , where R a and R b are independently selected from the group consisting of: optionally 1 to 6 each independently selected from C 1-6 Alkoxy, C 3-6 The C-substituted substituent group is a cycloalkyl group or a halogen group. 1-6 Alkyl; optionally 1 to 3 each independently selected from C 1-3 C substituted with a substituent consisting of an alkyl group and a halogen group 3-6 Cycloalkyl; and optionally 1 to 3 independently selected C 1-3 Alkyl substituted C 6-10 aryl; or R a and R b Together with the phosphorus atoms to which they are attached, they form a ring containing 5 to 8 ring atoms, of which 0 to 2 ring atoms (excluding those with R a and R b The attached phosphorus) is a heteroatom each independently selected from the group consisting of O, S and N, wherein the ring is optionally substituted with 1 to 3 independently selected C 1-6 Alkyl substitution; Each R QA are independently selected from the group consisting of: (a) halide; (b) cyano; (c) OH; (d) -NRcR d ; (e)C(═O)NRcR d ; (f) S(═O) 0-2 Re; (g) optionally 1 to 6 independently selected R f Substituted C 1-6 (h) optionally substituted with 1 to 6 groups independently selected from hydroxyl, halogen and C 1-6 The substituents consisting of alkoxy groups are substituted with C 1-6 Alkoxy; (i) optionally substituted with one or more independently selected from C 1-6 Alkyl and C(=O)(C 1-6 alkyl) substituted with 1 to 3 independently selected C(═O)(C 1-6 Alkyl) substituted C 6-10 aryl; and (k) 5- to 10-membered heteroaryl optionally substituted with 1 to 6 independently selected Rg; or R on adjacent carbon atoms QA The ring is optionally substituted with 1 to 2 independently selected R h Group substitution; L 2 is selected from the group consisting of: and Where aa represents the 1 To Q 5 The connection point of the ring; n1 is an integer from 1 to 3; L 2A For key or C 1-10 Alkylene; R L a is selected from H, C 1-6 Alkyl and C(=O)(C 1-6 alkyl) group; R Lb and R L Each of c is independently selected from H and C 1-6 The group consisting of alkyl groups; 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 optionally substituted by 1 to 5 groups independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Substitution of the substituents of the group consisting of alkoxy groups; R 1 , R 2 and R 3 are each independently selected from the group consisting of: H and optionally 1 to 6 each independently selected from halogen, -OH and C 1-6 The substituents consisting of alkoxy groups are substituted with C 1-6 alkyl; L 1 is selected from the group consisting of: -C(=O)-, -CH2-, -CH(C 1-6 alkyl)- and -S(=O)2; Ring B is selected from the group consisting of: and Where bb represents the 1 The connection point; R 4 , R 5 , R 6 and R 7 are independently selected from the group consisting of: H, halogen and C 1-6 alkyl; L 3 For key or C 1-3 Alkylene; L 4 For key or C 1-5 Alkylene; R 8 a and R 8b are independently selected from the group consisting of: H and optionally substituted by one or more independently selected from halogen and C 3-15 The substituents of the group consisting of cycloalkyl groups are substituted with C 1-6 Alkyl; or R 8 a and R 8b Together with the carbon atoms to which they are attached, they form optionally 1 to 3 independently selected C 1-6 Alkyl substituted C 3-15 Cycloalkyl ring, wherein the C 1-6 The alkyl group is optionally substituted with 1 to 6 independently selected R f replace; R 9 is selected from the group consisting of: C(=O)OH, C(=O)(OC 1-6 alkyl), C(=O)NR 9 a 9b , (IX-1), (IX-2), (IX-3) and (IX-4): and R 9 a is H or C 1-6 alkyl; R 9b H, C 1-6 Alkyl, C(=O)(C 1-6 Alkyl), S(O) 0-2 (C 1-6 alkyl) or cyano; R 9 c. R 9d , R 9 e、R 9f and R 9 g are each independently selected from the group consisting of: H; and optionally 1 to 6 independently selected halo and C 1-6 Alkoxy substituted C 1-6 Alkyl; and C(=O)(C 1-6 alkyl); Ring C is selected from 3- to 12-membered heterocyclic groups; 3-15 Cycloalkyl; and a group consisting of 5- to 10-membered heteroaryl, each of which is optionally substituted by 1 to 3 R C a replace; Each R C a is independently selected from the group consisting of: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and NRcR d ; or R on the same or different ring atoms C a, together with the one or more ring atoms to which they are attached, form a carbocyclic ring containing 3 to 8 ring atoms; Each Rc and R d are independently selected from the group consisting of: H, C 1-6 Alkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 Cycloalkyl), C(=O)O(C 1-6 Alkyl), S(O) 1-2 (C 1-6 Alkyl) and S(O) 1-2 (C 3-6 cycloalkyl), wherein the 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 optionally substituted with 1 to 6 groups independently selected from -OH, halogen and C 1-6 Substitution of the substituents of the group consisting of alkoxy groups; R e H, C 1-6 Alkyl or C 1-6 Haloalkyl; Each R f are independently selected from the group consisting of: halogen, -OH, NR c R d , C 1-6 Alkoxy, C 1-6 The halogenated alkoxy group is optionally substituted by 1 to 4 groups independently selected from -OH, C 1-6 A 3- to 12-membered heterocyclic group substituted with a substituent selected from the group consisting of an alkyl group and a 3- to 12-membered heterocyclic group; Each R g are independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Alkoxy, NR c R d and optionally one or more independently selected from C 1-6 Alkyl and C(=O)C 1-6 A 3- to 12-membered heterocyclic group substituted with a substituent selected from the group consisting of an alkyl group; and Each R h are independently selected from the group consisting of: halogen, 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 Halogenated alkoxy.

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

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

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

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

6. A compound as claimed in any one of claims 2 to 5, wherein Q 1 For CH.

7. A compound as claimed in any one of claims 2 to 6, wherein Q 2 For CH.

8. A compound as claimed in any one of claims 2 to 7, wherein Q 5 CR QA .

9. A compound as claimed in any one of claims 2 to 7, wherein Q 5 For CH.

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