Heterocyclic GLP-1 agonists

Abstract

The present invention relates to compounds of formula (I), including pharmaceutically acceptable salts and solvates thereof. JPEG2023540558000111.jpg5168 and a pharmaceutical composition containing the same.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of International Patent Application PCT / CN2020 / 113758, filed September 7, 2020, which is incorporated herein by reference in its entirety.

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

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

[0004] Diabetes refers to a group of metabolic diseases characterized by persistent hyperglycemia. Type 2 diabetes mellitus (T2DM), the most common type, is an acquired condition that accounts for more than 90% of diabetes cases. The typical onset occurs in obese or otherwise sedentary adults and begins with insulin resistance. While lifestyle changes can be useful in managing this disorder, T2DM patients may need to take diabetes treatments, including dipeptidyl peptidase-4 inhibitors, SGLT2 inhibitors, and sulfonylureas, among others.

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

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

[0007] Thus, provided herein are compounds of formula I [ka] [During the ceremony, Ring D is C 3-15 Cycloalkyl; 3- to 12-membered heterocyclyl; 5- to 10-membered heteroaryl; and C 6-10 aryl, each of which is optionally R QA and R QB and is substituted with 1 to 6 substituents independently selected from the group consisting of: However, (aa) or (bb) (aa) Ring D has at least one R QB is replaced by; or (bb) Ring D is a 4- to 12-membered heterocyclyl or a 7- to 10-membered bicyclic heteroaryl, wherein Ring D contains an endocyclic S(O)2 group. apply, and Each R QA teeth (a) Halo; (b) cyano; (c) OH or oxo; (d) -NR a R b ; (e) -C(=O)NR c R d ; (f) optionally 1 to 6 independently selected R f C is replaced by 1-6 alkyl; (g) optionally 1 to 6 independently selected R f C is replaced by 1-6 Alkoxy; (h) optionally 1 to 6 independently selected R g 3- to 12-membered heterocyclyl substituted with; (i) optionally, 1 to 6 independently selected R g C is replaced by 6-10 aryl; (j) optionally 1 to 6 independently selected R g 5-10 membered heteroaryl substituted with; and (k) optionally 1 to 6 independently selected R g C is replaced by 3-8 cycloalkyl independently selected from the group consisting of: Each R QB teeth: -L a -S(O)2-L b -R e ; and a 4- to 12-membered heterocyclyl or a 7- to 10-membered bicyclic heteroaryl, each containing an endocyclic S(O) group, wherein the heterocyclyl or heteroaryl is optionally selected from 1 to 6 independently selected R g is replaced by independently selected from the group consisting of: L a -N(H)-, -N(R c )- and -(CR h R h ) q1 - selected from the group consisting of; L b -O-, -N(H)-, -N(Rc )- and -(CR h R h ) q2 - selected from the group consisting of; q1 and q2 are independently 0, 1, 2, 3, or 4; However, L a -(CR h R h ) q1 - and if q1 is 0, then -L b -R e is unsubstituted C 1-3 is other than alkyl; L 2 teeth [ka] is selected from the group consisting of where aa is the point of attachment to ring D; n1 is an integer from 1 to 3; L 2A is a bond or C 1-10 is alkylene; R La is H, C 1-6 Alkyl and C(=O)(C 1-6 alkyl); R Lb and R Lc Each of 1-6 independently selected from the group consisting of alkyl; Ring A is C 6-10 Aryl, C 5-10 cycloalkyl, 5- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is optionally and independently selected from halo, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 substituted with 1 to 5 substituents selected from the group consisting of alkoxy; R 1 , R 2 and R 3 are each independently H and optionally halo, —OH and C 1-6 C substituted with 1 to 6 substituents independently selected from the group consisting of alkoxy1-6 selected from the group consisting of alkyl; L 1 -C(=O)-, -CH2-, -CH(C 1-6 -S(=O)2; Ring B is [ka] is selected from the group consisting of where bb is L 1 represents the attachment point to; R 4 , R 5 , R 6 and R 7 are independently H, halo, and C 1-6 selected from the group consisting of alkyl; L 3 is a bond or C 1-3 is alkylene; L 4 is a bond or C 1-5 is alkylene; R 8a and R 8b are independently H and optionally halo and C 3-15 cycloalkyl, halo, and C 3-15 cycloalkyl; or R 8a and R 8b Each carbon atom is bonded to a C 3-15 Forms a cycloalkyl ring, which optionally includes C 1-6 substituted with 1 to 3 groups independently selected from alkyl, wherein C 1-6 alkyl optionally has 1 to 6 independently selected R f is replaced by; R 9 C(=O)OH, C(=O)(OC 1-6 alkyl), C(=O)NR 9a R 9b , (IX-1), (IX-2), (IX-3) and (IX-4): [ka] R 9a is H or C 1-6 is alkyl; R 9b is H, C 1-6 Alkyl, C(=O)(C 1-6 alkyl), S(O) 0-2 (C 1-6 alkyl) or cyano; R 9c , R 9d , R 9e , R 9f and R 9g each independently represents H; 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 a 3- to 12-membered heterocyclyl; C 3-15 cycloalkyl; and 5- to 10-membered heteroaryl, each of which optionally has 1 to 3 R Ca is replaced by; Each R Ca is halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and NR c R d independently selected from the group consisting of: or a pair of R on the same or different ring carbons Ca each together with the ring atom to which it is attached forms a carbocyclic ring containing 3 to 8 ring atoms; Each R a and R b is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 cycloalkyl) and C(=O)O(C 1-6 alkyl), wherein C 1-6 Alkyl, C 3-6Cycloalkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 cycloalkyl) and C(=O)O(C 1-6 alkyl) are each optionally —OH, halo and C 1-6 substituted with 1 to 6 substituents independently selected from the group consisting of alkoxy; Each R c and R d is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 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 3-6 Cycloalkyl, 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 —OH, halo, and C 1-6 substituted with 1 to 6 substituents independently selected from the group consisting of alkoxy; R e is H or R e is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 cycloalkyl and 3- to 8-membered heterocyclyl, each of which is optionally halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, NH2, NH(C 1-3 alkyl), N(C 1-3 Alkyl)2, C1-3 Alkoxy and C 1-3 substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy; Each R f is halo, -OH, NR c R d , C 1-6 Alkoxy, C 1-6 Haloalkoxy and optionally -OH, C 1-6 independently selected from the group consisting of 3- to 12-membered heterocyclyl substituted with 1 to 4 substituents each independently selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; Each R g is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6ア Lukoxi, C 1-6 Haloalkoxy, NR c R d , Cyano, Halo, C 3-6 Cycloalkyl and optionally C 1-6 Alkyl and C(=O)C 1-6 independently selected from the group consisting of 3- to 12-membered heterocyclyl substituted with one or more substituents each independently selected from the group consisting of alkyl; and R h In each case, H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 independently selected from the group consisting of cycloalkyl and halo; or A pair of R on the same or different carbons h together with the carbon atoms to which they are attached, 3-6 cycloalkyl or 4- to 8-membered heterocyclyl, each of which is optionally halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, C 1-3 Alkoxy and C 1-3 and substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy. or a pharmaceutically acceptable salt or solvate thereof.

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

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

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

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

[0012] In some embodiments, the method further comprises obtaining a sample from the patient. In some embodiments, the sample is a bodily 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 weighs about 22 kg / m 2 In certain embodiments, the patient has a body mass index (BMI) of about 30 kg / m or greater.2 Have a BMI of 100 or above.

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

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

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

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

[0017] In certain embodiments, the method for treating type 2 diabetes includes reducing BMI. In certain embodiments, BMI is about 25 kg / m 2 It decreases to the following:

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

[0019] In some embodiments, the method for treating type 2 diabetes further comprises administering an additional therapy or treatment to the patient. In some embodiments, the additional therapy or treatment is selected from the group consisting of an antidiabetic agent, an antiobesity agent, a GLP-1 receptor agonist, a nonalcoholic steatohepatitis (NASH) treatment, an antiemetic agent, gastric electrical stimulation, dietary monitoring, physical activity, or any combination thereof. In some embodiments, the antidiabetic agent is selected from the group consisting of a biguanide, a sulfonylurea, a glitazar, a thiazolidinedione, a dipeptidyl peptidase 4 (DPP-4) inhibitor, a meglitinide, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, a glitazone, a GRP40 agonist, a glucose-dependent insulinotropic polypeptide (GIP), insulin or an insulin analog, an alpha-glucosidase inhibitor, a sodium-glucose cotransporter 1 (SGLT1) inhibitor, or any combination thereof. In some embodiments, the biguanide is metformin. In certain embodiments, the anti-obesity agent is a neuropeptide Y receptor type 2 (NPYR2) agonist, an NPYR1 or NPYR5 antagonist, a human islet peptide precursor (HPI) inhibitor, or a steroid inhibitor. peptide) (HIP), cannabinoid receptor type 1 (CB1R) antagonists, lipase inhibitors, melanocortin receptor 4 agonists, farnesoid X receptor (FXR) agonists, phentermine, zonisamide, norepinephrine / dopamine reuptake inhibitors, GDF-15 analogs, opioid receptor antagonists, cholecystokinin agonists, serotonergic agents, methionine aminopeptidase 2 (MetAP2) inhibitors, diethylpropion, phendimetrazine, benzphetamine, fibroblast growth factor receptor (FGFR) modulators, AMP-activated protein kinase (AMPK) activators, sodium-glucose transporter 1 (SGLT-1) inhibitors, or any combination thereof.In certain embodiments, the GLP-1 receptor agonist is selected from the group consisting of liraglutide, exenatide, dulaglutide, albiglutide, taspoglutide, lixisenatide, semaglutide, or any combination thereof. In some embodiments, the NASH treatment agent is selected from the group consisting of FXR agonist, PF-05221304, synthetic fatty acid bile conjugate, anti-lysyl oxidase homolog 2 (LOXL2) monoclonal antibody, caspase inhibitor, MAPK5 inhibitor, galectin 3 inhibitor, fibroblast growth factor 21 (FGF21) agonist, niacin analog, leukotriene D4 (LTD4) receptor antagonist, acetyl-CoA carboxylase (ACC) inhibitor, ketohexokinase (KHK) inhibitor, ileal bile acid transporter (IBAT) inhibitor, apoptosis signal-regulating kinase 1 (ASK1) inhibitor, peroxisome proliferator-activated receptor (PPAR) agonist, diacylglycerol acyltransferase 2 (DGAT2) inhibitor or any combination thereof.In some embodiments, the compound of Formula I or its pharmaceutically acceptable salt or solvate or its pharmaceutical composition and additional treatment agent are administered sequentially in any order as separate preparations.

[0020] Also provided herein is a method for modulating insulin levels in a patient in need thereof, comprising administering to the patient an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In certain embodiments, the modulation results in an increase in insulin levels.

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

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

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

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

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

[0026] definition When numerical values ​​are described as ranges, such description is understood to include all possible subranges within such ranges as well as specific numerical values ​​within such ranges, whether or not a specific numerical value or specific subrange is explicitly stated.

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

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

[0029] As used herein, the term "alkylene" refers to a divalent alkyl containing the indicated number of carbon atoms. For example, "C 1-3 "Alkylene" means a divalent alkyl having 1 to 3 carbon atoms (e.g., -CH2-, -CH(CH3)-, -CH2CH2-, or -CH2CH2CH2-).

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

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

[0032] As used herein, the term "cycloalkyl" means a saturated or partially saturated cyclic hydrocarbon containing the indicated number of carbon atoms. For example, "C 3-6"Cycloalkyl" means a saturated or partially saturated cyclic hydrocarbon having 3 to 6 ring carbon atoms. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A cycloalkylcycloalkyl may contain multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyls include bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, and the like. Cycloalkyl also includes spirocycles (e.g., spirocyclic bicycles in which the two rings are joined by only one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like.

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

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

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

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

[0037] The term "alkoxy" as used herein refers to an -O-alkyl radical, where the radical is on the oxygen atom. For example, "C 1-6 "Alkoxy" is -O-(C 1-6 "Alkoxy" refers to an -O-haloalkyl radical in which the radical is on the oxygen atom. Examples of alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy. Thus, the term "haloalkoxy," as used herein, refers to an -O-haloalkyl radical in which the radical is on the oxygen atom.

[0038] Used here [ka] represents any single or double bond allowed by valence. [ka] indicates the point of attachment to the parent molecule.

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

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

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

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

[0043] As used herein, the term "GLP-1 agonist" or "GLP-1RA" refers to an agonist of the glucagon-like peptide 1 (GLP-1) receptor. GLP-1RAs enhance glucose-dependent insulin secretion; suppress inappropriately elevated glucagon levels in both fasting and postprandial states; and delay gastric emptying. Karla et al., Glucagon-like peptide-1 receptor agonists in the treatment of type 2 diabetes: Past, present, and future, Indian J Endocrinol Metab. 2016 Mar-Apr; 20(2): 254-267. GLP-1RAs have been shown to treat type 2 diabetes. Examples of GLP-1RAs include, but are not limited to, albiglutide (TANZEMM®), dulaglutide (LY2189265, TRULICITY®), efpeglenatide, exenatide (BYETTA®, BYDUREON®, exendin-4), liraglutide (VICTOZA®, NN2211), lixisenatide (LYXMMIA®), semaglutide (OZEMPIC®), tirzepatide, ZP2929, NNC0113-0987, BPI-3016, and TT401. See also, for example, US Pat. Nos. 10,370,426; 10,308,700; 10,259,823; 10,208,019; 9,920,106; 9,839,664; 8,129,343; 8,536,122; 7,919,598; 6,414,126; 6,628,343; and RE45313 for additional GLP-1 receptor agonists.

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

[0045] As used herein, the term "therapeutic compound" is intended to include, but is not limited to, any compound of Formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., any compound of Formula IA, IB, IC, and ID, or a pharmaceutically acceptable salt or solvate thereof), and any composition (e.g., pharmaceutical composition) in which a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., any compound of Formula IA, IB, IC, and ID, or a pharmaceutically acceptable salt or solvate thereof) is a component of the composition.

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

[0047] As used herein, the terms "effective amount," "effective dose," "pharmaceutically effective amount," or "therapeutically effective amount" refer to a sufficient quantity of an administered chemical entity (e.g., a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., any of Formulas IA, IB, IC, and ID, or a pharmaceutically acceptable salt or solvate thereof)) to relieve to some extent one or more of the symptoms of the disease or condition being treated, and may include curing the disease. "Cure" refers to the elimination of active disease symptoms. Such results include the reduction and / or alleviation of the signs, symptoms, or pathogenesis of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant reduction in disease symptoms. The appropriate "effective" amount in any individual case may be determined using any suitable technique, such as a dose escalation study. In certain embodiments, a "therapeutically effective amount" of a compound provided herein refers to an amount of the compound that is effective as a monotherapy or combination therapy.

[0048] The term "excipient" or "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In certain embodiments, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and suitable for use in contact with the tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. For example, Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical See Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

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

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

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

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

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

[0054] As used herein, the term "pharmaceutical combination" means a pharmaceutical treatment that involves mixing or combining more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients.

[0055] As used herein, the term "combination therapy" refers to a dosing regimen of two different therapeutically active agents (i.e., components of a combination or combination partners), which therapeutically active agents, as defined herein, are administered together or separately in a manner desired by a healthcare professional or in accordance with regulatory authorities.

[0056] As used herein, the term "modulation" means regulation or modulation (e.g., increase or decrease) and can include, for example, agonism, partial agonism, or antagonism.

[0057] compound In some embodiments, provided herein is a compound of formula (I): [ka] [During the ceremony, Ring D is C 3-15 Cycloalkyl; 3- to 12-membered heterocyclyl; 5- to 10-membered heteroaryl; and C 6-10 aryl, each of which is optionally R QA and R QB and is substituted with 1 to 6 substituents independently selected from the group consisting of: However, (aa) or (bb) (aa) Ring D has at least one R QB is replaced by; or (bb) Ring D is a 4- to 12-membered heterocyclyl or a 7- to 10-membered bicyclic heteroaryl, wherein Ring D contains an endocyclic S(O)2 group. apply, and Each R QA teeth (a) Halo; (b) cyano; (c) OH or oxo; (d) -NR a R b ; (e) -C(=O)NR c R d ; (f) optionally 1 to 6 independently selected Rf C is replaced by 1-6 alkyl; (g) optionally 1 to 6 independently selected R f C is replaced by 1-6 Alkoxy; (h) optionally 1 to 6 independently selected R g 3- to 12-membered heterocyclyl substituted with; (i) optionally, 1 to 6 independently selected R g C is replaced by 6-10 aryl; (j) optionally 1 to 6 independently selected R g 5-10 membered heteroaryl substituted with; and (k) optionally 1 to 6 independently selected R g C is replaced by 3-8 cycloalkyl independently selected from the group consisting of: Each R QB teeth -L a -S(O)2-L b -R e ; and a 4- to 12-membered heterocyclyl or a 7- to 10-membered bicyclic heteroaryl, each containing an endocyclic S(O) group, wherein the heterocyclyl or heteroaryl is optionally selected from 1 to 6 independently selected R g is replaced by independently selected from the group consisting of: L a -N(H)-, -N(R c )- and -(CR h R h ) q1 - selected from the group consisting of; L b -O-, -N(H)-, -N(R c )- and -(CR h R h ) q2 - selected from the group consisting of; q1 and q2 are independently 0, 1, 2, 3, or 4; However, L a-(CR h R h ) q1 - and if q1 is 0, then -L b -R e is unsubstituted C 1-3 is other than alkyl; L 2 teeth [ka] is selected from the group consisting of where aa is the point of attachment to ring D; n1 is an integer from 1 to 3; L 2A is a bond or C 1-10 is alkylene; R La is H, C 1-6 Alkyl and C(=O)(C 1-6 alkyl); R Lb and R Lc Each of 1-6 independently selected from the group consisting of alkyl; Ring A is C 6-10 Aryl, C 5-10 cycloalkyl, 5- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is optionally and independently selected from halo, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 substituted with 1 to 5 substituents selected from the group consisting of alkoxy; R 1 , R 2 and R 3 are each independently H and optionally halo, —OH and C 1-6 C substituted with 1 to 6 substituents independently selected from the group consisting of alkoxy 1-6 selected from the group consisting of alkyl; L 1 -C(=O)-, -CH2-, -CH(C 1-6 -S(=O)2; Ring B is [ka] is selected from the group consisting of where bb is L 1 represents the attachment point to; R 4 , R 5 , R 6 and R 7 are independently H, halo, and C 1-6 selected from the group consisting of alkyl; L 3 is a bond or C 1-3 is alkylene; L 4 is a bond or C 1-5 is alkylene; R 8a and R 8b are independently H and optionally halo and C 3-15 cycloalkyl, halo, and C 3-15 cycloalkyl; or R 8a and R 8b Each carbon atom is bonded to a C 3-15 Forms a cycloalkyl ring, which optionally includes C 1-6 substituted with 1 to 3 groups independently selected from alkyl, wherein C 1-6 alkyl optionally has 1 to 6 independently selected R f is replaced by; R 9 C(=O)OH, C(=O)(OC 1-6 alkyl), C(=O)NR 9a R 9b , (IX-1), (IX-2), (IX-3) and (IX-4): [ka] R 9a is H or C 1-6 is alkyl; R 9b is H, C1-6 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 each independently represents H; 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 a 3- to 12-membered heterocyclyl; C 3-15 cycloalkyl; and 5- to 10-membered heteroaryl, each of which optionally has 1 to 3 R Ca is replaced by; Each R Ca is halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and NR c R d independently selected from the group consisting of: or a pair of R on the same or different ring carbons Ca each together with the ring atom to which it is attached forms a carbocyclic ring containing 3 to 8 ring atoms; Each R a and R b is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 cycloalkyl) and C(=O)O(C 1-6 alkyl), wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 cycloalkyl) and C(=O)O(C 1-6 alkyl) are each optionally —OH, halo and C 1-6substituted with 1 to 6 substituents independently selected from the group consisting of alkoxy; Each R c and R d is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 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 3-6 Cycloalkyl, 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 —OH, halo, and C 1-6 substituted with 1 to 6 substituents independently selected from the group consisting of alkoxy; R e is H or R e is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 cycloalkyl and 3- to 8-membered heterocyclyl, each of which is optionally halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, NH2, NH(C 1-3 alkyl), N(C 1-3 Alkyl)2, C 1-3 Alkoxy and C 1-3 substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy; Each R f is halo, -OH, NR cR d , C 1-6 Alkoxy, C 1-6 Haloalkoxy and optionally -OH, C 1-6 independently selected from the group consisting of 3- to 12-membered heterocyclyl substituted with 1 to 4 substituents each independently selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; Each R g is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6ア Lukoxi, C 1-6 Haloalkoxy, NR c R d , Cyano, Halo, C 3-6 Cycloalkyl and optionally C 1-6 Alkyl and C(=O)C 1-6 independently selected from the group consisting of 3- to 12-membered heterocyclyl substituted with one or more substituents each independently selected from the group consisting of alkyl; and R h In each case, H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 independently selected from the group consisting of cycloalkyl and halo; or A pair of R on the same or different carbons h together with the carbon atoms to which they are attached, 3-6 cycloalkyl or 4- to 8-membered heterocyclyl, each of which is optionally halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, C 1-3 Alkoxy and C 1-3 and substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy. or a pharmaceutically acceptable salt or solvate thereof.

[0058] Embodiments may include any one or more of the features set forth below and / or in the claims.

[0059] In certain embodiments of formula (I), (aa) applies.

[0060] In certain embodiments of Formula (I), ring D is C 3-15 Cycloalkyl; 3- to 12-membered heterocyclyl; 5- to 10-membered heteroaryl; and C 6-10 aryl, each of which is selected from the group consisting of one R QB and optionally 1 to 5 independently selected R QA is replaced by .

[0061] In certain embodiments of Formula (I), Ring D is a 5- to 10-membered heteroaryl; and C6- 10 aryl, each of which is selected from the group consisting of one R QB and optionally 1 to 5 independently selected R QA In some embodiments, Ring D is a 5-6 membered heteroaryl or phenyl, each of which is substituted with one R QB and optionally 1 to 5 independently selected R QA is replaced by .

[0062] In certain embodiments of Formula (I), ring D is [ka] where Q 1 , Q 2 , Q 4 and Q 5 are each independently N, CH, or CR QA In one embodiment, Q 1 , Q 2 , Q 4 and Q 5 are independently CH or CR QA For example, Q 1 , Q 2 , Q 4 and Q 5 Each of Q can be CH. Other non-limiting examples include 1 , Q 2 , Q 4 and Q5 1-2 (for example, 1) of QA and Q 1 , Q 2 , Q 4 and Q 5 Each of the remaining Q's can be CH. 1 , Q 2 , Q 4 and Q 5 One of the is N; and Q 1 , Q 2 , Q 4 and Q 5 each of the remainder is independently CH or CR QA For example, Q 1 , Q 2 , Q 4 and Q 5 Each of the remainder may be CH.

[0063] In certain embodiments of Formula (I), ring D is [ka] where m1 is 0, 1, or 2. For example, m1 can be 0. As another non-limiting example, m1 can be 1; and optionally R QA is R QB It is meta to that.

[0064] In certain embodiments of Formula (I), ring D is [ka] where Q 1 , Q 2 , Q 3 and Q 5 are each independently N, CH, or CR QA In one embodiment, Q 1 , Q 2 , Q 3 and Q 5 are independently CH or CR QA For example, Q 1 , Q 2 , Q 3 and Q5 Each of Q can be CH. Other non-limiting examples include 1 , Q 2 , Q 3 and Q 5 1-2 (for example, 1) of QA and Q 1 , Q 2 , Q 3 and Q 5 Each of the remainder may be CH.

[0065] In certain embodiments of Formula (I), ring D is [ka] where m1 is 0, 1, or 2. For example, m1 can be 0. As another non-limiting example, m1 can be 1.

[0066] In certain embodiments of Formula (I), R QB Ha-L a -S(O)2-L b -R e In one embodiment, L a Ha-(CR h R h ) q1 -; and q1 is 1, 2, 3, or 4. For example, q1 can be 1. As another non-limiting example, q1 can be 2. In certain embodiments, R h is H in each occurrence. In some embodiments, R h One of them is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl or halo; and each remaining R h is H. In some embodiments, R h One of them is C 1-3 alkyl (e.g., methyl); and each remaining R h is H. In some embodiments, L b Ha-(CR h R h ) q2 In some embodiments, q2 is 0. In some embodiments, Re is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 cycloalkyl, each of which is optionally halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, NH2, NH(C 1-3 alkyl), N(C 1-3 Alkyl)2, C 1-3 Alkoxy and C 1-3 In one embodiment, R is substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy. e is C 1-6 Alkyl or C 1-6 haloalkyl, each of which is optionally halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, NH2, NH(C 1-3 alkyl), N(C 1-3 Alkyl)2, C 1-3 Alkoxy and C 1-3 In one embodiment, R is substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy. e is C 1-6 alkyl. For example, R e is C such as methyl or ethyl 1-3 It can be alkyl.

[0067] In certain embodiments of Formula (I), R QB Ha-L a -S(O)2-L b -R e and;L a Ha-(CR h R h ) q1 -; q1 is 1, 2, 3 or 4; and R h is H in each occurrence. In some embodiments, q1 is 1. In some embodiments, q1 is 2. In some embodiments, L b Ha-(CR h R h ) q2In some embodiments, q2 is 0. In some embodiments, R e is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 cycloalkyl, each of which is optionally halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, NH2, NH(C 1-3 alkyl), N(C 1-3 Alkyl)2, C 1-3 Alkoxy and C 1-3 In one embodiment, R is substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy. e is C 1-6 Alkyl or C 1-6 haloalkyl, each of which is optionally halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, NH2, NH(C 1-3 alkyl), N(C 1-3 Alkyl)2, C 1-3 Alkoxy and C 1-3 In one embodiment, R is substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy. e is C 1-6 alkyl. For example, R e is C such as methyl or ethyl 1-3 It can be alkyl.

[0068] In certain embodiments of Formula (I), R QB Ha-L a -S(O)2-L b -R e and;L a Ha-(CR h R h ) q1 -; q1 is 1, 2, 3 or 4; R h One of them is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl or halo; and each remaining R his H. In some embodiments, R h One of them is C 1-3 alkyl (e.g., methyl); and each remaining R h is H. In some embodiments, q1 is 1. For example, R QB teeth [ka] In some embodiments, q1 is 2. In some embodiments, L b Ha-(CR h R h ) q2 In some embodiments, q2 is 0. In some embodiments, R e is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 cycloalkyl, each of which is optionally halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, NH2, NH(C 1-3 alkyl), N(C 1-3 Alkyl)2, C 1-3 Alkoxy and C 1-3 In one embodiment, R is substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy. e is C 1-6 Alkyl or C 1-6 haloalkyl, each of which is optionally halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, NH2, NH(C 1-3 alkyl), N(C 1-3 Alkyl)2, C 1-3 Alkoxy and C 1-3 In one embodiment, R is substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy. e is C 1-6 alkyl. For example, R e is C such as methyl or ethyl 1-3 It can be alkyl.

[0069] In certain embodiments of Formula (I), R QB Ha-(CR h R h ) q1 -S(O)2-(CR h R h ) q2 -R e q1 is 1 or 2; and R e is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 cycloalkyl, each of which is optionally halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, NH2, NH(C 1-3 alkyl), N(C 1-3 Alkyl)2, C 1-3 Alkoxy and C 1-3 In certain embodiments, q2 is 0. In certain embodiments, q1 is 1. In certain embodiments, q1 is 2. In certain embodiments, R h In each case, H or C 1-3 In some embodiments, R e is C 1-6 Alkyl or C 1-6 haloalkyl, each of which is optionally halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, NH2, NH(C 1-3 alkyl), N(C 1-3 Alkyl)2, C 1-3 Alkoxy and C 1-3 substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy. For example, R e is C 1-3 C such as alkyl (e.g., methyl or ethyl) 1-6 It can be alkyl.

[0070] In certain embodiments of Formula (I), R QB is -CH2-S(O)2(C 1-6 alkyl). For example, RQB can be —CH—S(O)Me or —CH—S(O)Et.

[0071] In certain embodiments of Formula (I), R QB -CH(C 1-6 alkyl)-S(O)2(C 1-6 alkyl). For example, R QB is -CH(Me)S(O)2Me, etc. 1-3 alkyl).

[0072] In certain embodiments of Formula (I), R QB is -CH2CH2-S(O)2(C 1-6 alkyl). For example, R QB can be —CH2CH2S(O)2Me.

[0073] In certain embodiments of Formula (I), R QB Ha-L a -S(O)2-L b -R e where L a Ha-(CR h R h ) q1 and q1 is 0. In some embodiments, L b is -NH- or -N(R c In one embodiment, L b is -NH- or -N(C 1-3 alkyl)-. For example, L b can be -NH-. In some embodiments, q2 is 0. In some embodiments, R e is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 cycloalkyl, each of which is optionally halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, NH2, NH(C 1-3 alkyl), N(C 1-3 Alkyl)2, C 1-3 Alkoxy and C 1-3In one embodiment, R is substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy. e is C 1-6 alkyl. For example, R e is C such as methyl or ethyl 1-3 In some embodiments, R e is C 3-6 Cycloalkyl. For example, R e can be cyclopropyl.

[0074] In certain embodiments of Formula (I), R QB Ha-L a -S(O)2-L b -R e where L a Ha-(CR h R h ) q1 - and ; q1 is 0; and L b Ha-(CR h R h ) q2 In some embodiments, q2 is 0. In some embodiments, R e is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 cycloalkyl, each of which is optionally halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, NH2, NH(C 1-3 alkyl), N(C 1-3 Alkyl)2, C 1-3 Alkoxy and C 1-3 substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy, with the proviso that R e is unsubstituted C 1-3 In some embodiments, R e is C 3-6 Cycloalkyl. For example, R e can be cyclopropyl.

[0075] In certain embodiments of Formula (I), R QB-S(O)2NH-R e and R e is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 cycloalkyl, each of which is optionally halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, NH2, NH(C 1-3 alkyl), N(C 1-3 Alkyl)2, C 1-3 Alkoxy and C 1-3 In one embodiment, R is substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy. e is C 1-6 alkyl. For example, R e may be methyl or ethyl, such as methyl.

[0076] In certain embodiments of Formula (I), R QB -S(O)2-R e and R e is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 cycloalkyl, each of which is optionally halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, NH2, NH(C 1-3 alkyl), N(C 1-3 Alkyl)2, C 1-3 Alkoxy and C 1-3 substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy, with the proviso that R e is unsubstituted C 1-3 In some embodiments, R e is C 3-6 Cycloalkyl. For example, R e can be cyclopropyl.

[0077] In certain embodiments of Formula (I), R QB Ha-L a -S(O)2-L b -Re where L a is -NH- or -N(R c In one embodiment, L a is -NH- or -N(C 1-3 alkyl)-. For example, L a is -NH-. In some embodiments, L b Ha-(CR h R h ) q2 In some embodiments, q2 is 0. In some embodiments, R e is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 cycloalkyl, each of which is optionally halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, NH2, NH(C 1-3 alkyl), N(C 1-3 Alkyl)2, C 1-3 Alkoxy and C 1-3 In one embodiment, R is substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy. e is C 1-6 Alkyl or C 1-6 haloalkyl, each of which is optionally halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, NH2, NH(C 1-3 alkyl), N(C 1-3 Alkyl)2, C 1-3 Alkoxy and C 1-3 substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy. For example, R e is C 1-3 C such as alkyl (e.g., methyl or ethyl) 1-6 It can be alkyl.

[0078] In certain embodiments of Formula (I), R QB Ha-L a -S(O)2-L b -R e where La is -NH- or -N(R c )- and L b Ha-(CR h R h ) q2 In one embodiment, L a is -NH- or -N(C 1-3 In some embodiments, q2 is 0. In some embodiments, R e is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 cycloalkyl, each of which is optionally halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, NH2, NH(C 1-3 alkyl), N(C 1-3 Alkyl)2, C 1-3 Alkoxy and C 1-3 In one embodiment, R is substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy. e is C 1-6 Alkyl or C 1-6 haloalkyl, each of which is optionally halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, NH2, NH(C 1-3 alkyl), N(C 1-3 Alkyl)2, C 1-3 Alkoxy and C 1-3 substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy. For example, R e is C 1-3 C such as alkyl (e.g., methyl or ethyl) 1-6 It can be alkyl.

[0079] In certain embodiments of Formula (I), R QB -NHS(O)2-(CR h R h ) q2 -R e and R e is C 1-6 Alkyl, C 1-6Haloalkyl or C 3-6 cycloalkyl, each of which is optionally halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, NH2, NH(C 1-3 alkyl), N(C 1-3 Alkyl)2, C 1-3 Alkoxy and C 1-3 In certain embodiments, q2 is 0. In certain embodiments, R e is C 1-6 alkyl. For example, R e is C such as methyl or ethyl 1-3 It can be alkyl.

[0080] In certain embodiments of Formula (I), R QB Ha-L a -S(O)2-L b -R e where L b is -NH- or -N(R c )-. For example, L b is -NH- or -N(C 1-3 For example, L b can be -NH-. In some embodiments, L a Ha-(CR h R h ) q1 In some of these embodiments, q1 is 0. In certain embodiments, R e is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 cycloalkyl, each of which is optionally halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, NH2, NH(C 1-3 alkyl), N(C 1-3 Alkyl)2, C 1-3 Alkoxy and C 1-3 In one embodiment, R is substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy.e is C 1-6 alkyl. For example, R e is C such as methyl or ethyl 1-3 In some embodiments, R e is C 3-6 Cycloalkyl. For example, R e can be cyclopropyl.

[0081] In certain embodiments of Formula (I), R QB Ha-L a -S(O)2-L b -R e where L b Ha-(CR h R h ) q2 In some embodiments, q2 is 0. In some embodiments, R e is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 cycloalkyl, each of which is optionally halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, NH2, NH(C 1-3 alkyl), N(C 1-3 Alkyl)2, C 1-3 Alkoxy and C 1-3 In one embodiment, R is substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy. e is C 1-6 In some embodiments, R e C such as -NH- 3-6 In certain embodiments, L is cycloalkyl. a is -NH- or N(C 1-3 In one embodiment, L a Ha-(CR h R h ) q1 In some embodiments, q1 is 1 or 2. In some embodiments, q1 is 0.

[0082] In certain embodiments of Formula (I), R QB Ha-L a -S(O)2-L b -R e where R e is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 cycloalkyl, each of which is optionally halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, NH2, NH(C 1-3 alkyl), N(C 1-3 Alkyl)2, C 1-3 Alkoxy and C 1-3 In one embodiment, R is substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy. e is C 1-6 Alkyl or C 1-6 haloalkyl, each of which is optionally halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, NH2, NH(C 1-3 alkyl), N(C 1-3 Alkyl)2, C 1-3 Alkoxy and C 1-3 In one embodiment, R is substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy. e is C 1-6 alkyl. For example, R e is C such as methyl or ethyl 1-3 It can be alkyl.

[0083] In certain embodiments of Formula (I), R QB is a 4- to 12-membered heterocyclyl or a 7- to 10-membered bicyclic heteroaryl, each containing an endocyclic S(O) group, where the heterocyclyl or heteroaryl is optionally joined to 1 to 6 independently selected R g is replaced by .

[0084] In certain embodiments of Formula (I), R QB is within the ring [ka] a 4- to 10-membered heterocyclyl containing a group, where ** represents the point of attachment to ring D, and the heterocyclyl optionally contains 1 to 6 independently selected R g is replaced by .

[0085] In certain embodiments of Formula (I), R QB teeth [ka] where the ring Q 2 are N, O and S(O) respectively 0-2 and wherein ring Q is a 4-8 membered heterocyclyl containing 0-2 additional ring heteroatoms (in addition to the endocyclic NS(O)2 group) independently selected from the group consisting of: 2 optionally 1 to 4 independently selected R g In one embodiment, R QB teeth [ka] m2 is 0, 1, 2 or 3; and R QB optionally 1 to 4 independently selected R g For example, R QB teeth [ka] As a further non-limiting example, R QB teeth [ka] may be selected from the group consisting of:

[0086] In certain embodiments of Formula (I), R QA One of the is -halo. For example, R QA One of the groups can be -F.

[0087] In certain embodiments of formula (I), (bb) applies.

[0088] In certain embodiments of Formula (I), Ring D is a 4-12 membered heterocyclyl or a 7-10 membered bicyclic heteroaryl, wherein Ring D contains an endocyclic S(O) group; and wherein Ring D optionally contains 1-4 R QA is replaced by .

[0089] In certain embodiments of Formula (I), Ring D is a 4-12 membered heterocyclyl or a 7-10 membered bicyclic heteroaryl, wherein Ring D does not contain an endocyclic —N(H)S(O)— group or an —N(C 1-3 alkyl)S(O)2- group; wherein ring D optionally further comprises 1 to 3 R QA is replaced by .

[0090] In certain embodiments of Formula (I), Ring D is a 7-10 membered bicyclic heteroaryl, wherein Ring D does not contain an endocyclic —N(H)S(O)— group or an —N(C 1-3 alkyl)S(O)2- group; and ring D optionally further contains 1 to 3 R QA For example, ring D is [ka] where R N1 is H or C 1-3 It is alkyl.

[0091] In certain embodiments of Formula (I), R 1 is H. In certain embodiments of Formula (I), R 2 is H. In certain embodiments of Formula (I), R 3 is C 1-6 alkyl. For example, R 3 is C such as methyl 1-3 In some embodiments, R 3 is C 1-6 alkyl, and R 3 The carbon atom to which is attached has the (S)-configuration.

[0092] In certain embodiments of Formula (I), R 1 , R 2 and R 3 is H.

[0093] In certain embodiments of Formula (I), R 1 and R 2 is H; and R 3 is C 1-6 In some embodiments, R 1 and R 2 is H; and R 3 is methyl. In some embodiments, R 3 The carbon atom to which is attached has the (S)-configuration.

[0094] In certain embodiments of Formula (I), L 2 teeth [ka] is.

[0095] In certain embodiments of Formula (I), ring A is C 6-10 aryl or 5-10 membered heteroaryl, each of which is optionally halo, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 and substituted with 1 to 4 substituents independently selected from the group consisting of alkoxy.

[0096] In certain embodiments of Formula (I), ring A is phenyl or pyridyl, each of which is optionally each halo, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 It is substituted with 2 to 4 substituents independently selected from the group consisting of alkoxy.

[0097] In certain embodiments of Formula (I), ring A is phenyl, which is optionally each selected from halo and C 1-6 and substituted with 2 to 4 substituents independently selected from the group consisting of alkyl.

[0098] In certain embodiments of Formula (I), ring A is [ka] where R AA , R AB and R AC are independently halo or C 1-6 In some embodiments, R AA and R AC is independently C 1-6 Alkyl (e.g., C such as methyl) 1-3 In some embodiments, R AB is halo (e.g., -F).

[0099] In certain embodiments of Formula (I), ring A is pyridyl, which is optionally each selected from halo and C 1-6 and substituted with 2 to 4 substituents independently selected from the group consisting of alkyl.

[0100] In certain embodiments of Formula (I), L 1 is C(=O).

[0101] In certain embodiments of Formula (I), ring B is [ka] is.

[0102] In certain embodiments of Formula (I), R 4 , R 5 and R 6 are each H or halo. In some embodiments, R 4 , R 5 and R 6 are each H or -F. For example, R 4 , R 5 and R 6 can each be H. Other non-limiting examples include R 4 and R 5 can be H; and R 6 can be -F.

[0103] In certain embodiments of Formula (I), R 7 is H. In certain embodiments of Formula (I), R 7 is -F.

[0104] In certain embodiments of Formula (I), ring B is [ka] In some embodiments, R 4 , R 5 and R 6 are each H or halo. In some embodiments, R 4 , R 5 and R 6 are each H or -F. For example, R 4 , R 5 and R 6 can each be H. Other non-limiting examples include R 4 and R 5 can be H; and R 6 can be -F. In some embodiments, R 7 is H. In certain embodiments of Formula (I), R 7 is -F.

[0105] In certain embodiments of Formula (I), ring B is [ka] and R 4 , R 5 , R 6 and R 7 are each H.

[0106] In certain embodiments of Formula (I), L 3 and L 4 In some embodiments, at least one of L 3 and L 4 In some embodiments, both of L 3 is a bond; and L 4 is C 1-2In some embodiments, L is alkylene. 4 is a bond; and L 3 is C 1-2 It is alkylene.

[0107] In certain embodiments of Formula (I), L 3 and L 4 are each independently C 1-2 It is alkylene.

[0108] In certain embodiments of Formula (I), R 8a and R 8b each, together with the carbon atom to which it is attached, optionally represents 1 to 2 (e.g., 1) independently selected C 1-6 Alkyl-substituted C 3-8 Forms a cycloalkyl ring, where C 1-6 Alkyl is optionally R f In one embodiment, L is substituted with 1 to 3 groups independently selected from 3 is a bond; and L 4 is a bond.

[0109] In certain embodiments of Formula (I), R 8a and R 8b each, together with the carbon atom to which it is attached, optionally represents 1 to 2 (e.g., 1) independently selected C 1-6 Alkyl-substituted C 3-5 (e.g., C3 or C4) cycloalkyl ring, where C 1-6 Alkyl is optionally R f In one embodiment, L is substituted with 1 to 3 groups independently selected from 3 is a bond; and L 4 is a bond.

[0110] In certain embodiments of Formula (I), R 8a and R 8b each, together with the carbon atom to which it is attached, optionally represents 1 to 2 (e.g., 1) independently selected C 1-6Alkyl is substituted with C 3-4 Forms a cycloalkyl ring.

[0111] In certain embodiments of Formula (I), R 8a and R 8b are each bonded to a carbon atom. [ka] Form.

[0112] In certain embodiments of Formula (I), R 8a and R 8b are each bonded to a carbon atom. [ka] Form.

[0113] In certain embodiments of Formula (I), R 9 teeth [ka] In some embodiments, R 9d is H or C 1-6 alkyl. For example, R 9d can be H.

[0114] In certain embodiments of Formula (I), L 3 -C(R 8a R 8b )-L 4 -R 9 Part [ka] is.

[0115] In certain embodiments of Formula (I), L 3 -C(R 8a R 8b )-L 4 -R 9 Part [ka] where each stereocenter has the (S)-configuration.

[0116] In certain embodiments of Formula (I), R 9 is (IX-2), where L 3 -C(R 8a R 8b )-L 4 -R 9 Part [ka] where R 9d is H or C 1-6 alkyl. For example, R 9d is H. In one embodiment, [ka] Each stereocenter in has the (S)-configuration.

[0117] In certain embodiments of Formula (I), ring C optionally contains 1 to 3 independently selected R Ca In some embodiments, ring C is optionally substituted with 1 to 3 independently selected R Ca In some embodiments, ring C is optionally substituted with 1 to 3 independently selected R Ca For example, ring C is optionally substituted with 1 to 3 independently selected R Ca It may be tetrahydropyranyl substituted with

[0118] In certain embodiments of Formula (I), ring C is [ka] In some embodiments, ring C is selected from the group consisting of: [ka] In some embodiments, ring C is is.

[0119] In certain embodiments of Formula (I), R Ca is independently C 1-6 It is alkyl.

[0120] In certain embodiments of Formula (I), pairs of R Ca are taken together with the ring atoms to which they are each attached to form a carbocyclic ring containing 3 to 6 ring atoms.

[0121] In certain embodiments of Formula (I), a pair of R Ca are taken together with the ring atoms to which they are each attached to form a carbocyclic ring containing 3 to 6 ring atoms.

[0122] In certain embodiments, the compound of Formula (I) has the formula (IA) [ka] [During the ceremony, m1 is 0, 1 or 2; R QB Ha-(CR h R h ) q1 - and S(O)2-(CR h R h ) q2 -R e where R QB is L 2 is meta or para to; q1 is 1 or 2; Ring E is C 3-6 is cycloalkyl; and R 8c is H and optionally 1 to 3 independently selected R f C selected from the group consisting of 1-6 alkyl. or a pharmaceutically acceptable salt or solvate thereof.

[0123] In certain embodiments of Formula (IA), q2 is 0.

[0124] In some embodiments of Formula (IA), q1 is 1.

[0125] In some embodiments of Formula (IA), q1 is 2.

[0126] In certain embodiments of Formula (IA), R h In each case, H or C 1-3 For example, each R h can be H. Other non-limiting examples include R h One of them is C 1-3 C substituted with alkyl (e.g., methyl) 1-6 alkyl; and each remaining R h can be H.

[0127] In certain embodiments of Formula (IA), R e is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 cycloalkyl, each of which is optionally halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, NH2, NH(C 1-3 alkyl), N(C 1-3 Alkyl)2, C 1-3 Alkoxy and C 1-3 In one embodiment, R is substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy. e is C 1-6 alkyl. For example, R e is C such as methyl or ethyl 1-3 It can be alkyl.

[0128] In certain embodiments of Formula (IA), R QB is -CH2-S(O)2(C 1-6 alkyl). For example, R QB-CH2-S(O)2Me or -CH2-S(O)2Et, etc. 1-3 alkyl).

[0129] In certain embodiments of Formula (IA), R QB -CH(C 1-6 alkyl)-S(O)2(C 1-6 alkyl). For example, R QB -CH(Me)S(O)Me etc. 1-3 alkyl)S(O)2(C 1-3 alkyl).

[0130] In certain embodiments of Formula (IA), R QB is -CH2CH2-S(O)2(C 1-6 alkyl). For example, R QB -CH2CH2-S(O)2Me, etc. 1-3 alkyl).

[0131] In certain embodiments, the compound of Formula (I) has the formula (IB): [ka] [During the ceremony, m1 is 0, 1 or 2; R QB is -S(O)2N(R N2 )-R e where R QB is L 2 is meta or para to; R N2 is H or C 1-3 is alkyl; Ring E is C 3-6 is cycloalkyl; and R 8c is H and optionally 1 to 3 independently selected R f C selected from the group consisting of 1-6 alkyl. or a pharmaceutically acceptable salt or solvate thereof.

[0132] In certain embodiments of Formula (IB), R QB -S(O)2N(H)-R e is.

[0133] In certain embodiments of Formula (IB), R e is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 cycloalkyl, each of which is optionally halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, NH2, NH(C 1-3 alkyl), N(C 1-3 Alkyl)2, C 1-3 Alkoxy and C 1-3 and substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy.

[0134] In certain embodiments of Formula (IB), R e is C 1-6 alkyl. For example, R e is C such as methyl 1-3 It can be alkyl.

[0135] In certain embodiments, the compound of Formula (I) has the formula (IC) [ka] [During the ceremony, m1 is C substituted with 0, 1 or 2 1-6 is alkyl; R QB -N(R N2 )S(O)2-(CR h R h ) q2 -R e where R QB is L 2 is meta or para to; R N2 is H or C 1-3 is alkyl; Ring E is C3-6 is cycloalkyl; and R 8c is H and optionally 1 to 3 independently selected R f C selected from the group consisting of 1-6 alkyl. or a pharmaceutically acceptable salt or solvate thereof.

[0136] In certain embodiments of Formula (IC), R N2 is H.

[0137] In certain embodiments of Formula (IC), q2 is 0.

[0138] In certain embodiments of Formula (IC), R e is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 cycloalkyl, each of which is optionally halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, NH2, NH(C 1-3 alkyl), N(C 1-3 Alkyl)2, C 1-3 Alkoxy and C 1-3 and substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy.

[0139] In certain embodiments of Formula (IC), R e is C 1-6 alkyl. For example, R e is C such as methyl or ethyl 1-3 It can be alkyl.

[0140] In certain embodiments of Formula (IC), R QB is -N(H)S(O)2(C 1-6 alkyl). For example, R QB -N(H)S(O)2Me, etc. -N(H)S(O)2(C 1-3 alkyl).

[0141] In certain embodiments, the compound of Formula (I) has the formula (ID): [ka] [During the ceremony, m1 is C substituted with 0, 1 or 2 1-6 is alkyl; R QB teeth [ka] where the ring Q 2 are N, O and S(O) respectively 0-2 and wherein ring Q is a 4-8 membered heterocyclyl containing 0-2 additional ring heteroatoms (in addition to the endocyclic NS(O)2 group) independently selected from the group consisting of: 2 optionally 1 to 4 independently selected R g is replaced by; Ring E is C 3-6 is cycloalkyl; and R 8c is H and optionally 1 to 3 independently selected R f C selected from the group consisting of 1-6 alkyl. or a pharmaceutically acceptable salt or solvate thereof.

[0142] In certain embodiments of Formula (ID), R QB teeth [ka] C is replaced by 1-6 m2 is 0, 1, 2, or 3; and R QB optionally 1 to 4 independently selected R g is replaced by .

[0143] In certain embodiments of Formula (ID), R QB teeth [ka] is.

[0144] In certain embodiments of formula (IA), (IB), (IC) or (ID), R QB is L 2 It is meta to that.

[0145] In certain embodiments of formula (IA), (IB), (IC) or (ID), R QB is L 2 It is para.

[0146] In some embodiments of formula (IA), (IB), (IC) or (ID), m1 is 0.

[0147] In some embodiments of formula (IA), (IB), (IC) or (ID), m1 is 1 or 2.

[0148] In certain embodiments of formula (IA), (IB), (IC) or (ID), R QA One of the atoms is a halo. For example, R QA One of the groups can be -F.

[0149] In some embodiments of formula (IA), (IB), (IC) or (ID), ring E is cyclopropyl.

[0150] In some embodiments of formula (IA), (IB), (IC) or (ID), ring E is cyclobutyl.

[0151] In certain embodiments of formula (IA), (IB), (IC) or (ID), R 8c is H.

[0152] In certain embodiments of formula (IA), (IB), (IC) or (ID), R 8c is C 1-3 alkyl. For example, R 8c can be methyl.

[0153] In certain embodiments of formula (IA), (IB), (IC) or (ID), R9 teeth: [ka] In some embodiments, R 9d It's H.

[0154] In certain embodiments of formula (IA), (IB), (IC) or (ID), [ka] The parts are: [ka] is.

[0155] In certain embodiments of formula (IA), (IB), (IC) or (ID), [ka] The parts are: [ka] where each stereocenter has the (S)-configuration.

[0156] In some embodiments of formula (IA), (IB), (IC) or (ID), ring C optionally contains 1 to 3 independently selected R Ca is a 3- to 12-membered heterocyclyl substituted with

[0157] In some embodiments of formula (IA), (IB), (IC) or (ID), ring C optionally contains 1 to 3 independently selected R Ca is a 5- to 6-membered heterocyclyl substituted with

[0158] In some embodiments of formula (IA), (IB), (IC) or (ID), ring C optionally contains 1 to 3 independently selected R Ca and tetrahydropyranyl substituted with

[0159] In certain embodiments of formula (IA), (IB), (IC) and (ID), ring C is [ka] is selected from the group consisting of:

[0160] In certain embodiments of formula (IA), (IB), (IC) or (ID), each R Ca is independently C 1-6 It is alkyl.

[0161] In certain embodiments of formula (IA), (IB), (IC) or (ID), pairs of R Ca are taken together with the ring atoms to which they are each attached to form a carbocyclic ring containing 3 to 6 ring atoms.

[0162] In certain embodiments of formula (IA), (IB), (IC) or (ID), R 4 , R 5 , R 6 and R 7 are each H.

[0163] In certain embodiments of formula (IA), (IB), (IC) or (ID), L 1 is C(=O).

[0164] In certain embodiments of formula (IA), (IB), (IC) or (ID), R 1 and R 2 is H.

[0165] In certain embodiments of formula (IA), (IB), (IC) or (ID), R 3 is C 1-3 It is alkyl.

[0166] In certain embodiments of formula (IA), (IB), (IC) or (ID), R 3 is methyl.

[0167] In certain embodiments of formula (IA), (IB), (IC) or (ID), R 1 and R 2 is H; and R 3 is C 1-3 It is alkyl (eg, methyl).

[0168] In certain embodiments of formula (IA), (IB), (IC) or (ID), ring A is phenyl or pyridyl, each of which is optionally each halo, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 It is substituted with 2 to 4 substituents independently selected from the group consisting of alkoxy.

[0169] In certain embodiments of formula (IA), (IB), (IC) or (ID), ring A is phenyl, which is optionally selected from halo and C 1-6 and substituted with 2 to 4 substituents independently selected from the group consisting of alkyl.

[0170] In certain embodiments of formula (IA), (IB), (IC) or (ID), ring A is: [ka] where R AA , R AB and R AC are independently halo or C 1-6 In some embodiments, R AA and R AC is independently C 1-6 alkyl. For example, R AA and R AC are independently selected C such as methyl 1-3 In some embodiments, R AB -F and other halos.

[0171] In certain embodiments of formula (IA), (IB), (IC) or (ID), L 2 teeth: [ka] is.

[0172] In certain embodiments, the compounds of Formula I are independently selected from the compounds in Table C1 or a pharmaceutically acceptable salt or solvate thereof.

[0173] [Table 1] [Table 2] [Table 3]

[0174] In certain embodiments, the compound is selected from the compounds in Table C2 or a pharmaceutically acceptable salt or solvate thereof.

[0175] [Table 4] [Table 5] [Table 6]

[0176] The compounds of Formula I include pharmaceutically acceptable salts thereof. Additionally, the compounds of Formula I also include other salts of such compounds, not necessarily pharmaceutically acceptable salts, that may be useful as intermediate compounds for preparing and / or purifying compounds of Formula I and / or separating enantiomers of compounds of Formula I. Non-limiting examples of pharmaceutically acceptable salts of compounds of Formula I include trifluoroacetate salts.

[0177] Furthermore, the compounds of formula I or their salts may be isolated in the form of solvates, and it is therefore understood that all such solvates are included within the scope of the present invention. For example, the compounds of formula I and their salts can exist in unsolvated and solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.

[0178] Pharmaceutical Compositions and Administration When used as a pharmaceutical, the compound of Formula I (including its pharmaceutically acceptable salts or solvates) can be administered in the form of a pharmaceutical composition. These compositions can be prepared by methods well known in the pharmaceutical art and can be administered by various routes depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (including transdermal, epidermal, ocular, and mucosal delivery, including intranasal, vaginal, and rectal), pulmonary (e.g., powder or aerosol inhalation or insufflation (including nebulizer); intratracheal or intranasal), oral, or parenteral. Oral administration can include preparations formulated for once-daily or twice-daily (BID) administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection or infusion; or intracerebral, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose or, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder, or oily bases, fillers, and the like may be necessary or desirable.

[0179] Also provided herein are pharmaceutical compositions comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as an active ingredient in combination with one or more pharmaceutically acceptable excipients (carriers). For example, a pharmaceutical composition prepared using a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the composition is suitable for topical administration. When preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed within such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When an excipient serves as a diluent, it can be a solid, semi-solid, or liquid substance that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), ointment (e.g., containing 10% by weight of the active compound), soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In some embodiments, the composition is formulated for oral administration. In some embodiments, the composition is a solid oral formulation. In some embodiments, the composition is formulated as a tablet or capsule.

[0180] Further provided herein is a pharmaceutical composition comprising a compound of Formula I or its pharmaceutically acceptable salt or solvate together with a pharmaceutically acceptable additive.The pharmaceutical composition comprising a compound of Formula I or its pharmaceutically acceptable salt or solvate as an active ingredient can be prepared by intimately mixing the compound of Formula I or its pharmaceutically acceptable salt or solvate with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.The carrier can be in a wide variety of forms depending on the desired route of administration (e.g., oral, parenteral).In some embodiments, the composition is a solid oral composition.

[0181] Suitable pharmaceutically acceptable carriers are well known in the art, and descriptions of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients (published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain).

[0182] Methods for formulating pharmaceutical compositions are described in many publications, such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al.; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al.; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al.; published by Marcel Dekker, Inc.

[0183] In some embodiments, compound or pharmaceutical compositions can be administered in combination with one or more conventional pharmaceutical additives.Pharmaceutically acceptable additives include but are not limited to ion exchanger, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery system (SEDDS), such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical preparations, such as Tween, poloxamer or other similar polymer delivery matrix, serum protein, such as human serum albumin, buffer substances, such as phosphate, Tris, glycine, sorbic acid, potassium sorbate, saturated vegetable fatty acid partial glyceride mixture, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene polyoxypropylene block polymer and wool fat. Cyclodextrins, e.g., α-, β-, and γ-cyclodextrin, or chemically modified derivatives, e.g., hydroxyalkylcyclodextrins (including 2- and 3-hydroxypropyl-β-cyclodextrin) or other solubilized derivatives, can also be used to enhance delivery of the compounds described herein. Compositions containing the chemicals described herein in the range of 0.005% to 100%, with the balance being made up of non-toxic additives, can be prepared. Contemplated compositions may contain the compounds provided herein in the range of 0.001% to 100%, in one embodiment, 0.1 to 95%, in another embodiment, 75 to 85%, and in a further embodiment, 20 to 80%. Actual methods for preparing such formulations are known or apparent to those skilled in the art, and are described, for example, in Remington: The Science and Practice of Pharmacy, 22 nd Edition (Pharmaceutical Press, London, UK. 2012).

[0184] In certain embodiments, the compounds and pharmaceutical compositions described herein or pharmaceutical compositions thereof can be administered to a patient in need thereof by any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, intracervical, intraantral, intratracheal, intraintestinal, epidural, intrainterstitial, intraabdominal, intraarterial, intrabronchial, intravesical, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrarespiratory, intrathecal, intrasynovial, intratesticular, intrathecal, intraductal, intratumoral, intrauterine, intravascular, intravenous, intranasal (e.g., intranasal), nasogastric, oral, parenteral, transdermal, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and vaginal. In some embodiments, the preferred route of administration is parenteral (eg, intratumoral).

[0185] In some embodiments, the compound of Formula I described herein or a pharmaceutically acceptable salt or solvate thereof (e.g., any compound of Formulas IA, IB, IC, and ID, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition thereof can be formulated for parenteral administration, for example, for injection via intraarterial, intrasternal, intracerebral, intravenous, intramuscular, subcutaneous, or intraperitoneal route.For example, such compositions can be prepared as either an injectable liquid solution or suspension; a solid form suitable for preparing a solution or suspension by adding a liquid before injection can also be prepared; and the formulation can be emulsified.The preparation of such formulations is known to those skilled in the art in light of the present disclosure.In some embodiments, a device is used for parenteral administration.For example, such a device can include a needle injector, a microneedle injector, a needle-free injector, and injection technology.

[0186] In some embodiments, the pharmaceutical forms suitable for injection include sterile aqueous solution or dispersion; formulations containing sesame oil, peanut oil or propylene glycol solution; and sterile powders for the immediate preparation of sterile injectable solution or dispersion.In some embodiments, the form must be sterilized and fluid enough to be easily injected.In some embodiments, the form must be stable under the conditions of manufacture and storage, and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

[0187] In some embodiments, the carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. In some embodiments, proper fluidity can be maintained, for example, by using a coating such as lecithin, maintaining the required particle size in dispersion, and using surfactants. In some embodiments, the action of microorganisms can be prevented by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In some embodiments, isotonic agents, for example, sugars or sodium chloride, are included. In some embodiments, prolonged absorption of the injectable composition can be achieved by using agents that delay absorption, for example, aluminum monostearate and gelatin in the composition.

[0188] In some embodiments, sterile injectable solution is prepared by incorporating the required amount of a compound of Formula I or its pharmaceutically acceptable salt or solvate (e.g., any compound of Formulas IA, IB, IC and ID or its pharmaceutically acceptable salt or solvate) in a suitable solvent with various other ingredients listed above, and then optionally sterile-filtering.In some embodiments, dispersion is prepared by incorporating various sterilized active ingredients into a sterile medium containing a basic dispersion medium and other required ingredients listed above.In some embodiments, sterile powder is used to prepare sterile injectable solution.In some embodiments, the preparation method is vacuum drying and freeze-drying technology to obtain powder of active ingredient and additional desired ingredients from the solution previously sterile-filtered.

[0189] In some embodiments, pharmaceutically acceptable additives that can be used in rectal compositions as gels, creams, enemas, or rectal suppositories include, but are not limited to, cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (e.g., PEG ointment), glycerin, glycerin gelatin, hydrogenated vegetable oils, poloxamer, mixtures of polyethylene glycols and fatty acid esters of polyethylene glycol of various molecular weights, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxide SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxobenzoate, sodium propyl p-hydroxybenzoate, diethylamine, carbomer, carbopol, methyl hydroxybenzoate, macrogol cetostearyl ether, cocoyl Any one or more of caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins such as vitamins A and E, and potassium acetate.

[0190] 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 of Formulas IA, IB, IC, and ID, or a pharmaceutically acceptable salt or solvate thereof) or pharmaceutical composition described herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository wax, that is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum to release the active compound. In some embodiments, the composition for rectal administration is in the form of an enema.

[0191] In certain embodiments, a compound of Formula I described herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any of Formulas IA, IB, IC, and ID, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition thereof, is formulated for local delivery to the gastrointestinal or GI tract by oral administration (e.g., a solid or liquid formulation).

[0192] In some embodiments, the solid formulation for oral administration includes capsules, tablets, pills, powders and granules.In some embodiments, the compound of Formula I or its pharmaceutically acceptable salt or solvate (e.g., any compound of Formulas IA, IB, IC and ID or its pharmaceutically acceptable salt or solvate) can be administered with one or more pharmaceutically acceptable additives, such as sodium citrate or dicalcium phosphate, and / or: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and silicic acid; b) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose and acacia; c) humectants, such as glycerol; d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicic acid and sodium carbonate; e) solution retarders. The composition may be mixed with a soluble or non-soluble filler, such as ...

[0193] In some embodiments, the pharmaceutical composition is in the form of a unit dosage form such as a pill or tablet, and thus the composition may contain a compound of Formula I provided herein or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any of Formulas IA, IB, IC, and ID, or a pharmaceutically acceptable salt or solvate thereof), together with a diluent such as lactose, sucrose, dicalcium phosphate, etc.; a lubricant such as magnesium stearate, etc.; and a binder such as starch, gum arabic, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, etc. In some embodiments, a separate solid formulation, powder, marume solution, or suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglyceride) is encapsulated in a capsule (gelatin or cellulose-based capsule). In some embodiments, unit formulations in which one or more compounds provided herein and pharmaceutical compositions or additional active agents are physically separated are also included, such as granule capsules and granules (or tablets in capsules) of each agent; bilayer tablets; two-compartment gel capsules, etc. In some embodiments, enteric-coated or sustained-release oral formulations are also included.

[0194] In certain embodiments, other physiologically acceptable compounds may be included as wetting agents, emulsifying agents, dispersing agents, or preservatives, which are particularly useful for preventing the growth or action of microorganisms. For example, various preservatives are well known and include, for example, phenol and ascorbic acid.

[0195] In some embodiments, the additives are sterile and generally free of undesirable substances. For example, these compositions can be sterilized by conventional, well-known sterilization techniques. In some embodiments, for various oral formulation additives, such as tablets and capsules, sterilization is not required. For example, United States Pharmacopoeia / National Formulary (USP / NF) standards may be sufficient.

[0196] In some embodiments, the compound of Formula I described herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., any compound of Formulas IA, IB, IC, and ID, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition thereof, is formulated for ophthalmic administration. In some embodiments, the ophthalmic composition may include, but is not limited to, one or more of the following: viscogen (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., Pluronic (triblock copolymer), cyclodextrin); preservatives (e.g., benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloroisothiazolinone complex; Allergan, Inc.)).

[0197] In some embodiments, the compound of Formula I described herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any of Formulas IA, IB, IC, and ID, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition thereof, is formulated for topical administration to the skin or mucosa (e.g., dermal or transdermal). In some embodiments, topical compositions can include ointments and creams. In some embodiments, ointments are typically semi-solid preparations based on petrolatum or other petroleum derivatives. In some embodiments, creams containing a selected active agent are typically viscous liquid or semi-solid emulsions, often either oil-in-water or water-in-oil. For example, cream bases are typically water-washable and contain an oil phase, an emulsifier, and an aqueous phase. For example, the oil phase, also referred to as the "internal" phase, is generally composed of petrolatum and a fatty alcohol, such as cetyl or stearyl alcohol, and the aqueous phase usually, although not necessarily, exceeds the volume of the oil phase and generally contains a humectant. In some embodiments, the emulsifier in a cream formulation is generally a nonionic, anionic, cationic, or amphoteric surfactant. In some embodiments, the ointment base, like other carriers or vehicles, should be inert, stable, non-irritating, and non-sensitizing.

[0198] In any of the above embodiments, the pharmaceutical compositions described herein may comprise one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[0199] In some embodiments, the dosage of the compound of Formula I or its pharmaceutically acceptable salt or solvate (for example, any compound of Formulas IA, IB, IC and ID or its pharmaceutically acceptable salt or solvate) is determined based on many factors, including but not limited to, patient type, age, weight, sex, medical condition, severity of patient's medical condition, route of administration and the activity of the compound or its pharmaceutically acceptable salt or solvate.In some embodiments, the appropriate dose for a specific situation can be determined by those skilled in the medical field.In some embodiments, the total daily dose can be divided and administered in portions throughout the day or administered by a method that provides sustained delivery.

[0200] 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, and ID or a pharmaceutically acceptable salt or solvate thereof) is administered at a dose of about 0.01 to about 1000 mg. For example, about 0.1 to about 30 mg, about 10 to about 80 mg, about 0.5 to about 15 mg, about 50 mg to about 200 mg, about 100 mg to about 300 mg, about 200 to about 400 mg, about 300 mg to about 500 mg, about 400 mg to about 600 mg, about 500 mg to about 800 mg, about 600 mg to about 900 mg, or about 700 mg to about 1000 mg. In some embodiments, the dose is a therapeutically effective amount.

[0201] In certain embodiments, a compound of Formula I described herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any of Formulas IA, IB, IC, and ID, or a pharmaceutically acceptable salt or solvate thereof) is administered in a dose range of about 0.0002 mg / Kg to about 100 mg / Kg (e.g., about 0.0002 mg / Kg to about 50 mg / Kg; about 0.0002 mg / Kg to about 25 mg / Kg; about 0.0002mg / Kg~about 10mg / Kg;about 0.0002mg / Kg~about 5mg / Kg;about 0.0002mg / Kg~about 1mg / Kg;about 0.0002mg / Kg~about 0.5mg / Kg; Approx. 0.0002mg / Kg~Approx. 0.1mg / Kg;Approx. 0.001mg / Kg~Approx. 50mg / Kg;Approx. 0.001mg / Kg~Approx. 25mg / Kg;Approx. 0.001mg / Kg~Approx. 10mg / Kg;Approx. 0.001mg / Kg~about 5mg / Kg;about 0.001mg / Kg~about 1mg / Kg;about 0.001mg / Kg~about 0.5mg / Kg;about 0.001mg / Kg~about 0.1mg / Kg;about 0. 01mg / Kg~about 50mg / Kg;about 0.01mg / Kg~about 25mg / Kg;about 0.01mg / Kg~about 10mg / Kg;about 0.01mg / Kg~about 5mg / Kg;about 0.01mg / Kg~ In some embodiments, a compound of Formula I described herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of Formula IA, IB, IC, or ID, or a pharmaceutically acceptable salt or solvate thereof) is administered at a dosage of about 100 mg / Kg.

[0202] In certain embodiments, the dosage of the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any of Formulas IA, IB, IC, and ID, or a pharmaceutically acceptable salt or solvate thereof) can be administered on a daily basis (e.g., as a single dose or two or more divided doses) or off-daily (e.g., every day, every other day, every third day, once a week, twice a week, once every two weeks, once a month).

[0203] In certain embodiments, the administration period of a compound of Formula I described herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any of Formulas IA, IB, IC, and ID, or a pharmaceutically acceptable salt or solvate thereof) is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In some embodiments, the period of time during which administration is discontinued is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more. In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any of Formulas IA, IB, IC, and ID, or a pharmaceutically acceptable salt or solvate thereof) is administered to a patient for a period of time, followed by a separation period during which administration of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any of Formulas IA, IB, IC, and ID, or a pharmaceutically acceptable salt or solvate thereof) is discontinued. 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, and ID, or a pharmaceutically acceptable salt or solvate thereof) is administered for a first period of time, followed by a second period of time after the first period of time, during which administration is discontinued, followed by a third period of time during which administration of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any of Formulas IA, IB, IC, and ID, or a pharmaceutically acceptable salt or solvate thereof) is initiated, followed by a fourth period of time after the third period of time during which administration is discontinued.For example, a period of administration of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any of Formulas IA, IB, IC, and ID, or a pharmaceutically acceptable salt or solvate thereof) followed by a period of cessation of administration can be repeated for a predetermined or indefinite period. In some embodiments, the administration period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more. In some embodiments, the period of time for which administration is discontinued is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more.

[0204] In certain 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, and ID, or a pharmaceutically acceptable salt or solvate thereof) is orally administered to a patient one or more times daily (e.g., once daily, twice daily, three times daily, four times daily, or once daily dose).

[0205] In certain 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, and ID, or a pharmaceutically acceptable salt or solvate thereof) is parenterally administered to a patient one or more times daily (e.g., 1 to 4 times daily, twice daily, three times daily, four times daily, or once daily doses).

[0206] In certain 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, and ID, or a pharmaceutically acceptable salt or solvate thereof) is parenterally administered to a patient once a week.

[0207] Treatment method In certain embodiments, the present disclosure features methods of treating a patient (e.g., a human) having a disease, disorder, or condition in which modulation of GLP-1R (e.g., inhibited or impaired and / or increased or undesired GLP-1R) is beneficial for treating the underlying pathology and / or symptoms and / or progression of the disease, disorder, or condition. In certain embodiments, the methods described herein may include or further include one or more conditions related to, coexisting with, or secondary to any one or more of the conditions described herein.

[0208] Provided herein is a method for treating a GLP-1-related disease, disorder, or condition, comprising administering to a patient in need thereof an effective amount of a compound of Formula I disclosed herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any of Formulas IA, IB, IC, and ID, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition.

[0209] In certain embodiments, the disease, disorder, or condition includes, but is not limited to, type 1 diabetes, type 2 diabetes, juvenile-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of adults (LADA), obesity, weight gain due to the use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat accumulation, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, vascular restenosis, thrombosis, hypertension, pulmonary hypertension, post-angioplasty restenosis, intermittent Claudication, hyperglycemia, postprandial lipemia, 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, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, treatment of addiction, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, and polycystic ovarian syndrome (PCOS).

[0210] In certain embodiments, the disease, disorder, or condition includes, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, renal disease, adipocyte dysfunction, sleep apnea, visceral fat accumulation, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, hyperglycemia, postprandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia. , glucose metabolism disorders, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS) or any combination thereof.

[0211] In certain embodiments, the disease, disorder, or condition includes, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat accumulation, myocardial infarction, peripheral arterial disease, stroke, transient ischemic attack, hyperglycemia, postprandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, 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 disorders, foot ulcers, or any combination thereof.

[0212] In certain embodiments, the compounds and pharmaceutical compositions and patient treatment methods described herein induce one or more of blood glucose reduction (e.g., blood glucose level reduction), blood hemoglobin A1c (HbA1c) level reduction, insulin synthesis promotion, insulin secretion stimulation, beta-cell mass increase, gastric acid secretion regulation, gastric emptying regulation, body mass index (BMI) reduction, and / or glucagon production (e.g., glucagon level reduction). In certain embodiments, the compounds and pharmaceutical compositions and patient treatment methods described herein stabilize serum glucose and serum insulin levels (e.g., serum glucose and serum insulin concentrations). Also provided is a method for regulating glucose or insulin levels in a patient in need thereof, 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 of Formulas IA, IB, IC, and ID, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition described herein.

[0213] In certain embodiments, provided herein are methods for reducing the risk of major adverse cardiovascular events (MACE) in a patient in need thereof (e.g., by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%), comprising administering to the patient an effective amount of a compound of Formula I described herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any of Formulas IA, IB, IC, and ID, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition. In any of these embodiments, the patient is an adult diagnosed with type 2 diabetes (T2D). In certain embodiments, the patient is an adult diagnosed with heart disease. In certain embodiments, the patient is an adult diagnosed with type 2 diabetes (T2D) and heart disease. In certain embodiments, the patient is an adult diagnosed with type 2 diabetes (T2D). In certain embodiments, the patient is an adult diagnosed with heart disease. In certain embodiments, the patient has type 2 diabetes (T2D) and heart disease.

[0214] Indications Obesity In some embodiments, the condition, disease or disorder is obesity and the condition, disease or disorder associated with or related to obesity.Non-limiting examples of obesity and obesity-related conditions include symptomatic obesity, simple obesity, childhood obesity, morbid obesity and abdominal obesity (central obesity characterized by abdominal fat accumulation).Non-limiting examples of symptomatic obesity include endocrine obesity (e.g., Cushing's syndrome, hypothyroidism, insulinoma, obesity-related type 2 diabetes, pseudohypoparathyroidism, hypogonadism), hypothalamic obesity, genetic obesity (e.g., Prader-Willi syndrome, Laurence-Moon-Biedl syndrome) and drug-induced obesity (e.g., steroid-, phenothiazine-, insulin-, sulfonylurea-, or beta-blocker-induced obesity).

[0215] In some embodiments, the condition, disease or disorder is related to obesity. Examples of such condition, disease or disorder include, but are not limited to, impaired glucose tolerance, diabetes (e.g., type 2 diabetes, obesity-related diabetes), dyslipidemia, hyperlipidemia, hypertension, heart failure, hyperuricemia, gout, fatty liver (including non-alcoholic steatohepatitis (NASH)), coronary heart disease (e.g., myocardial infarction, angina pectoris), cerebral infarction (e.g., cerebral thrombosis, transient ischemic attack), bone or joint disease (e.g., knee osteoarthritis, hip osteoarthritis, spondylitis osteoarthritis, lower back pain), sleep apnea syndrome, obesity-hypoventilation syndrome (Pickwickian syndrome), menstrual disorders (e.g., abnormal menstrual cycle, menstrual bleeding and cycle abnormalities, amenorrhea, abnormal menstrual symptoms), visceral obesity syndrome and metabolic syndrome. In some embodiments, the compounds and pharmaceutical compositions described herein can be used to treat patients who show both symptoms of obesity and insulin deficiency.

[0216] diabetes In some embodiments, the condition, disease or disorder is diabetes.Non-limiting examples of diabetes include type 1 diabetes, type 2 diabetes (for example, diet-treated type 2 diabetes, sulfonylurea-treated type 2 diabetes, extreme type 2 diabetes, long-term insulin-treated type 2 diabetes), diabetes (for example, non-insulin-dependent diabetes, insulin-dependent diabetes), gestational diabetes, obesity-related diabetes, autoimmune diabetes and borderline diabetes.In some embodiments, the condition, disease or disorder is type 2 diabetes (for example, diet-treated type 2 diabetes, sulfonylurea-treated type 2 diabetes, extreme type 2 diabetes, long-term insulin-treated type 2 diabetes).

[0217] Provided herein are methods for treating diabetes in a patient, comprising: (a) determining that the patient has type 2 diabetes; and (b) administering to the patient a therapeutically effective amount of a compound of Formula I disclosed herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any of Formulas IA, IB, IC, and ID, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition).

[0218] Provided herein is a method for treating type 2 diabetes in a patient, comprising administering a therapeutically effective amount of a compound of Formula I disclosed herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any of Formulas IA, IB, IC, and ID, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof), to a patient identified or diagnosed as having type 2 diabetes.

[0219] Also provided is a method for treating type 2 diabetes in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula I disclosed herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any of Formulas IA, IB, IC, and ID, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof).

[0220] In certain embodiments, the compounds and pharmaceutical compositions and methods for treating patients with conditions, diseases, or disorders (e.g., type 2 diabetes) described herein reduce fasting blood glucose levels. In certain embodiments, the compounds and pharmaceutical compositions and methods for treating patients with conditions, diseases, or disorders (e.g., type 2 diabetes) described herein reduce non-fasting blood glucose levels. In certain embodiments, the compounds and pharmaceutical compositions and methods for treating patients with conditions, diseases, or disorders (e.g., type 2 diabetes) described herein reduce HbA1c levels. In certain embodiments, the compounds and pharmaceutical compositions and methods for treating patients with conditions, diseases, or disorders (e.g., type 2 diabetes) described herein reduce glucagon levels. In certain embodiments, the compounds and pharmaceutical compositions and methods for treating patients with conditions, diseases, or disorders (e.g., type 2 diabetes) described herein increase insulin levels. In certain embodiments, the compounds and pharmaceutical compositions and methods for treating patients with conditions, diseases, or disorders (e.g., type 2 diabetes) described herein reduce BMI.

[0221] In certain embodiments, treatment of type 2 diabetes mellitus demonstrates a reduction in fasting blood glucose levels of about 5% to about 95%. Treatment of type 2 diabetes mellitus demonstrates a reduction in fasting blood glucose levels of about 15% to about 80%. Treatment of type 2 diabetes mellitus demonstrates a reduction in fasting blood glucose levels of about 25% to about 60%. In certain embodiments, treatment of type 2 diabetes mellitus demonstrates a reduction in fasting blood glucose levels to about 126 mg / dL or less, about 110 mg / dL or less, or about 90 mg / dL or less.

[0222] In certain embodiments, treatment of type 2 diabetes mellitus demonstrates a reduction in non-fasting blood glucose levels of about 5% to about 95%. Treatment of type 2 diabetes mellitus demonstrates a reduction in non-fasting blood glucose levels of about 15% to about 80%. Treatment of type 2 diabetes mellitus demonstrates a reduction in non-fasting blood glucose levels of about 25% to about 60%. In certain embodiments, treatment of type 2 diabetes mellitus demonstrates a reduction in non-fasting blood glucose levels to about 200 mg / dL or less, about 150 mg / dL or less, or about 130 mg / dL or less.

[0223] In certain embodiments, treatment of type 2 diabetes mellitus demonstrates a reduction in HbA1c levels of about 5% to about 95%. Treatment of type 2 diabetes mellitus demonstrates a reduction in HbA1c levels of about 15% to about 80%. Treatment of type 2 diabetes mellitus demonstrates a reduction in HbA1c levels of about 25% to about 60%. In certain embodiments, treatment of type 2 diabetes mellitus demonstrates a reduction in HbA1c levels to about 6.5% or less, about 6.0% or less, or about 5.0% or less.

[0224] In certain embodiments, a reduction in glucagon levels of about 5% to about 95% is shown with treatment of type 2 diabetes. A reduction in glucagon levels of about 15% to about 80% is shown with treatment of type 2 diabetes. A reduction in glucagon levels of about 25% to about 60% is shown with treatment of type 2 diabetes. An increase in insulin levels of about 5% to about 95% is shown with treatment of type 2 diabetes. An increase in insulin levels of about 15% to about 80% is shown with treatment of type 2 diabetes. An increase in insulin levels of about 25% to about 60% is shown with treatment of type 2 diabetes.

[0225] In certain embodiments, a reduction in BMI of about 5% to about 95% is shown by treating type 2 diabetes. A reduction in BMI of about 15% to about 80% is shown by treating type 2 diabetes. A reduction in BMI of about 25% to about 60% is shown by treating type 2 diabetes. In certain embodiments, a reduction in BMI of about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% is shown by treating type 2 diabetes. In certain embodiments, a reduction in BMI of about 40 or less, about 30 or less, or about 20 or less is shown by treating type 2 diabetes.

[0226] In some embodiments, the condition, disease or disorder is related to diabetes (for example, diabetic complications).Non-limiting examples of the disorder related to diabetes include obesity, obesity-related disorder, metabolic syndrome, neuropathy, nephropathy (for example, diabetic nephropathy), retinopathy, diabetic cardiomyopathy, cataract, macroangiopathy, osteopenia, hyperosmolar diabetic coma, infectious diseases (for example, respiratory infection, urinary tract infection, gastrointestinal infection, skin and soft tissue infection, lower limb infection), diabetic gangrene, xerostomia, hearing impairment, cerebrovascular disease, diabetic cachexia, delayed wound healing, diabetic dyslipidemia, peripheral blood circulation disorder, cardiovascular risk factors (for example, coronary artery disease, peripheral artery disease, cerebrovascular disease, hypertension, and risk factors related to uncontrolled cholesterol and / or lipid levels and / or inflammation), NASH, fracture and cognitive dysfunction.

[0227] Other non-limiting examples of disorders related to diabetes include prediabetes, hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, hyper-LDL cholesterolemia, hypo-LDL cholesterolemia, postprandial dyslipidemia), metabolic syndrome (e.g., a metabolic disorder in which activation of GLP-1R is beneficial, metabolic syndrome X), hypertension, impaired glucose tolerance (IGT), insulin resistance, and sarcopenia.

[0228] In certain embodiments, the condition, disease, or disorder is diabetes and obesity (diabetic obesity). In certain embodiments, the compounds described herein are useful for improving the therapeutic effectiveness of metformin.

[0229] Disorders of metabolically important tissues In certain embodiments, the condition, disease, or disorder is a disorder of a metabolically significant tissue. Non-limiting examples of metabolically significant tissues include the liver, adipose tissue, pancreas, kidney, and intestine.

[0230] In some embodiments, the condition, disease, or disorder is fatty liver disease, including, but not limited to, non-alcoholic fatty liver disease (NAFLD), steatohepatitis, non-alcoholic steatohepatitis (NASH), fatty liver disease resulting from hepatitis, fatty liver disease resulting from obesity, fatty liver disease resulting from diabetes, fatty liver disease resulting from insulin resistance, fatty liver disease resulting from hypertriglyceridemia, abetalipoproteinemia, glycogen storage disease, Weber-Christian disease, Wolman disease, acute fatty liver of pregnancy, and lipodystrophy.

[0231] Nonalcoholic fatty liver disease (NAFLD) refers to a group of diseases that occur in the absence of alcohol abuse, and is typically characterized by the presence of fatty liver (fat in the liver).NAFLD is thought to be associated with various conditions, such as metabolic syndrome (including obesity, diabetes, and hypertriglyceridemia) and insulin resistance.This can cause liver disease in adults and children, and ultimately lead to cirrhosis (Skelly et al., J Hepatol 2001; 35: 195-9; Chitturi et al., Hepatology 2002; 35(2):373-9).The severity of NAFLD ranges from relatively benign, mainly isolated macrovesicular fatty liver (i.e., nonalcoholic fatty liver or NAFL) to nonalcoholic steatohepatitis (NASH) (Angulo et al., J Gastroenterol Hepatol 2002; 17 Suppl:S186-90). In some embodiments, the patient is a pediatric patient. As used herein, the term "pediatric patient" refers to a patient who is 21 years of age or younger at the time of diagnosis or treatment. The term "child" can be further divided into various subpopulations, including neonates (birth to 1 month old); infants (1 month to 2 years old); children (2 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 28 days of age, from 29 days of age to 2 years of age, from 2 to 12 years of age, or from 12 to 21 years of age (up to but not including the 22nd birthday).In certain embodiments, the pediatric patient is from birth to 28 days of age, from 29 days to 1 year of age, from 1 month to 4 months of age, from 3 months to 7 months of age, from 6 months to 1 year of age, from 1 year to 2 years of age, from 2 years to 3 years of age, from 2 years to 7 years of age, from 3 years to 5 years of age, from 5 years to 10 years of age, from 6 years to 13 years of age, from 10 years to 15 years of age, or from 15 years to 22 years of age. In certain embodiments, the patient is an adult patient.

[0232] Other non-limiting examples of disorders of metabolically important tissues include arthropathy (e.g., osteoarthritis, secondary osteoarthritis), fatty liver (e.g., liver); fibrosis (e.g., liver); cirrhosis (e.g., liver); gallstones; gallbladder disease; gastroesophageal reflux; sleep apnea; hepatitis; fatty liver; bone disorders characterized by alterations in bone metabolism, such as osteoporosis (including postmenopausal osteoporosis), decreased bone strength, osteopenia, Paget's disease, osteolytic metastases in cancer patients, osteodystrophy in liver disease and alterations in bone metabolism caused by renal failure or hemodialysis, fractures, bone surgery, aging, pregnancy, protection from fractures and malnutrition, polycystic ovary syndrome; renal disease (e.g., chronic renal failure, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease); muscular dystrophy, angina pectoris, acute or chronic diarrhea, testicular dysfunction, respiratory dysfunction, frailty, sexual dysfunction (e.g., erectile dysfunction) and geriatric syndromes. In certain embodiments, the compounds and pharmaceutical compositions described herein can be used to improve post-surgical recovery and / or treat surgical trauma by preventing the catabolic response caused by surgical trauma.

[0233] Cardiovascular and vascular diseases In some embodiments, the condition, disease or disorder is cardiovascular disease.Non-limiting examples of cardiovascular disease include congestive heart failure, atherosclerosis, arteriosclerosis, coronary heart disease, coronary artery disease, congestive heart failure, coronary heart disease, hypertension, heart failure, cerebrovascular disease (e.g., cerebral infarction), vascular insufficiency, myocardial infarction, elevated blood pressure (e.g., 130 / 85 mmHg or higher) and prothrombotic conditions (e.g., high blood fibrinogen or plasminogen activator inhibitor levels).

[0234] In some embodiments, the condition, disease or disorder is associated with vascular disease. Non-limiting examples of vascular disease include peripheral vascular disease, macrovascular complications (e.g., stroke), vascular insufficiency, peripheral arterial disease, abdominal aortic aneurysm, carotid artery disease, cerebrovascular disease (e.g., cerebral infarction), pulmonary embolism, chronic venous insufficiency, critical limb ischemia, retinopathy, nephropathy and neuropathy.

[0235] Neurological disorders In certain embodiments, the condition, disease, or disorder is a neurological disorder (e.g., a neurodegenerative disorder) or a psychiatric disorder. Non-limiting examples of neurological disorders include brain insulin resistance, mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), anxiety, dementia (e.g., senile dementia), traumatic brain injury, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, Morbus Parkinson's disease, Steele-Richard syndrome, Down's syndrome, myasthenia gravis, neurotrauma, brain trauma, vascular amyloidosis, cerebral hemorrhage with amyloidosis, encephalitis, Friedreich's ataxia, acute confusional disorder, amyotrophic lateral sclerosis (ALS), glaucoma, and apoptosis-mediated degenerative diseases of the central nervous system (e.g., Creutzfeldt-Jakob disease, bovine spongiform encephalopathy (mad cow disease), and chronic wasting syndrome). See, e.g., US Publication No. 20060275288A1.

[0236] Non-limiting examples of psychiatric disorders include drug addiction / addiction (narcotics and amphetamines) and attention deficit hyperactivity disorder (ADHD). The compounds and pharmaceutical compositions described herein can be useful for improving behavioral responses to addictive drugs, reducing drug dependence, preventing relapse to drug abuse, and alleviating anxiety caused by the absence of certain addictive substances. See, for example, US Publication No. 20120021979A1.

[0237] In certain embodiments, the compounds and pharmaceutical compositions described herein are useful for improving learning and memory by enhancing neuroplasticity and promoting cell differentiation, and for preserving dopaminergic neuronal and motor function in Parkinson's disease (Morbus Parkinson's).

[0238] Insulin-related In certain embodiments, the condition, disease or disorder is impaired fasting glucose (IFG), fasting hyperglycemia (IFG), hyperglycemia, insulin resistance (impaired glucose homeostasis), hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hypoglycemic conditions, insulin resistance syndrome, abnormal paresthesia caused by hyperinsulinemia, hyperlipidemia, hypercholesterolemia, poor wound healing, leptin resistance, glucose intolerance, elevated fasting glucose, dyslipidemia (e.g., atherogenic dyslipidemia characterized by hyperlipidemia, high triglycerides and low HDL cholesterol), glucagonoma, hyperuricemia, hypoglycemia (e.g., nocturnal hypoglycemia), and insulin-related concomitant comatose endpoint.

[0239] In certain embodiments, the compounds and pharmaceutical compositions described herein can reduce or delay the progression of borderline impaired fasting glucose or fasting hyperglycemia to diabetes.

[0240] autoimmune disorders In some embodiments, condition, disease or disorder is autoimmune disease.Non-limiting examples of autoimmune disease include multiple sclerosis, experimental autoimmune encephalomyelitis, autoimmune disease is associated with immune rejection, graft-versus-host disease, uveitis, optic neuropathy, optic neuritis, transverse myelitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, myasthenia gravis and Graves' disease.See, for example, US Publication 20120148586A1.

[0241] Gastrointestinal disorders In some embodiments, the condition, disease, or disorder is a stomach or intestinal disorder. Non-limiting examples of these disorders include ulcers of any etiology (e.g., gastric ulcer, Zollinger-Ellison syndrome, drug-induced ulcer, ulcer associated with infection or other pathogen), gastrointestinal disease, malabsorption, short bowel syndrome, blind-tube syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), celiac disease, hypogammaglobulinemia, chemotherapy- and / or radiotherapy-induced mucositis and diarrhea, gastroenteritis, short bowel syndrome, ulcerative colitis, gastric mucosal injury (e.g., aspirin-induced gastric mucosal injury), small intestinal mucosal injury, and cachexia (e.g., cancer cachexia, tuberculosis cachexia, cachexia associated with blood disorders, cachexia associated with endocrine disorders, cachexia associated with infectious diseases, and cachexia caused by acquired immune deficiency syndrome).

[0242] body weight In some embodiments, the compounds and pharmaceutical compositions described herein can be used to reduce weight (e.g., excess weight), prevent weight gain, induce weight loss, reduce body fat, or reduce food intake in a patient (e.g., a patient in need thereof). In some embodiments, the patient's weight gain may be due to excessive food intake or an unbalanced diet, or may be due to concomitant use of a drug (e.g., an insulin sensitizer with PPARγ agonist-like activity, such as troglitazone, rosiglitazone, englitazone, ciglitazone, pioglitazone, etc.). In some embodiments, the weight gain may be pre-obese or may be weight gain in an obese patient. In some embodiments, the weight gain may also be drug-induced weight gain or weight gain after smoking cessation.

[0243] In certain embodiments, the condition, disease or disorder is an eating disorder, eg, overeating, binge eating, bulimia, or compulsive overeating.

[0244] Inflammatory diseases In some embodiments, the condition, disease or disorder is inflammatory disease.Non-limiting examples of inflammatory disease include rheumatoid arthritis, spondylitis deformans, osteoarthritis, lower back pain, gout, post-operative or post-traumatic inflammation, abdominal distension, neuralgia, pharyngitis, cystitis, pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory bowel disease), and the inflammation and pro-inflammatory state (for example, the level of pro-inflammatory cytokines or inflammatory markers such as C-reactive protein in blood) of metabolically important tissues (including liver, fat, pancreas, kidney and intestine) are elevated.

[0245] cancer In some embodiments, the condition, disease, or disorder is cancer. Suitable examples of cancer include breast cancer (e.g., invasive ductal carcinoma, ductal carcinoma in situ, inflammatory breast cancer), prostate cancer (e.g., hormone-dependent prostate cancer, hormone-independent prostate cancer), pancreatic cancer (e.g., pancreatic ductal carcinoma), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), lung cancer (e.g., non-small cell lung cancer, small cell lung carcinoma, malignant mesothelioma), colon cancer (e.g., gastrointestinal stromal tumor), rectal cancer (e.g., gastrointestinal stromal tumor), and rectal cancer (e.g., gastrointestinal stromal tumor). stromal tumors), colon cancer (e.g., familial colorectal cancer, hereditary non-polyposis colorectal cancer, gastrointestinal stromal tumors), small intestine cancer (e.g., non-Hodgkin's lymphoma, gastrointestinal stromal tumors), esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer (e.g., nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer), salivary gland cancer, brain tumors (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma), schwannoma, liver cancer (e.g., primary hepatic liver cancer, extrahepatic bile duct cancer), kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter), bile duct cancer, uterine cancer, cervical cancer, ovarian cancer (e.g., ovarian epithelial cancer, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian tumor with low malignant potential), bladder cancer, urethral cancer, skin cancer (e.g., intraocular (ocular) melanoma, Merkel cell carcinoma), hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer (e.g., medullary thyroid carcinoma) , parathyroid cancer, nasal cavity cancer, sinus cancer, bone tumors (e.g., osteosarcoma, Ewing's tumor, uterine sarcoma, soft tissue sarcoma), angiofibroma, retinal sarcoma, penile cancer, testicular tumors, childhood solid tumors (e.g., Wilms' tumor, childhood kidney tumor), Kaposi's sarcoma, Kaposi's sarcoma caused by AIDS, maxillary sinus tumors, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia).

[0246] Hypothalamic-pituitary disorders In some embodiments, the condition, disease, or disorder is associated with the hypothalamic pituitary-gonadal axis. For example, the condition, disease, or disorder is associated with the hypothalamic pituitary-ovarian axis. In another example, the condition, disease, or disorder is associated with the hypothalamic pituitary-testicular axis. Diseases of the hypothalamic pituitary-gonadal axis include, but are not limited to, hypogonadism, polycystic ovary syndrome, hypothyroidism, hypopituitarism, sexual dysfunction, and Cushing's disease.

[0247] In certain embodiments, the diabetes-related condition, disease or disorder is related to the hypothalamic pituitary gonadal axis.

[0248] Pulmonary disease In certain embodiments, the condition, disease, or disorder is associated with a pulmonary disease, including, but not limited to, asthma, idiopathic pulmonary fibrosis, pulmonary hypertension, obstructive sleep apnea, and chronic obstructive pulmonary disease (COPD) (e.g., emphysema, chronic bronchitis, and refractory (irreversible) asthma).

[0249] In certain embodiments, the diabetes-related condition, disease or disorder is a pulmonary disease.

[0250] Combination therapy In certain embodiments, the present invention is intended to include both monotherapy and combination therapy regimens.

[0251] In certain embodiments, the methods described herein can further include administering one or more additional therapies (e.g., one or more additional therapeutic agents and / or one or more therapeutic regimens) in combination with the administration of the compounds described herein.

[0252] In certain embodiments, the methods described herein include administering a compound described herein in combination with one or more of dietary therapy (e.g., dietary monitoring for diabetes, dietary therapy), exercise therapy (e.g., physical activity), blood glucose monitoring, gastric electrical stimulation (e.g., TANTALUS®), and dietary modification.

[0253] In certain embodiments, the compounds of X described herein, or pharmaceutically acceptable salts or solvates thereof, can be administered in combination with one or more additional therapeutic agents.

[0254] Representative additional therapeutic agents include, but are not limited to, anti-obesity agents, treatments for diabetes, treatments for diabetic complications, treatments for hyperlipidemia, antihypertensive agents, diuretics, chemotherapeutic agents, immunotherapeutic agents, anti-inflammatory agents, antithrombotic agents, antioxidants, treatments for osteoporosis, vitamins, treatments for dementia, treatments for erectile dysfunction, treatments for urinary frequency or urinary incontinence, treatments for NAFLD, treatments for NASH, and treatments for dysuria.

[0255] In certain embodiments, the one or more additional therapeutic agents include, for example, those useful as anti-obesity agents. Non-limiting examples include monoamine reuptake inhibitors (e.g., tramadol, phentermine, sibutramine, mazindol, fluoxetine, tesofensine), serotonin 2C receptor agonists (e.g., lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptor modulators, GABA modulators (e.g., topiramate) (including GABA receptor agonists (e.g., gabapentin, pregabalin)), neuropeptide Y antagonists (e.g., verneperit), cannabinoid receptor antagonists, and the like. antihistamines (e.g., rimonabant, taranabant), ghrelin antagonists, ghrelin receptor antagonists, ghrelin acylation enzyme inhibitors, opioid receptor antagonists (e.g., GSK-1521498), 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, stearic acid-CoA desaturase inhibitors, microsomal triglyceride transfer protein inhibitors (e.g., R-256918), sodium glucose transporter 2 (SGLT-2) inhibitors (e.g., JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, remogliflozin), N FK inhibitors (e.g., HE-3286), PPAR agonists (e.g., GFT-505, DRF-11605, gemfibrozil, and fenofibrate), phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate, trodasquemine), GPR119 agonists (e.g., PSN-821, MBX-2982, APD597), glucokinase activators (e.g., pyragliatin, AZD-1656, AZD6370, TTP-355, W0006 / 112549, W0007 / 028135,compounds described in WO008 / 047821, W0008 / 050821, W0008 / 136428 and W0008 / 156757), leptin, leptin derivatives (e.g., metreleptin), leptin resistance improving agents, CNTF (ciliary neurotrophic factor), BDNF (brain-derived neurotrophic factor), cholecystokinin agonists, amylin preparations (e.g., pramlintide, AC-2307), neuropeptide Y agonists (e.g., PYY3-36, PYY3-36 derivatives, obineptide, TM-30339, TM-30335), oxyntomodulin (OXM) preparations, appetite suppressants (e.g., ephedrine), FGF21 preparations (e.g., These include animal FGF21 preparations extracted from chicken or porcine pancreas; human FGF21 preparations genetically synthesized using E. coli or yeast; fragments or derivatives of FGF21), appetite suppressants (e.g., P-57), human islet peptide precursor (HIP), farnesoid X receptor (FXR) agonists, phentermine, zonisamide, norepinephrine / dopamine reuptake inhibitors, GDF-15 analogs, methionine aminopeptidase 2 (MetAP2) inhibitors, diethylpropion, phendimetrazine, benzphetamine, fibroblast growth factor receptor (FGFR) modulators, and AMP-activated protein kinase (AMPK) activators.

[0256] In certain embodiments, the one or more additional therapeutic agents include, for example, an agent useful as an antidiabetic agent.Non-limiting examples include insulin and insulin preparations (e.g., animal insulin preparations extracted from bovine or porcine pancreas; human insulin preparations genetically synthesized using E. coli or yeast; zinc insulin; protamine zinc insulin; insulin fragments or derivatives (e.g., INS-1), oral insulin preparations, synthetic human insulin), insulin sensitizers (e.g., pioglitazone or a salt thereof), biguanides (e.g., metformin, buformin or a salt thereof (e.g., hydrochloride, fumarate, succinate)), glutamic acid, ... glucagon analogues (e.g., any of the glucagon analogues described in WO2010 / 011439), agents that antagonise the action of glucagon or reduce glucagon secretion, sulfonylurea drugs (e.g., chlorpropamide, tolazamide, gliclazide, glimepiride, tolbutamide, glibenclamide, gliclazide, acetohexamide, glyclopyramide, glybuzole, glyburide), thiazolidinediones (e.g., rosiglitazone or pioglitazone), α-glucosidase inhibitors (e.g., voglibose, acarbose, miglitol, emiglitate), insulin secretagogues, e.g., prandial glucose regulators (sometimes referred to as "short-acting secretagogues"), e.g., meglitinides (e.g., repaglinide and nateglinide), cholinesterase inhibitors (e.g., donepezil, galantamine, rivastigmine, tacrine), NMDA receptor antagonists, dual GLP-1 / GIP receptor agonists (e.g., LBT-2000, ZPD1-70), GLP-1R agonists (e.g., exenatide, liraglutide, albiglutide, dulaglutide, albiglutide), and dipeptidyl peptidase IV (DPP-4) inhibitors (e.g., vildagliptin, dutogliptin, gemigliptin, alogliptin, saxagliptin, sitagliptin, linagliptin, berberine, adgliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, SK-0403, ALS2-0426, TA-6666, TS-021, KRP-104, trelagliptin).

[0257] In some embodiments, the one or more additional therapeutic agents include, for example, agents useful for the treatment of NAFL and NASH. Non-limiting examples include FFXR agonists, PF-05221304, synthetic fatty acid bile conjugates, anti-lysyl oxidase homolog 2 (LOXL2) monoclonal antibodies, caspase inhibitors, MAPK5 inhibitors, galectin 3 inhibitors, fibroblast growth factor 21 (FGF21), niacin analogs, leukotriene D4 (LTD4) receptor antagonists, acetyl-CoA carboxylase (ACC) inhibitors, ketohexokinase (KHK) inhibitors, apoptosis signal-regulating kinase 1 (ASK1) inhibitors, ileal bile acid transactivators, and the like. Ingredients include: IBAT inhibitors, glycyrrhizin, scab extract, ascorbic acid, glutathione, silymarin, lipoic acid and d-alpha-tocopherol, ascorbic acid, glutathione, vitamin B complex, glitazones / thiazolidinediones (e.g., troglitazone, rosiglitazone, pioglitazone), metformin, cysteamine, sulfonylureas, alpha-glucosidase inhibitors, meglitinides, vitamin E, tetrahydrolipstatin, milk thistle protein, antivirals, and antioxidants.

[0258] In some embodiments, the one or more additional therapeutic agents include, for example, agents useful for treating diabetic complications. Non-limiting examples include aldose reductase inhibitors (e.g., tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat, lidrestat), neurotrophic factors and growth factors (e.g., NGF, NT-3, BDNF, neurotrophic production / secretion promoting agents described in WO2001 / 14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole), compounds described in WO2004 / 039365), PKC inhibitors (e.g., ruthenium, erythrocyte sedimentation inhibitors ... Examples of such anti-inflammatory drugs include benzodiazepines (e.g., benzodiazepine mesylate), AGE inhibitors (e.g., ALT946, N-phenacylthiazolium bromide (ALT766), EXO-226, pyridoline, pyridoxamine), serotonin and noradrenaline reuptake inhibitors (e.g., duloxetine), sodium channel inhibitors (e.g., lacosamide), reactive oxygen scavengers (e.g., thioctic acid), cerebral vasodilators (e.g., tiapride, mexiletine), somatostatin receptor agonists (e.g., BIM23190), and apoptosis signal-regulating kinase 1 (ASK-1) inhibitors.

[0259] In some embodiments, the one or more additional therapeutic agents include, for example, agents useful for treating hyperlipidemia. Non-limiting examples include HMG-COA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin, or salts thereof (e.g., sodium salts, calcium salts)), squalene synthase inhibitors (e.g., compounds described in WO97 / 10224, such as N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetate, and the like. [C11-tyl]piperidine-4-acetic acid), fibrates (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate), anion exchange resins (e.g., cholestyramine), nicotinic acid drugs (e.g., nicomol, niceritrol, niaspan), phytosterols (e.g., soy sterol, gamma oryzanol (γ-oryzanol)), cholesterol absorption inhibitors (e.g., zetia), CETP inhibitors (e.g., dalcetrapib, anacetrapib), and omega-3 fatty acid preparations (e.g., omega-3 fatty acid ethyl ester 90).

[0260] In some embodiments, the one or more additional therapeutic agents include, for example, drugs useful as antihypertensive agents.Non-limiting examples include angiotensin-converting enzyme inhibitors (e.g., captopril, enalapril, delapril), angiotensin II antagonists (e.g., candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil, azilsartan, azilsartan medoxomil), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine, cilnidipine) and β-blockers (e.g., metoprolol, atenolol, propranolol, carvedilol, pindolol).

[0261] In some embodiments, one or more additional therapeutic agents include, for example, drugs useful as diuretics.Non-limiting examples include xanthine derivatives (e.g., sodium theobromine salicylate, calcium theobromine salicylate), thiazides (e.g., ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penfluthiazide, polythiazide, methyclothiazide), antialdosterone drugs (e.g., spironolactone, triamterene), carbonic anhydrase inhibitors (e.g., acetazolamide) and chlorobenzenesulfonamides (e.g., chlorthalidone, mefruside, indapamide).

[0262] In some embodiments, the one or more additional therapeutic agents include, for example, agents useful as immunotherapeutic agents.Non-limiting examples include microbial or bacterial compounds (e.g., muramyl dipeptide derivatives, picibanil), polysaccharides with immune-enhancing activity (e.g., lentinan, sizofiran, krestin), cytokines obtained by genetic engineering (e.g., interferons, interleukins (IL), e.g., IL-1, IL-2, IL-12), and colony-stimulating factors (e.g., granulocyte colony-stimulating factor, erythropoietin).

[0263] In certain embodiments, the one or more additional therapeutic agents include, for example, agents useful as antithrombotic agents. Non-limiting examples include heparin (e.g., heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarin (e.g., warfarin potassium); antithrombin agents (e.g., argatroban, dabigatran); FXa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, YM150, WO02 / 06234, WO2004 / 048363, WO2005 / 030740, WO2 compounds described in WO2005 / 058823 and WO2005 / 113504); thrombolytic agents (e.g., urokinase, tisokinase, alteplase, nateplase, monteplase, pamiteplase) and platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cilostazol, ethyl icosapentate, beraprost sodium and sarpogrelate hydrochloride).

[0264] In some embodiments, the one or more additional therapeutic agents include, for example, drugs useful for treating osteoporosis.Non-limiting examples include alfacalcidol, calcitriol, elcatonin, salmon calcitonin, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium, and risedronate disodium.Suitable examples of vitamins include vitamin B1 and vitamin B12.Suitable examples of agents for treating erectile dysfunction include apomorphine and sildenafil citrate.Suitable examples of agents for treating urinary frequency or urinary incontinence include flavoxate hydrochloride, oxybutynin hydrochloride, and propiverine hydrochloride.Suitable examples of agents for treating urinary disorders include acetylcholinesterase inhibitors (e.g., distigmine).Suitable examples of anti-inflammatory agents include nonsteroidal anti-inflammatory agents, such as aspirin, acetaminophen, and indomethacin.

[0265] Other exemplary additional therapeutic agents include drugs that regulate hepatic glucose balance (e.g., fructose 1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glycogen synthase kinase inhibitors, glucokinase activators), drugs designed to treat complications of persistent hyperglycemia, such as aldose reductase inhibitors (e.g., epalrestat and ranirestat), drugs used to treat complications associated with microangiopathy, anti-dyslipidemic agents, such as HMG-CoA reductase inhibitors (statins, e.g., loxacin), and the like. savastatin), cholesterol-lowering agents, bile acid sequestrants (e.g., cholestyramine), cholesterol absorption inhibitors (e.g., plant sterols such as phytosterols), cholesteryl ester transfer protein (CETP) inhibitors, ileal bile acid transport system inhibitors (IBAT inhibitors), bile acid-binding resins, nicotinic acid (niacin) and its analogs, antioxidants (e.g., probucol), omega-3 fatty acids, antihypertensive agents including adrenergic receptor antagonists, e.g., beta-blockers (e.g., atenolol), alpha-blockers (e.g., doxazosin), and mixed adrenergic receptor antagonists. Adrenergic receptor agonists, including alpha / beta blockers (e.g., labetalol), 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 benzothiazepines (e.g., diltiazem), angiotensin II receptor antagonists (e.g., candesartan), aldosterone receptor antagonists (e.g., eplerenone), centrally acting adrenaline agents such as central alpha agonists (e.g., clonidine), diuretics (e.g., furosemide), antithrombotic (e.g., fibrinolytic activators), thrombin antagonists, factor VIIa inhibitors, anticoagulants (e.g., vitamin K antagonists, e.g., warfarin), heparin and its low molecular weight analogues, hemostatic modulators including factor Xa inhibitors and direct thrombin inhibitors (e.g., argatroban), antiplatelet agents (e.g., cyclooxygenase inhibitors (e.g., aspirin)), adenosine diphosphate (ADP) receptor inhibitors (e.g., clopidogrel),Phosphodiesterase inhibitors (e.g., cilostazol), glycoprotein IIB / IIA inhibitors (e.g., tirofiban), adenosine reuptake inhibitors (e.g., dipyridamole), noradrenergic agents (e.g., phentermine), rotonic agents (e.g., sibutramine), diacylglycerol acyltransferase (DGAT) inhibitors, feeding behavior modifiers, pyruvate dehydrogenase kinase (PDK) modulators, serotonin receptor modulators, monoamine transport modifiers, e.g., selective serotonin reuptake inhibitors (SSRIs) ) (e.g., fluoxetine), noradrenaline reuptake inhibitors (NARIs), noradrenaline-serotonin reuptake inhibitors (SNRIs) and monoamine oxidase inhibitors (MAOIs) (e.g., toloxatone and amiflamine), compounds described in WO2007 / 013694, WO2007 / 018314, WO2008 / 093639 and WO2008 / 099794, GPR40 agonists (e.g., fasiglifam or its hydrate, WO2004 / 041266, WO2004 / 106276, WO2005 / 063 729, compounds described in WO2005 / 063725, WO2005 / 087710, WO2005 / 095338, WO2007 / 013689 and WO2008 / 001931), SGLT1 inhibitors, adiponectin or its agonists, IKK inhibitors (e.g., AS-2868), somatostatin receptor agonists, ACC2 inhibitors, cachexia improvers such as cyclooxygenase inhibitors (e.g., indomethacin), progesterone derivatives (e.g., megestrol acetate), glucocorticoids (e.g., dexamethasone), sazon), metoclopramide agents, tetrahydrocannabinol agents, fat metabolism improvers (e.g., eicosapentaenoic acid), growth hormone, IGF-1, cachexia-inducing factor TNF-α, LIF, IL-6, and antibodies against 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, glycation inhibitors (e.g., ALT-711),Neuroregeneration promoters (e.g., Y-128, VX853, prosaptide), antidepressants (e.g., desipramine, amitriptyline, imipramine), antiepileptics (e.g., lamotrigine, trileptal, Keppra, Zonegran, pregabalin, hercoceride, carbamazepine), antiarrhythmics (e.g., mexiletine), acetylcholine receptor ligands (e.g., ABT-594), endothelin receptor antagonists (e.g., ABT -627), narcotic analgesics (e.g., morphine), alpha 2 receptor agonists (e.g., clonidine), topical analgesics (e.g., capsaicin), anxiolytics (e.g., benzothiazepines), phosphodiesterase inhibitors (e.g., sildenafil), dopamine receptor agonists (e.g., apomorphine), cytotoxic antibodies (e.g., T cell receptor and IL-2 receptor specific antibodies), B cell depletion therapies (e.g., anti-CD20 antibodies (e.g., Rituxan), i-BLyS antibodies), drugs affecting T cell migration (e.g., anti-integrin alpha 4 / beta 1 antibodies (e.g., Tysabri), drugs acting on immunophilins (e.g., cyclosporine, tacrolimus, sirolimus, rapamycin), interferons (e.g., IFN-β), immunomodulators (e.g., glatiramer), TNF binding proteins (e.g., circulating TNF receptors), immunosuppressants (e.g., mycophenolic acid), and methicillin-resistant Staphylococcus aureus (MTCA). These include taglidasene, AMG-131, balaglitazone, MBX-2044, rivoglitazone, aleglitazar, tiglitazar, lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, exenatide, exendin-4, memantine, midazolam, ketoconazole, ethyl icosapentate, clonidine, azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, etoposide,

[0266] In some embodiments, the one or more additional therapeutic agents include, for example, those useful as antiemetic agents. As used herein, an "antiemetic" agent refers to any agent that counters (e.g., reduces or eliminates) nausea or emesis (vomiting). Without wishing to be bound by theory, it is believed that administering one or more antiemetic agents in combination with the compounds of Formula (I) described herein may allow for higher dosages of the compounds of Formula (I), for example, so that patients can consume a normal diet, thereby responding more quickly to treatment.

[0267] Non-limiting examples of antiemetic agents include 5HT3 receptor antagonists (serotonin receptor antagonists), neuroleptics / antipsychotics, antihistamines, anticholinergics, steroids (e.g., corticosteroids), NK1 receptor antagonists (e.g., neurokinin 1 substance P receptor antagonists), antidopaminergics / dopamine receptor antagonists, benzodiazepines, cannabinoids.

[0268] For example, the antiemetic agent is selected from the group consisting of neuroleptics, antihistamines, anticholinergics, steroids, 5HT-3 receptor antagonists, NK1 receptor antagonists, antidopaminergics / dopamine receptor antagonists, benzodiazepines and non-psychoactive cannabinoids.

[0269] In certain embodiments, the antiemetic agent is a 5HT3 receptor antagonist (serotonin receptor antagonist). Non-limiting examples of 5HT3 receptor antagonists (serotonin receptor antagonists) include granisetron (Kytril), dolasetron, ondansetron (Zofran), tropisetron, ramosetron, palonosetron, alosetron, azasetron, bemesetron, zatisetron, batanopride, MDL-73147EF; metoclopramide, N-3389 (endo-3,9-dimethyl-3,9-diazabicyclo[3,3,1]non-7-yl-1H-indazole-3-carboxamide dihydrochloride), Y-25130 hydrochloride, MDL 72222, tropanyl-3,5-dimethylbenzoate, 3-(4-allylpiperazin-1-yl)-2-quinoxalinecarbonitrile maleate, zacopride hydrochloride, and mitrazepine. Other non-limiting examples of 5HT3 receptor antagonists (serotonin receptor antagonists) include cilansetron, clozapine, cyproheptadine, dazopride, hydroxyzine, lerisetron, metoclopramide, mianserin, olanzapine, palonosetron (plus netupitant), quetiapine, camosetron, ramosetron, licasetron, risperidone, ziprasidone, and zatosterone.

[0270] In certain embodiments, the 5HT-3 receptor antagonist is granisetron, dolasetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemesetron, zatisetron, batanopride, MDL-73147EF, metoclopramide, N-3389, Y-25130 hydrochloride, MDL 72222, tropanyl-3,5-dimethylbenzoate 3-(4-allyl-piperazin-1-yl)-2-quinoxalinecarbonitrile maleate, zacopride hydrochloride, and mirtazepine.

[0271] In certain embodiments, the 5HT-3 receptor antagonist is granisetron, dolasetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemesetron, and zatisetron.

[0272] In certain embodiments, the 5HT-3 receptor antagonists are granisetron, dolasetron and ondansetron.

[0273] In certain embodiments, the 5HT-3 receptor antagonist is granisetron.

[0274] In certain embodiments, the 5HT-3 receptor antagonist is ondansetron.

[0275] In some embodiments, the antiemetic agent is an antihistamine. Non-limiting examples of antihistamines include piperazine derivatives (e.g., cyclizine, meclizine, and cinnarizine); promethazine; dimenhydrinate (Dramamine, Gravol); diphenhydramine; hydroxyzine; clizine; and meclizine hydrochloride (Bonine, Antivert), doxylamine, and mitrazepine.

[0276] In some embodiments, the antiemetic agent is an anticholinergic (acetylcholine receptor inhibitor). Non-limiting examples of anticholinergic agents include atropine, scopolamine, Glycopyrron, hyoscine, Artane (trihexy-5 trihexyphenidyl hydrochloride), Cogentin (benztropine mesylate), Akineton (biperiden hydrochloride), Disipal (Norflex orphenadrine citrate), diphenhydramine, hydroxyzine, hyoscyamine, and Kemadrin (procyclidine hydrochloride).

[0277] In some embodiments, the antiemetic agent comprises a steroid (e.g., a corticosteroid). Non-limiting examples of steroids include betamethasone, dexamethasone, methylprednisolone, Prednisone®, and trimethobenzamide (Tigan).

[0278] In certain embodiments, the antiemetic agent is an NK1 receptor antagonist (e.g., a neurokinin 1 substance P receptor antagonist). Non-limiting examples of NK1 receptor antagonists include aprepitant, casopitant, ezlopitant, fosaprepitant, maropitant, netupitant, rolapitant, and vestipitant.

[0279] Other non-limiting examples of NK1 receptor antagonists include MPC-4505, GW597599, MPC-4505, GR205171, L-759274, SR 140333, CP-96,345, BIIF 1149, NKP 608C, NKP 608A, CGP 60829, SR 140333 (norpitantium besylate / chloride), LY303870 (ranepitant), MDL-105172A, MDL-103896, MEN-11149, MEN-11467, DNK333A, YM-49244, YM-44778, ZM-274773, MEN-10930, S-19752, Neuronorm, YM-35375, DA-5018, MK-869, L-754030, CJ-11974, L-758298, DNK-33A, 6b-l, CJ-11974j. Benser azide and carbidopa k. Contains TAK-637 [(αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthyridine-6,13-dione], PD154075, ([(2-benzofuran)-CHOCO]-(R)-alpha-MeTrp-(S)-NHCH(CH)Ph), FK888, and (D-Pro, D-Trp, Phe)SP-11.

[0280] In some embodiments, the antiemetic agent is an antidopaminergic / dopamine receptor antagonist (e.g., a dopamine receptor antagonist, e.g., a D2 or D3 antagonist). Non-limiting examples include phenothiazines (e.g., promethazine, chlorpromazine, prochlorperazine, perphenazine, hydroxyzine, thiethylperazine, metopimazine, benzamides (e.g., metoclopramide, domperidone), butyrophenones (e.g., haloperidol, droperidol), alizapride, bromopride, clebopride, domperidone, itopride, metoclopramide, trimethobenzamide, and amisulpride.

[0281] In some embodiments, the antiemetic agent comprises a non-psychoactive cannabinoid (e.g., cannabidiol (CBD), cannabidiol dimethylheptyl (CBD-DMH), tetra-hydro-cannabinol (THC), a cannabinoid agonist such as WIN55-212 (aCB1 and CB2 receptor agonist), dronabinol (Marinol®), and nabilone (Cesamet)).

[0282] Other examples of antiemetics include c-9280 (Merck); benzodiazepines (diazepam, midazolam, lorazepam); neuroleptic / antipsychotics (e.g., dixyrazine, haloperidol, and prochlorperazine (Compazine®)); cerium oxalate; propofol; sodium citrate; dextrose; fructose (Nauzene); orthophosphate; fructose; glucose (Emetrol); bismuth subsalicylate (Pepto Bismol); ephedrine; vitamin B6; peppermint, lavender, and lemon essential oils; and ginger.

[0283] Still further examples of antiemetic agents include those described in US20120101089A1; US10,071,088B2; US6,673,792B1; US6,197,329B1; US10,828,297B2; US10,322,106B2; US10,525,033B2; WO2009080351A1; WO2019203753A2; WO2002020001A2; US8,119,697B2; US5,039,528; US20090305964A1; and WO2006 / 111169, each of which is incorporated herein by reference in its entirety.

[0284] In certain embodiments, the additional treatment or regimen is administered to the patient prior to contact or administration of the compound and pharmaceutical composition (e.g., about 1 hour, about 6 hours, about 12 hours, about 24 hours, about 48 hours, about 1 week, or about 1 month).

[0285] In some embodiments, the additional treatment or regimen is administered to the patient at approximately the same time as the contact or administration of the compound and the pharmaceutical composition.In one example, the additional treatment or regimen and the compound and the pharmaceutical composition are simultaneously provided to the patient in the same formulation.In another example, the additional treatment or regimen and the compound and the pharmaceutical composition are simultaneously provided to the patient in separate formulations.

[0286] Patient Selection In certain embodiments, the methods described herein further include identifying a patient (e.g., subject) in need of such treatment (e.g., by blood assay, body mass index, or other conventional methods known in the art).

[0287] In certain embodiments, the methods described herein further include a step of identifying a patient (e.g., a subject) having a disease, disorder, or condition (e.g., a GLP-1-associated disease, disorder, or condition) provided herein.

[0288] In certain embodiments, the methods described herein further include identifying a patient (e.g., a patient) with type 2 diabetes. In certain embodiments, determining whether a patient has type 2 diabetes includes performing an assay to determine hemoglobin A1c (HbA1c) levels, fasting blood glucose, non-fasting blood glucose, or any combination thereof. In certain embodiments, the HbA1c level is about 6.5% to about 24.0%. In certain embodiments, the HbA1c level is about 6.5% or higher. In certain embodiments, the HbA1c level is about 8.0% or higher. In certain embodiments, the HbA1c level is about 10.0% or higher. In certain embodiments, the HbA1c level is about 12.0% or higher. In certain embodiments, the HbA1c level is about 14.0% or higher. In certain embodiments, the HbA1c level is about 16.0% or higher. In certain embodiments, the HbA1c level is about 18.0% or higher. In some embodiments, the HbA1c level is about 20.0% or greater. In some embodiments, the HbA1c level is about 22.0% or greater. In some embodiments, the HbA1c level is about 24.0% or greater.

[0289] In some embodiments, fasting blood glucose levels are from about 120 mg / dL or higher to about 750 mg / dL or higher. In some embodiments, fasting blood glucose levels are from about 200 mg / dL or higher to about 500 mg / dL or higher. In some embodiments, fasting blood glucose levels are from about 300 mg / dL or higher to about 700 mg / dL or higher.

[0290] In some embodiments, non-fasting blood glucose levels are from about 190 mg / dL or higher to about 750 mg / dL or higher. In some embodiments, non-fasting blood glucose levels are from about 250 mg / dL or higher to about 450 mg / dL or higher. In some embodiments, non-fasting blood glucose levels are from about 400 mg / dL or higher to about 700 mg / dL or higher.

[0291] In some embodiments, determining whether a patient has type 2 diabetes further includes determining the patient's BMI. In some embodiments, the patient's BMI is about 22 kg / m 2 From the above, it is about 100 kg / m 2 In one embodiment, the patient's BMI is about 30 kg / m 2 From the above, it is about 90 kg / m 2 In one embodiment, the patient's BMI is about 40 kg / m 2 From the above, it is about 80 kg / m 2 In one embodiment, the patient's BMI is about 50 kg / m 2 From the above, it is about 70 kg / m 2 That's all.

[0292] In certain embodiments, additional factors (e.g., risk factors) used to determine whether a patient has type 2 diabetes further include the patient's age and ethnicity. In certain embodiments, the patient is about 10 years of age or older. In certain embodiments, the patient is about 15 years of age or older. In certain embodiments, the patient is about 20 years of age or older. In certain embodiments, the patient is about 25 years of age or older. In certain embodiments, the patient is about 30 years of age or older. In certain embodiments, the patient is about 35 years of age or older. In certain embodiments, the patient is about 40 years of age or older. In certain embodiments, the patient is about 42 years of age or older. In certain embodiments, the patient is about 44 years of age or older. In certain embodiments, the patient is about 46 years of age or older. In certain embodiments, the patient is about 48 years of age or older. In certain embodiments, the patient is about 50 years of age or older. In certain embodiments, the patient is about 52 years of age or older. In certain embodiments, the patient is about 54 years of age or older. In certain embodiments, the patient is about 56 years of age or older. In certain embodiments, the patient is about 58 years of age or older. In some embodiments, the patient is about 60 years of age or older. In some embodiments, the patient is about 62 years of age or older. In some embodiments, the patient is about 64 years of age or older. In some embodiments, the patient is about 66 years of age or older. In some embodiments, the patient is about 68 years of age or older. In some embodiments, the patient is about 70 years of age or older. In some embodiments, the patient is about 72 years of age or older. In some embodiments, the patient is about 74 years of age or older. In some embodiments, the patient is about 76 years of age or older. In some embodiments, the patient is about 78 years of age or older. In some embodiments, the patient is about 80 years of age or older. In some embodiments, the patient is about 85 years of age or older. In some embodiments, the patient is about 90 years of age or older. In some embodiments, the patient is about 95 years of age or older.In certain embodiments, the patient's ethnicity can be African American, American Indian or Alaska Native, Asian American, Hispanic or Latino, or Native Hawaiian or Pacific Islander. [Example]

[0293] The present invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

[0294] Example 1 3-((1S,2S)-1-(2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(4-((methylsulfonyl)methyl)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 101a) [ka] Step A: 1-Bromo-4-((methylsulfonyl)methyl)benzene A solution of 1-bromo-4-(bromomethyl)benzene (500 mg, 2.00 mmol) and sodium methanesulfinate (306 mg, 3.00 mmol) in DMF (5 mL) was heated at 65° C. for 1 h. The mixture was then cooled to room temperature, diluted with water (15 mL), and extracted with EA (3 × 20 mL). The combined organic phases were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the compound 1-bromo-4-((methylsulfonyl)methyl)benzene (470 mg crude), which was used directly in the next step. 1 H NMR (400 MHz, CDCl3) δ 7.53 - 7.59 (m, 2H), 7.25 - 7.33 (m, 2H), 4.20 (s, 2H), 2.78 (s, 3H)

[0295] Step B: (S)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(4-((methylsulfonyl)methyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate 1-Bromo-4-((methylsulfonyl)methyl)benzene (86.0 mg, 0.350 mmol), (S)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (100 mg, 0.230 mmol), (1S,2S)-N 1 ,N 2 A mixture of 1,2-dimethylcyclohexane-1,2-diamine (49.0 mg, 0.350 mmol), KCO (63.0 mg, 0.460 mmol), and CuI (66.0 mg, 0.350 mmol) in NMP (3 mL) was stirred at 130 °C under N for 3 h. The mixture was diluted with water and extracted with DCM. The organic layer was concentrated and purified to give (S)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(4-((methylsulfonyl)methyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate as a yellow oil (85.0 mg, 61% yield). 1 H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 6.0 Hz, 2H), 6.71 (d, J = 3.2 Hz, 1H), 6.31 (s, 1H), 5.21 - 5.42 (m, 1H), 4.30 - 4.54 (m, 1H), 4.27 (s, 2H), 3.08 - 3.20 (m, 1H), 2.75 - 2.85 (m, 5H), 2.21 (d, J = 2.0 Hz, 6H), 1.49 (s, 9H), 1.28 - 1.32 (m, 3H)

[0296] Step C: (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(4-((methylsulfonyl)methyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-ium chloride A solution of (S)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(4-((methylsulfonyl)methyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (85.0 mg, 0.140 mmol) in 4 M HCl solution in 1,4-dioxane (3 mL) was stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure. The residue was washed with EtO and dried under reduced pressure to give (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(4-((methylsulfonyl)methyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-ium chloride (60.0 mg, crude). 1 H NMR (400 MHz, CD3OD) δ 7.64 - 7.66 (m, 2H), 7.56 - 7.58 (m, 2H), 7.10 - 7.12 (m, 3H), 6.71 (d, J = 3.2 Hz, 1H), 4.72 (q, J = 6.8 Hz, 1H), 4.47 (s, 2H), 3.76 - 3.79 (m, 1H), 3.34 - 3.51 (m, 1H), 3.11 - 3.13 (m, 2H), 2.90 (s, 3H), 2.23 (d, J = 2.0 Hz, 6H), 1.49 (d, J = 6.8 Hz, 3H). LC-MS: m / z 510.3 (M+H) +

[0297] Step D: 3-((1S,2S)-1-(2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(4-((methylsulfonyl)methyl)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 [ka] (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(4-((methylsulfonyl)methyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-ium chloride (60.0 mg, 0.110 mmol), 1-((1S,2S)-2-methyl A solution of 1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (46.0 mg, 0.120 mmol), HATU (125 mg, 0.330 mmol), and TEA (222 mg, 2.20 mmol) in DMF (5 mL) was stirred overnight at room temperature. The mixture was diluted with water and extracted with DCM. The organic layer was washed with brine, dried over NaSO, concentrated and purified by preparative HPLC to give 3-((1S,2S)-1-(2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(4-((methylsulfonyl)methyl)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 as a white solid (20.0 mg, 21% yield). 1H NMR (400 MHz, DMSO-d6, 80℃) δ 11.59 (br.s, 1H), 7.66 (br.s, 2H), 7.46 - 7.57 (m, 3H), 7.43 (d, J = 8.4 Hz, 1H), 7.28 (dd, J = 8.4, 1.2 Hz, 1H), 7.19 - 7.25 (m, 1H), 7.15 (d, J = 6.4 Hz, 2H), 6.87 (br.s, 2H), 5.57 (br.s, 1H), 4.48 (s, 3H), 3.91 - 4.07 (m, 2H), 3.40 - 3.71 (m, 3H), 3.01 - 3.03 (m, 1H), 2.70 - 2.90 (m, 5H), 2.22 (d, J = 1.6 Hz, 6H), 1.56 - 1.85 (m, 7H), 1.41 - 1.48 (m, 3H), 1.12 - 1.21 (m, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -121.98. LC-MS: m / z 875.2 (M+H) +

[0298] The following compound was synthesized in a manner analogous to Example 1 (compound 101a). 3-((1S,2S)-1-(2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(3-((methylsulfonyl)methyl)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 102a) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) δ 11.59 (br.s, 1H), 7.72 (s, 1H), 7.62 (s, 1H), 7.53 (s, 1H), 7.46 - 7.50 (m, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.28 (dd, J = 8.0, 4.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 3H), 6.86 (d, J = 8.0 Hz, 2H), 5.56 (br.s, 1H), 4.49 (s, 3H), 3.95 - 4.02 (m, 2H), 3.46 - 3.64 (m, 3H), 2.99 - 3.05 (m, 1H), 2.81 - 2.94 (m, 5H), 2.23 (d, J = 4.0 Hz, 6H), 1.59 - 1.83 (m, 7H), 1.41 -1.49 (m, 3H), 1.11 - 1.20 (m, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -121.96. LCMS: m / z = 875.2 (M+H) +

[0299] 3-((1S,2S)-1-(2-((S)-3-(3-(4-((ethylsulfonyl)methyl)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 103a) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) δ 11.62 (br.s, 1H), 7.66 (s, 2H), 7.43 - 7.53 (m, 4H), 7.14 - 7.29 (m, 4H), 6.86 (s, 2H), 5.58 (br.s, 1H), 4.45 (s, 3H), 3.97 - 4.00 (m, 2H), 3.46 - 3.53 (m, 3H), 3.01 - 3.05 (m, 3H), 2.84 - 2.91 (m, 2H), 2.22 (d, J = 2.0 Hz, 6H), 1.63 - 1.78 (m, 7H), 1.39 - 1.47 (m, 3H), 1.25 (t, J = 7.6 Hz, 3H), 1.11 - 1.20 (m, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -121.xx. LCMS: m / z = 889.2 (M+H) +

[0300] 4-(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)-N-methylbenzenesulfonamide (Compound 104a) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) δ 11.59 (br.s, 1H), 7.78 - 7.80 (m, 4H), 7.52 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.32 (s, 1H), 7.23 - 7.29 (m, 2H), 7.15 (d, J = 6.4 Hz, 2H), 6.93 (s, 1H), 6.88 (s, 1H), 5.57 (br.s, 1H), 4.46 (br.s, 1H), 3.97 - 3.99 (m, 2H). 3.44 - 3.58 (m, 3H), 3.02 - 3.05 (m, 1H), 2.84 - 2.92 (m, 2H), 2.47 (d, J = 5.2 Hz, 3H), 2.22 (d, J = 2.0 Hz, 6H), 1.68 - 1.78 (m, 6H), 1.62 - 1.66 (m, 1H), 1.40 - 1.47 (m, 3H), 1.11 - 1.19 (br.s, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -121.85. LCMS: m / z = 876.2 (M+H) +

[0301] 3-((1S,2S)-1-(2-((S)-3-(3-(3-(1,1-dioxidoisothiazolidin-2-yl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 106a) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) δ 11.59 (br.s, 1H), 7.53 (s, 1H), 7.50 (s, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.35 (bs, 1H), 7.27 (dd, J = 12.0, 4.0 Hz, 1H), 7.10 - 7.25 (m, 4H), 6.86 (s, 2H), 5.58 (br.s, 1H), 4.46 (br.s, 1H), 3.97 - 4.05 (m, 2H), 3.77 (t, J = 8.0 Hz, 2H), 3.46 - 3.70 (m, 5H), 2.88 - 3.00 (m, 2H), 2.42 - 2.47 (m, 3H), 2.23 (d, J = 4.0 Hz, 6H), 1.72 - 1.78 (m, 6H), 1.61 - 1.67 (m, 1H), 1.40 - 1.49 (m, 3H), 1.10 - 1.20 (m, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -121.96. LC-MS: m / z 902.2 (M+H) +

[0302] 3-((1S,2S)-1-(2-((S)-3-(3-(4-(1,1-dioxidoisothiazolidin-2-yl)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 107a) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) δ 11.53 (br.s, 1H), 7.53 - 7.69 (m, 3H), 7.43 (d, J = 8.4 Hz, 1H), 7.22 - 7.36 (m, 3H), 7.05 - 7.20 (m, 3H), 6.75 - 6.87 (m, 2H), 5.56 (br.s, 1H), 4.46 (br.s, 1H), 3.93 - 4.04 (m, 2H), 3.77 (t, J = 6.4 Hz, 2H), 3.43 - 3.57 (m, 5H), 2.84 - 2.94 (m, 3H), 2.41 - 2.50 (m, 2H), 2.22 (d, J = 0.8 Hz, 6H), 1.69 - 1.77 (m, 6H), 1.61 - 1.69 (m, 1H), 1.39 - 1.49 (m, 3H), 1.09 - 1.22 (m, 3H).. 19 F NMR (377 MHz, DMSO-d6) δ -122.01, -122.06. LC-MS: m / z 451.7 (M / 2+H) +

[0303] N-(4-(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 105a) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) δ 11.60 (br.s, 1H), 9.59 (s, 1H), 7.43 - 7.60 (m, 4H), 7.27 - 7.31 (m, 3H), 7.10 - 7.25 (m, 3H), 6.85 (d, J = 8.4 Hz, 2H), 5.57 (br.s, 1H), 4.47 (br.s, 1H), 3.99 (d, J = 10.8 Hz, 2H), 3.46 - 3.61 (m, 3H), 3.00 (s, 3H), 2.87 - 2.91 (m, 3H), 2.22 (d, J = 1.2 Hz, 6H), 1.65 - 1.78 (m, 7H), 1.34 - 1.52 (m, 3H), 1.08 - 1.24 (m, 3H).. 19 F NMR (377 MHz, DMSO-d6) δ -121.XX. LC-MS: m / z 876.2 (M+H) +

[0304] 3-((1S,2S)-1-(2-((S)-3-(3-(4-(cyclopropylsulfonyl)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 108a) [ka] 1H NMR (400 MHz, DMSO-d6, 80℃) δ 11.60 (br.s, 1H), 7.81 - 8.07 (m, 4H), 7.52 (s, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.35 (s, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 6.0 Hz, 2H), 6.94 (s, 1H), 6.86 (s, 1H), 5.58 (br.s, 1H), 4.47 (br.s, 1H), 3.98 (d, J = 10.4 Hz, 2H), 3.46 - 3.54 (m, 3H), 2.82 - 3.03 (m, 4H), 2.22 (s, 6H), 1.65 - 1.77 (m, 7H), 1.44 (s, 3H), 1.06 - 1.55 (m, 7H). 19 F NMR (377 MHz, DMSO-d6) δ -121.85. LC-MS: m / z 887.4 (M+H) +

[0305] 3-((1S,2S)-1-(2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(3-(2-(methylsulfonyl)ethyl)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 109a) [ka] 1H NMR (400 MHz, DMSO-d6) δ 11.58 (br.s, 1H), 7.34 - 7.63 (m, 5H), 7.17 - 7.30 (m, 3H), 7.15 (d, J = 6.4 Hz, 2H), 6.75 - 7.00 (m, 2H), 5.56 (br.s, 1H), 4.47 (br.s, 1H), 3.98 (d, J = 10.8 Hz, 2H), 3.36 - 3.71 (m, 5H), 3.10 - 3.18 (m, 3H), 2.96 (s, 3H), 2.87 - 2.91 (m, 2H), 2.22 (s, 6H), 1.59 - 1.84 (m, 7H), 1.34 - 1.52 (m, 3H), 1.08 - 1.24 (m, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -121.99. LC-MS: m / z 889.4 (M+H) +

[0306] 3-((1S,2S)-1-(2-((4S)-3-(3-(4-(1-(ethylsulfonyl)ethyl)-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 111a) [ka] 1HNMR (400 MHz, DMSO-d6, 80℃) δ 11.59 (brs, 1H), 7.43 - 7.75 (m, 3H), 7.30 - 7.43 (m, 2H), 7.25 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 6.0 Hz, 2H), 6.94 (s, 1H), 6.68 - 6.90 (m, 2H), 5.54 (br.s, 1H), 4.61 (q, J = 7.2 Hz, 1H), 4.34 - 4.53 (m, 1H), 3.96 (d, J = 10.4 Hz, 2H), 3.37 - 3.71 (m, 3H), 2.91 - 3.01 (m, 3H), 2.81 - 2.90 (m, 2H), 2.23 (s, 6H), 1.68 - 1.96 (m, 4H), 1.65 (d, J = 6.8 Hz, 6H), 1.44 (s, 3H), 0.97 - 1.24 (m, 6H). 19 F NMR (377 MHz, DMSO-d6) δ -121.44, -122.18. LC-MS: m / z 921.4 (M+H) +

[0307] (S)-3-(1-(2-(3-(3-(4-((ethylsulfonyl)methyl)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 112a) [ka] 1 H NMR (400 MHz, DMSO-d6, 80 oC) δ 11.78 (s, 1H), 7.63 (d, J = 6.4 Hz, 2H), 7.47 (d, J = 8.8 Hz, 4H), 7.19 - 7.23 (m, 2H), 7.12 (d, J = 6.0 Hz, 2H), 6.82 (s, 1H), 6.76 (s, 1H), 5.53 (br.s, 1H), 4.40 - 4.52 (m, 1H), 4.42 (s, 2H), 3.96 (d, J = 10.8 Hz, 2H), 3.44 - 3.51 (m, 3H), 2.98 - 3.01 (m, 1H), 2.79 - 2.90 (m, 2H), 2.20 (s, 6H), 1.68 - 1.80 (m, 7H), 1.51 (brs, 1H), 1.36 (d, J = 6.4 Hz, 3H), 1.29 (d, J = 7.2 Hz, 2H), 1.23 (t, J = 7.2 Hz, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -122.09. LC-MS: m / z 875.4 (M+H) +

[0308] 3-(1-(2-((4S)-3-(3-(4-(1-(ethylsulfonyl)ethyl)-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)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 113a) [ka] 1 H NMR (400 MHz, DMSO-d6, 80 oC) δ 11.80 (s, 1H), 7.43 - 7.60 (m, 4H), 7.39 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 9.2 Hz, 1H), 7.13 (d, J = 6.0 Hz, 2H), 6.93 (s, 1H), 6.78 (d, J = 7.2 Hz, 2H), 5.52 (br.s, 1H), 4.57 - 4.65 (m, 1H), 4.32 - 4.56 (m, 1H), 3.89 - 4.03 (m, 2H), 3.48 (td, J = 10.8, 3.2 Hz, 3H), 2.92 - 3.02 (m, 3H), 2.78 - 2.89 (m, 2H), 2.22 (s, 6H), 1.61 - 1.86 (m, 10H), 1.46 - 1.61 (m, 1H), 1.38 (d, J = 6.4 Hz, 3H), 1.19 (t, J = 7.6 Hz, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -69.20, -71.09, -121.44, -122.26. LC-MS: m / z 907.4 (M+H) +

[0309] Example 2 3-((1S,2S)-1-(2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(2-fluoro-4-(2-(methylsulfonyl)ethyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 110a) [ka] Step A: Methyl 2-(4-bromo-3-fluorophenyl)acetate To a mixture of 2-(4-bromo-3-fluorophenyl)acetic acid (2.70 g, 11.6 mmol) in methanol (22 mL) was added thionyl chloride (1.6 mL) at room temperature. The resulting mixture was stirred at 50° C. for 6 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica column chromatography (PE / EA= 3 / 1) to give methyl 2-(4-bromo-3-fluorophenyl)acetate as an oil (2.90 g, 100% yield). LC-MS: m / z 247.0 (M+H) +

[0310] Step B: 2-(4-bromo-3-fluorophenyl)ethan-1-ol To a mixture of methyl 2-(4-bromo-3-fluorophenyl)acetate (2.90 g, 11.7 mmol) in THF (10 mL) was added lithium borohydride (510 mg, 23.4 mmol) at 0 °C. The resulting mixture was then stirred at room temperature for 2 h. Methanol (10 mL) was added to the mixture to quench the reaction, and the mixture was then concentrated under reduced pressure and purified by silica column chromatography (PE / EA = 10 / 1 to 3 / 1) to give 2-(4-bromo-3-fluorophenyl)ethan-1-ol as an oil (2.00 g, 77.8% yield). LC-MS: m / z 220.0 (M+H) +

[0311] Step C: 1-Bromo-4-(2-bromoethyl)-2-fluorobenzene To a mixture of 2-(4-bromo-3-fluorophenyl)ethan-1-ol (2.00 g, 9.13 mmol) in DCM (22 mL) was added triphenylphosphine (2.99 g, 11.4 mmol) and N-bromosuccinimide (2.11 g, 11.9 mmol) at 0 °C. The resulting mixture was stirred at 0 °C to room temperature for 1 h. Water (20 mL) was added to the mixture to quench the reaction, and then DCM (30 mL) was added to the mixture. The aqueous phase was extracted with DCM (30 mL). The combined organic layers were washed three times with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography (PE / EA = 6 / 1) to give 1-bromo-4-(2-bromoethyl)-2-fluorobenzene as an oil (2.35 g, 91.3% yield).1 H NMR (400 MHz, CDCl3) δ 7.46 - 7.52 (m, 1H), 7.00 (dd, J = 9.6, 2.0 Hz, 1H), 6.86 - 6.92 (m, 1H), 3.55 (t, J = 7.2 Hz, 2H), 3.13 (t, J = 7.2 Hz, 2H) [ka] 3-((1S,2S)-1-(2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(2-fluoro-4-(2-(methylsulfonyl)ethyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-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 then synthesized according to the route of Example 1, using 1-bromo-4-(2-bromoethyl)-2-fluorobenzene in Step A. 1 H NMR (400 MHz, DMSO-d6, 80 o C) δ 11.60 (s, 1H), 7.53 (s, 1H), 7.32 - 7.47 (m, 3H), 7.27 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 6.0 Hz, 2H), 6.73 - 6.97 (m, 3H), 5.55 (br.s, 1H), 4.34 - 4.58 (m, 1H), 3.98 (d, J = 10.4 Hz, 2H), 3.40 - 3.68 (m, 5H), 3.13 - 3.18 (m, 1H), 2.99 (s, 3H), 2.81 - 2.93 (m, 2H), 2.24 (s, 6H), 1.58 - 1.81 (m, 7H), 1.40 - 1.51 (m, 3H), 1.16-1.26 (m, 5H). 19F NMR (377 MHz, DMSO-d6) δ -122.03, -122.22. LC-MS: m / z 907.4 (M+H) +

[0312] Example A: cAMP Assay Activation of the GLP-1 receptor is mediated by the G protein heterotrimer G αs It is known that G activates the production of cyclic AMP (cAMP) in cells that exhibit initial binding to the G subunit. αs These results suggest that inducible cAMP-stimulated signaling provides a desirable pharmacological response for insulin release from pancreatic β-cells.

[0313] G αs To optimize functional activity for binding, the HEK293 / CRE-Luc cell line developed by HDB, which stably expresses the GLP-1 receptor, was used. A 200x compound working solution (Agilent Technologies Bravo) was prepared in a 1 / 2 log serial dilution in a 384-well Echo LDV plate (Labcyte, Cat# LP-0200). 50 nL / well of the 200x compound working solution was transferred to a 384-well white low-volume plate (Greiner, Cat# 784075) using a Labcyte ECHO550. 1x10 5 Cells / mL of HEK293 / GLP1R / CRE-LUC (HD Biosciences) cell suspension is prepared in assay buffer (DPBS containing 0.5mM IBMX (Sigma, Cat#I5879) and 0.1% BSA (GENVIEW, Cat#FA016-100g)). 10 μL of cell suspension is added to each well of the pre-made assay plate containing 50nL of compound at 200x concentration using ThermoFisher Multidrop Combi (1000 cells / well). The plate is sealed and incubated at 37°C under 5% CO2 for 30 minutes.

[0314] After incubation, the cAMP assay signal was developed using a cAMP dynamic 2 Kit (Cisbio). Five microliters of cAMP-d2 working solution was added to each well, followed by 5 μL of anti-cAMP antibody-cryptate working solution using a ThermoFisher Multidrop Combi. The plates were incubated at room temperature for 1 hour, protected from light. Luminescence was read at 665 nm and 615 nm using a PerkinElmer EnVision reader. % Activity = 100% x (mean RLU of test sample - mean RLU of vehicle control) / (mean RLU of MAX control - mean RLU of vehicle control)

[0315] Table 1 shows the cAMP stimulation assay (EC 50 ) [nM] indicates the biological activity of the compound. [Table 7]

[0316] Other embodiments While the present invention has been described in conjunction with its detailed description, it is to be understood that the description is intended to be illustrative and not limiting of the scope of the invention, which is defined by the claims. Other aspects, advantages, and modifications are within the scope of the following claims. Furthermore, the present invention encompasses the following aspects. 1. Formula (I) [ka] [During the ceremony, Ring D is C 3-15 Cycloalkyl; 3- to 12-membered heterocyclyl; 5- to 10-membered heteroaryl; and C 6-10 aryl, each of which is optionally R QA and R QB and is substituted with 1 to 6 substituents independently selected from the group consisting of: However, (aa) or (bb) (aa) Ring D has at least one RQB is replaced by; or (bb) Ring D is a 4- to 12-membered heterocyclyl or a 7- to 10-membered bicyclic heteroaryl, wherein Ring D is an endocyclic S(O) 2 Contains groups apply, and Each R QA teeth (a) Halo; (b) cyano; (c) OH or oxo; (d) -NR a R b ; (e) -C(=O)NR c R d ; (f) optionally 1 to 6 independently selected R f C is replaced by 1-6 alkyl; (g) optionally 1 to 6 independently selected R f C is replaced by 1-6 Alkoxy; (h) optionally 1 to 6 independently selected R g 3- to 12-membered heterocyclyl substituted with; (i) optionally, 1 to 6 independently selected R g C is replaced by 6-10 aryl; (j) optionally 1 to 6 independently selected R g 5-10 membered heteroaryl substituted with; and (k) optionally 1 to 6 independently selected R g C is replaced by 3-8 cycloalkyl independently selected from the group consisting of: Each R QB teeth -L a -S(O) 2 -L b -R e ; and 4-12 membered heterocyclyl or 7-10 membered bicyclic heteroaryl, each having an endocyclic S(O) 2 group, where heterocyclyl or heteroaryl is optionally present in 1 to 6 independently selected R g is replaced by independently selected from the group consisting of: L a -N(H)-, -N(R c )- and -(CR h R h ) q1 - selected from the group consisting of; L b -O-, -N(H)-, -N(R c )- and -(CR h R h ) q2 - selected from the group consisting of; q1 and q2 are independently 0, 1, 2, 3, or 4; However, L a -(CR h R h ) q1 - and if q1 is 0, then -L b -R e is unsubstituted C 1-3 is other than alkyl; L 2 teeth

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Claims

1. Formula (I) 【Chemistry 1】 [During the ceremony, Ring D is a 5- to 10-membered heteroaryl and C ６－１０ aryl, each of which is optionally R ＱＡ and R ＱＢ substituted with 1 to 6 substituents independently selected from the group consisting of: however Ring D is at least one R ＱＢ is replaced by Each R ＱＡ teeth (a) halo; (b) cyano; (c) OH or oxo; (d) -NR ａ R ｂ ; (e) -C(=O)NR ｃ R ｄ ; (f) optionally 1 to 6 independently selected R ｆ C substituted with １－６ Alkyl; (g) optionally 1 to 6 independently selected R ｆ C substituted with １－６ Alkoxy; (h) optionally 1 to 6 independently selected R ｇ 3- to 12-membered heterocyclyl substituted by (i) optionally 1 to 6 independently selected R ｇ C substituted with ６－１０ aryl; (j) optionally 1 to 6 independently selected R ｇ 5-10 membered heteroaryl substituted with; and (k) optionally 1 to 6 independently selected R ｇ C substituted with ３－８ cycloalkyl are independently selected from the group consisting of: Each R ＱＢ teeth (a)-L ａ -S(O) ２ -L ｂ -R ｅ and (b) a 4- to 12-membered heterocyclyl or a 7- to 10-membered bicyclic heteroaryl, each of which is an endocyclic S(O) ２ group, where heterocyclyl or heteroaryl is optionally present at 1 to 6 independently selected R ｇ is replaced by are independently selected from the group consisting of: L ａ is -N(H)-, -N(R ｃ )- and -(CR ｈ R ｈ ) ｑ１ - selected from the group consisting of; L ｂ is -O-, -N(H)-, -N(R ｃ )- and -(CR ｈ R ｈ ) ｑ２ - selected from the group consisting of; q1 is 1, 2, 3 or 4, and q2 is 0, 1, 2, 3 or 4; L ２ teeth 【Chemistry 2】 is selected from the group consisting of where aa is the point of attachment to Ring D; n1 is an integer from 1 to 3; L ２Ａ is a bond or C １－１０ alkylene; R Ｌａ is H, C １－６ Alkyl and C(=O)(C １－６ alkyl); R Ｌｂ and R Ｌｃ Each of １－６ independently selected from the group consisting of alkyl; Ring A is C ６－１０ aryl or 5- to 10-membered heteroaryl, each of which is optionally and independently selected from halo, C １－６ Alkyl, C １－６ Haloalkyl and C １－６ substituted with 1 to 5 substituents selected from the group consisting of alkoxy; R １ , R ２ and R ３ are each independently H and optionally halo, —OH and C １－６ C substituted with 1 to 6 substituents independently selected from the group consisting of alkoxy １－６ selected from the group consisting of alkyl; L １ is —C(═O)—; Ring B is 【Transformation 3】 is selected from the group consisting of where bb is L １ represents a point of attachment to R ４ , R ５ , R ６ and R ７ are independently H, halo, and C １－６ selected from the group consisting of alkyl; L ３ is a bond or C １－３ alkylene; L ４ is a bond or C １－５ alkylene; R ８ａ and R ８ｂ are independently H and optionally halo and C ３－１５ halo and C substituted with one or more substituents selected from the group consisting of cycloalkyl ３－１５ cycloalkyl; or R ８ａ and R ８ｂ Each carbon atom is bonded to a carbon atom. ３－１５ Forms a cycloalkyl ring, which optionally includes C １－６ substituted with 1 to 3 groups independently selected from alkyl, wherein C １－６ Alkyl is optionally 1 to 6 independently selected R ｆ is substituted with; R ９ is C(=O)OH, C(=O)(OC １－６ alkyl), C(=O)NR ９ａ R ９ｂ , (IX-1), (IX-2), (IX-3) and (IX-4): 【Chemistry 4】 R ９ａ is H or C １－６ is alkyl; R ９ｂ is H, C １－６ Alkyl, C(=O)(C １－６ alkyl), S(O) ０－２ (C １－６ alkyl) or cyano; R ９ｃ , R ９ｄ , R ９ｅ , R ９ｆ and R ９ｇ are each independently H; optionally 1 to 6 independently selected halo and C １－６ C substituted with alkoxy １－６ alkyl; and C(═O)(C １－６ alkyl); Ring C is a 3- to 12-membered heterocyclyl and C ３－１５ cycloalkyl, each of which optionally has 1 to 3 R Ｃａ is substituted with; Each R Ｃａ Halo, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy and NR ｃ R ｄ are independently selected from the group consisting of: or a pair of R on the same or different ring carbons Ｃａ each taken together with the ring atom to which it is attached forms a carbocyclic ring containing 3 to 8 ring atoms; Each R ａ and R ｂ is H, C １－６ Alkyl, C ３－６ Cycloalkyl, C(=O)(C １－６ alkyl), C(=O)(C ３－６ cycloalkyl) and C(=O)O(C １－６ alkyl), wherein C １－６ Alkyl, C ３－６ Cycloalkyl, C(=O)(C １－６ alkyl), C(=O)(C ３－６ cycloalkyl) and C(=O)O(C １－６ alkyl) are each optionally —OH, halo, and C １－６ substituted with 1 to 6 substituents independently selected from the group consisting of alkoxy; Each R ｃ and R ｄ is H, C １－６ Alkyl, C ３－６ Cycloalkyl, 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 ３－６ Cycloalkyl, 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 —OH, halo, and C １－６ substituted with 1 to 6 substituents independently selected from the group consisting of alkoxy; R ｅ is H or R ｅ is C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C ３－６ cycloalkyl and 3- to 8-membered heterocyclyl, each of which is optionally halo, cyano, C １－３ Alkyl, C １－３ Haloalkyl, —OH, NH ２ , NH(C １－３ alkyl), N(C １－３ alkyl) ２ , C １－３ Alkoxy and C １－３ substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy; Each R ｆ is halo, -OH, NR ｃ R ｄ , C １－６ Alkoxy, C １－６ Haloalkoxy and optionally —OH, C １－６ independently selected from the group consisting of 3- to 12-membered heterocyclyl substituted with 1 to 4 substituents each independently selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; Each R ｇ is C １－６ Alkyl, C １－６ Haloalkyl, C １－６ア Lukoxi, C １－６ Haloalkoxy, NR ｃ R ｄ , Cyano, Halo, C ３－６ Cycloalkyl and optionally C １－６ Alkyl and C(=O)C １－６ independently selected from the group consisting of 3- to 12-membered heterocyclyl substituted with one or more substituents each independently selected from the group consisting of alkyl; and R ｈ In each case, H and C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ independently selected from the group consisting of cycloalkyl and halo; or A pair of R on the same or different carbons ｈ are C together with the carbon atoms to which they are attached. ３－６ cycloalkyl or 4- to 8-membered heterocyclyl, each of which is optionally halo, cyano, C １－３ Alkyl, C １－３ Haloalkyl, —OH, C １－３ Alkoxy and C １－３ and haloalkoxy. or a pharmaceutically acceptable salt or solvate thereof.

2. Ring D is a 5- to 10-membered heteroaryl; and C ６ ~ １０ aryl, each of which is selected from the group consisting of one R ＱＢ and optionally substituted with 1 to 5 independently selected R ＱＡ 10. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R is substituted with R.

3. Ring D 【Transformation 5】 where Q １ , Q ２ , Q ４ and Q ５ are each independently N, CH, or CR ＱＡ or ring D is 【Transformation 6】 where Q １ , Q ２ , Q ３ and Q ５ are each independently N, CH, or CR ＱＡ 3. The compound of claim 1 or 2, wherein:

4. Ring D 【Transformation 7】 or 【Transformation 8】 The compound of any one of claims 1 to 3, wherein m1 is 0, 1 or 2, or a pharmaceutically acceptable salt or solvate thereof.

5. R ＱＢ but -(CR ｈ R ｈ ) ｑ１ -S(O) ２ -(CR ｈ R ｈ ) ｑ２ -R ｅ q1 is 1 or 2; -NHS(O) ２ -(CR ｈ R ｈ ) ｑ２ -R ｅ and q2 is 0; and R ｅ is C １－６ Alkyl, C １－６ haloalkyl or C ３－６ cycloalkyl, each of which is optionally halo, cyano, C １－３ Alkyl, C １－３ Haloalkyl, —OH, NH ２ , NH(C １－３ alkyl), N(C １－３ alkyl) ２ , C １－３ Alkoxy and C １－３ substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy; A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof.

6. R ＱＢ Ga-CH ２ -S(O) ２ (C １－６ alkyl), -CH(C １－６ alkyl)-S(O) ２ (C １－６ alkyl) or -CH ２ CH ２ -S(O) ２ (C １－６ 6. The compound of claim 1, wherein R is 1 or 2; R is 2 or 3; R is 3 or 4; R is 4 or 5; R is 5 or 6; R is 6 or 7; R is 7 or 8; R is 8 or 9; R is 9 or 10;

7. R ＱＢ but 【Chemistry 9】 where the ring Q ２ But the ring N-S(O) ２ In addition to the groups N, O and S(O) ０－２ and wherein ring Q is a 4-8 membered heterocyclyl containing 0-2 additional ring heteroatoms independently selected from the group consisting of: ２ optionally 1 to 4 independently selected R ｇ and ring Q is substituted with ２ optionally 1 to 4 independently selected R ｇ 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, substituted with:

8. R ＱＢ but 【Chemistry 10】 8. The compound of claim 7, wherein:

9. R ＱＡ 9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, wherein one of is -halo.

10. R １ and R ２ is H; and R ３ is C １－６ 10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, wherein:

11. R ３ 11. The compound of claim 10, or a pharmaceutically acceptable salt or solvate thereof, wherein is methyl.

12. L ２ but 【Chemistry 11】 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt or solvate thereof.

13. Ring A is phenyl or pyridyl, each of which is optionally halo, C １－６ Alkyl, C １－６ Haloalkyl and C １－６ 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt or solvate thereof, substituted with 2 to 4 substituents independently selected from the group consisting of alkoxy.

14. Ring A is 【Chemistry 12】 where R ＡＡ , R ＡＢ and R ＡＣ are independently halo or C １－６ 14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt or solvate thereof, wherein:

15. L １ The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt or solvate thereof, wherein is C(=O).

16. Ring B 【Chemistry 13】 16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt or solvate thereof.

17. R ４ , R ５ and R ６ 17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, wherein each is H or halo.

18. R ８ａ and R ８ｂ together with the carbon atoms to which they are bonded, 【Chemistry 14】 18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt or solvate thereof, which forms:

19. R ９ but 【Chemistry 15】 19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt or solvate thereof:

20. 20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt or solvate thereof, wherein Ring C is a 3- to 12-membered heterocyclyl optionally substituted with a 3- to 12-membered heterocyclyl.

21. Ring C 【Chemistry 16】 21. The compound of claim 20, selected from the group consisting of: or a pharmaceutically acceptable salt or solvate thereof.

22. The compound of formula (IA) 【Chemistry 17】 [During the ceremony, m1 is 0, 1 or 2; R ＱＢ But-(CR ｈ R ｈ ) ｑ１ - and S(O) ２ -(CR ｈ R ｈ ) ｑ２ -R ｅ where R ＱＢ L ２ is meta or para to; q1 is 1 or 2; Ring E is C ３－６ is cycloalkyl; and R ８ｃ is H and optionally 1 to 3 independently selected R ｆ C selected from the group consisting of １－６ alkyl.

22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:

23. A compound or a pharmaceutically acceptable salt or solvate thereof selected from the following compounds or a pharmaceutically acceptable salt or solvate thereof: Table 1 Table 2 Table 3 Table 4

24. A compound or a pharmaceutically acceptable salt or solvate thereof selected from the following compounds or a pharmaceutically acceptable salt or solvate thereof: Table 5 Table 6 Table 7 Table 8

25. A pharmaceutical composition comprising a compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient.

26. 26. The pharmaceutical composition of claim 25 for treating type 2 diabetes.

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