Heterocyclic GLP-1 agonists

Abstract

The present invention relates to GLP-1 agonists, pharmaceutical compositions and methods of use thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of International Patent Application Nos. PCT / CN2022 / 079865, filed March 9, 2022, and PCT / CN2022 / 141072, filed December 22, 2022, each of which is incorporated herein by reference in its entirety.

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

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

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

[0005] In healthy individuals, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) provide tandem regulation of the insulin secretory response to glucose digestion. Although this incretin effect is significantly reduced (if present) in 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 T2DM patients. Summary of the Invention

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

[0007] Thus, Formula I: [ka] [During the ceremony, X is C and Y is N, or Y is C and X is N, and the dashed line represents the part [ka] but [ka] where bond y is bonded to Y and bond x is bonded to X; 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 selected from halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-6 optionally substituted with 1 to 5 substituents each independently selected from the group consisting of cycloalkyl; R 1 , R 2 and R 3 is H and halo, -OH and C 1-6 C optionally substituted with 1 to 6 substituents each independently selected from the group consisting of alkoxy 1-6 each independently selected from the group consisting of alkyl; L 1 -C(=O)-, -CH2-, -CH(C 1-6 -S(=O)2; Ring B is [ka] [ka] (In the formula, 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 halo and C 3-15 C optionally substituted with one or more substituents independently selected from cycloalkyl 1-6 selected from alkyl; or R 8a and R 8b Each independently selected 1 to 3 C's, together with the carbon atom to which it is bonded, 1-6 C optionally substituted with alkyl 3-15 Form a cycloalkyl ring, wherein said C 1-6 alkyl is 1 to 6 independently selected R f may be substituted with; or Part-L 3 -C(R 8a R 8b )-L 4 -R 9 is substituted with C(=O)OH and R f phenyl optionally substituted with 1 to 4 additional substituents independently selected from R 9 are C(=O)OH, C(=O)(OC 1-6 alkyl), C(=O)NR 9a R 9b , (IX-1), (IX-2), (IX-3) and (IX-4): [ka] selected from the group consisting of: R 9a is H or C 1-6 is alkyl; R 9b is H, C 1-6 Alkyl, C(=O)(C 1-6 alkyl), S(O) 0-2 (C 1-6 alkyl) or cyano; R 9c , R 9d , R 9e , R 9f and R 9g H, independently selected 1 to 6 halo groups, and C 1-6 C optionally substituted with alkoxy 1-6 Alkyl and C(=O)(C 1-6 alkyl) selected from the group consisting of: Ring C is a 3- to 12-membered heterocyclyl, C 3-15 cycloalkyl and 5- to 10-membered heteroaryl, each of which is selected from 1 to 3 R Ca may be substituted with; Each R Ca independently, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and NRc R d or selected from the group consisting of; or a pair of R on the same or different ring atoms Ca each together with the ring atom to which it is attached forms a carbocyclic ring containing 3 to 8 ring atoms; Ring C is a 3- to 12-membered heterocyclyl, C 3-15 cycloalkyl and 5- to 10-membered heteroaryl, each of which is selected from the group consisting of 1 to 3 R Ca may be substituted with; Each R Ca independently, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and NR c R d or selected from the group consisting of; or a pair of R on the same or different ring atoms Ca each together with the ring atom to which it is attached forms a carbocyclic ring containing 3 to 8 ring atoms; L 2 teeth, [ka] (In the formula, aa represents the point of attachment to Q; n1 is an integer of 1 to 3; L 2A is a bond or C 1-10 is alkylene; R La is H, C 1-6 Alkyl and C(=O)(C 1-6 alkyl); R Lb and R Lc each independently represents H and C 1-6 alkyl) selected from the group consisting of: Q is C 1-10 Alkyl; C 3-15 Cycloalkyl; 3- to 12-membered heterocyclyl; 5- to 10-membered heteroaryl; and C 6-10aryl, wherein said Q is selected from the group consisting of -P(=O)R a R b and R Q and optionally substituted with 1 to 6 further substituents selected from: Each R Q are independently the following (a) to (n): (a) Halo; (b) cyano; (c) OH or oxo; (d)-NR c R d ; (e)-C(=O)NR c R d or -S(O)NR c R d ; (f)-S(=O) 0-2 R e ; (g) 1 to 6 independently selected R f C optionally substituted with 1-6 alkyl; (h) 1 to 6 independently selected R f C optionally substituted with 1-6 Alkoxy; (i) 1 to 6 independently selected R g 3- to 12-membered heterocyclyl optionally substituted by; (j) 1 to 6 independently selected R g C optionally substituted with 6-10 aryl; (k) 1 to 6 independently selected R g 5-10 membered heteroaryl optionally substituted by; (l) 1 to 6 independently selected R g C optionally substituted with 3-8 cycloalkyl; (m)-P(=O)R a R b ; and (n)q1 is 1, 2 or 3 - (CR h R h ) q1 -S(O)2-L e -Re ; or selected from the group consisting of Or, Q is C 3-15 cycloalkyl; 3- to 12-membered heterocyclyl; 5- to 10-membered heteroaryl; or C 6-10 aryl, each of which is R QA and R QB may be substituted with 1 to 6 substituents each independently selected from the group consisting of However, the following (aa) or (bb): (aa) Q is at least one R QB is replaced by, or (bb) Q is a 4- to 12-membered heterocyclyl or a 7- to 10-membered bicyclic heteroaryl containing an endocyclic S(O)2 group; and / or Each R QA are independently the following (a) to (k): (a) Halo; (b) cyano; (c) OH or oxo; (d)-NR a R b ; (e)-C(=O)NR c R d ; (f) 1 to 6 independently selected R f C optionally substituted with 1-6 alkyl; (g) 1 to 6 independently selected R f C optionally substituted with 1-6 Alkoxy; (h) 1 to 6 independently selected R g 3- to 12-membered heterocyclyl optionally substituted by; (i) 1 to 6 independently selected R g C optionally substituted with 6-10 aryl; (j) 1 to 6 independently selected R g 5-10 membered heteroaryl optionally substituted with (k) 1 to 6 independently selected R gC optionally substituted with 3-8 cycloalkyl; selected from the group consisting of: Each R QB are independently (a) to (b): (a)-L a -S(O)2-L b -R e ; and (b) 1 to 6 R independently selected from heterocyclyl or heteroaryl g 4- to 12-membered heterocyclyl or 7- to 10-membered bicyclic heteroaryl, each containing an endocyclic S(O)2 group, optionally substituted with 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 when q1 is 0, -L b -R e is unsubstituted C 1-3 is other than alkyl; R a and R b independently, C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents each independently selected from the group consisting of cycloalkyl and halo 1-6 Alkyl; C 1-3 C optionally substituted with 1 to 3 substituents each independently selected from the group consisting of alkyl and halo 3-6 cycloalkyl; and 1 to 3 independently selected C1-3 C optionally substituted with alkyl 6-10 aryl; or R a and R b each together with the phosphorus atom to which it is attached forms a ring containing 5 to 8 ring atoms, where 0 to 2 ring atoms (R a and R b (in addition to the phosphorus bonded to the ring) are heteroatoms each independently selected from the group consisting of O, S, and N, wherein the ring is 1-6 optionally substituted with alkyl; Each R c and R d are independently 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 said C 1-6 Alkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 cycloalkyl), C(=O)O(C 1-6 alkyl), S(O) 1-2 (C 1-6 alkyl) and S(O) 1-2 (C 3-6 cycloalkyl) are each -OH, halo and C 1-6 optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkoxy; R e is H or R e is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6cycloalkyl and 3- to 8-membered heterocyclyl, each of which is selected from the group consisting of 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 optionally substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy; L e is a bond, NR c or O; Each R f are independently halo, -OH, NR c R d , C 1-6 Alkoxy, C 1-6 Haloalkoxy and -OH, C 1-6 selected from the group consisting of 3- to 12-membered heterocyclyl optionally substituted by 1 to 4 substituents, each independently selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; Each R g independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, NR c R d , Cyano, Halo, C 3-6 Cycloalkyl and C 1-6 Alkyl and C(=O)C 1-6 3- to 12-membered heterocyclyl optionally substituted with one or more substituents, each independently selected from the group consisting of alkyl; R in each case h are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 selected from cycloalkyl and halo; or A pair of R on the same or different carbon atoms h together with the carbon atom bonded to it, C 3-6cycloalkyl or 4-8 membered heterocyclyl, each of which is selected from halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, C 1-3 Alkoxy and C 1-3 and optionally substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy. or a pharmaceutically acceptable salt, deuterated analog or solvate thereof.

[0008] Also provided is a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt, deuterated analog, 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, deuterated analog, 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, deuterated analog, or solvate thereof, or a pharmaceutical composition thereof, to a patient identified or diagnosed as having type 2 diabetes.

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

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

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

[0014] In certain embodiments, the method for 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 for treating type 2 diabetes comprises reducing glucagon levels.

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

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

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

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

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

[0022] Also provided herein is a method for treating a GLP-1-associated disease, disorder, or condition, comprising administering to a patient in need thereof an effective amount of a compound of Formula I or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof, or a pharmaceutical composition thereof. In certain embodiments, the disease, disorder, or condition is selected from the group consisting of type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of adults (LADA), obesity (including hypothalamic obesity and monogenic obesity), weight gain due to the use of other medications, idiopathic intracranial hypertension, Wolfram syndrome, gout, excessive sugar cravings, high triglycerides of fatty acids, and the like. Glyceridemia, 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, vascular Restenosis after plastic surgery, intermittent claudication, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, alcohol intake disorders, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, treatment of addiction, cocaine dependence , bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, psychogenic polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof.In certain embodiments, the disease, disorder, or condition is selected from the group consisting of type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat accumulation, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, and glucose metabolism. abnormalities, insulin resistance, hepatic insulin resistance, alcohol use disorders, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, psychogenic polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS), or any combination thereof. In certain embodiments, the disease, disorder, or condition includes, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar cravings, 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] Detailed Description definition The following description describes exemplary embodiments of the present invention, however, it should be recognized that such description is not intended as a limitation on the scope of the disclosure, but rather provides exemplary embodiments.

[0024] As used herein, the following words, phrases and symbols are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0025] When numerical values ​​are described as ranges, it is understood that all possible subranges within such ranges, as well as the recitation of specific numerical values ​​within such ranges, are included, whether or not a specific numerical value or specific subrange is explicitly stated.

[0026] As used herein, the term "halo" or "halogen" means -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").

[0027] As used herein, the term "alkyl" refers to a saturated straight- or branched-chain monovalent hydrocarbon radical containing the indicated number of carbon atoms. For example, "C1-C6 alkyl" refers to a saturated straight- or branched-chain monovalent hydrocarbon radical of 1 to 6 carbon atoms. Non-limiting examples of alkyl include methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, 2-methyl-2-propyl, pentyl, neopentyl, and hexyl.

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

[0029] As used herein, the term "alkenyl" means 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.

[0030] As used herein, the term "alkynyl" means 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.

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

[0032] As used herein, the term "heterocyclyl" means a mono-, bi-, tri-, or polycyclic non-aromatic ring group containing the indicated number of ring atoms (e.g., a 3- to 8-membered monocyclic, an 8- to 12-membered bicyclic, or an 11- to 14-membered tricyclic ring group) having 1 to 3 heteroatoms (in the case of a monocycle), 1 to 6 heteroatoms (in the case of a bicycle), or 1 to 9 heteroatoms (in the case of a tricycle or polycycle), wherein the heteroatoms are selected from O, N, or S (e.g., carbon atoms and 1 to 3, 1 to 6, or 1 to 9 heteroatoms in the case of a monocycle, bicycle, or tricycle, respectively). The heterocyclyl groups are selected from 9 heteroatoms (N, O, or S), with 0, 1, 2, or 3 atoms in each ring optionally being substituted by substituents. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Heterocyclyls can include multiple fused and bridged rings. Non-limiting examples of fused / bridged heterocyclyls include 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, and 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[1.1.0]butane Examples include bicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, etc. Heterocyclyl also includes spirocycles (e.g., spirocyclic bicycles in which the two rings are joined by only one atom).Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[2. 2]pentane, 4-oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane, and the like.

[0033] 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.

[0034] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group having the indicated number of ring atoms (e.g., 5-6 ring atoms; e.g., 5, 6, 9, 10, or 14 ring atoms), in which at least one ring is aromatic (but not necessarily a heteroatom-containing ring, e.g., tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl)) and at least one ring in the group contains one or more heteroatoms independently selected from the group consisting of N, O, and S. Heteroaryl groups can be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolylbenzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, and pyrido[2, 3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chroman, 2,3-dihydrobenzo[b][1,4]dioxone, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]xathiin, isoindoline, and the like.

[0035] As used herein, the term "haloalkyl" refers to an alkyl group, as defined herein, in which one or more hydrogen atoms are replaced with one or more halogen atoms. Non-limiting examples include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, chloromethyl, dichloromethyl, chloroethyl, trichloroethyl, bromomethyl, and iodomethyl.

[0036] As used herein, the term "alkoxy" refers to an -O-alkyl group, wherein the group is on an oxygen atom. For example, "C 1-6 "Alkoxy" is -O-(C 1-6 "Alkoxy" refers to an -O-haloalkyl group in which the group is on the oxygen atom. Examples of alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy. Thus, as used herein, the term "haloalkoxy" refers to an -O-haloalkyl group in which the group is on the oxygen atom.

[0037] As used herein, " [ka] " indicates any single or double bond, as valence allows. As used herein, " [ka] " indicates the point of attachment to the parent molecule.

[0038] 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.

[0039] As used herein, the term "tautomer" means a compound whose structure differs significantly in the arrangement of atoms but 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 disclosure, and the name of the compound does not exclude the tautomers.

[0040] 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.

[0041] As used herein, the term "GLP-1 associated disease" is meant 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.

[0042] 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, additional GLP-1 receptor agonists described in U.S. Patent Nos. 10,370,426; 10,308,700; 10,259,823; 10,208,019; 9,920,106; 9,839,664; 8,129,343; 8,536,122; 7,919,598; 6,414,126; 6,628,343; and RE45313.

[0043] As used herein, the term "pharmaceutically acceptable" indicates that a compound, or a salt thereof, or a composition thereof is chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the patient being treated.

[0044] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salt" or "physiologically acceptable salt" includes, for example, salts with inorganic acids and organic acids. Furthermore, if a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be obtained by dissolving the free base in a suitable organic solvent and treating with a solution containing an acid, according to conventional methods for preparing acid addition salts from base compounds. Those skilled in the art will recognize a variety of synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, for example, acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of NH or primary, secondary, and tertiary amines, e.g., N-containing heterocycles, N-containing heteroaryls, or salts of the formula N(R N )3 (e.g., HN + (R N )3 or (alkyl)N + (R N ) 3) an amine of formula (I), wherein each R Nare independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more (e.g., 1 to 5 or 1 to 3) substituents (e.g., halo, cyano, hydroxy, amino, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, or haloalkoxy). Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0045] As used herein, the term "therapeutic compound" is meant to include, but is not limited to, any compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any of Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof), and all compositions (e.g., pharmaceutical compositions) in which any compound of Formula I, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any of Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof) is a component.

[0046] A "solvate" is formed by the interaction of a solvent and a compound. Solvates of the salts of the compounds described herein are also provided. Hydrates of the salts of the compounds described herein are also provided.

[0047] The term "deuterated analog" of a compound described herein refers to a compound in which one or more hydrogen atoms, e.g., hydrogen atoms on a carbon atom, are replaced with deuterium atoms. The concentration of such a heavy isotope, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds described herein, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of the atom. Unless otherwise specified, when a position is not specifically designated as "H" or "hydrogen," the position is understood to have hydrogen at natural abundance isotopic composition. Thus, in the compounds described herein, any atom specifically designated as deuterium (D) is intended to represent deuterium.

[0048] 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.

[0049] 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, deuterated analog, or solvate thereof (e.g., a compound of any of Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof)) to relieve to some extent one or more of the symptoms of the disease or condition being treated, and may include curing the disease. "Cure" refers to the elimination of active disease symptoms. Such results include reduction and / or alleviation of the signs, symptoms, or pathogenesis of 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 is determined using any suitable technique, such as a dose escalation study. In certain embodiments, a "therapeutically effective amount" of a compound provided herein refers to an amount of the compound that is effective as a monotherapy or in combination therapy.

[0050] The term "excipient" or "pharmaceutically acceptable excipient" means a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In certain embodiments, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and suitable for use in contact with the tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problem or complication, commensurate with a reasonable benefit / risk ratio. For example, Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical See Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0051] The term "pharmaceutical composition" refers to a mixture of a compound of Formula I described herein, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any of Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt, deuterated analog, 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 compounds, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0052] The terms "treat," "treating," and "treatment" in the context of treating a disease, disorder, or condition include alleviating or arresting the disorder, disease, or condition, or one or more symptoms associated with said disorder, disease, or condition; or slowing the progression, spread, or worsening of the disease, disorder, or condition, or one or more symptoms thereof.

[0053] As used herein, the term "preventing" refers to the prevention of the onset, recurrence or spread, in whole or in part, of a disease or condition as described herein, or a symptom thereof.

[0054] 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.

[0055] The terms "treatment regimen" and "administration regimen" are used interchangeably to refer to the dosage and timing of administration of each therapeutic agent.

[0056] As used herein, the term "pharmaceutical combination" means a pharmaceutical treatment that results in the mixing or combining of more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients.

[0057] As used herein, the term "combination therapy" refers to a dosing regimen of two different therapeutically active agents (i.e., components or combination partners of the combination), which are administered together or separately as desired by a medical practitioner or in accordance with regulatory authorities, as defined herein.

[0058] As used herein, the term "modulation" means regulation or modulation (eg, increase or decrease) and can include, for example, agonism, partial agonism, or antagonism.

[0059] 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.

[0060] In certain embodiments, a compound of Formula I: [ka] [During the ceremony, X is C and Y is N, or Y is C and X is N, and the dashed line indicates the moiety [ka] but [ka] where bond y is bonded to Y and bond x is bonded to X; Ring A is C 6-10 Aryl, C 5-10cycloalkyl, 5- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-6 optionally substituted with 1 to 5 substituents each independently selected from the group consisting of cycloalkyl; R 1 , R 2 and R 3 is H and halo, -OH and C 1-6 C optionally substituted with 1 to 6 substituents each independently selected from the group consisting of alkoxy 1-6 each independently selected from the group consisting of alkyl; L 1 -C(=O)-, -CH2-, -CH(C 1-6 -S(=O)2; Ring B is [ka] [ka] (In the formula, 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 halo and C 3-15 C optionally substituted with one or more substituents independently selected from cycloalkyl 1-6 selected from alkyl; or R8a and R 8b Each independently selected 1 to 3 C's, together with the carbon atom to which it is bonded, 1-6 C optionally substituted with alkyl 3-15 Form a cycloalkyl ring, wherein said C 1-6 alkyl is 1 to 6 independently selected R f may be substituted with; or Part-L 3 -C(R 8a R 8b )-L 4 -R 9 is substituted with C(=O)OH and R f phenyl optionally substituted with 1 to 4 additional substituents independently selected from R 9 are C(=O)OH, C(=O)(OC 1-6 alkyl), C(=O)NR 9a R 9b , (IX-1), (IX-2), (IX-3) and (IX-4): [ka] selected from the group consisting of: R 9a is H or C 1-6 is alkyl; R 9b is H, C 1-6 Alkyl, C(=O)(C 1-6 alkyl), S(O) 0-2 (C 1-6 alkyl) or cyano; R 9c , R 9d , R 9e , R 9f and R 9g H, independently selected 1 to 6 halo groups, and C 1-6 C optionally substituted with alkoxy 1-6 Alkyl and C(=O)(C 1-6 alkyl) selected from the group consisting of: Ring C is a 3- to 12-membered heterocyclyl, C 3-15 cycloalkyl and 5- to 10-membered heteroaryl, each of which is selected from the group consisting of 1 to 3 R Ca may be substituted with; Each R Ca independently, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and NR c R d or selected from the group consisting of; or a pair of R on the same or different ring atoms Ca each together with the ring atom to which it is attached forms a carbocyclic ring containing 3 to 8 ring atoms; L 2 teeth, [ka] (In the formula, aa represents the point of attachment to Q; n1 is an integer of 1 to 3; L 2A is a bond or C 1-10 is alkylene; R La is H, C 1-6 Alkyl and C(=O)(C 1-6 alkyl); R Lb and R Lc each independently represents H and C 1-6 alkyl) selected from the group consisting of: Q is C 1-10 Alkyl; C 3-15 Cycloalkyl; 3- to 12-membered heterocyclyl; 5- to 10-membered heteroaryl; and C 6-10 aryl, wherein said Q is selected from the group consisting of -P(=O)R a R b and R Q and optionally substituted with 1 to 6 additional substituents independently selected from: Each R Qare independently the following (a) to (n): (a) Halo; (b) cyano; (c) OH or oxo; (d)-NR c R d ; (e)-C(=O)NR c R d or -S(O)NR c R d ; (f)-S(=O) 0-2 R e ; (g) 1 to 6 independently selected R f C optionally substituted with 1-6 alkyl; (h) 1 to 6 independently selected R f C optionally substituted with 1-6 Alkoxy; (i) 1 to 6 independently selected R g 3- to 12-membered heterocyclyl optionally substituted by; (j) 1 to 6 independently selected R g C optionally substituted with 6-10 aryl; (k) 1 to 6 independently selected R g 5-10 membered heteroaryl optionally substituted by; (l) 1 to 6 independently selected R g C optionally substituted with 3-8 cycloalkyl; (m)-P(=O)R a R b ; and (n)q1 is 1, 2 or 3 - (CR h R h ) q1 -S(O)2-L e -R e ; or selected from the group consisting of Or, Q is C 3-15 cycloalkyl; 3- to 12-membered heterocyclyl; 5- to 10-membered heteroaryl; or C 6-10 aryl, each of which is RQA and R QB may be substituted with 1 to 6 substituents each independently selected from the group consisting of However, the following (aa) or (bb): (aa) Q is at least one R QB is replaced by, or (bb) Q is a 4- to 12-membered heterocyclyl or a 7- to 10-membered bicyclic heteroaryl containing an endocyclic S(O)2 group; and / or Each R QA are independently the following (a) to (k): (a) Halo; (b) cyano; (c) OH or oxo; (d)-NR a R b ; (e)-C(=O)NR c R d ; (f) 1 to 6 independently selected R f C optionally substituted with 1-6 alkyl; (g) 1 to 6 independently selected R f C optionally substituted with 1-6 Alkoxy; (h) 1 to 6 independently selected R g 3- to 12-membered heterocyclyl optionally substituted by; (i) 1 to 6 independently selected R g C optionally substituted with 6-10 aryl; (j) 1 to 6 independently selected R g 5-10 membered heteroaryl optionally substituted with (k) 1 to 6 independently selected R g C optionally substituted with 3-8 cycloalkyl; selected from the group consisting of: Each R QB are independently: a)~b): a)-L a -S(O)2-Lb -R e ; and b) 1 to 6 R independently selected from heterocyclyl or heteroaryl; g 4- to 12-membered heterocyclyl or 7- to 10-membered bicyclic heteroaryl, each containing an endocyclic S(O)2 group, optionally substituted with 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 when q1 is 0, -L b -R e is unsubstituted C 1-3 is other than alkyl; R a and R b independently, C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents each independently selected from the group consisting of cycloalkyl and halo 1-6 Alkyl; C 1-3 C optionally substituted with 1 to 3 substituents each independently selected from the group consisting of alkyl and halo 3-6 cycloalkyl; and 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 aryl; or R a and R beach together with the phosphorus atom to which it is attached forms a ring containing 5 to 8 ring atoms, where 0 to 2 ring atoms (R a and R b (in addition to the phosphorus bonded to the ring) are heteroatoms each independently selected from the group consisting of O, S, and N, wherein the ring is 1-6 optionally substituted with alkyl; Each R c and R d are independently 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 said C 1-6 Alkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 cycloalkyl), C(=O)O(C 1-6 alkyl), S(O) 1-2 (C 1-6 alkyl) and S(O) 1-2 (C 3-6 cycloalkyl) are each -OH, halo and C 1-6 optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkoxy; R e is H 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 selected from the group consisting of halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, NH2, NH(C 1-3 alkyl), N(C 1-3 Alkyl)2, C 1-3Alkoxy and C 1-3 optionally substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy; L e is a bond, NR c or O; Each R f are independently halo, -OH, NR c R d , C 1-6 Alkoxy, C 1-6 Haloalkoxy and -OH, C 1-6 selected from the group consisting of 3- to 12-membered heterocyclyl optionally substituted by 1 to 4 substituents, each independently selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; Each R g independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, NR c R d , Cyano, Halo, C 3-6 Cycloalkyl and C 1-6 Alkyl and C(=O)C 1-6 3- to 12-membered heterocyclyl optionally substituted with one or more substituents, each independently selected from the group consisting of alkyl; R in each case h are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 selected from cycloalkyl and halo; or A pair of R on the same or different carbon atoms h together with the carbon atom bonded to it, C 3-6 cycloalkyl or 4-8 membered heterocyclyl, each of which is selected from halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, C 1-3 Alkoxy and C 1-3 and optionally substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy. or a pharmaceutically acceptable salt, deuterated analog or solvate thereof.

[0061] In one embodiment, the moiety [ka] teeth [ka] wherein bond y is bonded to Y and bond x is bonded to X. is.

[0062] In one embodiment, the moiety [ka] teeth [ka] wherein bond y is bonded to Y and bond x is bonded to X. is.

[0063] In certain embodiments, a compound of formula II: [ka] [During the ceremony, Q 1 , Q 2 , Q 3 , Q 4 and Q 5 is either (AA) or (BB) below: (AA) Q 1 and Q 5 are independently N, CH and CR QC selected from the group consisting of: Q 2 , Q 3 and Q 4 are independently N, CH, CR QC and CR QD and wherein Q is selected from the group consisting of 2 , Q 3 and Q 4At least one of the following is CR QD and; each [ka] is a single or double bond, provided that Q 1 ~Q 5 The ring containing is aromatic; (BB) Q 1 is a bond; Q 2 , Q 3 , Q 4 and Q 5 are independently O, S, N, NH, and NR c , C.H., C.R. QC and CR QD and wherein Q is selected from the group consisting of 2 , Q 3 , Q 4 and Q 5 At least one of the following is CR QD and; each [ka] is a single or double bond, provided that Q 1 ~Q 5 The ring containing is aromatic; as defined by; R QD is P(=O)R a R b where R a and R b independently, C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents each independently selected from the group consisting of cycloalkyl and halo 1-6 Alkyl; C 1-3 C optionally substituted with 1 to 3 substituents each independently selected from the group consisting of alkyl and halo 3-6 cycloalkyl; and 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10aryl; or R a and R b each together with the phosphorus atom to which it is attached forms a ring containing 5 to 8 ring atoms, where 0 to 2 ring atoms (R a and R b (in addition to the phosphorus atom bonded to the ring) are heteroatoms each independently selected from the group consisting of O, S, and N, wherein the ring is 1-6 optionally substituted with alkyl; Each R QC are independently: (a) halo; (b) cyano; (c) OH; (d) -NR c R d ;(e)C(=O)NR c R d ;(f)S(=O) 0-2 R e (g) 1 to 6 independently selected R f C optionally substituted with 1-6 Alkyl; (h) hydroxy, halo and C 1-6 C optionally substituted with 1 to 6 substituents each independently selected from the group consisting of alkoxy 1-6 Alkoxy; (i) C 1-6 Alkyl and C(=O)(C 1-6 (j) a 3- to 12-membered heterocyclyl optionally substituted by one or more substituents independently selected from the group consisting of C(=O)(C 1-6 C optionally substituted with alkyl 6-10 aryl; and (k) 1 to 6 independently selected R g or a 5- to 10-membered heteroaryl optionally substituted with Or, a pair of R on adjacent carbon atoms QC each together with the atom to which it is attached forms a ring containing 5 to 8 ring atoms, wherein 0 to 2 ring atoms are heteroatoms each independently selected from the group consisting of O, N, and S, and wherein the ring is joined to 1 to 2 independently selected R h optionally substituted with a group; L2 teeth, [ka] (In the formula, aa is Q 1 ~Q 5 represents the point of attachment to the ring containing n1 is an integer from 1 to 3; L 2A is a bond or C 1-10 is alkylene; R La is H, C 1-6 Alkyl and C(=O)(C 1-6 alkyl); R Lb and R Lc each independently represents H and C 1-6 alkyl) is selected from the group consisting of Ring A is C 6-10 Aryl, C 5-7 cycloalkyl, 5- to 7-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-6 optionally substituted with 1 to 5 substituents each independently selected from the group consisting of cycloalkyl; R 1 , R 2 and R 3 is H and halo, -OH and C 1-6 C optionally substituted with 1 to 6 substituents each independently selected from the group consisting of alkoxy 1-6 each independently selected from the group consisting of alkyl; L 1 -C(=O)-, -CH2-, -CH(C 1-6 -S(=O)2; Ring B is [ka] [ka] (In the formula, 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 halo and C 3-15 C optionally substituted with one or more substituents selected from the group consisting of cycloalkyl 1-6 alkyl; or R 8a and R 8b Each independently selected 1 to 3 C's, together with the carbon atom to which it is bonded, 1-6 C optionally substituted with alkyl 3-15 Form a cycloalkyl ring, wherein said C 1-6 Alkyl is 1 to 6 independently selected R f may be substituted with; R 9 are C(=O)OH, C(=O)(OC 1-6 alkyl), C(=O)NR 9a R 9b , (IX-1), (IX-2), (IX-3) and (IX-4): [ka] selected from the group consisting of: R 9a is H or C 1-6 is alkyl; R 9b is H, C 1-6 Alkyl, C(=O)(C 1-6alkyl), S(O) 0-2 (C 1-6 alkyl) or cyano; R 9c , R 9d , R 9e , R 9f and R 9g H; 1 to 6 independently selected halo and C 1-6 C optionally substituted with alkoxy 1-6 alkyl; and C(=O)(C 1-6 alkyl) selected from the group consisting of: Ring C is a 3- to 12-membered heterocyclyl; C 3-15 cycloalkyl; and 5- to 10-membered heteroaryl, each of which is selected from the group consisting of 1 to 3 R Ca may be substituted with; Each R Ca independently, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and NR c R d or selected from the group consisting of; or a pair of R on the same or different ring atoms Ca each together with the ring atom to which it is attached forms a carbocyclic ring containing 3 to 8 ring atoms; Each R c and R d are independently H, C 1-6 Alkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 cycloalkyl), C(=O)O(C 1-6 alkyl), S(O) 1-2 (C 1-6 alkyl) and S(O) 1-2 (C 3-6 cycloalkyl), wherein said C 1-6 Alkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 cycloalkyl), C(=O)O(C 1-6 alkyl), S(O) 1-2(C 1-6 alkyl) and S(O) 1-2 (C 3-6 cycloalkyl) are each -OH, halo and C 1-6 optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkoxy; R e is H, C 1-6 Alkyl or C 1-6 is haloalkyl; Each R f are independently halo, -OH, NR c R d , C 1-6 Alkoxy, C 1-6 Haloalkoxy and -OH, C 1-6 selected from the group consisting of 3- to 12-membered heterocyclyl optionally substituted by 1 to 4 substituents, each independently selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; Each R g independently, C 1-6 Alkyl, C 1-6 Alkoxy, NR c R d and C 1-6 Alkyl and C(=O)C 1-6 3- to 12-membered heterocyclyl optionally substituted with one or more substituents, each independently selected from the group consisting of alkyl; Each R h are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, -OH, NH2, NH(C 1-3 alkyl), N(C 1-3 Alkyl)2, C 1-3 Alkoxy and C 1-3 haloalkoxy] or a pharmaceutically acceptable salt, deuterated analog or solvate thereof.

[0064] In certain embodiments, a compound of formula III: [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 selected from the group consisting of R QA and R QB may be substituted with 1 to 6 substituents each independently selected from the group consisting of However, (aa) or (bb): (aa) Ring D is 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 containing an endocyclic S(O)2 group; and / or Each R QA are independently the following (a) to (k): (a) Halo; (b) cyano; (c) OH or oxo; (d)-NR a R b ; (e)-C(=O)NR c R d ; (f) 1 to 6 independently selected R f C optionally substituted with 1-6 alkyl; (g) 1 to 6 independently selected R f C optionally substituted with 1-6 Alkoxy; (h) 1 to 6 independently selected R g 3- to 12-membered heterocyclyl optionally substituted by; (i) 1 to 6 independently selected R g C optionally substituted with 6-10 aryl; (j) 1 to 6 independently selected R g 5-10 membered heteroaryl optionally substituted with (k) 1 to 6 independently selected R g C optionally substituted with 3-8cycloalkyl; Each R QB are independently: a)~b): a)-L a -S(O)2-L b -R e ; and b) 1 to 6 R independently selected from heterocyclyl or heteroaryl; g a 4- to 12-membered heterocyclyl or a 7- to 10-membered bicyclic heteroaryl containing an endocyclic S(O)2 group, optionally substituted with 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 when q1 is 0, -L b -R e is unsubstituted C 1-3 is other than alkyl; L 2 teeth, [ka] (In the formula, aa represents 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); RLb and R Lc each independently represents H and C 1-6 alkyl) selected from the group consisting of: 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 substituted with halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-6 optionally substituted with 1 to 5 substituents each independently selected from the group consisting of cycloalkyl; R 1 , R 2 and R 3 is H and halo, -OH and C 1-6 C optionally substituted with 1 to 6 substituents each independently selected from the group consisting of alkoxy 1-6 each independently selected from the group consisting of alkyl; L 1 -C(=O)-, -CH2-, -CH(C 1-6 -S(=O)2; Ring B is [ka] [ka] (In the formula, 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 halo and C 3-15 C optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl 1-6 alkyl; or R 8a and R 8b Each independently selected 1 to 3 C's, together with the carbon atom to which it is bonded, 1-6 C optionally substituted with alkyl 3-15 Form a cycloalkyl ring, wherein said C 1-6 Alkyl is 1 to 6 independently selected R f may be substituted with; R 9 are C(=O)OH, C(=O)(OC 1-6 alkyl), C(=O)NR 9a R 9b , (IX-1), (IX-2), (IX-3) and (IX-4): [ka] selected from the group consisting of: R 9a is H or C 1-6 is alkyl; R 9b is H, C 1-6 Alkyl, C(=O)(C 1-6 alkyl), S(O) 0-2 (C 1-6 alkyl) or cyano; R 9c , R 9d , R 9e , R 9f and R 9g H; 1 to 6 independently selected halo and C 1-6 C optionally substituted with alkoxy 1-6 alkyl; and C(=O)(C 1-6 alkyl) selected from the group consisting of: Ring C is a 3- to 12-membered heterocyclyl; C 3-15cycloalkyl; and 5- to 10-membered heteroaryl, each of which is selected from the group consisting of 1 to 3 R Ca may be substituted with; Each R Ca independently, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and NR c R d or selected from the group consisting of; or a pair of R on the same or different ring atoms Ca each together with the ring atom to which it is attached forms a carbocyclic ring containing 3 to 8 ring atoms; Each R a and R b are independently 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 said 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 -OH, halo and C 1-6 optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkoxy; Each R c and R d are independently 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 said C 1-6 Alkyl, C 3-6Cycloalkyl, 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 -OH, halo and C 1-6 optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkoxy; R e is H 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 selected from the group consisting of 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 optionally substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy; Each R f are independently halo, -OH, NR c R d , C 1-6 Alkoxy, C 1-6 Haloalkoxy and -OH, C 1-6 selected from the group consisting of 3- to 12-membered heterocyclyl optionally substituted by 1 to 4 substituents, each independently selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; Each R g independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, NR c R d , Cyano, Halo, C 3-6Cycloalkyl and C 1-6 Alkyl and C(=O)C 1-6 3- to 12-membered heterocyclyl optionally substituted with one or more substituents, each independently selected from the group consisting of alkyl; R in each case h are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 is selected from the group consisting of cycloalkyl and halo; or A pair of R on the same or different carbon atoms h together with the carbon atom bonded to it, C 3-6 cycloalkyl or 4-8 membered heterocyclyl, each of which is selected from halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, C 1-3 Alkoxy and C 1-3 and optionally substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy. or a pharmaceutically acceptable salt, deuterated analog or solvate thereof.

[0065] In certain embodiments, a compound of Formula IV: [ka] [During the ceremony, 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 substituted with halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-6 optionally substituted with 1 to 5 substituents each independently selected from the group consisting of cycloalkyl; R 1 , R 2 and R 3 is H and halo, -OH and C 1-6C optionally substituted with 1 to 6 substituents each independently selected from the group consisting of alkoxy 1-6 each independently selected from the group consisting of alkyl; L 1 -C(=O)-, -CH2-, -CH(C 1-6 -S(=O)2; Ring B is [ka] (In the formula, 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 halo and C 3-15 C optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl 1-6 alkyl; or R 8a and R 8b Each independently selected 1 to 3 C's, together with the carbon atom to which it is bonded, 1-6 C optionally substituted with alkyl 3-15 Form a cycloalkyl ring, wherein said C 1-6 Alkyl is 1 to 6 independently selected R f may be substituted with; R 9 are C(=O)OH, C(=O)(OC 1-6 alkyl), C(=O)NR 9a R 9b, (IX-1), (IX-2), (IX-3) and (IX-4): [ka] selected from the group consisting of: R 9a is H or C 1-6 is alkyl; R 9b is H, C 1-6 Alkyl, C(=O)(C 1-6 alkyl), S(O) 0-2 (C 1-6 alkyl) or cyano; R 9c , R 9d , R 9e , R 9f and R 9g H; 1 to 6 independently selected halo and C 1-6 C optionally substituted with alkoxy 1-6 alkyl; and C(=O)(C 1-6 alkyl) selected from the group consisting of: Ring C is a 3- to 12-membered heterocyclyl; C 3-10 cycloalkyl; and 5- to 10-membered heteroaryl, each of which is selected from the group consisting of 1 to 3 R Ca may be substituted with; Each R Ca independently, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and NR c R d or selected from the group consisting of; or a pair of R on the same or different ring atoms Ca each together with the ring atom to which it is attached forms a carbocyclic ring containing 3 to 8 ring atoms; L 2 teeth, [ka] (In the formula, aa represents the point of attachment to Q; n1 is an integer of 1 to 3; L 2A is a bond or C 1-10 is alkylene; R La is H, C 1-6 Alkyl and C(=O)(C 1-6 alkyl); R Lb and R Lc each independently represents H and C 1-6 alkyl) selected from the group consisting of: Q is C 1-10 Alkyl; 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 1 to 6 independently selected R Q may be substituted with; Each R Q are independently the following (a) to (n): (a) Halo; (b) cyano; (c) OH or oxo; (d)-NR c R d ; (e)-C(=O)NR c R d or -S(O)NR c R d ; (f)-S(=O) 0-2 R e ; (g) 1 to 6 independently selected R f C optionally substituted with 1-6 alkyl; (h) 1 to 6 independently selected R f C optionally substituted with 1-6 Alkoxy; (i) 1 to 6 independently selected R g 3- to 12-membered heterocyclyl optionally substituted by; (j) 1 to 6 independently selected R gC optionally substituted with 6-10 aryl; (k) 1 to 6 independently selected R g 5-10 membered heteroaryl optionally substituted by; (l) 1 to 6 independently selected R g C optionally substituted with 3-8 cycloalkyl; (m)P(=O)R a R b ; and (n)q1 is 1, 2 or 3 - (CR h R h ) q1 -S(O)2-L e -R e ; selected from the group consisting of: R a and R b independently, C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents each independently selected from the group consisting of cycloalkyl and halo 1-6 Alkyl; C 1-3 C optionally substituted with 1 to 3 substituents each independently selected from the group consisting of alkyl and halo 3-6 cycloalkyl; and 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 aryl; or R a and R b each together with the phosphorus atom to which it is attached forms a ring containing 5 to 8 ring atoms, where 0 to 2 ring atoms (R a and R b (in addition to the phosphorus atom bonded to the ring) are heteroatoms each independently selected from the group consisting of O, S, and N, wherein the ring is 1-6 optionally substituted with alkyl; Each R c and R d are independently H, C 1-6 Alkyl, C 3-6Cycloalkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 cycloalkyl), C(=O)O(C 1-6 alkyl), S(O) 1-2 (C 1-6 alkyl) and S(O) 1-2 (C 3-6 cycloalkyl), wherein said C 1-6 Alkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 cycloalkyl), C(=O)O(C 1-6 alkyl), S(O) 1-2 (C 1-6 alkyl) and S(O) 1-2 (C 3-6 cycloalkyl) are each -OH, halo and C 1-6 optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkoxy; R e is H 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 selected from the group consisting of 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 optionally substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy; L e is the bond NR c or O; Each R f are independently halo, -OH, NR c R d , C 1-6 Alkoxy, C 1-6 Haloalkoxy and -OH, C 1-6selected from the group consisting of 3- to 12-membered heterocyclyl optionally substituted by 1 to 4 substituents, each independently selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; Each R g independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, NR c R d , Cyano, Halo, C 3-6 Cycloalkyl and C 1-6 Alkyl and C(=O)C 1-6 3- to 12-membered heterocyclyl optionally substituted with one or more substituents, each independently selected from the group consisting of alkyl; R in each case h are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 is selected from the group consisting of cycloalkyl and halo; or A pair of R on the same or different carbon atoms h together with the carbon atom bonded to it, C 3-6 cycloalkyl or 4-8 membered heterocyclyl, each of which is selected from halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, C 1-3 Alkoxy and C 1-3 and optionally substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy. or a pharmaceutically acceptable salt, deuterated analog or solvate thereof.

[0066] In certain embodiments, ring A is halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-6 C optionally substituted with 1 to 5 substituents each independently selected from the group consisting of cycloalkyl 6-10 It is aryl.

[0067] In certain embodiments, ring A is phenyl optionally substituted with 1 to 3 substituents each independently selected from the group consisting of fluoro, methyl and cyclopropyl.

[0068] In some embodiments, R 1 and R 2 is H.

[0069] In some embodiments, R 3 is C 1-6 It is alkyl.

[0070] In some embodiments, R 3 is methyl.

[0071] In one embodiment, L 1 is -C(=O)-.

[0072] In certain embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] is.

[0073] In certain embodiments, ring B is [ka] In some embodiments, ring B is [ka] [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] is.

[0074] In certain embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] is.

[0075] In certain embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] is.

[0076] In some embodiments, R 4 , R 5 , R 6 and R 7 is H.

[0077] In one embodiment, L 3 is a bond

[0078] In some embodiments, R 8a and R 8b Each carbon atom is bonded to a carbon atom, and the carbon atoms are bonded to the carbon atom. 3-15 Forms a cycloalkyl.

[0079] In some embodiments, R 8a and R 8b taken together with the carbon atom to which they are attached form a cyclopropyl.

[0080] In some embodiments, R 9 teeth [ka] is.

[0081] In some embodiments, R9d is H.

[0082] In some embodiments, the moiety -L 3 -C(R 8a R 8b )-L 4 -R 9 is substituted with C(=O)OH and R f In certain embodiments, the moiety -L 3 -C(R 8a R 8b )-L 4 -R 9 is phenyl substituted with C(=O)OH. In certain embodiments, the moiety -L 3 -C(R 8a R 8b )-L 4 -R 9 teeth [ka] is.

[0083] In certain embodiments, Ring C is a 3- to 12-membered heterocyclyl.

[0084] In certain embodiments, Ring C is tetrahydropyranyl.

[0085] In one embodiment, L 2 teeth [ka] wherein aa represents the point of attachment to Q. is.

[0086] In one embodiment, L 2A is a bond.

[0087] Provided are compounds of Formula I or II, or pharmaceutically acceptable salts or solvates thereof, that include any one or more of the following features:

[0088] In one embodiment, Q 1 , Q 2 , Q 3 , Q 4 and Q 5 is as defined by (AA).

[0089] In one embodiment, Q 3 is CR QD In one embodiment, Q 4 is N, CH or CR QC is

[0090] In one embodiment, Q 4 is CR QD In one embodiment, Q 3 is N, CH or CR QC is.

[0091] In one embodiment, Q 1 is CH or CR QC In one embodiment, Q 1 is CH.

[0092] In one embodiment, Q 2 is CH or CR QC In one embodiment, Q 2 is CH.

[0093] In one embodiment, Q 5 is CH or CR QC In one embodiment, Q 5 is CH. In some embodiments, Q 5 is CR QC is.

[0094] In one embodiment, Q 3 is CR QD and Q 1 , Q 2 , Q 4 and Q 5 each independently represents CH or CR QC In one embodiment, Q1 , Q 2 , Q 4 and Q 5 Each of the is CH.

[0095] In one embodiment, (Q 3 is CR QD and Q 1 , Q 2 , Q 4 and Q 5 each independently represents CH or CR QC ), Q 1 , Q 2 , Q 4 and Q 5 One of them is CR QC and the remaining Q 1 , Q 2 , Q 4 and Q 5 Each of Q is CH. In some embodiments, Q 4 is CR QC and Q 1 , Q 2 and Q 5 is CH.

[0096] In one embodiment (Q 3 is CR QD and Q 1 , Q 2 , Q 4 and Q 5 each independently being CH or CR QC When 1 , Q 2 , Q 4 and Q 5 The two are independent, CR QC Selected from Q 1 , Q 2 , Q 4 and Q 5 Each of the remainder is CH.

[0097] In one embodiment, Q 3 is CR QD and Q 1 , Q 2 , Q 4 and Q 5One of the N is Q 1 , Q 2 , Q 4 and Q 5 each of the remainder is independently CH or CR QC In one embodiment, Q 4 is N. In some embodiments, Q 1 , Q 2 and Q 5 is CH.

[0098] In one embodiment, Q 3 is CR QD and [ka] Part [ka] is selected from the group consisting of:

[0099] In one embodiment, Q 3 is CR QD and [ka] Part [ka] is selected from the group consisting of:

[0100] In one embodiment, [ka] Part [ka] is.

[0101] In one embodiment, [ka] Part [ka] is.

[0102] In one embodiment, Q 3 is CR QD and [ka] Part [ka] is selected from the group consisting of:

[0103] In one embodiment, [ka] Part [ka] is.

[0104] In one embodiment, [ka] Part [ka] It could be.

[0105] In one embodiment, Q 4 is CR QD and Q 1 , Q 2 , Q 3 and Q 5 each independently represents CH or CR QC In one embodiment, Q 1 , Q 2 , Q 3 and Q 5 Each of the is CH.

[0106] In one embodiment (Q 4is CR QD and Q 1 , Q 2 , Q 3 and Q 5 each independently represents CH or CR QC When 1 , Q 2 , Q 3 and Q 5 One of them is CR QC and the remaining Q 1 , Q 2 , Q 3 and Q 5 Each of Q is CH. In some embodiments, Q 5 is CR QC and Q 1 , Q 2 and Q 3 is CH.

[0107] In one embodiment (Q 4 is CR QD and Q 1 , Q 2 , Q 3 and Q 5 each independently represents CH or CR QC When 1 , Q 2 , Q 3 and Q 5 The two are independent, CR QC are selected from the remaining Q 1 , Q 2 , Q 3 and Q 5 Each of Q is CH. In some embodiments, Q 2 and Q 3 independently, CR QC Selected from Q 1 and Q 5 is CH.

[0108] In one embodiment, Q 4 is CR QD and Q 1 , Q 2 , Q 3 and Q 5 One of the numbers is N and the remaining Q 1, Q 2 , Q 3 and Q 5 each independently represents CH or CR QC is.

[0109] In one embodiment, Q 4 is CR QD and [ka] Part [ka] is selected from the group consisting of:

[0110] In one embodiment, [ka] Part [ka] [In the formula, Q 4 and Q 5 are independently N, CH and CR QC selected from the group consisting of In one embodiment, Q 4 and Q 5 Each of Q is CH. 4 is CR QC and Q 5 is CH. In some embodiments, Q 4 is N and Q 5 is CR QC or CH. In certain embodiments, Q 5 is CH.

[0111] In one embodiment, [ka] Part [ka] [In the formula, Q 2 , Q 3 and Q 5 are independently N, CH and CR QC selected from the group consisting of In one embodiment, Q 2 , Q 3 and Q 5 Each of Q is CH. 5 is CR QC and Q 2 and Q 3 Each of Q is CH. 5 is CH and Q 2 and Q 3 independently, CR QC is selected from.

[0112] In some embodiments, R QD is R a and R b independently, C 1-6 Alkyl and C 3-6 P(=O)R selected from the group consisting of cycloalkyl a R b In one embodiment, CR QD is R a and R b are each independently C 1-6 P(=O)R is alkyl a R b In one embodiment, CR QD is R a and R b are each independently C 1-3 P(=O)R is alkyl a R b is.

[0113] In some embodiments, R a and R b are identical.

[0114] In some embodiments, R a and R b are each methyl (i.e., RQD is P(=O)Me2).

[0115] In some embodiments, R a and R b are each ethyl (i.e., R QD is P(=O)Et2).

[0116] In some embodiments, R a and R b are each propyl, e.g., isopropyl. For example, R QD can be P(=O)iPr2.

[0117] In some embodiments, R QD is P(=O)R a R b and R a and R b are each independently C 1-6 alkyl; R a and R b are different. In some embodiments, R a is C 1-3 alkyl (e.g., methyl or ethyl); R b is C 4-6 alkyl (e.g., butyl, such as tert-butyl). For example, R a can be methyl; R b can be tert-butyl (i.e., R QD can be P(=O)(Me)(tBu). In some embodiments, R a and R b independently, C 1-3 alkyl, with the proviso that R a and R b is different.

[0118] In some embodiments, R QD is R a and R b are each independently C 3-6 Cycloalkyl P(=O)R a R b In these embodiments, Ra and R b are identical. For example, R a and R b can both be cyclopropyl (i.e., R QD teeth [ka] (It may be possible).

[0119] In some embodiments, R QD is P(=O)R a R b where R a and R b each together with the phosphorus atom to which it is attached forms a ring containing 5 to 8 ring atoms, where 0 to 2 ring atoms (R a and R b (in addition to the phosphorus atom bonded to the ring) are heteroatoms each independently selected from the group consisting of O, S, and N, wherein the ring is 1-6 It may be substituted with alkyl.

[0120] In some embodiments, R QD is P(=O)R a R b where R a and R b each together with the phosphorus atom to which it is attached forms a ring containing 5 to 6 ring atoms, where 0 to 1 ring atom (R a and R b (in addition to the phosphorus atom bonded to the ring) are heteroatoms each independently selected from the group consisting of O, S, and N, wherein the ring is 1-6 It may be substituted with alkyl.

[0121] In some embodiments, R QD teeth [ka] [In the formula, L Q is a bond CH2, O, S, NH or N(C1-6 alkyl) For example, R QD teeth [ka] It could be.

[0122] In certain embodiments, each R QC Halo, Cyano, C 1-6 Alkyl, C 1-6 Alkoxy, OH and NR c R d is selected from the group consisting of:

[0123] In certain embodiments, each R QC are halo, cyano, OH and NR c R d is selected from the group consisting of:

[0124] In some embodiments, R QC In certain of these embodiments, one of R QC One of them is -F.

[0125] In some embodiments, R QC One of the is -OH.

[0126] In some embodiments, R QC One of them is NR c R d is.

[0127] In some embodiments, R QC One of them is NH(C 1-3 alkyl) (e.g., NHMe, NHEt, or NHiPr.

[0128] In some embodiments, R QC One of them is NH2.

[0129] In some embodiments, R QC One of them is N(C 1-3 alkyl)2 (e.g., NMe2).

[0130] In some embodiments, R QC One of them is NHC(=O)(C 1-6 alkyl), NHC(=O)(C 3-6 cycloalkyl), NHC(=O)O(C 1-6 alkyl), NHS(O) 1-2 (C 1-6 alkyl) and NHS(O) 1-2 (C 3-6 cycloalkyl).

[0131] In some embodiments, R QC One of them is NHC(=O)(C 1-3 alkyl), NHC(=O)(C 3-6 cycloalkyl) (e.g., NHC(=O)(cyclopropyl)) or NHS(O)2(C 1-3 alkyl) (e.g., NHS(O)Me).

[0132] In some embodiments, R QC One of them is C 1-6 Alkyl and C(=O)(C 1-6 In one embodiment, R is a 5- to 6-membered heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl. QC One of the groups is morpholinyl.

[0133] In some embodiments, R QC One of the groups is hydroxy, halo and C 1-6 C optionally substituted with 1 to 6 substituents each independently selected from the group consisting of alkoxy 1-6 In some embodiments, R QC C, one of which is optionally substituted with 1 to 6 (e.g., 1 to 3) independently selected halo. 1-6 In some embodiments, R QC can be -OMe, -OCF, or -OCHF. In certain embodiments, R QCis -OMe. In some embodiments, R QC is -OCF. In some embodiments, R QC is -OCHF2.

[0134] In some embodiments, R QC is 1 to 6 independently selected R f C optionally substituted with 1-6 In some embodiments, R QC is C 1-3 In some embodiments, R QC is methyl.

[0135] In some embodiments, R QC one of which is C substituted with 1 to 6 independently selected halo 1-3 In some embodiments, R QC is CF, CHF, or CHF. In certain embodiments, R QC is CF3 or CHF2.

[0136] In some embodiments, R QC One of them is NR c R d C replaced with 1-3 In some embodiments, R QC is CH2NHMe.

[0137] In some embodiments, the remaining R QC Each of, when present, is independently selected halo, eg, —F.

[0138] In some embodiments, a pair of R on adjacent carbon atoms QC each together with the atom to which it is attached forms a ring containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms each independently selected from the group consisting of O, N, and S, and wherein the ring is joined to 1-2 independently selected R h It may be substituted with a group.

[0139] In some embodiments, a pair of R on adjacent carbon atoms QC are united with the atoms to which they are bonded, [ka] Form.

[0140] In some embodiments, a pair of R on adjacent carbon atoms QC are united with the atoms to which they are bonded, [ka] Form.

[0141] In some embodiments, the remaining R QC each, when present, is independently halo, cyano or C 1-3 It is alkyl.

[0142] In one embodiment, L 2 teeth [ka] In one embodiment, L 2A In certain embodiments, L is a bond. 2A is CH2.

[0143] In one embodiment, L 2 teeth [ka] is.

[0144] In one embodiment, L 2 teeth [ka] In certain embodiments, n1 is 1. In other particular embodiments, n1 is 2 or 3. In certain embodiments, L 2A is a bond. In certain embodiments, L 2A is C1-2 It is alkylene.

[0145] In one embodiment, L 2 teeth [ka] In one embodiment, L 2A In certain embodiments, L is a bond. 2A C 1-2 It is alkylene.

[0146] In one embodiment, L 2 teeth [ka] is.

[0147] In certain embodiments, ring A is C 6-10 aryl or 5-10 membered heteroaryl, each of which is selected from halo, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 It may be substituted with 1 to 4 substituents each independently selected from the group consisting of alkoxy.

[0148] In certain embodiments, ring A is phenyl or pyridyl, each of which is selected from the group consisting of halo, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 It may be substituted with 2 to 4 substituents each independently selected from the group consisting of alkoxy.

[0149] In some embodiments, ring A, halo (e.g., —F) and C 1-6 Alkyl (e.g., C 1-3 In one embodiment, ring A is phenyl, optionally substituted with 2 to 4 substituents each independently selected from the group consisting of alkyl, aryl, aryls ... [ka] [In the formula, RAA , R AB and R AC are independently halo or C 1-6 alkyl] In some embodiments, R AA and R AC independently, C 1-3 alkyl (e.g., methyl); and / or R AB is halo (e.g., -F).

[0150] In certain embodiments, ring A is selected from the group consisting of halo and C 1-6 In some embodiments, ring A is optionally substituted with 2 to 4 substituents each independently selected from the group consisting of halo and C 1-6 In some embodiments, ring A is 4-pyridyl optionally substituted with 2 to 4 substituents each independently selected from the group consisting of halo and C 1-6 In some embodiments, ring A is 3-pyridyl optionally substituted with 2 to 4 substituents each independently selected from the group consisting of halo and C 1-6 and 2-pyridyl which may be substituted with 2 to 4 substituents each independently selected from the group consisting of alkyl.

[0151] In some embodiments, R 1 is H. In some embodiments, R 1 is C 1-6 It is alkyl.

[0152] In some embodiments, R 2 is H. In some embodiments, R 2 is C 1-6 It is alkyl.

[0153] In some embodiments, R 3 is H. In some embodiments, R 3 is C 1-6 Alkyl (e.g., C such as methyl) 1-3 alkyl).

[0154] In some embodiments, R 1 , R 2 and R 3 is H. In some embodiments, R 1 and R 2 is H and R 3 is C 1-6 In some embodiments, R 3 is methyl.

[0155] In some embodiments, R 1 is H and R 2 and R 3 independently, C 1-6 alkyl.

[0156] In one embodiment, L 1 is C(=O).

[0157] In one embodiment, L 1 is -CH2- or -CH(C 1-6 alkyl)-.

[0158] In one embodiment, L 1 is -S(=O)2.

[0159] In some embodiments, R 4 , R 5 and R 6 are each H or halo. In certain embodiments, R 4 , R 5 and R 6 are each H or -F. In some embodiments, R 4 , R 5 and R 6 are each H. As another non-limiting example, R 4 and R 5 is H and R 6 is -F. In some embodiments, R 7 is H. In some embodiments, R 7 is -F.

[0160] In some embodiments, R 4 , R 5 , R 6 and R 7 , when present, are each independently selected from the group consisting of —H and halo. 4 , R 5 , R 6 and R 7 When present, each is independently selected from the group consisting of -H and -F.

[0161] In one embodiment, L 3 and L 4 In certain embodiments, at least one of L is a bond. 3 and L 4 Both are bonds.

[0162] In one embodiment, L 3 is a bond and L 4 is C 1-2 It is alkylene.

[0163] In one embodiment, L 4 is a bond and L 3 is C 1-2 It is alkylene.

[0164] In one embodiment, L 3 and L 4 are each independently C 1-2 It is alkylene.

[0165] In some embodiments, R 8a and R 8b Each of them, together with the carbon atom to which it is bonded, is independently selected from 1 to 2 C 1-6 C optionally substituted with alkyl 3-8 Form a cycloalkyl ring, wherein said C 1-6 The alkyl group is one to three independently selected R f may be substituted with.

[0166] In some embodiments, R 8aand R 8b Each of them, together with the carbon atom to which it is bonded, is independently selected from 1 to 2 C 1-6 C optionally substituted with alkyl 3-5 Form a cycloalkyl ring, wherein said C 1-6 The alkyl group is one to three independently selected R f may be substituted with.

[0167] In some embodiments, R 8a and R 8b Each of them, together with the carbon atom to which it is bonded, is independently selected from 1 to 2 C 1-6 C optionally substituted with alkyl 3-4 Forms a cycloalkyl ring.

[0168] In some embodiments, R 8a and R 8b are, together with the carbon atoms to which they are bonded, [ka] In one embodiment, R 8a and R 8b are, together with the carbon atoms to which they are bonded, [ka] Form.

[0169] In some embodiments, R 8a and R 8b is H and C 1-6 alkyl. For example, R 8a and R 8b and R can both be H. In some embodiments, R 8a and R 8b are each independently C 1-6 Alkyl (e.g., C 1-3 In some embodiments, R 8a is H and R 8b is C 1-6 Alkyl (e.g., C1-3 alkyl).

[0170] In one embodiment, L 3 -C(R 8a R 8b )-L 4 -R 9 Part [ka] In some embodiments, R 9d is H or C 1-6 It is alkyl.

[0171] In one embodiment, L 3 -C(R 8a R 8b )-L 4 -R 9 Part [ka] In certain of these embodiments, R 9d is H or C 1-6 alkyl. For example, R 9d can be H.

[0172] In some embodiments, R 9 teeth [ka] In some embodiments, R 9d is H or C 1-6 In some embodiments, R 9d is H.

[0173] In some embodiments, R 9 teeth [ka] In some embodiments, R 9 teeth [ka] In some embodiments, R 9 teeth [ka] is.

[0174] In some embodiments, R 9 is C(=O)OH.

[0175] In some embodiments, R 9 is C(=O)(OC 1-6 alkyl).

[0176] In some embodiments, R 9 is C(=O)NR 9a R 9b In some embodiments, R 9a is H. In some embodiments, R 9b is H. In some embodiments, R 9b is C 1-6 In some embodiments, R 9b is C(=O)(C 1-6 alkyl), S(O) 0-2 (C 1-6 alkyl) and cyano.

[0177] In one embodiment, [ka] Part [ka] [Wherein, ring D is C 3-6 is cycloalkyl, and R 8c is H and 1 to 3 independently selected R f C optionally substituted with 1-6 alkyl] A non-limiting example is: [ka] Includes.

[0178] In some embodiments (part [ka] but [ka] When 9 teeth [ka] In some embodiments, R 9d is H or C 1-6 In some embodiments, R 9d is H.

[0179] In certain embodiments, ring C is selected from 1 to 3 independently selected R Ca and optionally substituted 3- to 12-membered heterocyclyl.

[0180] In certain embodiments, ring C is selected from 1 to 3 independently selected R Ca and optionally substituted 4- to 8-membered heterocyclyl.

[0181] In certain embodiments, ring C is selected from 1 to 3 independently selected R Ca and optionally substituted 5- or 6-membered heterocyclyl.

[0182] In some embodiments, ring C is selected from 1 to 3 independent R Ca In some embodiments, ring C is tetrahydropyranyl optionally substituted with [ka] In some embodiments, ring C is selected from the group consisting of: [ka] is.

[0183] In certain embodiments, ring C is selected from 1 to 3 independently selected R Ca For example, ring C is morpholinyl optionally substituted with [ka] It could be.

[0184] In certain embodiments, ring C is selected from 1 to 3 independently selected R Ca and optionally substituted 5- or 6-membered heteroaryl.

[0185] In certain embodiments, ring C is selected from 1 to 3 R Ca C optionally substituted with 3-10 In some embodiments, ring C is cycloalkyl. ... Ca C optionally substituted with 3-8 In some embodiments, ring C is cycloalkyl. [ka] is.

[0186] In certain embodiments, each R Ca independently, halo, C 1-6 Alkyl, C 1-6 Alkoxy and NR c R d is selected from the group consisting of:

[0187] In certain embodiments, each R Ca are independently halo and C 1-6 alkyl.

[0188] In certain embodiments, each R Ca independently, C 1-6 For example, each R Ca can be methyl.

[0189] In certain embodiments, each RCa are independently selected halo groups. For example, each R Ca can be -F.

[0190] In certain embodiments, a pair of R on the same or different ring atoms Ca are taken together with the ring atom to which they are attached to form a carbocyclic ring containing 3 to 6 ring atoms. In some embodiments, a pair of R Ca , each taken together with the ring atom to which it is attached, form a carbocyclic ring containing 3 to 5 ring atoms.

[0191] In certain embodiments, the compound of formula I has formula IIA: [ka] [In the formula, Q 4 and Q 5 are independently N, CH and CR QC selected from the group consisting of or a pharmaceutically acceptable salt, deuterated analog or solvate thereof.

[0192] In some embodiments of Formula IIA, Q 4 and Q 5 Each of the is CH.

[0193] In some embodiments of Formula IIA, Q 4 is CR QC and Q 5 is CH.

[0194] In some embodiments of Formula IIA, Q 4 is CR QC and Q 5 is CR QC In certain of these embodiments, Q 4 is CR QC and Q 5 is C-halo, e.g., CF.

[0195] In some embodiments of Formula IIA, Q 4 is N and Q5 is CR QC or CH. In certain of these embodiments, Q 5 is CH.

[0196] In certain embodiments, the compound of Formula I has Formula IIB: [ka] [In the formula, Q 2 , Q 3 and Q 5 are independently N, CH and CR QC selected from the group consisting of or a pharmaceutically acceptable salt, deuterated analog or solvate thereof.

[0197] In some embodiments of formula IIB, Q 2 , Q 3 and Q 5 Each of the is CH.

[0198] In some embodiments of formula IIB, Q 5 is CR QC and Q 2 and Q 3 Each of the is CH.

[0199] In some embodiments of formula IIB, Q 5 is CH and Q 2 and Q 3 are independently selected CRs QC is.

[0200] In one embodiment, L 3 and L 4 At least one of L is a bond. 3 and L 4 Both are bonds.

[0201] In some embodiments of Formula IIA or Formula IIB, R 8a and R 8bEach of them, together with the carbon atom to which it is bonded, is independently selected from 1 to 2 C 1-6 C optionally substituted with alkyl 3-5 Form a cycloalkyl ring, wherein said C 1-6 The alkyl group is one to three independently selected R f may be substituted with.

[0202] In some embodiments, R 8a and R 8b Each of them, together with the carbon atom to which it is bonded, is independently selected from 1 to 2 C 1-6 C optionally substituted with alkyl 3-4 Forms a cycloalkyl ring.

[0203] In some embodiments, R 8a and R 8b are, together with the carbon atoms to which they are bonded, [ka] Form.

[0204] In some embodiments of formula IIA or formula IIB, ring C is selected from 1 to 3 independently selected R Ca In some embodiments, ring C is a 3- to 12-membered heterocyclyl optionally substituted with 1 to 3 independently selected R Ca In some embodiments, ring C is a 5- to 6-membered heterocyclyl optionally substituted with 1 to 3 R Ca In some embodiments, ring C is tetrahydropyranyl optionally substituted with [ka] In certain embodiments, ring C can be selected from the group consisting of 1 to 3 independently selected R Ca For example, ring C is morpholinyl optionally substituted with [ka] It could be.

[0205] In some embodiments of formula (IA) or formula (IB), ring C is selected from 1 to 3 R Ca C optionally substituted with 3-8 For example, ring C is [ka] It could be.

[0206] In some embodiments of formula IIA or IIB, each R Ca independently, C 1-6 In certain embodiments, each R Ca is H. In certain embodiments, each R Ca is C 1-3 In some embodiments of formula IIA or IIB, each R Ca are independently selected halo (e.g., —F).

[0207] In certain embodiments of formula IIA or IIB, 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.

[0208] In some embodiments of formula IIA or IIB, a pair of R Ca are taken together with the ring atoms to which they are each attached to form a carbocyclic ring containing 3 to 5 ring atoms.

[0209] In certain embodiments, the compound of Formula I has Formula IIC: [ka] [During the ceremony, Ring D is C 3-6 is cycloalkyl; R 8c is H and 1 to 3 independently selected R f C optionally substituted with 1-6 selected from the group consisting of alkyl; Each R Cb are independently H and R Ca selected from the group consisting of or a pharmaceutically acceptable salt, deuterated analog or solvate thereof.

[0210] In some embodiments of formula IIC, ring D is cyclopropyl.

[0211] In some embodiments of formula IIC, ring D is cyclobutyl.

[0212] In certain embodiments of formula IIC, R 8c is H.

[0213] In certain embodiments of formula IIC, R 8c is C 1-3 alkyl. For example, R 8c can be methyl.

[0214] In certain embodiments of formula IIC, each R Cb is H.

[0215] In certain embodiments of formula IIC, each R Cb independently, C 1-6 Alkyl (e.g., C 1-3 alkyl (e.g., methyl).

[0216] In certain embodiments of formula IIC, Q 1 , Q 2 , Q 3 , Q 4 and Q 5 is as defined by (AA).

[0217] In certain embodiments of Formula IIC, [ka] Part [ka] [In the formula, Q 4 and Q 5 are independently N, CH and CR QC is selected from the group consisting of:

[0218] In one embodiment, Q 4 and Q 5 Each of the is CH.

[0219] In one embodiment, Q 4 is CR QC and Q 5 is CH.

[0220] In one embodiment, Q 4 is CR QC and Q 5 is CR QC In one embodiment, Q 4 is CR QC and Q 5 is C-halo, e.g., CF.

[0221] In one embodiment, Q 4 is N and Q 5 is CR QC or CH. In some embodiments, Q 5 is CH.

[0222] In certain embodiments of Formula IIC, [ka] Part [ka] [In the formula, Q 2 , Q 3 and Q 5 are independently N, CH and CR QC selected from the group consisting of is.

[0223] In one embodiment, Q 2 , Q 3 and Q5 Each of the is CH.

[0224] In one embodiment, Q 5 is CR QC and Q 2 and Q 3 Each of these is CH.

[0225] In one embodiment, Q 5 is CH and Q 2 and Q 3 independently, CR QC is selected from.

[0226] In certain embodiments of formula IIC, L 1 is C(=O).

[0227] In some embodiments of Formula IIA, Formula IIB, or Formula IIC, R a and R b is C 1-6 Alkyl and C 3-6 cycloalkyl.

[0228] In some embodiments of Formula IIA, Formula IIB, or Formula IIC, R a and R b are each independently 1-3 In some embodiments, R a and R b Each R is methyl. a and R b Each R can be ethyl. a and R b may each be isopropyl.

[0229] In some embodiments of Formula IIA, Formula IIB, or Formula IIC, R a is methyl and R b is tert-butyl.

[0230] In some embodiments of Formula IIA, Formula IIB, or Formula IIC, Ra and R b independently, C 3-6 For example, R a and R b may both be cyclopropyl.

[0231] In some embodiments of Formula IIA, Formula IIB, or Formula IIC, each R QC is halo;cyano;OH;NR c R d 1 to 6 independently selected R f C optionally substituted with 1-6 Alkyl; Hydroxy, Halo and C 1-6 C optionally substituted with 1 to 6 substituents each independently selected from the group consisting of alkoxy 1-6 Alkoxy; and C 1-6 Alkyl and C(=O)(C 1-6 and 3- to 12-membered heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl.

[0232] In certain embodiments, each R QC is selected from the group consisting of -F, OH, NH2, NHMe, NHEt, NHiPr, N(Me)2, NHC(=O)(cyclopropyl), NHS(O)2Me, methyl, CF3, CHF2, OMe, OCF3, OCHF2, and morpholinyl.

[0233] In some embodiments, R QC is selected from the group consisting of -F, OH, NH2, NHMe, NHEt, NHC(=O)(cyclopropyl), NHS(O)2Me, methyl, OMe, OCF3, and morpholinyl.

[0234] In some embodiments of Formula IIA, Formula IIB, or Formula IIC, each R QC are halo, cyano, OH and NR c R d is selected from the group consisting of:

[0235] In certain embodiments, each R QC is selected from the group consisting of —F, OH, and NHMe.

[0236] In some embodiments of formula IIA, formula IIB, or formula IIC, a pair of R QC each together with the atom to which it is attached forms a ring containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms each independently selected from the group consisting of O, N, and S, and wherein the ring is joined to 1-2 independently selected R h In some embodiments, a pair of R groups on adjacent carbon atoms may be substituted. QC are united with the atoms to which they are bonded, [ka] In some embodiments, a pair of R on adjacent carbon atoms forms QC are united with the atoms to which they are bonded, [ka] (For example, R h is methyl).

[0237] In some embodiments of Formula IIA, Formula IIB, or Formula IIC, L 2 teeth [ka] is.

[0238] In some embodiments of formula IIA, formula IIB, or formula IIC, ring A is phenyl or pyridyl, each of which may be selected from the group consisting of halo, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 It may be substituted with 2 to 4 substituents each independently selected from the group consisting of alkoxy.

[0239] In some embodiments of formula IIA, formula IIB, or formula IIC, ring A is selected from halo and C1-6 and phenyl optionally substituted with 2 to 4 substituents each independently selected from the group consisting of alkyl.

[0240] In certain embodiments, ring A is [ka] [In the formula, R AA , R AB and R AC are independently halo or C 1-6 alkyl] For example, R AA and R AC Each of the 1-6 Alkyl, e.g., C 1-3 alkyl (e.g., methyl); and / or R AB can be halo (eg, —F).

[0241] In some embodiments of Formula IIA, Formula IIB, or Formula IIC, R 1 and R 2 is H.

[0242] In some embodiments of Formula IIA, Formula IIB, or Formula IIC, R 3 is H.

[0243] In some embodiments of Formula IIA, Formula IIB, or Formula IIC, R 3 is C 1-6 It is alkyl.

[0244] In some embodiments of Formula IIA, Formula IIB, or Formula IIC, R 1 and R 2 is H and R 3 is C 1-6 alkyl. For example, R 3 can be methyl.

[0245] In some embodiments of Formula IIA, Formula IIB, or Formula IIC, R 4 , R 5 and R 6are each H or halo.

[0246] In some embodiments of Formula IIA, Formula IIB, or Formula IIC, R 4 , R 5 and R 6 is each H or -F. In certain embodiments of formula IIA, formula IIB, or formula IIC, R 4 , R 5 and R 6 are each H. In some embodiments of formula IIA, formula IIB, or formula IIC, R 4 and R 5 is H and R 6 is -F.

[0247] In some embodiments of Formula IIA, Formula IIB, or Formula IIC, R 7 is H.

[0248] In some embodiments of Formula IIA, Formula IIB, or Formula IIC, R 7 is -F.

[0249] In some embodiments of Formula IIA, Formula IIB, or Formula IIC, R 9 teeth [ka] In some embodiments, R 9d is H.

[0250] In certain embodiments, the compound of Formula I has Formula IID: [ka] [During the ceremony, R AA , R AB and R AC are independently halo or C 1-6 is alkyl; R QC is H or halo; Each R Cb are independently H and R Ca selected from the group consisting of or a pharmaceutically acceptable salt, deuterated analog or solvate thereof.

[0251] In certain embodiments of formula IID, R 1 and R 2 is H.

[0252] In certain embodiments of formula IID, R 3 is C 1-3 In some embodiments, R 3 is methyl.

[0253] In certain embodiments of formula IID, R 4 , R 5 , R 6 and R 7 is H.

[0254] In certain embodiments of formula IID, R 9d is H.

[0255] In certain embodiments of formula IID, R AA and R AC independently, C 1-6 In certain of these embodiments, R AA and R AC is methyl.

[0256] In certain embodiments of formula IID, R AB is halo. In certain embodiments, R AB is -F.

[0257] In certain embodiments of formula IID, each R Cb is H. In certain embodiments of formula IID, each R Cb is C 1-3 In certain embodiments, each R Cb is methyl.

[0258] In certain embodiments of formula IID, R a and R b independently, C1-3 In certain of these embodiments, R a and R b is methyl. In some embodiments, R a and R b is ethyl. In some embodiments, R a and R b is isopropyl.

[0259] In certain embodiments of formula IID, R a is methyl and R b is tert-butyl.

[0260] In certain embodiments of formula IID, R a and R b independently, C 3-6 Cycloalkyl. For example, R a and R b may both be cyclopropyl.

[0261] In certain embodiments of Formula IID, P(=O)R a R b teeth [ka] [In the formula, L Q is a bond CH2, O, S, NH or N(C 1-6 alkyl) In some embodiments, P(═O)R a R b teeth [ka] is.

[0262] In certain embodiments of formula IID, R QC is -F.

[0263] In certain embodiments of formula IID, R QC is -OH.

[0264] In certain embodiments of formula IID, R QC is NR c R d In some embodiments, R QC is NH(C 1-3 alkyl) (e.g., NHMe or NHEt). In some embodiments, R QC is NH. In some embodiments, R QC is N(C 1-3 alkyl)2 (e.g., NMe2). In certain embodiments, R QC is NHC(=O)(C 1-3 alkyl), NHC(=O)(C 3-6 cycloalkyl) or NHS(O)2(C 1-3 alkyl).

[0265] In certain embodiments of formula IID, R QC is C 1-6 Alkyl and C(=O)(C 1-6 and alkyl).

[0266] In certain embodiments of formula IID, R QC C is optionally substituted with 1 to 6 independently selected halo groups. 1-6 In some embodiments, R QC is -OMe, -OCF3 or -OCHF2.

[0267] In certain embodiments of formula IID, R QC is C 1-3 In some embodiments, R QC is methyl. In certain embodiments of formula IID, R QC is C substituted with 1 to 3 independently selected halo groups 1-3 In some embodiments, R QC is -CF3 or -CHF2.

[0268] In certain embodiments of formula IID, R QC is H.

[0269] In certain embodiments of formula IID, R QC is halo. In certain embodiments, R QC is -F. In some embodiments, R QC is P(=O)R a R b In one embodiment, R QC is P(=O)R a R b It is meta to R QC In some embodiments, R QC is R QC In some embodiments, R QC is P(=O)R a R b Meta and R QC is ortho-F.

[0270] In some embodiments of Formula IID, the compound has the formula (S,S,S)-IID: [ka] [In the formula, R 3 is C 1-3 alkyl] or a pharmaceutically acceptable salt thereof.

[0271] In certain embodiments, the compound of formula I has formula IIE: [ka] [During the ceremony, R AA , R AB and R AC each independently represents halo or C 1-3 is alkyl; R 3 is H or C 1-3 is alkyl; R QC is H or halo; R QDare (a) H; (b) -NH; (c) -NH(C 1-3 (d) halo; (e) C optionally substituted with 1 to 3 independently selected halo. 1-3 alkoxy; and (f) C optionally substituted with 1 to 3 independently selected halo. 1-3 selected from the group consisting of alkyl; R a and R b is C 1-4 Alkyl and C 3-6 cycloalkyl; R a and R b Each of these forms a ring containing 5 to 8 ring atoms together with the phosphorus atom to which it is attached, and 0 to 1 ring atom (R a and R b (in addition to the phosphorus atom bonded to) are heteroatoms independently selected from the group consisting of O, S, and N; R 8c is H or C 1-3 is alkyl; X B is CH or N; Each R Cb are independently H and C 1-3 alkyl] or a pharmaceutically acceptable salt, deuterated analog or solvate thereof.

[0272] In some embodiments, R QD is (a) H; (b) —NH; (c) —NH(CD); (d) halo; (e) C optionally substituted with 1 to 3 independently selected halo; 1-3 alkoxy; and (f) C optionally substituted with 1 to 3 independently selected halo. 1-3 alkyl.

[0273] In certain embodiments, ring B of Formula IIC, Formula IID, Formula (S,S,S)-IID, Formula IIE, or Formula (S,S,S)-IIE is [ka] [During the ceremony, R 4 , R 5 , R 6 and R 7 are each independently as defined herein; bb represents the point of attachment to -C(O)-; xx represents the point of attachment to the Ring C moiety described in Formula I. is selected from the group consisting of:

[0274] In certain embodiments, the compound of formula I has formula IIE: [ka] [During the ceremony, Ring B is: [ka] (In the formula, bb represents the point of attachment to -C(O)-; xx is X b represents the attachment point to; R 4 , R 5 , R 6 and R 7 are independently H, halo and C 1-6 alkyl) selected from the group consisting of: R AA , R AB and R AC are each independently hydrogen, halo, or C 1-3 Alkyl or C 3-6 is cycloalkyl; R 3 is H or C 1-3 is alkyl; R QC is H or halo; R QD are (a) H; (b) -NH; (c) -NH(C 1-3 (d) halo; (e) C optionally substituted with 1 to 3 independently selected halo. 1-3alkoxy; and (f) C optionally substituted with 1 to 3 independently selected halo. 1-3 selected from the group consisting of alkyl; R a and R b is C 1-4 Alkyl and C 3-6 cycloalkyl; R a and R b each together with the phosphorus atom to which it is attached forms a ring containing 5 to 8 ring atoms, where 0 to 1 ring atom (R a and R b (in addition to the phosphorus atom bonded to) are heteroatoms independently selected from the group consisting of O, S, and N; R 8c is H or C 1-3 is alkyl; X B is CH or N; Each R Cb are independently H and C 1-3 alkyl] or a pharmaceutically acceptable salt, deuterated analog or solvate thereof.

[0275] In certain embodiments of formula IIE, R AA and R AC are each independently C 1-3 alkyl. For example, R AA and R AC Each of may be methyl.

[0276] In certain embodiments of formula IIE, R AB is a halo. For example, R AB can be F.

[0277] In certain embodiments of formula IIE, R AA and R AC are each independently C 1-3 alkyl, and R AB is a halo. For example, R AA and RAC are each methyl; R AB can be F.

[0278] In certain embodiments of formula IIE, R 3 is C 1-3 alkyl. For example, R 3 can be methyl.

[0279] In certain embodiments of formula IIE, R QD is H.

[0280] In certain embodiments of formula IIE, R QD -NH2 and -NH(C 1-3 For example, R QD can be -NH2. As another non-limiting example, R QD As a further non-limiting example, R QD can be NHEt.

[0281] In certain embodiments of formula IIE, R QD is a halo. For example, R QD can be -F or -Cl.

[0282] In certain embodiments of formula IIE, R QD C optionally substituted with 1 to 3 independently selected halo 1-3 Alkoxy. For example, R QD As another non-limiting example, R QD can be OCF3. As a further non-limiting example, R QD may be OCHF2.

[0283] In certain embodiments of formula IIE, R QD C may be substituted with 1 to 3 independently selected halo groups. 1-3 alkyl. For example, R QD can be methyl. Another non-limiting example is R QD can be CF3. As another non-limiting example, R3 can be -CHF2.

[0284] In certain embodiments of formula IIE, R a and R b are each independently selected C 1-4 alkyl. For example, R a and R b Each of R can be methyl. a and R b Each of R can be ethyl. a and R b Each of R can be isopropyl. a is methyl and R b can be tert-butyl.

[0285] In certain embodiments of formula IIE, R a and R b are each independently selected C 3-6 Cycloalkyl. For example, R a and R b Each may be cyclopropyl.

[0286] In certain embodiments of formula IIE, R a and R b each together with the phosphorus atom to which it is attached forms a ring containing 5 to 8 ring atoms, where 0 to 1 ring atom (R a and R b (in addition to the phosphorus atom bonded to R) are heteroatoms independently selected from the group consisting of O, S, and N. For example, R a and R b together with the phosphorus atom to which each is bonded, [ka] can be formed.

[0287] In certain embodiments of formula IIE, R QC is H.

[0288] In certain embodiments of formula IIE, R QC is a halo. For example, R QC can be -F. In some embodiments, R QC is R QD In one embodiment, R QC is R QD In some embodiments, R QC is R QD It is meta to that.

[0289] In certain embodiments of formula IIE, R 8c is H. In some embodiments of formula IIE, R 8c is C 1-3 alkyl. For example, R 8c can be methyl.

[0290] In certain embodiments of formula IIE, X B In some embodiments of formula IIE, X B is N.

[0291] In some embodiments of formula IIE, each R Cb is H. In some embodiments of formula IE, each R Cb are independently selected C 1-3 For example, each R Cb can be methyl.

[0292] In certain embodiments of formula IIE, X B is CH, and each R Cb is H. In some embodiments of formula IIE, X B is CH, and each R Cb are independently selected C 1-3 In certain embodiments of formula IIE, X is alkyl (e.g., methyl). B is N, and each R Cb is H. In some embodiments of formula IIE, X B is N, and each R Cb are independently selected C 1-3It is alkyl (eg, methyl).

[0293] In some embodiments of formula IIE, the compound has the formula (S,S,S)-IIE: [ka] [In the formula, R 3 is C 1-3 alkyl] or a pharmaceutically acceptable salt thereof.

[0294] In some embodiments of Formula IIE: R AA and R AC is methyl; R AB is -F; R 3 is methyl; R QC is H or -F; R QD is selected from the group consisting of H; -NHMe; -NHEt; -NH2; -OMe; -OCF3; -OCHF2; -Me; -CF3; and -CHF2; R a and R b is independently selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, and cyclopropyl; R 8c is H or methyl; X B is CH; Each R Cb are independently H or methyl.

[0295] In certain of these embodiments, the compound is of formula (S,S,S)-IIE.

[0296] In certain embodiments, provided are compounds of Formula III or pharmaceutically acceptable salts or solvates thereof, comprising any one or more of the following characteristics:

[0297] In certain embodiments of Formula I or Formula III, (aa) applies.

[0298] In certain embodiments, 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 1 to 5 independently selected R QA It may be further substituted with.

[0299] In certain embodiments, 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 1 to 5 independently selected R QA In some embodiments, ring D is a 5- to 6-membered heteroaryl or phenyl, each of which may be further substituted with one R QB and 1 to 5 independently selected R QA It may be further substituted with.

[0300] In certain embodiments, ring D is [ka] [In the formula, Q 1 , Q 2 , Q 4 and Q 5 each independently represents N, CH, or CR QA is] In one embodiment, Q 1 , Q 2 , Q 4 and Q 5 are independently CH or CR QA In one embodiment, Q 1 , Q 2 , Q 4 and Q 5 Each of Q is CH. 1 , Q 2 , Q 4 and Q 5 One or two (e.g., one) ofQA and the remaining Q 1 , Q 2 , Q 4 and Q 5 Each of Q is CH. In some embodiments, Q 1 , Q 2 , Q 4 and Q 5 One of the numbers is N and the remaining Q 1 , Q 2 , Q 4 and Q 5 each independently represents CH or CR QA In some embodiments, the remaining Q 1 , Q 2 , Q 4 and Q 5 Each of the is CH.

[0301] In certain embodiments, ring D is [ka] wherein m1 is 0, 1 or 2. For example, m1 can be 0. In some embodiments, m1 can be 1 and R QA is R QB It can also be meta to.

[0302] In certain embodiments, ring D is [ka] [In the formula, Q 1 , Q 2 , Q 3 and Q 5 each independently represents N, CH, or CR QA is] In one embodiment, Q 1 , Q 2 , Q 3 and Q 5 are independently CH or CR QA In one embodiment, Q 1 , Q 2 , Q 3 and Q 5Each of Q is CH. 1 , Q 2 , Q 3 and Q 5 1-2 (e.g., 1) of QA and the remaining Q 1 , Q 2 , Q 3 and Q 5 Each of the is CH.

[0303] In certain embodiments, ring D is [ka] wherein m1 is 0, 1 or 2. In some embodiments, m1 is 0. In some embodiments, m1 is 1.

[0304] In some embodiments, 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, each occurrence of R h is H. 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, R e is C1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 cycloalkyl, each of which is selected from 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 e is C 1-6 Alkyl or C 1-6 Haloalkyl, each of which is 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 e is C 1-6 alkyl. For example, R e is C 1-3 It may be alkyl, for example methyl or ethyl.

[0305] In some embodiments, 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 in each case R h is H. In some embodiments, q1 is 1. 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 eis C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 cycloalkyl, each of which is selected from 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 e is C 1-6 Alkyl or C 1-6 haloalkyl, each of which is selected from 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 e is C 1-6 alkyl. For example, R e is C 1-3 It may be alkyl, for example methyl or ethyl.

[0306] In some embodiments, 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 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 1-3alkyl (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 selected from 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 e is C 1-6 Alkyl or C 1-6 haloalkyl, each of which is selected from 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 e is C 1-6 alkyl. For example, R e is C such as methyl or ethyl 1-3 It can be alkyl.

[0307] In some embodiments, R QB Ha-(CR h Rh ) q1 -S(O)2-(CR h R h ) q2 -R e q1 is 1 or 2; R e is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 cycloalkyl, each of which is selected from 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 some embodiments, q2 is 0. In some embodiments, q1 is 1. In some embodiments, q1 is 2. In some embodiments, each occurrence of R h is H or C 1-3 In some embodiments, R e is C 1-6 Alkyl or C 1-6 haloalkyl, each of which is selected from 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 optionally substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy. For example, R e C 1-6 Alkyl is C 1-3 It can be alkyl (eg, methyl or ethyl).

[0308] In some embodiments, R QB is -CH2-S(O)2(C 1-6 alkyl). For example, R QB can be —CH—S(O)Me or —CH—S(O)Et.

[0309] In some embodiments, 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).

[0310] In some embodiments, R QB is -CH2CH2-S(O)2(C 1-6 alkyl). For example, R QB can be —CH2CH2S(O)2Me.

[0311] In some embodiments, 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 selected from 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 e is C1-6 alkyl. For example, R e is C 1-3 It can be alkyl, for example, methyl or ethyl. In some embodiments, R e is C 3-6 Cycloalkyl. For example, R e can be cyclopropyl.

[0312] In some embodiments, 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; 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 selected from 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 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.

[0313] In some embodiments, R QB -S(O)2NH-R e and R e is C 1-6 Alkyl, C 1-6Haloalkyl or C 3-6 cycloalkyl, each of which is selected from 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 e is C 1-6 alkyl. For example, R e may be methyl or ethyl, for example methyl.

[0314] In some embodiments, 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 selected from 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 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

[0315] In some embodiments, R QB Ha-L a -S(O)2-L b -R e , where L a is -NH- or -N(R c In one embodiment, L ais -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 selected from 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 e is C 1-6 Alkyl or C 1-6 haloalkyl, each of which is selected from 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 optionally substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy. For example, R e is C 1-6 Alkyl, e.g., C 1-3 It can be alkyl (eg, methyl or ethyl).

[0316] In some embodiments, R QB Ha-L a -S(O)2-L b -R e where L a 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 selected from 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 e is C 1-6 Alkyl or C 1-6 haloalkyl, each of which is selected from 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 optionally substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy. For example, R e is C 1-6 Alkyl, e.g., C 1-3 It can be alkyl (eg, methyl or ethyl).

[0317] In some embodiments, R QB -NHS(O)2-(CR h R h ) q2 -R e and R e C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 cycloalkyl, each of which is selected from halo, cyano, C 1-3 Alkyl, C 1-3Haloalkyl, -OH, NH2, NH(C 1-3 alkyl), N(C 1-3 Alkyl)2, C 1-3 Alkoxy and C 1-3 In one embodiment, q2 is 0. In one embodiment, R e is C 1-6 alkyl. For example, R e is C 1-3 It may be alkyl, for example methyl or ethyl.

[0318] In some embodiments, R QB Ha-L a -S(O)2-L b -R e and 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 some embodiments, R e is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 cycloalkyl, each of which is selected from 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 e is C 1-6 alkyl. For example, R e is C 1-3It can be alkyl, for example, methyl or ethyl. In some embodiments, R e is C3-6 cycloalkyl. For example, R e can be cyclopropyl.

[0319] In some embodiments, 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 selected from 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 e is C 1-6 In some embodiments, R e is C cycloalkyl. In certain embodiments, L a is -NH- or N(C 1-3 alkyl), for example -NH-. In some embodiments, L a Ha-(CR h R h ) q1 In some embodiments, q1 is 1 or 2. In some embodiments, q1 is 0.

[0320] In some embodiments, R QB Ha-L a -S(O)2-L b -R e where R eis C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 cycloalkyl, each of which is selected from 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 e is C 1-6 Alkyl or C 1-6 haloalkyl, each of which is selected from 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 e is C 1-6 alkyl. For example, R e is C 1-3 It may be alkyl, for example methyl or ethyl.

[0321] In some embodiments, R QB is a 4- to 12-membered heterocyclyl or a 7- to 10-membered bicyclic heteroaryl, each of which contains an endocyclic S(O) group, wherein said heterocyclyl or heteroaryl is joined to one to six independently selected R g may be substituted with.

[0322] In some embodiments, 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 is a 4- to 10-membered heterocyclyl containing 1-6 independently selected R g may be substituted with.

[0323] In some embodiments, R QB teeth [ka] where the ring Q 2 are N, O and S(O) 0-2 wherein the ring Q is a 4- to 8-membered heterocyclyl containing 0 to 2 ring heteroatoms (in addition to the endocyclic NS(O)2 groups) each independently selected from the group consisting of 2 are 1 to 4 independently selected R g In some embodiments, R QB teeth [ka] m2 is 0, 1, 2 or 3; R QB are 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:

[0324] In some embodiments, R QA is -halo. For example, in some cases R QA can be -F.

[0325] In certain embodiments of formula I or III, (bb) applies.

[0326] In some embodiments, Ring D is a 4- to 12-membered heterocyclyl or a 7- to 10-membered bicyclic heteroaryl, Ring D contains an endocyclic S(O) group, and Ring D contains 1 to 4 R QA may be substituted with.

[0327] In certain embodiments, Ring D is a 4- to 12-membered heterocyclyl or a 7- to 10-membered bicyclic heteroaryl, wherein said Ring D is an endocyclic —N(H)S(O)— group or an —N(C 1-3 alkyl)S(O)2- group, and ring D contains 1 to 3 R QA It may be further substituted with.

[0328] In certain embodiments, Ring D is a 7-10 membered bicyclic heteroaryl, wherein said Ring D is an endocyclic —N(H)S(O)— group or —N(C 1-3 alkyl)S(O)2- group, and ring D contains 1 to 3 R QA For example, ring D may be further substituted with [ka] [In the formula, R N1 is H or C 1-3 alkyl] It could be.

[0329] In some embodiments, R 1 is H. In some embodiments, R 2 is H. In some embodiments, 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 attached to has the (S)-configuration.

[0330] In some embodiments, R 1 , R 2 and R 3 is H.

[0331] In some embodiments, 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 attached to has the (S)-configuration.

[0332] In one embodiment, L 2 teeth [ka] is.

[0333] In some embodiments, ring A is C 6-10 aryl or 5-10 membered heteroaryl, each of which is selected from halo, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 It may be substituted with 1 to 4 substituents each independently selected from the group consisting of alkoxy.

[0334] In certain embodiments, ring A is phenyl or pyridyl, each of which is selected from the group consisting of halo, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 It may be substituted with 2 to 4 substituents each independently selected from the group consisting of alkoxy.

[0335] In some embodiments, ring A is selected from the group consisting of halo and C 1-6 and phenyl optionally substituted with 2 to 4 substituents each independently selected from the group consisting of alkyl.

[0336] In certain embodiments, ring A is [ka] [In the formula, R AA , R AB and RAC are independently halo or C 1-6 alkyl] In some embodiments, R AA and R AC independently, C 1-6 Alkyl (e.g., C 1-3 alkyl, e.g., methyl). In some embodiments, R AB is halo (e.g., -F).

[0337] In certain embodiments, ring A is selected from the group consisting of halo and C 1-6 and pyridyl which may be substituted with 2 to 4 substituents each independently selected from the group consisting of alkyl.

[0338] In one embodiment, L 1 is C(=O).

[0339] In some embodiments, R 4 , R 5 and R 6 are each H or halo. In certain embodiments, R 4 , R 5 and R 6 are each H or -F. For example, R 4 , R 5 and R 6 can be H. As another non-limiting example, R 4 and R 5 can be H and R 6 can be -F.

[0340] In some embodiments, R 7 is H. In some embodiments, R 7 is -F.

[0341] In one embodiment, L 3 and L 4 In certain embodiments, at least one of L is a bond. 3 and L 4 In some embodiments, both of L 3 is a bond and L4 is C 1-2 In some embodiments, L is alkylene. 4 is a bond and L 3 is C 1-2 It is alkylene.

[0342] In one embodiment, L 3 and L 4 are each independently C 1-2 It is alkylene.

[0343] In some embodiments, R 8a and R 8b Each of these, together with the carbon atom to which it is attached, represents 1 to 2 (e.g., 1) independently selected C 1-6 C optionally substituted with alkyl 3-8 Form a cycloalkyl ring, wherein said C 1-6 Alkyl is 1 to 3 independently selected R f In one embodiment, L 3 is a bond and L 4 is a bond

[0344] In some embodiments, R 8a and R 8b and each of the carbon atoms to which it is bonded is selected from 1 to 2 (e.g., 1) independently selected C 1-6 C optionally substituted with alkyl 3-5 (e.g., C3 or C4) cycloalkyl ring, wherein said C 1-6 The alkyl group is one to three independently selected R f In one embodiment, L 3 is a bond and L 4 is a bond.

[0345] In some embodiments, R 8a and R 8b Each of these, together with the carbon atom to which it is attached, represents 1 to 2 (e.g., 1) independently selected C 1-6 C optionally substituted with alkyl 3-4Forms a cycloalkyl ring.

[0346] In some embodiments, R 8a and R 8b are, together with the carbon atoms to which they are bonded, [ka] Form.

[0347] In some embodiments, R 8a and R 8b are, together with the carbon atoms to which they are bonded, [ka] Form.

[0348] In some embodiments, R 9 teeth [ka] In some embodiments, R 9d is H or C 1-6 alkyl. For example, R 9d can be H.

[0349] In one embodiment, L 3 -C(R 8a R 8b )-L 4 -R 9 portion [ka] is.

[0350] In one embodiment, L 3 -C(R 8a R 8b )-L 4 -R 9 Part [ka] wherein each stereocenter has the (S)-configuration. is.

[0351] In some embodiments, R 9 is (IX-2), where L 3 -C(R 8a R 8b )-L 4 -R 9 Part [ka] [In the formula, 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.

[0352] In certain embodiments, ring C is selected from 1 to 3 independently selected R Ca In some embodiments, ring C is a 3- to 12-membered heterocyclyl optionally substituted with 1 to 3 independently selected R Ca In some embodiments, ring C is a 4- to 8-membered heterocyclyl optionally substituted with 1 to 3 independently selected R Ca For example, ring C is a 5- to 6-membered heterocyclyl optionally substituted with 1 to 3 independent R Ca It may be tetrahydropyranyl optionally substituted by:

[0353] In certain embodiments, ring C is [ka] In some embodiments, ring C is selected from the group consisting of: [ka] In some embodiments, ring C is [ka] is.

[0354] In some embodiments, R Ca independently, C 1-6 It is alkyl.

[0355] In certain embodiments, a pair of R on the same or different ring atoms 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.

[0356] In some embodiments, the same pair of ring atoms, R Ca are taken together with the ring atoms to which they are each attached to form a carbocyclic ring containing 3 to 5 ring atoms.

[0357] In certain embodiments, the compound of Formula I has Formula IIIA: [ka] [During the ceremony, m1 is 0, 1 or 2; R QB is -(CR h R h ) q1 -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; R 8c is H and 1 to 3 independently selected R f C optionally substituted with 1-6 alkyl] or a pharmaceutically acceptable salt, deuterated analog or solvate thereof.

[0358] In some embodiments of formula IIIA, q2 is 0.

[0359] In some embodiments of formula IIIA, q1 is 1.

[0360] In some embodiments of formula IIIA, q1 is 2.

[0361] In certain embodiments of Formula IIIA, each occurrence of R h is H or C 1-3 For example, each R h can be H. As another non-limiting example, R h One of them is C 1-3 alkyl (e.g., methyl), and each remaining R h can be H.

[0362] In certain embodiments of Formula IIIA, R e is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 cycloalkyl, each of which is selected from 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 e is C 1-6 alkyl. For example, R e is C such as methyl or ethyl 1-3 It can be alkyl.

[0363] In certain embodiments of Formula IIIA, R QB is -CH2-S(O)2(C 1-6 alkyl). For example, R QB is -CH2-S(O)2(C) such as -CH2-S(O)2Me or -CH2-S(O)2Et 1-3 alkyl).

[0364] In certain embodiments of Formula IIIA, R QB -CH(C 1-6 alkyl)-S(O)2(C 1-6 alkyl). For example, R QB is -CH(Me)S(O)Me, etc. 1-3 alkyl)S(O)2(C 1-3 alkyl).

[0365] In certain embodiments of Formula IIIA, R QB is -CH2CH2-S(O)2(C 1-6 alkyl). For example, R QB is -CH2CH2-S(O)2(C such as -CH2CH2-S(O)2Me 1-3 alkyl).

[0366] In certain embodiments, the compound of Formula I has Formula IIIB: [ka] [During the ceremony, m1 is 0, 1 or 2; R QB is -S(O)2N(R N2 )-R e where R QB 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; R 8c is H and 1 to 3 independently selected R f C optionally substituted with 1-6 alkyl] or a pharmaceutically acceptable salt, deuterated analog or solvate thereof.

[0367] In certain embodiments of Formula IIIB, RQB -S(O)2N(H)-R e is.

[0368] In certain embodiments of Formula IIIB, R e is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 cycloalkyl, each of which is selected from 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 It may be substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy.

[0369] In certain embodiments of Formula IIIB, R e is C 1-6 alkyl. For example, R e is C 1-3 It may be alkyl, for example methyl.

[0370] In certain embodiments, the compound of Formula I has Formula IIIC: [ka] wherein m1 is 0, 1 or 2; R QB -N(R N2 )S(O)2-(CR h R h ) q2 -R e where R QB 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; R 8c is H and 1 to 3 independently selected R f C optionally substituted with1-6 alkyl] or a pharmaceutically acceptable salt, deuterated analog or solvate thereof.

[0371] In certain embodiments of Formula IIIC, R N2 is H.

[0372] In some embodiments of Formula IIIC, q2 is 0.

[0373] In certain embodiments of Formula IIIC, R e is C 1-6 Alkyl, C 1-6 Haloalkyl, or C 3-6 cycloalkyl, each of which is selected from 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 It may be substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy.

[0374] In certain embodiments of Formula IIIC, R e is C 1-6 alkyl. For example, R e is C 1-3 It may be alkyl, for example methyl or ethyl.

[0375] In certain embodiments of Formula IIIC, R QB is -N(H)S(O)2(C 1-6 alkyl). For example, R QB is -N(H)S(O)2(C 1-3 alkyl), for example, —N(H)S(O)Me.

[0376] In certain embodiments, the compound of Formula I has Formula IIID: [ka] wherein m1 is 0, 1 or 2; R QB teeth [ka] (In the formula, Ring Q 2 are N, O and S(O) 0-2 and wherein said ring Q is a 4-8 membered heterocyclyl containing 0-2 additional ring heteroatoms (in addition to the endocyclic NS(O)2 group) each independently selected from the group consisting of: 2 are 1 to 4 independently selected R g (which may be substituted with and Ring E is C 3-6 is cycloalkyl; R 8c is H and 1 to 3 independently selected R f C optionally substituted with 1-6 alkyl] or a pharmaceutically acceptable salt, deuterated analog or solvate thereof.

[0377] In certain embodiments of Formula IIID, R QB teeth [ka] m2 is 0, 1, 2 or 3; R QB are 1 to 4 independently selected R g may be substituted with.

[0378] In certain embodiments of Formula IIID, R QB teeth [ka] is.

[0379] In some embodiments of Formula IIIA, Formula IIIB, Formula IIIC, or Formula IIID, R QB is L 2 It is meta to that.

[0380] In some embodiments of Formula IIIA, Formula IIIB, Formula IIIC, or Formula IIID, R QB is L 2 It is para.

[0381] In some embodiments of Formula IIIA, Formula IIIB, Formula IIIC, or Formula IIID, m1 is 0.

[0382] In some embodiments of Formula IIIA, Formula IIIB, Formula IIIC, or Formula IIID, m1 is 1 or 2.

[0383] In certain embodiments of Formula IIIA, Formula IIIB, Formula IIIC, or Formula IIID, any occurrence of R QA is a halo. For example, in some cases R QA can be -F.

[0384] In some embodiments of formula IIIA, formula IIIB, formula IIIC, or formula IIID, ring E is cyclopropyl.

[0385] In some embodiments of formula IIIA, formula IIIB, formula IIIC, or formula IIID, ring E is cyclobutyl.

[0386] In some embodiments of Formula IIIA, Formula IIIB, Formula IIIC, or Formula IIID, R 8c is H.

[0387] In some embodiments of Formula IIIA, Formula IIIB, Formula IIIC, or Formula IIID, R 8c is C 1-3 alkyl. For example, R 8c can be methyl.

[0388] In some embodiments of Formula IIIA, Formula IIIB, Formula IIIC, or Formula IIID, R 9 teeth [ka] In some embodiments, R9d is H.

[0389] In certain embodiments of Formula IIIA, Formula IIIB, Formula IIIC, or Formula IIID, [ka] Part [ka] is.

[0390] In certain embodiments of Formula IIIA, Formula IIIB, Formula IIIC, or Formula IIID, [ka] Part [ka] wherein each stereocenter has the (S)-configuration. is.

[0391] In some embodiments of Formula IIIA, Formula IIIB, Formula IIIC, or Formula IIID, Ring C is selected from 1 to 3 independently selected R Ca and optionally substituted 3- to 12-membered heterocyclyl.

[0392] In some embodiments of Formula IIIA, Formula IIIB, Formula IIIC, or Formula IIID, Ring C is selected from 1 to 3 independently selected R Ca and optionally substituted 5- or 6-membered heterocyclyl.

[0393] In some embodiments of formula IIIA, formula IIIB, formula IIIC, or formula IIID, ring C is selected from 1 to 3 independent R Ca and tetrahydropyranyl optionally substituted by:

[0394] In some embodiments of formula IIIA, formula IIIB, formula IIIC, or formula IIID, ring C is [ka] is selected from the group consisting of:

[0395] In certain embodiments of Formula IIIA, Formula IIIB, Formula IIIC, or Formula IIID, each R Ca independently, C 1-6 It is alkyl.

[0396] In certain embodiments of Formula IIIA, Formula IIIB, Formula IIIC, or Formula IIID, a pair of R on the same or different ring atoms 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.

[0397] In some embodiments of Formula IIIA, Formula IIIB, Formula IIIC, or Formula IIID, R 4 , R 5 , R 6 and R 7 are each H.

[0398] In some embodiments of Formula IIIA, Formula IIIB, Formula IIIC, or Formula IIID, L 1 is C(=O).

[0399] In some embodiments of Formula IIIA, Formula IIIB, Formula IIIC, or Formula IIID, R 1 and R 2 is H.

[0400] In some embodiments of Formula IIIA, Formula IIIB, Formula IIIC, or Formula IIID, R 3 is C 1-3 It is alkyl.

[0401] In some embodiments of Formula IIIA, Formula IIIB, Formula IIIC, or Formula IIID, R 3 is methyl.

[0402] In some embodiments of Formula IIIA, Formula IIIB, Formula IIIC, or Formula IIID, R 1 and R 2 is H and R 3 is C 1-3It is alkyl (eg, methyl).

[0403] In some embodiments of formula IIIA, formula IIIB, formula IIIC, or formula IIID, ring A is phenyl or pyridyl, each of which may be selected from the group consisting of halo, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 It may be substituted with 2 to 4 substituents each independently selected from the group consisting of alkoxy.

[0404] In some embodiments of formula IIIA, formula IIIB, formula IIIC, or formula IIID, ring A is selected from the group consisting of halo and C 1-6 and phenyl optionally substituted with 2 to 4 substituents each independently selected from the group consisting of alkyl.

[0405] In some embodiments of formula IIIA, formula IIIB, formula IIIC, or formula IIID, ring A is [ka] [In the formula, R AA , R AB and R AC are each independently hydrogen, halo, or C 1-3 Alkyl or C 3-6 cycloalkyl] is.

[0406] In some embodiments of formula IIIA, formula IIIB, formula IIIC, or formula IIID, ring A is [ka] [In the formula, R AA , R AB and R AC are independently halo or C 1-6 alkyl] In some embodiments, R AA and R AC independently, C 1-6 alkyl. For example, R AA and R AC are independently selected C1-3 It can be alkyl, for example, methyl. In some embodiments, R AB is a halo, e.g., -F.

[0407] In some embodiments of Formula IIIA, Formula IIIB, Formula IIIC, or Formula IIID, L 2 teeth [ka] is.

[0408] In certain embodiments, provided are compounds of Formula IV, or pharmaceutically acceptable salts or solvates thereof, comprising any one or more of the following characteristics:

[0409] In some embodiments, Q 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 1 to 6 independently selected R Q In some embodiments, Q is substituted with 5- to 10-membered heteroaryl and C6- 10 aryl, each of which is selected from the group consisting of 1 to 6 independently selected R Q In some embodiments, Q is optionally substituted with 1 to 6 independently selected R Q In some embodiments, Q is a 5- to 10-membered heteroaryl optionally substituted with 1 to 6 independently selected R Q In some embodiments, Q is a 9- to 10-membered heteroaryl optionally substituted with 1 to 6 independently selected R Q In some embodiments, Q is a 9-membered heteroaryl optionally substituted with 1 to 2 independently selected R Q is a 9-membered heteroaryl optionally substituted with

[0410] In some embodiments, Q is [ka] [In the formula, Q 1 is NH or NR Q and Q 2 and Q 3 each independently represents N, CH, or CR Q and Q 4 , Q 5 , Q 6 and Q 7 One of them is L 2 is a carbon atom bonded to another Q 4 , Q 5 , Q 6 and Q 7 are each independently N, CH or CR Q is] In one embodiment, Q 1 is NH or NR Q and Q 2 and Q 3 each independently represents N, CH, or CR Q and Q 4 , Q 5 , Q 6 and Q 7 One of them is L 2 is a carbon atom bonded to another Q 4 , Q 5 , Q 6 and Q 7 Each of the three is independently CH or CR Q In one embodiment, Q 1 is NH or NR Q and Q 2 and Q 3 each independently represents N, CH, or CR Q and Q 4 , Q 5 , Q 6 and Q 7 One of them is L 2 is a carbon atom bonded to another Q 4 , Q 5 , Q 6 and Q 7 Each of the three is independently CH or CR Q is.

[0411] In one embodiment, Q 1is NH. In some embodiments, Q 1 is NR Q is.

[0412] In one embodiment, Q 2 is N and Q 3 is N, CH or CR Q is.

[0413] In one embodiment, Q 4 , Q 5 , Q 6 and Q 7 One of them is L 2 is a carbon atom bonded to Q 4 , Q 5 , Q 6 and Q 7 The two are CH and Q 4 , Q 5 , Q 6 and Q 7 One of them is CH or CR Q (e.g., CR Q )

[0414] In some embodiments, one R Q In some embodiments, two R Q In some embodiments, there are three R Q In some embodiments, at least one R Q is attached to the six-membered ring. In some embodiments, two R Q There exist two R Q At least one of these is bonded to a six-membered ring.

[0415] In some embodiments, Q is [ka] [During the ceremony, Q 1 is NH or NR Q and; Q 2 and Q 3 each independently represents N, CH, or CR Q and; n1 is 0 or 1. is.

[0416] In one embodiment, Q 1 is NH. In some embodiments, Q 1 is NR Q is.

[0417] In one embodiment, Q 2 is N and Q 3 is N, CH or CR Q is.

[0418] In some embodiments, one R Q In some embodiments, two R Q In some embodiments, there are three R Q In some embodiments, at least one R Q is attached to the six-membered ring. In some embodiments, two R Q There exist two R Q At least one of these is bonded to a six-membered ring.

[0419] In some embodiments, Q is [ka] [During the ceremony, Q 1 is NH or NR Q and; n1 is 0 or 1. is.

[0420] In one embodiment, Q 1 is NH. In some embodiments, Q 1 is NR Q is.

[0421] In some embodiments, one R Q In some embodiments, two R Q In some embodiments, two R Q There exist two RQ At least one of these is bonded to a six-membered ring.

[0422] In some embodiments, Q is [ka] wherein n1 is 0 or 1. is.

[0423] In some embodiments, Q is [ka] wherein n1 is 0 or 1. is.

[0424] In some embodiments, n1 is 0. In some embodiments, n1 is 1.

[0425] In some embodiments, Q is [ka] is.

[0426] In some embodiments, Q is [ka] is.

[0427] In some embodiments, at least one R Q (For example, R bonded to ring N Q ) exists, one R Q is the following (a) to (n): (a) Halo; (b) cyano; (c)OH; (d)-NR c R d ; (e)-C(=O)NR c R d or -S(O)NR c R d ; (f)-S(=O) 0-2 R e ; (g) 1 to 6 independently selected R f C optionally substituted with 1-6 alkyl; (h) 1 to 6 independently selected R f C optionally substituted with 1-6 Alkoxy; (i) 1 to 6 independently selected R g 3- to 12-membered heterocyclyl optionally substituted by; (j) 1 to 6 independently selected R g C optionally substituted with 6-10 aryl; (k) 1 to 6 independently selected R g 5-10 membered heteroaryl optionally substituted by; (l) 1 to 6 independently selected R g C optionally substituted with 3-8 cycloalkyl; (m)P(=O)R a R b ; and (n)q1 is 1, 2 or 3 - (CR h R h ) q1 -S(O)2-L e -R e ; is selected from the group consisting of When present, each remaining R Q are halo, cyano, OH, C 1-6 Alkyl and C 1-6 alkoxy.

[0428] In some embodiments, at least one R Q (For example, R bonded to ring N Q ) exists, one R Q are the following (a) to (h): (a) Halo; (b) cyano; (c)OH; (d)-NR cR d ; (e)-C(=O)NR c R d or -S(O)NR c R d ; (f)-S(=O) 0-2 R e ; (g) 1 to 6 independently selected R f C optionally substituted with 1-6 alkyl; and (h) 1 to 6 independently selected R f C optionally substituted with 1-6 Alkoxy; and when present, each remaining R Q are independently selected halos.

[0429] In some embodiments, at least one R Q When there exists one R Q (For example, R bonded to ring N Q ) is 1 to 6 independently selected R f and independently selected C, each of which may be substituted with 1-6 alkyl, and when present, each remaining R Q is an independently selected halo. In some embodiments, at least one R Q When there exists one R Q (For example, R bonded to ring N Q ) is 1 to 6 independently selected R f and independently selected C, each of which may be substituted with 1-3 alkyl, and when present, each remaining R Q is fluoro. In some embodiments, at least one R Q When there exists one R Q (For example, R bonded to ring N Q ) are independently selected unsubstituted C 1-3 alkyl, and when present, each remaining R Q is fluoro. In some embodiments, at least one R QWhen there exists one R Q (For example, R bonded to ring N Q ) is methyl, and when present, each remaining R Q is fluoro.

[0430] In some embodiments, two R Q exists, and one R Q (For example, R bonded to ring N Q ) are 1 to 6 independently selected R f and independently selected C, each of which may be substituted with 1-6 alkyl, and the other R Q is halo. In some embodiments, two R Q exists, and one R Q (For example, R bonded to ring N Q ) are 1 to 6 independently selected R f and independently selected C, each of which may be substituted with 1-3 alkyl, and the other R Q is fluoro. In some embodiments, two R Q exists, and one R Q (For example, R bonded to ring N Q ) are independently selected unsubstituted C 1-3 alkyl, and the other R Q is fluoro. In some embodiments, two R Q exists, and one R Q (For example, R bonded to ring N Q ) is methyl, and the other R Q is fluoro.

[0431] In some embodiments, one R Q (For example, R bonded to ring N Q ) are present, which are 1 to 6 independently selected R f and independently selected C, each of which may be substituted with 1-6 In some embodiments, one R Q (For example, R bonded to ring N Q ) are present, which are 1 to 6 independently selected R fand independently selected C, each of which may be substituted with 1-3 In some embodiments, one R Q (For example, R bonded to ring N Q ) are present, which are independently selected unsubstituted C 1-3 In some embodiments, one R Q (For example, R bonded to ring N Q ) is present and is methyl.

[0432] In some embodiments, Q is [ka] is.

[0433] In some embodiments, Q is 1 to 6 independently selected R Q C optionally substituted with 6-10 In some embodiments, Q is 1 to 6 independently selected R Q In some embodiments, Q is phenyl optionally substituted with 1 to 2 independently selected R Q In some embodiments, Q is phenyl optionally substituted with 1 to 2 independently selected R Q and phenyl optionally substituted with .

[0434] In some embodiments, Q is [ka] [In the formula, Y 1 , Y 2 , Y 4 and Y 5 are each independently N, CH, or CR Q is] In one embodiment, Y 1 , Y 2 , Y 4 and Y 5 are each independently CH or CR Q In one embodiment, Y 1 , Y2 , Y 4 and Y 5 one or two of each independently represent CH or CR Q and the remaining Y 1 , Y 2 , Y 4 and Y 5 is CH.

[0435] In some embodiments, Q is [ka] wherein m1 is 0, 1 or 2. is.

[0436] In one embodiment, L 2 Para's R Q are the following (e) to (n): (e)-C(=O)NR c R d or -S(O)NR c R d ; (f)-S(=O) 0-2 R e ; (m)P(=O)R a R b ; and (n)-(CR h R h ) q1 -S(O)2-L e -R e is selected from the group consisting of:

[0437] In one embodiment, L 2 Para's R Q is -P(=O)R a R b is.

[0438] In some embodiments, R a and R b is C 1-6 Alkoxy, C 3-6an independently selected C optionally substituted with 1 to 6 substituents, each independently selected from the group consisting of cycloalkyl and halo; 1-6 In some embodiments, R a and R b is C 1-6 Alkoxy, C 3-6 an independently selected C optionally substituted with 1 to 2 substituents each independently selected from the group consisting of cycloalkyl and halo; 1-6 In some embodiments, R a and R b is an independently selected C optionally substituted with 1 to 2 independently selected halo; 1-3 In some embodiments, R a and R b are independently selected unsubstituted C 1-3 In some embodiments, R a and R b are each ethyl.

[0439] In some embodiments, m1 is 0. In some embodiments, m1 is 1. In some embodiments, m1 is 2.

[0440] In some embodiments, Q is [ka] In one embodiment, L 2 Meta's R Q is NR c R d In some embodiments, each R c and R d are independently H, C 1-6 Alkyl, C(=O)(C 1-6 alkyl), wherein said C 1-6 Alkyl and C(=O)(C 1-6 alkyl) are each -OH, halo and C 1-6In one embodiment, each R c and R d are independently H, C 1-6 Alkyl, C(=O)(C 1-6 alkyl), wherein said C 1-6 Alkyl and C(=O)(C 1-6 alkyl) are each -OH, halo and C 1-6 In one embodiment, each R c and R d are independently H and C 1-6 alkyl, wherein said C 1-6 Alkyl is substituted with -OH, halo and C 1-6 In one embodiment, each R c and R d are independently H and C 1-3 In some embodiments, R c and R d One of them is H and the other is R c and R d The other is C 1-3 In some embodiments, R c and R d One of them is H and the other is R c and R d The other is methyl.

[0441] In some embodiments, Q is [ka] is.

[0442] In some embodiments, R 1 is H. In some embodiments, R 2 is H. In some embodiments, R 3 is C 1-6 alkyl. For example, R3 is C 1-3 It can be alkyl, for example, methyl. In some embodiments, R 3 is C 1-6 alkyl, and R 3 The carbon atom attached to has the (S)-configuration.

[0443] In some embodiments, R 1 , R 2 and R 3 is H.

[0444] In some embodiments, 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 attached to has the (S)-configuration.

[0445] In one embodiment, L 2 teeth [ka] is.

[0446] In some embodiments, ring A is C 6-10 aryl or 5-10 membered heteroaryl, each of which is selected from halo, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 It may be substituted with 1 to 4 substituents each independently selected from the group consisting of alkoxy.

[0447] In certain embodiments, ring A is phenyl or pyridyl, each of which is selected from the group consisting of halo, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 It may be substituted with 2 to 4 substituents each independently selected from the group consisting of alkoxy.

[0448] In certain embodiments, ring A is selected from the group consisting of halo and C 1-6 and phenyl optionally substituted with 2 to 4 substituents each independently selected from the group consisting of alkyl.

[0449] In certain embodiments, ring A is [ka] [In the formula, R AA , R AB and R AC are each independently hydrogen, halo, or C 1-3 Alkyl or C 3-6 cycloalkyl] is.

[0450] In certain embodiments, ring A is [ka] [In the formula, R AA , R AB and R AC are independently halo or C 1-6 alkyl] is. In some embodiments, R AA and R AC independently, C 1-6 Alkyl (e.g., C 1-3 alkyl, e.g., methyl). In some embodiments, R AB is halo (e.g., -F).

[0451] In some embodiments, ring A is halo and C 1-6 and pyridyl which may be substituted with 2 to 4 substituents each independently selected from the group consisting of alkyl.

[0452] In one embodiment, L 1 is C(=O).

[0453] In some embodiments, R 4 , R 5and R 6 are each H or halo. In certain embodiments, R 4 , R 5 and R 6 are each H or -F. For example, R 4 , R 5 and R 6 Each of R 4 and R 5 is H and R 6 can be -F.

[0454] In one embodiment, L 3 and L 4 At least one of L is a bond. 3 and L 4 In some embodiments, both of L 3 is a bond and L 4 is C 1-2 In some embodiments, L is alkylene. 4 is a bond and L 3 is C 1-2 It is alkylene.

[0455] In one embodiment, L 3 and L 4 are each independently C 1-2 It is alkylene.

[0456] In some embodiments, R 8a and R 8b Each of these, together with the carbon atom to which it is attached, represents 1 to 2 (e.g., 1) independently selected C 1-6 C optionally substituted with alkyl 3-8 Form a cycloalkyl ring, wherein said C 1-6 The alkyl group is one to three independently selected R f In one embodiment, L 3 is a bond and L 4 is a bond.

[0457] In some embodiments, R 8a and R8b Each of these, together with the carbon atom to which it is attached, represents 1 to 2 (e.g., 1) independently selected C 1-6 C optionally substituted with alkyl 3-5 (e.g., C3 or C4) cycloalkyl ring, wherein said C 1-6 The alkyl group is one to three independently selected R f In one embodiment, L 3 is a bond and L 4 is a bond.

[0458] In some embodiments, R 8a and R 8b Each of these, together with the carbon atom to which it is attached, represents 1 to 2 (e.g., 1) independently selected C 1-6 C optionally substituted with alkyl 3-4 Forms a cycloalkyl ring.

[0459] In some embodiments, R 8a and R 8b are, together with the carbon atoms to which they are bonded, [ka] Form.

[0460] In some embodiments, R 8a and R 8b are, together with the carbon atoms to which they are bonded, [ka] Form.

[0461] In some embodiments, R 9 teeth [ka] In some embodiments, R 9d is H or C 1-6 alkyl. For example, R 9d can be H.

[0462] In one embodiment, L 3 -C(R 8a R 8b )-L 4 -R 9 Part [ka] is.

[0463] In one embodiment, L 3 -C(R 8a R 8b )-L 4 -R 9 Part [ka] is.

[0464] In one embodiment, L 3 -C(R 8a R 8b )-L 4 -R 9 Part [ka] In one embodiment, L 3 -C(R 8a R 8b )-L 4 -R 9 Part [ka] wherein each stereocenter has the (S)-configuration. is.

[0465] In some embodiments, R 9 is (IX-2), where L 3 -C(R 8a R 8b )-L 4 -R 9 Part [ka] [In the formula, R 9d is H or C 1-6 alkyl] For example, R 9d can be H. In some embodiments, [ka] Each stereocenter in has the (S)-configuration.

[0466] In some embodiments, R 9 is C(=O)OH.

[0467] In certain embodiments, ring C is selected from 1 to 3 independently selected R Ca In some embodiments, ring C is a 3- to 12-membered heterocyclyl optionally substituted with 1 to 3 independently selected R Ca In some embodiments, ring C is a 4- to 8-membered heterocyclyl optionally substituted with 1 to 3 independently selected R Ca For example, ring C is a 5- to 6-membered heterocyclyl optionally substituted with 1 to 3 independent R Ca It may be tetrahydropyranyl optionally substituted by:

[0468] In certain embodiments, ring C is [ka] In some embodiments, ring C is selected from the group consisting of: [ka] In some embodiments, ring C is [ka] is.

[0469] In some embodiments, R Ca independently, C 1-6 It is alkyl.

[0470] In certain embodiments, a pair of R on the same or different ring atoms 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.

[0471] In some embodiments, a pair of R Ca are taken together with the ring atoms to which they are each attached to form a carbocyclic ring containing 3 to 5 ring atoms.

[0472] In certain embodiments, the compound of Formula I has Formula IVA: [ka] [During the ceremony, Q 1 is NH or NR Q and; Q 2 and Q 3 each independently represents N, CH, or CR Q and; n1 is 0 or 1; Ring E is C 3-6 is cycloalkyl; R 8c is H and 1 to 3 independently selected R f C optionally substituted with 1-6 alkyl] or a pharmaceutically acceptable salt, deuterated analog or solvate thereof.

[0473] In some embodiments of Formula IVA, Q 1 is NR Q is.

[0474] In certain embodiments of Formula IVA, R attached to N Q is the following (a) to (n): (a) Halo; (b) cyano; (c)OH; (d)-NR c R d ; (e)-C(=O)NR c R d or -S(O)NR c R d ; (f)-S(=O) 0-2 R e ; (g) 1 to 6 independently selected R f C optionally substituted with 1-6 alkyl; and (h) 1 to 6 independently selected R f C optionally substituted with 1-6 Alkoxy is selected from the group consisting of:

[0475] Non-limiting examples include R attached to N Q is the unsubstituted C 1-3 It can be alkyl.

[0476] In some embodiments of Formula IVA, Q 2 and Q 3 are each independently N or CH. Non-limiting examples include Q 2 is N and Q 3 can be CH.

[0477] In some embodiments of Formula IVA, n1 is 0. In some embodiments of Formula IVA, n1 is 1.

[0478] In certain embodiments of formula IVA, R attached to the 6-membered ring Q are halo, cyano, OH, C 1-6 Alkyl and C 1-6 In certain embodiments, R attached to the 6-membered ring is selected from alkoxy. Q is a halo.

[0479] In certain embodiments of Formula IVA, L 2 Q 1 It binds in the para position to

[0480] In certain embodiments of formula IVA, R attached to the 6-membered ring Q Q3 binds ortho to

[0481] In certain embodiments, the compound of Formula I has Formula IVB: [ka] [During the ceremony, m1 is 0, 1 or 2; L 2 Para's R Q is -P(=O)R a R b and; Ring E is C 3-6 is cycloalkyl; R 8c is H, and 1 to 3 independently selected R f C optionally substituted with 1-6 alkyl] or a pharmaceutically acceptable salt, deuterated analog or solvate thereof.

[0482] In certain embodiments of formula IVB, R a and R b is C 1-6 Alkoxy, C 3-6 an independently selected C optionally substituted with 1 to 2 substituents each independently selected from the group consisting of cycloalkyl and halo; 1-6 In some embodiments, R a and R b are independently selected unsubstituted C 1-3 It is alkyl.

[0483] In some embodiments of formula IVB, m1 is 1 and L 2 R which is not a para Q L 2 In one embodiment, L 2 R, which is meta to Q is -NR c R d is.

[0484] In certain embodiments of formula IVB, each R c and R d are independently H, C 1-6 Alkyl, C(=O)(C 1-6 alkyl), wherein said C 1-6 Alkyl and C(=O)(C 1-6 alkyl) are each -OH, halo and C 1-6 In one embodiment, R c and R d One of them is H and the other is R c and R d The other is methyl.

[0485] In some embodiments of formula IVA or formula IVB, ring E is cyclopropyl.

[0486] In some embodiments of formula IVA or formula IVB, ring E is cyclobutyl.

[0487] In certain embodiments of Formula IVA or Formula IVB, R 8c is H.

[0488] In certain embodiments of Formula IVA or Formula IVB, R 8c is C 1-3 alkyl. For example, R 8c can be methyl.

[0489] In certain embodiments of Formula IVA or Formula IVB, R 9 teeth [ka] In some embodiments, R 9d is H.

[0490] In certain embodiments of Formula IVA or Formula IVB, [ka] Part [ka] is.

[0491] In certain embodiments of Formula IVA or Formula IVB, [ka] Part [ka] wherein each stereocenter has the (S)-configuration. is.

[0492] In certain embodiments of Formula IVA or Formula IVB, [ka] Part [ka] is.

[0493] In certain embodiments of Formula IVA or Formula IVB, [ka] Part [ka] is.

[0494] In certain embodiments of Formula IVA or Formula IVB, R 9 is C(=O)OH.

[0495] In some embodiments of formula IVA or formula IVB, ring C is selected from 1 to 3 independently selected R Ca and optionally substituted 3- to 12-membered heterocyclyl.

[0496] In some embodiments of formula IVA or formula IVB, ring C is selected from 1 to 3 independently selected R Ca and optionally substituted 5- or 6-membered heterocyclyl.

[0497] In some embodiments of formula IVA or formula IVB, ring C is selected from 1 to 3 independent R Ca and tetrahydropyranyl optionally substituted by:

[0498] In some embodiments of formula IVA or formula IVB, ring C is [ka] is selected from the group consisting of:

[0499] In some embodiments of Formula IVA or Formula IVB, each R Ca independently, C 1-6 It is alkyl.

[0500] In certain embodiments of formula IVA or formula IVB, 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.

[0501] In certain embodiments of Formula IVA or Formula IVB, R 4 , R 5 , R 6 and R 7 are each H.

[0502] In certain embodiments of Formula IVA or Formula IVB, L 1 is C(=O).

[0503] In certain embodiments of Formula IVA or Formula IVB, R 1 and R 2 is H.

[0504] In certain embodiments of Formula IVA or Formula IVB, R 3 is C 1-3 It is alkyl.

[0505] In certain embodiments of Formula IVA or Formula IVB, R 3 is methyl.

[0506] In certain embodiments of Formula IVA or Formula IVB, R 1 and R 2 is H and R 3 is C 1-3 It is alkyl (eg, methyl).

[0507] In some embodiments of formula IVA or formula IVB, ring A is phenyl or pyridyl, each of which may be selected from the group consisting of halo, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 It may be substituted with 2 to 4 substituents each independently selected from the group consisting of alkoxy.

[0508] In some embodiments of formula IVA or formula IVB, ring A is selected from the group consisting of halo and C 1-6 and phenyl optionally substituted with 2 to 4 substituents each independently selected from the group consisting of alkyl.

[0509] In some embodiments of formula IVA or formula IVB, ring A is [ka] [In the formula, R AA , R AB and R AC are independently halo or C 1-6 alkyl] In some embodiments, R AA and R AC are each independently C 1-6 In some embodiments, R AA and R AC independently, C 1-3 In some embodiments, R AB is a halo, e.g., -F.

[0510] In certain embodiments of Formula IVA or Formula IVB, L 2 teeth [ka] is.

[0511] In certain embodiments, a compound selected from Table 1 or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof is provided. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8]

[0512] 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 the compounds of Formula I and / or separating the enantiomers of the compounds of Formula I. Non-limiting examples of pharmaceutically acceptable salts of the compounds of Formula I include trifluoroacetate salts.

[0513] 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 this disclosure. For example, the compounds of formula I and their salts can exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.

[0514] Treatment Methods and Uses In some embodiments, the present disclosure features a method of treating a patient (e.g., a human) suffering from a disease, disorder, or condition in which modulation of GLP-1R (e.g., inhibited or impaired and / or increased or undesired GLP-1R) is beneficial for treating the underlying pathology and / or symptoms and / or progression of the disease, disorder, or condition. In some embodiments, the methods described herein may include, or may further include, one or more conditions related to, coexisting with, or secondary to any one or more of the conditions described herein.

[0515] Provided herein are methods for treating a GLP-1-related disease, disorder, or condition, comprising administering to a patient in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof, as disclosed herein (e.g., a compound of any of Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof), or a pharmaceutical composition.

[0516] In certain embodiments, the disease, disorder, or condition includes, but is not limited to, type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of adults (LADA), obesity (including hypothalamic obesity and monogenic obesity), weight gain due to the use of other medications, idiopathic intracranial hypertension, Wolfram syndrome group, gout, excessive sugar craving, 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, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, alcohol intake disorders, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, joint inflammation, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, psychogenic polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, and polycystic ovarian syndrome (PCOS).

[0517] In certain embodiments, the disease, disorder, or condition includes, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, idiopathic intracranial hypertension, Wolfram syndrome, weight gain due to the use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, kidney disease (e.g., acute kidney injury, renal tubular dysfunction, inflammatory changes in the proximal tubules), adipocyte dysfunction, sleep apnea, visceral fat accumulation, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, hyperglycemia, These conditions include postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, alcohol use disorders, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, psychogenic polydipsia, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS), or any combination thereof.

[0518] In certain embodiments, the disease, disorder, or condition includes, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, idiopathic intracranial hypertension, Wolfram syndrome, weight gain due to the use of other medications, gout, excessive sugar cravings, 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.

[0519] In some embodiments, the compounds and pharmaceutical compositions and patient treatment methods described herein include one or more of the following: reduced blood glucose levels (e.g., reduced blood glucose levels), reduced blood hemoglobin A1c (HbA1c) levels, promoted insulin synthesis, activated insulin secretion, increased beta cell population, regulated gastric acid secretion, regulated gastric emptying, reduced body mass index (BMI), and / or reduced glucagon production (level). In some embodiments, the compounds and pharmaceutical compositions and patient treatment methods described herein result in one or more of the following: reduced blood glucose levels (e.g., reduced blood glucose levels), reduced blood hemoglobin A1c (HbA1c) levels, promoted insulin synthesis, activated insulin secretion, increased beta cell population, regulated gastric acid secretion, regulated gastric emptying, reduced body mass index (BMI), reduced glucagon production (e.g., level), or any combination thereof. In some 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, deuterated analog, or solvate thereof (e.g., a compound of any one of Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof), or a pharmaceutical composition described herein.

[0520] 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 or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any of Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof), or a pharmaceutical composition described herein. In any of these embodiments, the patient is an adult diagnosed with type 2 diabetes (T2D). In certain embodiments, the patient is an adult diagnosed with heart disease. In certain embodiments, the patient is an adult diagnosed with type 2 diabetes (T2D) and heart disease. In certain embodiments, the patient is an adult diagnosed with type 2 diabetes (T2D). In certain embodiments, the patient is an adult diagnosed with heart disease. In certain embodiments, the patient has type 2 diabetes (T2D) and cardiovascular disease.

[0521] Indications obesity In some embodiments, the disease, illness, or disorder is obesity and illness, illness, or disorder associated with or related to obesity.Non-limiting examples of obesity and obesity-related conditions include symptomatic obesity, simple obesity, childhood obesity, morbid obesity, and abdominal obesity (central obesity characterized by abdominal fat accumulation).Non-limiting examples of symptomatic obesity include endocrine obesity (e.g., Cushing's syndrome, hypothyroidism, insulinoma, obesity-related type 2 diabetes, pseudohypoparathyroidism, hypogonadism), hypothalamic obesity, genetic obesity (e.g., Prader-Willi syndrome, Laurence-Moon-Biedl syndrome), and drug-induced obesity (e.g., steroid-, phenothiazine-, insulin-, sulfonylurea-, or beta-blocker-induced obesity).

[0522] In some embodiments, the disease, disorder or disorder is related to obesity.Examples of such disease, disorder or disorder include, but are not limited to, impaired glucose tolerance, diabetes (e.g., type 2 diabetes, obesity-related diabetes), dyslipidemia, hyperlipidemia, hypertension, heart failure, hyperuricemia, gout, fatty liver (including non-alcoholic steatohepatitis (NASH)), coronary heart disease (e.g., myocardial infarction, angina pectoris), cerebral infarction (e.g., cerebral thrombosis, transient ischemic attack), bone or joint disease (e.g., knee osteoarthritis, hip osteoarthritis, spondylitis osteoarthritis, lower back pain), sleep apnea syndrome, obesity-hypoventilation syndrome (Pickwickian syndrome), menstrual disorders (e.g., abnormal menstrual cycle, menstrual bleeding and cycle abnormalities, amenorrhea, abnormal menstrual symptoms), visceral obesity syndrome, urinary incontinence and metabolic syndrome.In some embodiments, the compounds and pharmaceutical compositions described herein can be used to treat patients who show both symptoms of obesity and insulin deficiency.

[0523] diabetes In some embodiments, the disease, disorder or disorder is diabetes.Non-limiting examples of diabetes include type 1 diabetes, type 2 diabetes (e.g., diet-treated type 2 diabetes, sulfonylurea-treated type 2 diabetes, more advanced stage type 2 diabetes, long-term insulin-treated type 2 diabetes), diabetes (e.g., non-insulin-dependent diabetes, insulin-dependent diabetes), gestational diabetes, obesity-related diabetes, autoimmune diabetes, and borderline diabetes.In some embodiments, the disease, disorder or disorder is type 2 diabetes (e.g., diet-treated type 2 diabetes, sulfonylurea-treated type 2 diabetes, more advanced stage type 2 diabetes, long-term insulin-treated type 2 diabetes).

[0524] Provided herein are methods for treating diabetes in a patient, the method comprising: (a) determining that the patient has type 2 diabetes; and (b) administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof, as disclosed herein (e.g., a compound of Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof), or a pharmaceutical composition.

[0525] Provided herein is a method for treating type 2 diabetes in a patient, the method comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof, as disclosed herein (e.g., a compound of any of Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof), or a pharmaceutical composition, to a patient identified or diagnosed as having type 2 diabetes.

[0526] 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, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof, as disclosed herein (e.g., a compound of any of Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof), or a pharmaceutical composition.

[0527] In certain embodiments, the compounds and pharmaceutical compositions and methods for treating patients with a disease, disorder, or disorder (e.g., type 2 diabetes) described herein reduce fasting blood glucose levels. In certain embodiments, the compounds and pharmaceutical compositions and methods for treating patients with a disease, disorder, or disorder (e.g., type 2 diabetes) described herein reduce non-fasting blood glucose levels. In certain embodiments, the compounds and pharmaceutical compositions and methods for treating patients with a disease, disorder, or disorder (e.g., type 2 diabetes) described herein reduce HbA1c levels. In certain embodiments, the compounds and pharmaceutical compositions and methods for treating patients with a disease, disorder, or disorder (e.g., type 2 diabetes) described herein reduce glucagon levels. In certain embodiments, the compounds and pharmaceutical compositions and methods for treating patients with a disease, disorder, or disorder (e.g., type 2 diabetes) described herein increase insulin levels. In certain embodiments, the compounds and pharmaceutical compositions and methods for treating patients with a disease, disorder, or disorder (e.g., type 2 diabetes) described herein reduce BMI.

[0528] In certain embodiments, treatment of type 2 diabetes mellitus demonstrates a reduction in fasting blood glucose levels of about 5% to about 95%. Treatment of type 2 diabetes mellitus demonstrates a reduction in fasting blood glucose levels of about 15% to about 80%. Treatment of type 2 diabetes mellitus demonstrates a reduction in fasting blood glucose levels of about 25% to about 60%. In certain embodiments, treatment of type 2 diabetes mellitus demonstrates a reduction in fasting blood glucose levels of about 126 mg / dL or less, about 110 mg / dL or less, or about 90 mg / dL or less.

[0529] 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 of about 200 mg / dL or less, about 150 mg / dL or less, or about 130 mg / dL or less.

[0530] In certain embodiments, treatment of type 2 diabetes mellitus demonstrates a reduction in HbA1c levels of about 5% to about 95%. Treatment of type 2 diabetes mellitus demonstrates a reduction in HbA1c levels of about 15% to about 80%. Treatment of type 2 diabetes mellitus demonstrates a reduction in HbA1c levels of about 25% to about 60%. In certain embodiments, treatment of type 2 diabetes mellitus demonstrates a reduction in HbA1c levels of about 6.5% or less, about 6.0% or less, or about 5.0% or less.

[0531] 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.

[0532] In certain embodiments, a reduction in BMI of about 5% to about 95% is demonstrated with treatment of type 2 diabetes. A reduction in BMI of about 15% to about 80% is demonstrated with treatment of type 2 diabetes. A reduction in BMI of about 25% to about 60% is demonstrated with treatment of type 2 diabetes. In certain embodiments, a reduction in BMI of about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% is demonstrated with treatment of type 2 diabetes. In certain embodiments, a reduction in BMI of about 40 or less, about 30 or less, or about 20 or less is demonstrated with treatment of type 2 diabetes.

[0533] In some embodiments, the disease, disorder or disorder is associated with diabetes (for example, diabetic complications).Non-limiting examples of disorders associated with diabetes include obesity, obesity-related disorders, metabolic syndrome, neuropathy, nephropathy (for example, diabetic nephropathy), retinopathy, diabetic cardiomyopathy, cataract, macroangiopathy, osteopenia, hyperosmolar diabetic coma, infectious diseases (for example, respiratory infection, urinary tract infection, gastrointestinal infection, skin and soft tissue infection, lower limb infection), diabetic gangrene, xerostomia, hearing impairment, cerebrovascular disease, diabetic cachexia, delayed wound healing, diabetic dyslipidemia, peripheral blood circulation disorder, cardiovascular risk factors (for example, coronary artery disease, peripheral arterial disease, cerebrovascular disease, hypertension, and risk factors related to uncontrolled cholesterol and / or lipid levels, and / or inflammation), NASH, fracture and cognitive dysfunction.

[0534] 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.

[0535] In certain embodiments, the disease, condition, or disorder is diabetes and obesity. In certain embodiments, the compounds described herein are also useful for improving the therapeutic effectiveness of metformin.

[0536] Disorders of metabolically important tissues In certain embodiments, the disease, condition, or disorder is a disorder of a metabolically significant tissue. Non-limiting examples of metabolically significant tissue include liver, adipose tissue, pancreas, kidney, and intestine.

[0537] In some embodiments, the disease, condition, or disorder is fatty liver disease, including, but not limited to, non-alcoholic fatty liver disease (NAFLD), steatohepatitis, non-alcoholic steatohepatitis (NASH), fatty liver disease resulting from hepatitis, fatty liver disease resulting from obesity, fatty liver disease resulting from diabetes, fatty liver disease resulting from insulin resistance, fatty liver disease resulting from hypertriglyceridemia, abetalipoproteinemia, hyperlipoproteinemia, glycogen storage disease, Weber-Christian disease, Wolman disease, acute fatty liver of pregnancy, and lipodystrophy.

[0538] Nonalcoholic fatty liver disease (NAFLD) refers to a group of diseases that occur in the absence of alcohol abuse and is typically characterized by the presence of fatty liver (fat in the liver). NAFLD is thought to be associated with various diseases, such as metabolic syndrome (including obesity, diabetes, and hypertriglyceridemia) and insulin resistance. This can cause liver disease in adults and children, ultimately resulting in cirrhosis (Skelly et al., J Hepatol 2001; 35: 195-9; Chitturi et al., Hepatology 2002; 35(2):373-9). The severity of NAFLD ranges from relatively benign, primarily isolated macrovesicular fatty liver (i.e., nonalcoholic fatty liver or NAFL) to nonalcoholic steatohepatitis (NASH) (Angulo et al., J Gastroenterol Hepatol 2002; 17 Suppl:S186-90).

[0539] In some embodiments, the patient is a pediatric patient. As used herein, the term "pediatric patient" refers to a patient who is 21 years old or younger at the time of diagnosis or treatment. The term "child" can be further divided into various subgroups, 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 their 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 certain 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 of age 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.

[0540] Other non-limiting examples of disorders of metabolically important tissues include arthropathy (e.g., osteoarthritis, secondary osteoarthritis), fatty liver (e.g., liver); fibrosis (e.g., liver); cirrhosis (e.g., liver); gallstones; gallbladder disease; gastroesophageal reflux; sleep apnea; hepatitis; fatty liver; bone disorders characterized by altered bone metabolism, such as osteoporosis (including postmenopausal osteoporosis), decreased bone strength, osteopenia, Paget's disease, osteolytic metastases in cancer patients, osteodystrophy in liver disease and altered bone metabolism caused by renal failure or hemodialysis, fractures, bone surgery, aging, pregnancy, protection from fractures, and malnutrition; polycystic ovary syndrome; renal disease (e.g., chronic renal failure, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease); muscular dystrophy, angina pectoris, acute or chronic diarrhea, testicular dysfunction, respiratory dysfunction, frailty, sexual dysfunction (e.g., erectile dysfunction), and geriatric syndromes. In certain embodiments, the compounds and pharmaceutical compositions described herein can be used to improve post-surgical recovery and / or treat surgical trauma by preventing the catabolic response caused by surgical trauma.

[0541] Cardiovascular and vascular diseases In some embodiments, the disease, disorder, or disorder is a cardiovascular disease.Non-limiting examples of cardiovascular disease include congestive heart failure, atherosclerosis, arteriosclerosis, coronary heart disease, coronary artery disease, congestive heart failure, coronary heart disease, hypertension, heart failure, cerebrovascular disease (e.g., cerebral infarction), vascular insufficiency, myocardial infarction, elevated blood pressure (e.g., 130 / 85 mmHg or higher), and prothrombotic conditions (e.g., elevated blood fibrinogen or plasminogen activator inhibitor levels).

[0542] In some embodiments, the disease, disorder, or disorder is associated with vascular disease. Non-limiting examples of vascular disease include peripheral vascular disease, macrovascular complications (e.g., stroke), vascular insufficiency, peripheral arterial disease, abdominal aortic aneurysm, carotid artery disease, cerebrovascular disease (e.g., cerebral infarction), pulmonary embolism, chronic venous insufficiency, critical limb ischemia, retinopathy, nephropathy, and neuropathy.

[0543] Neurological disorders In certain embodiments, the disease, condition, or disorder is a neurological disorder (eg, a neurodegenerative disorder) or a psychiatric disorder. Non-limiting examples of neurological disorders include idiopathic intracranial hypertension, 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, for example, U.S. Application No. 20060275288A1.

[0544] In some embodiments, the disease, condition, or disorder is idiopathic intracranial hypertension. It is characterized by elevated intracranial pressure and papilledema. See, e.g., Virdee et al. Ophthalmol Ther. 2020; 9(4):767-781. In some embodiments, the compounds, pharmaceutical compositions, and methods described herein reduce cerebrospinal fluid secretion in patients with idiopathic intracranial hypertension. In some embodiments, the compounds, pharmaceutical compositions, and methods described herein reduce intracranial pressure in patients with idiopathic intracranial hypertension. In some embodiments, the compounds, pharmaceutical compositions, and methods described herein reduce one or more symptoms in patients with idiopathic intracranial hypertension. Symptoms of idiopathic intracranial hypertension may include severe headaches and visual impairment. In some embodiments, the patient with idiopathic intracranial hypertension is female. In some embodiments, the patient with idiopathic intracranial hypertension is about 20 to about 30 years old. In certain embodiments, the patient with idiopathic intracranial hypertension is obese.

[0545] In some embodiments, the disease, disorder, or condition is Wolfram syndrome. Wolfram syndrome is caused by biallelic mutations in the Wolframin ER transmembrane glycoprotein (Wfs1) gene. See, for example, Seppa et al. Sci Rep 9, 15742 (2019). Wolfram syndrome initially manifests as diabetes, followed by symptoms of optic atrophy, hearing loss, and neurodegeneration. Patients with Wolfram syndrome may exhibit symptoms of ataxia, sleep apnea, dysphagia, hearing loss, and loss of taste due to brainstem atrophy. In some embodiments, the compounds, pharmaceutical compositions, and methods described herein reduce neuroinflammation in patients with Wolfram syndrome. In some embodiments, neuroinflammation is reduced in the inferior olive of patients. In some embodiments, the compounds, pharmaceutical compositions, and methods described herein reduce retinal ganglion cell death in patients with Wolfram syndrome. In some embodiments, the compounds, pharmaceutical compositions, and methods described herein reduce axonal degeneration in patients with Wolfram syndrome. In certain embodiments, the compounds and pharmaceutical compositions and methods described herein reduce one or more symptoms (e.g., any of the symptoms described herein) in patients with Wolfram Syndrome.

[0546] 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 of drug abuse, and alleviating the anxiety caused by the absence of certain addictive substances.See, for example, US Application No. 20120021979A1.

[0547] In certain embodiments, the compounds and pharmaceutical compositions described herein are useful for improving learning and memory by enhancing neuroplasticity and promoting cell differentiation, and for maintaining dopaminergic neuronal and motor function in Parkinson's disease (Morbus Parkinson's).

[0548] Insulin-related In certain embodiments, the disease, condition, or disorder is impaired fasting blood glucose (IFG), fasting hyperglycemia (IFG), hyperglycemia, insulin resistance (impaired glucose homeostasis), hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hypoglycemic conditions, insulin resistance syndrome, abnormal paresthesia caused by hyperinsulinemia, hyperlipidemia, hypercholesterolemia, poor wound healing, leptin resistance, glucose intolerance, elevated fasting glucose, dyslipidemia (e.g., atherogenic dyslipidemia characterized by hyperlipidemia, high triglycerides, and low HDL cholesterol), glucagonoma, hyperuricemia, hypoglycemia (e.g., nocturnal hypoglycemia), and insulin-related concomitant comatose endpoint.

[0549] In certain embodiments, the compounds and pharmaceutical compositions described herein can reduce or delay the progression of borderline impaired fasting blood glucose or fasting hyperglycemia to diabetes.

[0550] autoimmune disease In some embodiments, the disease, disorder or disorder is an autoimmune disease.Non-limiting examples of autoimmune disease include multiple sclerosis, experimental autoimmune encephalomyelitis, autoimmune disease 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 Application No. 20120148586A1.

[0551] Gastrointestinal disorders In some embodiments, the disease, disorder, or disorder is a stomach or intestinal disorder. Non-limiting examples of these disorders include ulcers of any etiology (e.g., gastric ulcer, Zollinger-Ellison syndrome, drug-induced ulcer, ulcer associated with infection or other pathogens), gastrointestinal disease, malabsorption, short bowel syndrome, blind-tube syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), celiac disease, hypogammaglobulinemia, chemotherapy- and / or radiotherapy-induced mucositis and diarrhea, gastroenteritis, short bowel syndrome, ulcerative colitis, gastric mucosal injury (e.g., aspirin-induced gastric mucosal injury), small intestinal mucosal injury, and cachexia (e.g., cancer cachexia, tuberculosis cachexia, cachexia associated with blood disorders, cachexia associated with endocrine disorders, cachexia associated with infectious diseases, and cachexia caused by acquired immune deficiency syndrome).

[0552] body weight In some embodiments, the compounds and pharmaceutical compositions described herein can be used to reduce weight (e.g., excess weight), prevent weight gain, induce weight loss, reduce body fat, or reduce food intake in a patient (e.g., a patient in need thereof). In some embodiments, the patient's weight gain may be due to excessive food intake or an unbalanced diet, or may be due to concomitant medication (e.g., an insulin sensitizer with PPARγ agonist-like activity, such as troglitazone, rosiglitazone, englitazone, ciglitazone, pioglitazone, etc.). In some embodiments, the weight gain may be pre-obese or may be weight gain in an obese patient. In some embodiments, the weight gain may also be drug-induced weight gain or weight gain after smoking cessation.

[0553] In some embodiments, the weight gain is induced by the use of steroids or antipsychotics.

[0554] In certain embodiments, the disease, condition or disorder is an eating disorder, eg, overeating, binge eating, bulimia, compulsive overeating or syndromic obesity such as Prader-Willi and Bardet-Biedl syndromes.

[0555] Inflammatory diseases In some embodiments, the disease, illness or disorder is inflammatory disease.Non-limiting examples of inflammatory disease include rheumatoid arthritis, spondylitis deformans, osteoarthritis, lower back pain, gout, post-operative or post-traumatic inflammation, abdominal distension, neuralgia, pharyngitis, cystitis, pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory bowel disease), inflammation of metabolically important tissues (including liver, fat, pancreas, kidney and intestine), and pro-inflammatory condition (for example, elevated level of pro-inflammatory cytokines or inflammatory markers such as C-reactive protein in blood).

[0556] cancer In some embodiments, the disease, condition, 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). gastrointestinal stromal tumor), colon cancer (e.g., familial colorectal cancer, hereditary non-polyposis colorectal cancer, gastrointestinal stromal tumor), small intestine cancer (e.g., non-Hodgkin's lymphoma, gastrointestinal stromal tumor), esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer (e.g., nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer), salivary gland cancer, brain tumors (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma), schwannoma, liver cancer (e.g., primary liver cancer, extrahepatic bile duct cancer), kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter), bile duct cancer, uterine cancer, cervical cancer, ovarian cancer (e.g., ovarian epithelial cancer, extragonadal germ cell tumor, ovarian germ cell tumor, low-grade ovarian tumor), bladder cancer, urethral cancer, skin cancer (e.g., intraocular (ocular) melanoma, Merkel cell carcinoma), hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer (e.g., medullary thyroid carcinoma), These include thyroid cancer, nasal cancer, sinus cancer, bone tumors (e.g., osteosarcoma, Ewing's tumor, uterine sarcoma, soft tissue sarcoma), angiofibroma, retinal sarcoma, penile cancer, testicular tumors, childhood solid tumors (e.g., Wilms' tumor, childhood kidney tumor), Kaposi's sarcoma, Kaposi's sarcoma caused by AIDS, maxillary sinus tumors, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia).

[0557] Hypothalamic-pituitary disorders In one embodiment, the disease, disorder, or condition is associated with the hypothalamic pituitary-gonadal axis. For example, the disease, disorder, or condition is associated with the hypothalamic pituitary-ovarian axis. In another example, the disease, disorder, or condition is associated with the hypothalamic pituitary-testicular axis. Disorders of the hypothalamic pituitary-gonadal axis include, but are not limited to, hypogonadism, polycystic ovary syndrome, hypothyroidism, hypopituitarism, sexual dysfunction, and Cushing's disease.

[0558] In certain embodiments, the diabetes-related disease, condition, or disorder is associated with the hypothalamic pituitary gonadal axis.

[0559] Pulmonary disease In certain embodiments, the disease, condition, or disorder is associated with a pulmonary disease, including, but not limited to, asthma, idiopathic pulmonary fibrosis, pulmonary hypertension, obstructive sleep apnea, and chronic obstructive pulmonary disease (COPD) (e.g., emphysema, chronic bronchitis, and refractory (irreversible) asthma).

[0560] In certain embodiments, the diabetes-related condition, disease, or disorder is a pulmonary disease.

[0561] Combination therapy In certain embodiments, the present disclosure includes both monotherapy and combination therapy regimens.

[0562] 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.

[0563] 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.

[0564] In certain embodiments, the compounds of X described herein, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof, can be administered in combination with one or more additional therapeutic agents.

[0565] Representative additional therapeutic agents include, but are not limited to, anti-obesity agents, therapeutic agents for diabetes, therapeutic agents for diabetic complications, therapeutic agents for hyperlipidemia, antihypertensive agents, diuretics, chemotherapy agents, immunotherapeutic agents, anti-inflammatory agents, antithrombotic agents, antioxidant agents, therapeutic agents for osteoporosis, vitamins, therapeutic agents for dementia, therapeutic agents for erectile dysfunction, therapeutic agents for urinary frequency or urinary incontinence, therapeutic agents for NAFLD, therapeutic agents for NASH, therapeutic agents for dysuria, and antiemetic agents.

[0566] 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)), and neuropeptide Y antagonists. (e.g., velneperit), peptide YY or its analogs, cannabinoid receptor antagonists (e.g., rimonabant, taranabant), ghrelin antagonists, ghrelin receptor antagonists, ghrelin acylation enzyme inhibitors, opioid receptor antagonists (e.g., GSK-1521498, naltrexone), orexin receptor antagonists, melanocortin 4 receptor agonists, 11β-hydroxysteroid dehydrogenase inhibitors, Drugase inhibitors (e.g., AZD-4017, BVT-3498, INCB-13739), pancreatic lipase inhibitors (e.g., orlistat, cetilistat), β3 agonists (e.g., N-5984), diacylglycerol acyltransferase 1 (DGAT1) inhibitors, acetyl-CoA carboxylase (ACC) inhibitors (e.g., those described in WO 2020 / 234726, WO 2020 / 044266, and U.S. Pat. No. 8,859,577 ), stearate-CoA desaturase inhibitors, microsomal triglyceride transfer protein inhibitors (e.g., R-256918), sodium glucose transporter 2 (SGLT-2) inhibitors (e.g., JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, remogliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, or ertugliflozin), SGLT-1inhibitors, MCR-4 agonists, monoamine reuptake inhibitors, melanocyte-stimulating hormone analogs, 5HT2c agonists, galanin antagonists, appetite suppressants (e.g., bombesin agonists), thyroid hormone mimetics, dehydroepiandrosterone or its analogs, human gout-related protein (AGRP) inhibitors, neuromedin U agonists, NFK inhibitors (e.g., HE-3286 ), PPAR agonists (e.g., GFT-505, DRF-11605, gemfibrozil, fenofibrate, balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone, CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767, and SB-219994), phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate, trodasquemine), GPR119 agonists (e.g., PSN-821, MBX-2982, APD597, compounds described in WO 2010 / 140092, WO 2010 / 128425, WO 2010 / 128414, WO 2010 / 106457), glucokinase activators (e.g., pyragliatin, AZD-165 6, AZD6370, TTP-355, TTP-399, TTP547, ARRY403, MK-0599, TAK-329, AZD5658 or GKM-001, WO 2010 / 103437, WO 2010 / 103438, WO 2010 / 013161, WO 2007 / 122482, WO 2006 / 112549, WO 2007 / 028135, WO 2008 / 047821, WO 2009 / 047822, WO 2010 / 103437, WO 2010 / 103438, WO 2010 / 013161, WO 2007 / 122482, WO 2006 / 112549, WO 2007 / 028135, WO 2008 / 047821, WO 2010 / 04782 ... compounds described in WO 2008 / 050821, WO 2008 / 136428, and WO 2008 / 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., animal FGF21 preparations extracted from bovine or porcine pancreas; human FGF21 preparations genetically synthesized using E. coli or yeast; fragments or derivatives of FGF21), appetite suppressants (e.g., P-57), human proislet peptide (human proislet peptide),peptide) (HIP), melanocortin receptor 4 agonists (e.g., setomelanotide), melanin-concentrating hormone receptor 1 antagonists, serotonergic agents (e.g., sibutramine, lorcaserin), farnesoid X receptor (FXR) agonists (e.g., obeticholic acid, tropifexor, cilofexor, LY2562175, Met409, TERN-101, EDP305, compounds described in WO 2020 / 234726 and WO 2020 / 044266), phentermine, zonisamide, norepinephrine / dopamine reuptake inhibitors (e.g., Examples of suitable anti-inflammatory drugs include bupropion, GDF-15 analogs, methionine aminopeptidase 2 (MetAP2) inhibitors (e.g., beloranib or ZGN-1061), diethylpropion, phendimetrazine, benzphetamine, fibroblast growth factor receptor (FGFR) modulators, biotin, MAS receptor modulators, glucagon receptor agonists, CCKa agonists (e.g., compounds described in WO 2005 / 116034 and U.S. Patent Publication No. 2005 / 0287100), and AMP-activated protein kinase (AMPK) activators.

[0567] In some embodiments, the one or more additional therapeutic agents include, for example, agents useful as antidiabetic agents. Non-limiting examples include insulin and insulin preparations (e.g., animal insulin preparations extracted from bovine or porcine pancreas; human insulin preparations genetically synthesized using E. coli or yeast; zinc insulin; protamine zinc insulin; insulin fragments or derivatives (e.g., INS-1), oral insulin preparations, synthetic human insulin), insulin sensitizers (e.g., pioglitazone or a salt thereof), biguanides (e.g., metformin, buformin or a salt thereof (e.g., hydrochloride, fumarate, succinate)), glucagon analogs (e.g., any of the glucagon analogs described in WO 2010 / 011439), agents that antagonize the action of glucagon or reduce glucagon secretion, sulfonylurea drugs (e.g., chlorpropamide, tolazamide, , glimepiride, tolbutamide, glibenclamide, gliclazide, acetohexamide, glyclopyramide, glybuzole, glyburide, glipizide), thiazolidinedione drugs (e.g., rosiglitazone, lobeglitazone, troglitazone, balaglitazone, rivoglitazone, lobeglitazone, or pioglitazone), glitazars (e.g., aleglitazar, tiglitazar, saroglitazar, gal, muraglitazar, tesaglitazar), SGLT2 inhibitors (e.g., JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, THR1474, TS-071, ISIS388626, LX4211, remogliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozinetabonate, ertugliflozin, compounds described in WO 2010 / 023594), GPR40 agonists (e.g., FFAR1 / FFA1 agonists, e.g., fasiglifam), α-glucosidase inhibitors (e.g., adipocin, camiglibose, pradimicin-Q, salbostacin, voglibose, acarbose, miglitol, emiglitate), insulin secretagogues, e.g., prandial glucose regulators (sometimes also 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, GLP-1 / GIP receptor dual agonists (e.g., LBT-2000, ZPD1-70), GLP-1R agonists (e.g., exenatide, liraglutide, albiglutide, dulaglutide, albiglutide, taspoglutide, lixisenatide, semaglutide, AVE-0010, S4P, and Boc5), and dipeptidyl peptidase IV (DPP-4) inhibitors (e.g., vildagliptin, dutogliptin, gemigliptin, alogliptin, sa Examples of anti-inflammatory drugs include xagliptin, sitagliptin, linagliptin, berberine, adogliptin, anagliptin (SK0403), teneligliptin, omarigliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, ALS2-0426, TA-6666, TS-021, KRP-104, and trelagliptin.

[0568] In some embodiments, the one or more additional therapeutic agents include, for example, drugs useful for treating NAFL and NASH. Non-limiting examples include FXR agonists (e.g., obeticholic acid), PF-05221304, PPARα / δ agonists (e.g., elafibranor), synthetic fatty acid bile conjugates (e.g., aramchol), anti-lysyl oxidase analog 2 (LOXL2) monoclonal antibodies (e.g., simtuzumab), caspase inhibitors (e.g., emricasan), MAPK5 inhibitors (e.g., GS-4997), galectin 3 inhibitors (e.g., GR-MD-02), fibroblast growth factor 21 (FGF21) (e.g., BMS- 986036), niacin analogs (e.g., ARJ3037MO), leukotriene D4 (LTD4) receptor antagonists (e.g., tipelukast), acetyl-CoA carboxylase (ACC) inhibitors (e.g., NDI010976, and compounds described in WO 2009 / 144554, WO 2003 / 072197, WO 2009 / 144555, and WO 2008 / 065508), ketohexokinase (KHK) inhibitors (e.g., compounds described in WO 2020 / 234726, compounds described in), apoptosis signal-regulating kinase 1 (ASK1) inhibitors, ileal bile acid transporter (IBAT) inhibitors, dual antagonists of chemokine receptor 2 (CCR2) and CCR5 (e.g., cenicriviroc), diacylglyceryl acyltransferase 2 (DGAT2) inhibitors (e.g., compounds described in WO 2020 / 234726 and U.S. Patent Publication No. 20180051012), CB1 receptor antagonists, anti-CB1R antibodies, glycyrrhizin, Scizoria extract, and These include scorbic acid, glutathione, silymarin, lipoic acid, and d-alpha-tocopherol, ascorbic acid, glutathione, vitamin B complex, glitazones / thiazolidinediones (e.g., troglitazone, rosiglitazone, pioglitazone, balaglitazone, rivoglitazone, lobeglitazone), metformin, cysteamine, sulfonylureas, alpha-glucosidase inhibitors, meglitinides, vitamin E, tetrahydrolipstatin, milk thistle protein, antivirals, and antioxidants.

[0569] 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 WO 01 / 14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxyl)propyl]oxazole), compounds described in WO 2004 / 039365), PKC inhibitors (e.g., Examples of such anti-inflammatory drugs include ruboxistaurin 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.

[0570] In certain embodiments, the one or more additional therapeutic agents include, for example, drugs useful for treating hyperlipidemia. Non-limiting examples include HMG-COA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin, or salts thereof (e.g., sodium salts, calcium salts)), squalene synthase inhibitors (e.g., compounds described in WO 97 / 10224, such as N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl]piperidine-4-acetic acid), fibrates (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate), anion exchange resins (e.g., cholestyramine), nicotinic acid drugs (e.g., nicomol, niceritrol, niaspan), phytosterols (e.g., soy sterol, gamma oryzanol (γ-oryzanol)), cholesterol absorption inhibitors (e.g., zetia), CETP inhibitors (e.g., dalcetrapib, anacetrapib), and omega-3 fatty acid preparations (e.g., omega-3 fatty acid ethyl ester 90).

[0571] In certain embodiments, the one or more additional therapeutic agents include, for example, agents useful as antihypertensive agents. Non-limiting examples include angiotensin-converting enzyme inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cirazopril, delapril, pentopril, quinapril, ramipril, lisinopril), angiotensin II antagonists (e.g., candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil, azilsartan, azilsartan methyl), and the like. doxomil), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine, cilnidipine), and beta-blockers (e.g., metoprolol, atenolol, propranolol, carvedilol, pindolol). Further non-limiting examples of antihypertensive agents include diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazides, benzthiazide, ethacrynic acid), triclinafen, chlorthalidone, torsemide, furosemide, musolimine, bumetanide, triamterene, amiloride, spironolactone), alpha-adrenergic blockers, beta-adrenergic blockers, calcium channel blockers (e.g., diltiazem, verapamil, nifedipine, and amlodipine), vasodilators (e.g., hydralazine), renin inhibitors, AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan), ET receptor antagonists These include receptor antagonists (e.g., sitaxsentan, atrasentan, compounds described in U.S. Pat. Nos. 5,612,359 and 6,043,265), dual ET / AII antagonists (e.g., compounds described in WO 2000 / 01389), neutral endopeptidase (NEP) inhibitors, If channel blockers, ivabradine, vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., gemopatrilat and nitrates).

[0572] In some embodiments, the one or more additional therapeutic agents include, for example, drugs useful as diuretics.Non-limiting examples include xanthine derivatives (e.g., sodium theobromine salicylate, calcium theobromine salicylate), thiazides (e.g., ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penfluthiazide, polythiazide, methyclothiazide), antialdosterone drugs (e.g., spironolactone, triamterene), carbonic anhydrase inhibitors (e.g., acetazolamide), and chlorobenzenesulfonamides (e.g., chlorthalidone, mefruside, indapamide).

[0573] In some embodiments, the one or more additional therapeutic agents include, for example, agents useful as immunotherapeutics. Non-limiting examples include microbial or bacterial compounds (e.g., muramyl dipeptide derivatives, picibanil), polysaccharides with immune-enhancing activity (e.g., lentinan, sizofiran, krestin), cytokines obtained by genetic engineering (e.g., interferons, interleukins (IL), e.g., IL-1, IL-2, IL-12), and colony-stimulating factors (e.g., granulocyte colony-stimulating factor, erythropoietin).

[0574] In certain embodiments, the one or more additional therapeutic agents include, for example, drugs useful as antithrombotic agents. Non-limiting examples include heparin (e.g., heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarin (e.g., warfarin potassium); antithrombin drugs (e.g., argatroban, dabigatran, boroarginine derivatives, boropeptides, heparin, hirudin, and melagatran), FXa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, YM150, and the like) described in WO 2002 / 06234, WO 2004 / 048363, WO 2005 / 030740, WO 2005 / 058823, and WO 2005 / 113504. compounds described herein), thrombolytic agents (e.g., anistreplase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), urokinase, tisokinase, alteplase, nateplase, monteplase, pamiteplase, factor VIla inhibitors, PAI-1 inhibitors, α2-antiplasin inhibitors and aninosylated plasminogen streptokinase activator complex), and platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cilostazol, ethyl icosapentate, beraprost sodium, and sarpogrelate hydrochloride).

[0575] In some embodiments, the one or more additional therapeutic agents include, for example, drugs useful for treating osteoporosis.Non-limiting examples include alfacalcidol, calcitriol, elcatonin, salmon calcitonin, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium, and risedronate disodium.Suitable examples of vitamins include vitamin B1 and vitamin B12.Suitable examples of drugs for treating erectile dysfunction include apomorphine and sildenafil citrate.Suitable examples of drugs for treating urinary frequency or urinary incontinence include flavoxate hydrochloride, oxybutynin hydrochloride, and propiverine hydrochloride.Suitable examples of drugs for treating urinary disorders include acetylcholinesterase inhibitors (e.g., distigmine).Suitable examples of anti-inflammatory drugs include nonsteroidal anti-inflammatory drugs, such as aspirin, acetaminophen, and indomethacin.

[0576] Other exemplary additional therapeutic agents include agents that regulate hepatic glucose balance (e.g., fructose 1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glycogen synthase kinase inhibitors, glucokinase activators), agents designed to treat complications of persistent hyperglycemia, such as aldose reductase inhibitors (e.g., epalrestat and ranirestat), agents used to treat complications associated with microangiopathy, agents for treating dyslipidemia, such as HMG-CoA reductase inhibitors (statins, e.g., rosuvastatin, pravastatin, pitavastatin, lovastatin, atorvastatin, synthase inhibitors, thiazol-3-one), and thiazol-3-one. vastatin, fluvastatin, itavastatin, ZD-4522), HMG-CoA synthase inhibitors, cholesterol-lowering drugs, bile acid sequestrants (e.g., cholestyramine, questran, colestipol, and colesevelam), cholesterol absorption inhibitors (e.g., plant sterols such as phytosterols), cholesteryl ester transfer protein (CETP) inhibitors, ileal bile acid transport system inhibitors (IBAT inhibitors), diacylglyceryl acyltransferase 1 (DGAT1) inhibitors (e.g., AZD7687, LCQ908, and compounds described in WO 2009 / 016462 and WO 2010 / 086820), monoacylglycerol O-acyltransferase inhibitors, α-amylase inhibitors (e.g., tendamistat, trestatin, AL-3688), α-glucoside hydrolase inhibitors, SIRT-1 activators, c-Jun N-terminal kinase (JNK) inhibitors, VPAC2 receptor agonists, TGR5 receptor modulators (e.g., compounds described in), GPBAR1 receptor modulators, GPR120 modulators, high affinity nicotinic acid receptor (HM74A) activators, carnitine palmitoyltransferase enzyme inhibitors, mineralocorticoid receptor inhibitors, TORC2 inhibitors, fatty acid synthetase inhibitors, serine palmitoyltransferase inhibitors, GPR81 modulators, GPR39 modulators, GPR43 modulators, GPR41 modulators, GPR105 modulators, Kv1.3 modulators, retinol binding protein 4 modulators, somatostatin receptor modulators,PDHK2 modulators, PDHK4 modulators, MAP4K4 inhibitors, IL1 family modulators (e.g., ILIβ modulators), ACAT inhibitors, MTP inhibitors (e.g., diliotapide, mitratapide, and implitapide), lipoxygenase inhibitors, PCSK9 modulators (e.g., alirocumab and evolocumab), RXR alpha modulators, cysteamine, cystamine, RNA antisense building agents for inhibiting protein tyrosine phosphatase PTPRU, vitamin B complex, pentraxin proteins, protein tyrosine phosphatase-1 B (PTP-1 B) inhibitors (e.g., trodascumin, hyrtiosal extract, and Zhang et al. Drug Discovery Today. 2007, 12(9-10): 373-381), ezetimibe, betaine, pentoxifylline, α,δ-9 desaturase, BCKDK inhibitors, branched-chain α-keto acid dehydrogenase kinase (BCBK) inhibitors, PNPLA3 inhibitors, FGF1 9 analogs, SCD1 inhibitors, bile acid-binding resins, nicotinic acid (niacin) and its analogs, antioxidants (e.g., probucol), omega-3 fatty acids, antihypertensive agents, for example, adrenoceptor antagonists, for example, beta-blockers (e.g., atenolol), alpha-blockers (e.g., doxazosin), and mixed alpha / beta-blockers (e.g., labetalol), adrenoceptor agonists, for example, alpha-2 agonists (e.g., clonidine), angiotensin-converting enzyme (ACE) inhibitors (e.g., lisinopril), calcium channel blockers, for example, dihydro Pyridines (e.g., nifedipine), phenylalkylamines (e.g., verapamil), and benzothiazepines (e.g., diltiazem), angiotensin II receptor antagonists (e.g., candesartan), aldosterone receptor antagonists (e.g., eplerenone, spironolactone), centrally acting adrenergic drugs, such as central alpha agonists (e.g., clonidine), diuretics (e.g., furosemide, torsemide, bemethanide, ethacrynic acid, thiazide-type diuretics (e.g., chlorothiazide, hydrochlorothiazide, benzthiazide, hydroflumethiazide,bendroflumethiazide, methychlorthiazide, polythiazide, trichlormethiazide, indapamide), phthalimidine-type diuretics (e.g., chlorthalidone, metolazone), quinazoline-type diuretics (e.g., quinethazone), potassium-sparing diuretics (e.g., triamterene and amiloride), thyroid receptor agonists (e.g., compounds described in WO 2020 / 117987), hemostatic modifiers (including antithrombotic agents (e.g., fibrinolytic activators)), thrombin antagonists, factor VIIa inhibitors, anticoagulants (e.g., vitamin K antagonists), anti-inflammatory drugs (e.g., thromboxane-A2 receptor antagonists (e.g., ifetroban), thromboxane-A2 synthetase inhibitors, PDE inhibitors (e.g., pletal, dipyridamole), purinergic receptor antagonists (e.g., P2Y1 and P2Y12), adenosine diphosphate Acid diphosphate (ADP) receptor inhibitors (e.g., clopidogrel), phosphodiesterase inhibitors (e.g., cilostazol), glycoprotein IIB / IIA inhibitors (e.g., tirofiban, eptifibatide, and abciximab), adenosine reuptake inhibitors (e.g., dipyridamole), noradrenergic agonists (e.g., phentermine), serotonergic agents (e.g., sibutramine, lorcaserin), diacylglycerol acyltransferase (DGAT) inhibitors, feeding behavior modifiers, pyruvate dehydrogenase kinase (PDK) modulators, serotonin receptor receptor modifiers, monoamine transport modifiers, such as selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine), noradrenaline reuptake inhibitors (NARIs), noradrenaline-serotonin reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs) (e.g., toloxatone and amiflamine), the compounds described in WO 2007 / 013694, WO 2007 / 018314, WO 2008 / 093639 and WO 2008 / 099794, GPR40 agonists (e.g.,fasiglifam or its hydrate, compounds described in WO 2004 / 041266, WO 2004 / 106276, WO 2005 / 063729, WO 2005 / 063725, WO 2005 / 087710, WO 2005 / 095338, WO 2007 / 013689 and WO 2008 / 001931), SGLT-1 inhibitors, adiponectin or or its agonists, IKK inhibitors (e.g., AS-2868), somatostatin receptor agonists, ACC2 inhibitors, anti-cachexia drugs, for example, cyclooxygenase inhibitors (e.g., indomethacin), progesterone derivatives (e.g., megestrol acetate), glucocorticoids (e.g., dexamethasone), metoclopramide drugs, tetrahydrocannabinol drugs, drugs for improving fat metabolism (e.g., eicosapentaenoic acid), anti-inflammatory drugs (e.g., steroids, steroid hormones, steroid drugs), growth hormone, IGF-1, antibodies against cachexia-inducing factors TNF-α, LIF, IL-6, and oncostatin M, metabolism-improving proteins or peptides, e.g., glucokinase (GK), glucokinase regulatory protein (GKRP), uncoupling proteins 2 and 3 (UCP2 and UCP3), peroxisome proliferator-activated receptor α (PPARα), MC4r agonists, insulin receptor agonists, PDE5 inhibitors, glycation inhibitors (e.g., ALT-711), neuroregeneration promoters (e.g., Y-128, VX853, prosaptide), antidepressants (e.g., desipramine, amitriptyline, imipramine), antiepileptic drugs (e.g., lamotrigine, trileptal, keppra, zonegran, pregabalin, harkoseride, carbamazepine), antiarrhythmic drugs (e.g., K, +channel openers, mexiletine, propafenone, metoprolol, atenolol, carbaziol, propranolol, sotalol, dofetilide, amiodarone, azimilide, ibutilide, ditiazem and verapamil), acetylcholine receptor ligands (e.g., ABT-594), endothelin receptor antagonists (e.g., ABT-627), narcotic analgesics (e.g., morphine), α2 receptor agonists (e.g., clonidine), local anesthetics (e.g., capsaicin), anxiolytics (e.g., benzothiazepines), phosphodiesterase inhibitors (e.g., sildenafil), dopamine receptor agonists (e.g., apomorphine), cytotoxic antibodies (e.g., T cell receptor and IL-2 receptor-specific antibodies), B cell depletion therapy drugs (e.g., anti-CD20 antibodies (e.g., Rituxan), i-BLyS antibodies), drugs affecting T cell migration (e.g., anti-integrin alpha 4 / beta 1 antibodies (e.g., Tysabri), immunophilin-acting drugs Drugs used in the treatment of rheumatoid arthritis include cyclosporine, tacrolimus, sirolimus, and rapamycin, interferons (e.g., IFN-β), immunomodulators (e.g., glatiramer), TNF-binding proteins (e.g., circulating receptors), immunosuppressants (e.g., mycophenolic acid), and other drugs, including metaglidasen, AMG-131, balaglitazone, MBX-2044, rivoglitazone, aleglitazar, chiglitazar, and saroglitaza. ol, muraglitazar, tesaglitazar, lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, exenatide, exendin-4, memantine, midazolam, ketoconazole, ethyl icosapentate, clonidine, azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, etoposide, piroxicam, NO donors (e.g., organic nitrates), and NO promoters (e.g., phosphodiesterase inhibitors).

[0577] In some embodiments, the one or more additional therapeutic agents include, for example, therapeutic agents useful as antiemetics. As used herein, an "antiemetic" agent refers to any agent that counteracts (e.g., reduces or eliminates) nausea or emesis (vomiting). When referring to a therapeutically effective amount of an antiemetic, it should be understood that the amount administered is the amount necessary to counteract (e.g., reduce or eliminate) nausea or emesis (vomiting). Without being bound by theory, it is believed that administering one or more antiemetics in combination with the compound of formula (I) described herein may allow a patient to, for example, consume a normal diet, thereby allowing a higher dose of the compound of formula (I) to be administered, thereby resulting in a more rapid response to treatment.

[0578] 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 substance 1 P receptor antagonists), antidopaminergics / dopamine receptor antagonists, benzodiazepines, cannabinoids.

[0579] For example, the antiemetic may be 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.

[0580] 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, batanopiride, 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, MDL72222, tropanyl-3,5-dimethylbenzoate, 3-(4-allylpiperazin-1-yl)-2-quinoxalinecarbonitrile maleate, zacopride hydrochloride, and mirtazapine. Non-limiting examples of other 5HT3-receptor antagonists (serotonin receptor antagonists) include cilansetron, clozapine, cyproheptadine, dazopride, hydroxyzine, lerisetron, metoclopramide, mianserin, olanzapine, palonosetron (plus netupitant), quetiapine, quamosetron, ramosetron, licasetron, risperidone, ziprasidone, and zatosetron.

[0581] In certain embodiments, the 5HT-3-receptor antagonist is granisetron, dolasetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemesetron, zatisetron, batanopiride, 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 mirtazapine.

[0582] In certain embodiments, the 5HT-3-receptor antagonist is granisetron, dolasetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemesetron, and zatisetron.

[0583] In certain embodiments, the 5HT-3-receptor antagonists are granisetron, dolasetron and ondansetron.

[0584] In certain embodiments, the 5HT-3-receptor antagonist is granisetron.

[0585] In certain embodiments, the 5HT-3-receptor antagonist is ondansetron.

[0586] In some embodiments, the antiemetic drug is an antihistamine. Non-limiting examples of antihistamines include piperazine derivatives (e.g., cyclizine, meclizine, and cinnarizine); promethazine; dimenhydrinate (Dramamine, Gravol); diphenhydramine; hydroxyzine; buclizine; and meclizine hydrochloride (Bonine, Antivert), doxylamine, and mirtazapine.

[0587] In some embodiments, the antiemetic drug is an anticholinergic (acetylcholine receptor inhibitor). Non-limiting examples of anticholinergics include atropine, scopolamine, glycopyrone, hyoscine, Artane (trihexy-5-trihexyphenidyl hydrochloride), Cogentin (benztropine mesylate), Akineton (biperiden hydrochloride), Dicypal (Norflex, orphenadrine citrate), diphenhydramine, hydroxyzine, hyoscyamine, and Camadoline (procyclidine hydrochloride).

[0588] In some embodiments, the antiemetic agent is a steroid (e.g., a corticosteroid). Non-limiting examples of steroids include betamethasone, dexamethasone, methylprednisolone, Prednisone®, and trimethobenzamide (Tigan).

[0589] In some embodiments, the antiemetic agent is an NK1-receptor antagonist (e.g., a neurokinin substance 1 P receptor antagonist). Non-limiting examples of NK1-receptor antagonists include aprepitant, casopitant, ezlopitant, fosaprepitant, maropitant, netupitant, rolapitant, and vestipitant.

[0590] Other non-limiting examples of NK1-receptor antagonists include MPC-4505, GW597599, MPC-4505, GR205171, L-759274, SR140333, CP-96,345, BIIF1149, NKP608C, NKP608A, CGP60829, SR140333 (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. Benserazide and carbidopak. This includes 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)-α-MeTrp-(S)-NHCH(CH)Ph), FK888, and (D-Pro4, D-Trp7,9,10, Phe11)SP4-11.

[0591] In some embodiments, the antiemetic drug is an antidopamine agonist / 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.

[0592] In some embodiments, the antiemetic agent is a non-psychoactive cannabinoid (e.g., cannabidiol (CBD), cannabidiol dimethylheptyl (CBD-DMH), tetrahydrocannabinol (THC), a cannabinoid agonist such as WIN55-212 (a CB1 and CB2 receptor agonist), dronabinol (Marinol®), and nabilone (Cesamet)).

[0593] Other exemplary 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.

[0594] In certain embodiments, the additional therapeutic agent or regimen is administered to the patient prior to contact or administration of the compound and pharmaceutical composition (e.g., about 1 hour, about 6 hours, about 12 hours, about 24 hours, about 48 hours, about 1 week, or about 1 month).

[0595] In some embodiments, the additional therapeutic agent or regimen is administered to the patient at approximately the same time as the contact or administration of the compound and pharmaceutical composition. In one example, the additional therapeutic agent or regimen and the compound and pharmaceutical composition are administered to the patient simultaneously in the same formulation. In another example, the additional therapeutic agent or regimen and the compound and pharmaceutical composition are administered to the patient simultaneously in separate formulations.

[0596] Pharmaceutical Compositions and Methods of Administration When used as a pharmaceutical, the compound of Formula I (including its pharmaceutically acceptable salts or solvates) can be administered in the form of a pharmaceutical composition. These compositions can be prepared by methods well known in the pharmaceutical art and can be administered by various routes depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (including transdermal, epidermal, ocular, and mucosal delivery, including intranasal, vaginal, and rectal), pulmonary (e.g., powder or aerosol inhalation or insufflation (including nebulizer); intratracheal or intranasal), oral, or parenteral. Oral administration can include preparations formulated for once-daily or twice-daily (BID) administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracerebral, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose or, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, fillers and the like may be necessary or desirable.

[0597] Also provided herein are pharmaceutical compositions comprising a compound of Formula I or a pharmaceutically acceptable salt, deuterated analog, 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, deuterated analog, 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 the excipient serves as a diluent, it can be a solid, semi-solid, or liquid substance that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments (e.g., containing 10% by weight of the active compound), soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.In some embodiments, the composition is formulated for oral administration.In some embodiments, the composition is a solid oral formulation.In some embodiments, the composition is formulated as a tablet or capsule.

[0598] Further provided herein is a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof together with a pharmaceutically acceptable excipient. Pharmaceutical compositions comprising a compound of Formula I or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof as an active ingredient can be prepared by intimately mixing a compound of Formula I or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the desired route of administration (e.g., oral, parenteral). In some embodiments, the composition is a solid oral composition.

[0599] 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).

[0600] 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.

[0601] In some embodiments, the compound or pharmaceutical composition can be administered in combination with one or more conventional pharmaceutical excipients.Pharmaceutically acceptable excipients include but are not limited to ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery system (SEDDS), such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical preparations, such as Tween, poloxamer or other similar polymer delivery matrices, serum proteins, such as human serum albumin, buffer substances, such as phosphate, Tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salt or electrolytes, 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 chemical entities described herein in the range of 0.005% to 100%, with the balance being composed of non-toxic excipients, can be prepared. Contemplated compositions may contain the compounds provided herein in the range of 0.001% to 100%, in one embodiment, 0.1 to 95%, in another embodiment, 75 to 85%, and in a further embodiment, 20 to 80%. Actual methods for preparing such formulations are known or apparent to those skilled in the art, and are described, for example, in Remington: The Science and Practice of Pharmacy, 22 nd Edition (Pharmaceutical Press, London, UK. 2012).

[0602] In certain embodiments, the compounds and pharmaceutical compositions described herein or pharmaceutical compositions thereof may be administered to a patient in need thereof by any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, intracervical, intrasinus, intratracheal, intraintestinal, peridural, 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, intratracheal, intrathecal, intrasynovial, intratesticular, intraarachnoid, intraductal, intratumoral, intrauterine, intravascular, intravenous, intranasal (e.g., intranasal), nasogastric, oral, parenteral, transdermal, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and vaginal. In certain embodiments, the route of administration is parenteral (eg, intratumoral).

[0603] In some embodiments, the compound of Formula I described herein or its pharmaceutically acceptable salt, deuterated analog or solvate (e.g., any compound of Formula II, Formula III or Formula IV or its pharmaceutically acceptable salt, deuterated analog or solvate) or its pharmaceutical composition can be formulated for parenteral administration, for example, for injection by intraarterial, intrasternal, intracerebral, intravenous, intramuscular, subcutaneous or intraperitoneal route.For example, such compositions can be prepared as either an injectable liquid solution or suspension; a solid form suitable for preparing a solution or suspension by adding liquid before injection can also be prepared; and the preparation can also 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 needle injectors, microneedle injectors, needleless injectors and injection technology.

[0604] In some embodiments, pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions; formulations containing sesame oil, peanut oil, or propylene glycol solutions; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.In some embodiments, the form must be sterile and fluid to the extent that it can be easily injected.In some embodiments, the form must be stable under the conditions of manufacture and storage, and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

[0605] In some embodiments, the carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. In some embodiments, proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in dispersion, and by the use of surfactants. In some embodiments, the action of microorganisms can be prevented by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In some embodiments, isotonic agents, for example, sugars or sodium chloride, are included. In some embodiments, prolonged absorption of injectable compositions can be achieved by using agents that delay absorption, for example, aluminum monostearate and gelatin in the composition.

[0606] In some embodiments, sterile injectable solutions are prepared by combining the required amount of a compound of Formula I or its pharmaceutically acceptable salt, deuterated analog or solvate (e.g., a compound of Formula II, Formula III or Formula IV or its pharmaceutically acceptable salt, deuterated analog or solvate) in a suitable solvent with various other ingredients listed above, and then optionally sterile-filtering.In some embodiments, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and the other required ingredients listed above.In some embodiments, sterile powders are used to prepare sterile injectable solutions.In some embodiments, the preparation method is vacuum drying and freeze-drying technology, which obtains a powder of the active ingredient and additional desired ingredients from the previously sterile-filtered solution.

[0607] In some embodiments, pharmaceutically acceptable excipients that can be used in rectal compositions as gels, creams, enemas, or rectal suppositories include, but are not limited to, cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (e.g., PEG ointment), glycerin, glycerinated gelatin, hydrogenated vegetable oils, poloxamer, mixtures of polyethylene glycols and fatty acid esters of polyethylene glycol of various molecular weights, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxide SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxobenzoate, sodium propyl p-hydroxybenzoate, diethylamine, carbomer, carbopol, methyl hydroxybenzoate, macrogol cetostearyl ether, cocoyl Any one or more of caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins such as vitamins A and E, and potassium acetate.

[0608] In some embodiments, suppositories can be prepared by mixing a compound of Formula I or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof) or a pharmaceutical composition described herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, that is solid at room temperature but liquid at body temperature and therefore melts in the rectum and releases the active compound. In some embodiments, the composition for rectal administration is in the form of an enema.

[0609] In certain embodiments, a compound of Formula I or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any of Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof) described herein 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 dosage form).

[0610] 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, deuterated analog, or solvate (e.g., any compound of Formula II, Formula III, or Formula IV, or its pharmaceutically acceptable salt, deuterated analog, or solvate) is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrants, such as agar, 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 a soluble or non-soluble filler, ...

[0611] 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 include a compound of Formula I provided herein or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any of Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof), along 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 dosage form, powder, marume, solution, or suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglyceride) is encapsulated in a capsule (e.g., a gelatin or cellulose-based capsule). In some embodiments, unit formulations in which one or more compounds provided herein and pharmaceutical compositions or additional active agents are physically separated are also included, such as granules, capsules, and granules (or tablets in capsules); bilayer tablets; two-compartment gel capsules, etc. In some embodiments, enteric-coated or sustained-release oral formulations are also included.

[0612] 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.

[0613] In some embodiments, the excipients are sterile and generally free of undesirable substances. For example, these compositions can be sterilized by conventional, well-known sterilization techniques. In some embodiments, for various oral formulation excipients, such as tablets and capsules, sterilization is not required. For example, United States Pharmacopeia / National Formulary (USP / NF) standards may be sufficient.

[0614] In some embodiments, the compound of Formula I described herein, or a pharmaceutically acceptable salt, deuterated analogue or solvate thereof (e.g., a compound of any of Formula II, Formula III or Formula IV, or a pharmaceutically acceptable salt, deuterated analogue or solvate thereof), or a pharmaceutical composition thereof, is formulated for ophthalmic administration. In some embodiments, the ophthalmic composition may include, but is not limited to, one or more of the following: viscogen (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizer (e.g., Pluronic (triblock copolymer), cyclodextrin); preservative (e.g., benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloroisothiazolinone complex; Allergan, Inc.)).

[0615] In some embodiments, the compound of Formula I described herein, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any of Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt, deuterated analog, 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 may include ointments and creams. In some embodiments, ointments are typically semi-solid preparations based on petrolatum or other petroleum derivatives. In some embodiments, creams containing selected active agents 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.

[0616] In any of the foregoing embodiments, the pharmaceutical compositions described herein may comprise one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[0617] In some embodiments, the dosage of a compound of Formula I or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof) is determined based on many factors, including, but not limited to, the type, age, weight, sex, medical condition, severity of the patient's medical condition, route of administration, and the activity of the compound or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof. In some embodiments, the appropriate dosage for a particular situation can be determined by those skilled in the pharmaceutical arts. In some embodiments, the total daily dosage can be divided and administered in portions throughout the day, or administered by a method that provides sustained delivery.

[0618] In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of Formula II, Formula III, or Formula IV or a pharmaceutically acceptable salt, deuterated analog, 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.

[0619] In certain embodiments, a compound of Formula I described herein, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any of Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt, deuterated analog, 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 100 mg / Kg). mg / Kg~about 25mg / Kg;about 0.0002mg / Kg~about 10mg / Kg;about 0.0002mg / Kg~about 5mg / Kg;about 0.0002mg / Kg~about 1mg / Kg;about 0.0002mg / Kg ~ approx. 0.5mg / Kg; approx. 0.0002mg / Kg ~ approx. 0.1mg / Kg; approx. 0.001mg / Kg ~ approx. 50mg / Kg; approx. 0.001mg / Kg ~ approx. 25mg / Kg; approx. 0.001mg / Kg ~About 10mg / Kg; Approx. 0.001mg / Kg ~ Approx. 5mg / Kg; Approx. 0.001mg / Kg ~ Approx. 1mg / Kg; Approx. 0.001mg / Kg ~ Approx. 0.5mg / Kg; Approx. 0.001mg / Kg ~ Approx. 0.1m g / Kg; about 0.01 mg / Kg to about 50 mg / Kg; about 0.01 mg / Kg to about 25 mg / Kg; about 0.01 mg / Kg to about 10 mg / Kg; about 0.01 mg / Kg to about 5 mg / Kg; about 0.01 In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof) described herein is administered at a dose of about 100 mg / Kg.

[0620] In certain embodiments, the dose of the compound of Formula I, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any of Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof) can be administered on a daily basis (e.g., as a single dose or two or more divided doses) or off-daily (e.g., every other day, every two days, every three days, once a week, twice a week, once every two weeks, once a month).

[0621] 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 Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof) is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In some embodiments, the period of time for which administration is discontinued is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more. In certain embodiments, a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any of Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt, deuterated analog, 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, deuterated analog, or solvate thereof (e.g., a compound of any of Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof) is discontinued. In certain embodiments, a compound of Formula I or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any of Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt, deuterated analog, 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, deuterated analog, or solvate thereof (e.g., a compound of any of Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt, deuterated analog, 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, deuterated analog, or solvate thereof (e.g., a compound of any of Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof), followed by a period during which administration is discontinued, is 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.

[0622] In certain embodiments, a compound of Formula I, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any of Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt, deuterated analog, 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 doses).

[0623] In certain embodiments, a compound of Formula I, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any of Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof) is parenterally administered to a patient one or more times daily (e.g., 1 to 4 times daily, 2 times daily, 3 times daily, 4 times daily, or once daily doses).

[0624] In certain embodiments, a compound of Formula I, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any of Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof) is parenterally administered to a patient once a week.

[0625] 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).

[0626] In certain embodiments, the methods described herein further include identifying a subject (e.g., a patient) suffering from a disease, disorder, or condition provided herein (e.g., a GLP-1-related disease, disorder, or condition).

[0627] In certain embodiments, the methods described herein further include identifying a patient (e.g., a patient) suffering from type 2 diabetes. In certain embodiments, determining whether a patient has type 2 diabetes includes performing an assay to determine hemoglobin A1c (HbA1c) levels, fasting blood glucose, non-fasting blood glucose, or any combination thereof. In certain embodiments, the HbA1c level is about 6.5% to about 24.0%. In certain embodiments, the HbA1c level is about 6.5% or higher. In certain embodiments, the HbA1c level is about 8.0% or higher. In certain embodiments, the HbA1c level is about 10.0% or higher. In certain embodiments, the HbA1c level is about 12.0% or higher. In certain embodiments, the HbA1c level is about 14.0% or higher. In certain embodiments, the HbA1c level is about 16.0% or higher. In some embodiments, the HbA1c level is about 18.0% or higher. In some embodiments, the HbA1c level is about 20.0% or higher. In some embodiments, the HbA1c level is about 22.0% or higher. In some embodiments, the HbA1c level is about 24.0% or higher.

[0628] In some embodiments, the fasting blood glucose level is from about 120 mg / dL or more to about 750 mg / dL or more. In some embodiments, the fasting blood glucose level is from about 200 mg / dL or more to about 500 mg / dL or more. In some embodiments, the fasting blood glucose level is from about 300 mg / dL or more to about 700 mg / dL or more.

[0629] In some embodiments, the non-fasting blood glucose level is from about 190 mg / dL or more to about 750 mg / dL or more. In some embodiments, the non-fasting blood glucose level is from about 250 mg / dL or more to about 450 mg / dL or more. In some embodiments, the non-fasting blood glucose level is from about 400 mg / dL or more to about 700 mg / dL or more.

[0630] In certain embodiments, determining whether a patient has type 2 diabetes further comprises determining the patient's BMI. In certain embodiments, the patient's BMI is about 22 kg / m 2 or more to about 100 kg / m 2 In certain embodiments, the patient's BMI is about 30 kg / m or greater. 2 or more to about 90 kg / m 2 In certain embodiments, the patient's BMI is about 40 kg / m or greater. 2 or more to about 80 kg / m 2 In certain embodiments, the patient's BMI is about 50 kg / m or greater. 2 or more to about 70 kg / m 2 Or even more.

[0631] In certain embodiments, additional factors (e.g., risk factors) used to determine whether a patient has type 2 diabetes further include the patient's age and ethnicity. In certain embodiments, the patient is about 10 years old or older. In certain embodiments, the patient is about 15 years old or older. In certain embodiments, the patient is about 20 years old or older. In certain embodiments, the patient is about 25 years old or older. In certain embodiments, the patient is about 30 years old or older. In certain embodiments, the patient is about 35 years old or older. In certain embodiments, the patient is about 40 years old or older. In certain embodiments, the patient is about 42 years old or older. In certain embodiments, the patient is about 44 years old or older. In certain embodiments, the patient is about 46 years old or older. In certain embodiments, the patient is about 48 years old or older. In certain embodiments, the patient is about 50 years old or older. In certain embodiments, the patient is about 52 years old or older. In some embodiments, the patient is about 54 years of age or older. In some embodiments, the patient is about 56 years of age or older. In some embodiments, the patient is about 58 years of age or older. In some embodiments, the patient is about 60 years of age or older. In some embodiments, the patient is about 62 years of age or older. In some embodiments, the patient is about 64 years of age or older. In some embodiments, the patient is about 66 years of age or older. In some embodiments, the patient is about 68 years of age or older. In some embodiments, the patient is about 70 years of age or older. In some embodiments, the patient is about 72 years of age or older. In some embodiments, the patient is about 74 years of age or older. In some embodiments, the patient is about 76 years of age or older. In some embodiments, the patient is about 78 years of age or older.In some embodiments, the patient is about 80 years old or older. In some embodiments, the patient is about 85 years old or older. In some embodiments, the patient is about 90 years old or older. In some embodiments, the patient is about 95 years old or older. In some embodiments, the patient's ethnicity may be African American, American Indian or Alaska Native, Asian American, Hispanic or Latino, or Native Hawaiian or Pacific Islander.

[0632] Compound synthesis The compounds can be prepared by the methods described herein and their routine modifications, which will be apparent in light of the disclosures herein and methods known in the art. In addition to the teachings herein, conventionally known methods can be used. The synthesis of typical compounds described herein can be achieved as described in the following examples. Where available, reagents can be purchased commercially, for example, from Sigma Aldrich or other chemical suppliers.

[0633] 11.5.General synthesis The compounds of the present invention can be prepared from readily available starting materials using, for example, the following general methods and procedures. Where specific process conditions (i.e., reaction temperature, time, molar ratios of reactants, solvents, pressure, etc.) are given, it is understood that other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0634] As will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting certain functional groups, are well known in the art.For example, many protecting groups are described in TW Greene and GM Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and the references cited therein.

[0635] Additionally, compounds of the present invention may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. Unless otherwise specified, all such stereoisomers (and enriched mixtures) are included within the scope of the present invention. Pure stereoisomers (or enriched mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, chiral resolving agents, and the like.

[0636] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bache (Torrance, California, USA), EMKA-Chemie GmbH & Co. KG (Eching, Germany) or Millipore Sigma (Burlington, Massachusetts, USA). Others may be prepared by procedures described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or obvious modifications thereof.

[0637] Scheme I illustrates a general method that may be used for the synthesis of the compounds described herein, and includes rings A, B, C, Q, X, Y, L, and R. 1 , L 2 , R 1 , R 2 and R 3 are independently as defined herein, and LG is a leaving group such as alkoxy, hydroxy, halo (e.g., Cl, Br, or I). [ka]

[0638] For Scheme I, under standard coupling conditions, e.g., L 1 Coupling of compound I-1 with compound I-2 under amide bond forming conditions when is -C(=O)-, for example, in the presence of a carboxyl activating agent such as HATU (e.g., in a polar aprotic solvent such as DMF), provides a compound of formula I. After completion of the reaction, the compound of formula I can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, and the like.

[0639] Scheme II illustrates a general method that may be used to synthesize compounds I-2, wherein ring B and ring C are independently as defined herein, and L 3 is a bond and R 8a and R 8b Each of them, together with the carbon atom to which it is attached, represents an optionally substituted C 3-15 Form a cycloalkyl (e.g., cyclopropyl), which is shown in Scheme II as ring D', and the dashed curve Lx may be optionally substituted as defined herein (e.g., 1 to 3 R f C optionally substituted with 1-6 optionally substituted with alkyl)C 2-14 represents alkylene, and R 50 is an optionally substituted alkyl group, and LG is a leaving group such as alkoxy, hydroxy, halo (eg, Cl, Br, or I). [ka]

[0640] Referring to Scheme II, compound II-1 can be reacted with a compound of formula (ring C)-Y 1 wherein Ring C is as defined for Formula I and Y 1Optionally, when Ring C is a saturated heterocyclyl, II-1 can be prepared by subjecting II-1 to a metal-catalyzed cross-coupling reaction (e.g., Suzuki coupling using Pd(dppf)ClCH2Cl2 in the presence of potassium carbonate) with a suitable coupling partner such as a reagent having a hydroxyl group such as B(OH)2 or a boric acid ester such as BPin to give compound I-2. Optionally, when Ring C is a saturated heterocyclyl, II-1 can be prepared by subjecting II-1 to a reaction of formula (Ring C)-Y where Ring C is a partially saturated heterocyclyl. 1 and optionally hydrogenated (e.g., with palladium on carbon) to give I-2. As a non-limiting example, when Ring C is tetrahydropyran-4-yl, II-1 can be obtained by coupling with a reagent of (Ring C)-Y 1 , for example, the formula: [ka] can be coupled with 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0641] Certain compounds of formula I-2 can be prepared from compound II-2 as shown in Scheme II. For example, reaction of II-2 with II-3 (e.g., in the presence of NaH in DMF) gives compound II-4, which can be hydrolyzed under standard conditions (e.g., using LiOH·HO / THF solution) to give compound II-5. Amide coupling of II-5 with NHMePh under standard conditions (e.g., HATU and Hunig's base) gives II-6. Then, reaction of II-6 with reagent II-6b under basic conditions (e.g., KHMDS, DMPU) gives II-7. For example, II-6b can be prepared by the following procedure: [ka] wherein ring D' in the corresponding product can be [ka] Treatment of II-7 with a hydroxylamine source (e.g., NHOH·HCl in EtOH at reflux) and reaction with a phosgene equivalent (e.g., CDI (e.g., in the presence of DBU and DMSO at 80°C)) provides compound II-8. Hydrolysis of the amide group of compound II-8 (e.g., with KOH in CHOCHCHOH at 125°C) provides compound II-9. Compound II- can be used as compound I-2 in Scheme I.

[0642] In certain embodiments, in ring B [ka] The method shown in Scheme II for the introduction of moieties can be carried out according to Scheme IIA shown below, wherein Ring A, Ring B, Ring C, Ring D', Q, X, Y, L 1 , L 2 , R 1 , R 2 and R 3 each independently as defined herein. [ka]

[0643] Scheme III illustrates a general method that can be used for the synthesis of exemplary compounds of Formula I-1 (e.g., compound III-7), which can be used in Scheme I to provide compounds of Formula I, and in which rings A, Q, X, Y, L 1 , L 2 , R 1 , R 2 and R 3 are each independently as defined herein, X is a leaving group such as halo (e.g., Cl, Br, or I), and PG is a protecting group. [ka]

[0644] In Scheme III, reaction of III-1 with III-2 (e.g., in the presence of a polar aprotic solvent such as DMA) affords compound III-3, followed by acid treatment (e.g., MeSO3H, THF, 60 °C), followed by reprotection of the secondary amino group (e.g., with Boc2O) to afford compound III-4, where PG is a nitrogen protecting group, such as a carbamate protecting group like Boc. Compound III-4 is then coupled with compound III-5, where X is halo (e.g., -Br or -I) or pseudohalo (e.g., -OTf), under typical Ullmann coupling conditions known in the art to afford compound III-6. As a non-limiting example, the coupling can be carried out using CuI, K2CO3, and [ka] The reaction can be carried out in NMP (e.g., at 130° C.) in the presence of HCl. Subsequent removal of the nitrogen protecting group (i.e., PG) of III-6 (e.g., under acidic conditions such as HCl-dioxane solution) provides compound III-7.

[0645] Appropriate starting materials and reagents for the steps shown in any of Schemes I, II, or III can be purchased or prepared by methods known to those skilled in the art. After completion of each reaction, each intermediate or final compound can be recovered and optionally purified by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, etc. Other modifications to obtain compounds of the present invention are within the purview of those skilled in the art.

[0646] In certain embodiments, when control of a stereocenter is desired, the formation of various stereoisomers can be at least partially defined or maintained by appropriate control of reaction conditions and selection of substituents on reagents. In some embodiments, various substituents (e.g., ring A, ring B, ring C, Q, X, Y, L) of various compounds of Scheme I, II, or III can be selected. 1 , L 2 , R 1 , R 2 and R 3) are each independently as defined herein. However, derivatization of the compounds of any of Schemes I, II, or III prior to the reaction step, and / or further derivatization of the resulting reaction product, provides a variety of compounds of Formula I.

[0647] In the synthetic sequences shown above in Scheme I, II, or III, it will be apparent to those skilled in the art that reactive groups such as NH, NH, and OH can be protected with suitable protecting groups and deprotected at an appropriate stage in the synthesis. It is also within the skill of the art to consider variations of the above method to synthesize other compounds of Formula I. For example, by replacing III-2 with other electrophiles, other L 3 -C(R 8a R 8b )-L 4 -R 9 As another example, compounds having other L groups can be obtained by replacing III-1 with other appropriate reagents. 2 Compounds having the moiety can be obtained.

[0648] The compounds provided in Table 1 can be prepared according to the methods shown in Schemes I, II and III. [Example]

[0649] The following embodiments are included to illustrate specific embodiments of the present invention. It should be understood by those skilled in the art that the techniques disclosed in the following examples represent techniques that work well in the practice of the present invention and can therefore be considered to constitute specific modes for its implementation. However, those skilled in the art will understand in light of the present invention that many changes can be made in the specific embodiments disclosed and still obtain the same or similar results without departing from the concept and scope of the present invention.

[0650] Abbreviations (used herein): [Table 2-1] [Table 2-2]

[0651] General information: All evaporations were performed using a rotary evaporator under reduced pressure. Analytical samples were dried under reduced pressure (1-5 mmHg) at room temperature. Thin-layer chromatography (TLC) was performed on silica gel plates, and spots were visualized by UV light (214 and 254 nm). Purification by column and flash chromatography was performed using silica gel (100-200 mesh). Solvent systems are reported as mixtures (by volume). NMR spectra were recorded on a Bruker 400 or Varian (400 MHz) spectrometer. 1 H chemical shifts are reported in δ values ​​(ppm) using deuterated solvents as internal standards. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad signal, m = multiplet), coupling constant (Hz), and integration. LCMS spectra were obtained using a SHIMADZU LC20-MS2020 or Agilent 1260 Series 6125B mass spectrometer or Agilent 1200 Series 6110 or 6120 mass spectrometer with electrospray ionization, unless otherwise indicated.

[0652] Example 1 3-(1-{2-[(4S)-3-{3-[4-(diethylphosphoryl)-3-(methylamino)phenyl]-2-oxo-2,3-dihydro-1H-imidazol-1-yl}-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-6-(oxan-4-yl)-1H-indol-3-yl}cyclopropyl)-2,5-dihydro-1,2,4-oxadiazol-5-one (Compound 28) [ka] [ka] [ka] Step A Methyl 6-(3,6-dihydro-2H-pyran-4-yl)-1H-indole-2-carboxylate [ka] To a mixture of methyl 6-bromo-1H-indole-2-carboxylate (5 g, 19.69 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.96 g, 23.62 mmol), and KCO (8.15 g, 59.06 mmol) in dioxane (80 mL) and HO (8 mL) was added Pd(dppf)Cl·CHCl (0.8 g, 0.98 mmol). After filling with nitrogen three times, the resulting mixture was stirred at 90 °C under nitrogen for 3 h. After cooling, the mixture was filtered and concentrated to dryness under reduced pressure. The residue was purified by flash silica gel chromatography (silica flash column, eluent: 0-25% EtOAc / PE gradient) to give methyl 6-(3,6-dihydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (3.58 g, 70.8% yield). LC-MS: m / z: 258.4 (M+H). + .

[0653] Step B Methyl 6-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate [ka] A solution of methyl 6-(3,6-dihydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (3.48 g, 13.54 mmol) and 5% Pd / C (348 mg) in MeOH (35 mL) was degassed and filled with H three times. The reaction mixture was stirred at room temperature under a balloon of H gas for 2 hours. The mixture was filtered and concentrated to give methyl 6-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (3.43 g, 98.0% yield). LC-MS: m / z: 260.1 (M+H). + .

[0654] Step C Methyl 3-bromo-6-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate [ka] To a solution of methyl 6-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (3.33 g, 12.86 mmol) in CHCN (30 mL) and CHCl (20 mL) was added NBS (1.6 g, 9.0 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with HO (300 mL) and extracted with CHCl (50 mL × 3). The organic layer was washed with brine, dried over anhydrous NaSO, filtered, and concentrated to give crude methyl 3-bromo-6-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (3.9 g, 90.7% yield). LC-MS: m / z: 338.1 (M+H). + .

[0655] Step D Methyl 3-(cyanomethyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate [ka] To a solution of methyl 3-bromo-6-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (300 mg, 0.89 mmol) in DMSO (6 mL) and HO (1 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (346 mg, 1.77 mmol), KF (154 mg, 2.66 mmol), and Pd(dppf)Cl (65 mg, 0.09 mmol). After filling with nitrogen three times, the resulting mixture was stirred at 130 °C under nitrogen for 3 h. After cooling, the mixture was concentrated and purified by flash silica gel chromatography (silica flash column, eluent: 0-20% EtOAc / PE gradient) to give methyl 3-(cyanomethyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (290 mg, 65.1% yield). LC-MS: m / z 299.3 (M+H). + .

[0656] Step E Methyl 3-(1-cyanocyclopropyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate [ka] A mixture of methyl 3-(cyanomethyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (100 mg, 0.34 mmol), ethenyldiphenylsulfanium trifluoromethanesulfonate (146 mg, 0.40 mmol), and DBU (153 mg, 1.01 mmol) in DMSO (1 mL) was stirred at room temperature for 2 hours under nitrogen. The mixture was diluted with HO (30 mL) and extracted with EtOAc (10 mL × 3). The organic layer was washed with brine, dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by preparative TLC (20% EtOAc / PE) to give methyl 3-(1-cyanocyclopropyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (38 mg, 35.0% yield). LC-MS: m / z 325.2 (M+H) + .

[0657] Step F 3-(1-cyanocyclopropyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid [ka] A mixture of methyl 3-(cyanocyclopropyl)-6-(3,4,5,6-tetrahydro-2H-pyran-4-yl)benzo[b]thiophene-2-carboxylate (38 mg, 0.12 mmol) and LiOH (9.8 mg, 0.23 mmol) in THF (1 mL) and HO (0.2 mL) was stirred at room temperature for 6 hours. The mixture was diluted with water (30 mL), acidified with 1 M aqueous HCl to pH = 5.0, and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over anhydrous NaSO, filtered, and concentrated to give 3-(1-cyanocyclopropyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (37 mg, crude). LC-MS: m / z 311.3 (M+H). + .

[0658] Step G (S)-1-(2-(3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclopropane-1-carbonitrile [ka] To a solution of 3-(1-cyanocyclopropyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (37 mg, 0.12 mmol) in DMF (2 mL) was added (S)-1-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (65 mg, 0.12 mmol) (HCl salt, prepared as described in WO 2021155841 A1), HATU (54 mg, 0.14 mmol), and DIPEA (46 mg, 0.36 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was then diluted with brine (30 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, 0-10% MeOH / CHCl gradient eluent, 50 mL / min) to give (S)-1-(2-(3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclopropane-1-carbonitrile (66 mg, 65.3% yield). LC-MS: m / z 843.4 (M+H). + .

[0659] Step H (S,Z)-1-(2-(3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)-N'-hydroxycyclopropane-1-carboximidamide [ka] To a solution of (S)-1-(2-(3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclopropane-1-carbonitrile (66 mg, 0.078 mmol) in EtOH (1 mL) was added DIPEA (30 mg, 0.234 mmol) and NHOH HCl (16.3 mg, 0.234 mmol). The resulting mixture was stirred at 70 °C for 6 h. After cooling, the mixture was diluted with brine (30 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, 0-5% MeOH / CHCl gradient eluent, 50 mL / min) to give the title compound (S,Z)-1-(2-(3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)-N'-hydroxycyclopropane-1-carboximidamide (36 mg, 57.6% yield). LC-MS: m / z 876.2 (M+H). + .

[0660] Step I 3-(1-{2-[(4S)-3-{3-[4-(diethylphosphoryl)-3-(methylamino)phenyl]-2-oxo-2,3-dihydro-1H-imidazol-1-yl}-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-6-(oxan-4-yl)-1H-indol-3-yl}cyclopropyl)-2,5-dihydro-1,2,4-oxadiazol-5-one (Compound 28) [ka] To a solution of (S,Z)-1-(2-(3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)-N'-hydroxycyclopropane-1-carboximidamide (36 mg, 0.041 mmol) in dioxane (1 mL) was added CDI (20 mg, 0.123 mmol). The resulting mixture was stirred at 60°C for 16 hours. After cooling, the reaction mixture was concentrated. The residue was purified by preparative HPLC (column: Pursuit XRs C18 19*250mm*10μm; mobile phase A: water (0.1% formic acid), mobile phase B: CH3CN; flow rate: 20mL / min; gradient: 57% B to 67% Purification by HPLC (HPLC: 9.2-10.3 min) gave 3-(1-{2-[(4S)-3-{3-[4-(diethylphosphoryl)-3-(methylamino)phenyl]-2-oxo-2,3-dihydro-1H-imidazol-1-yl}-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-6-(oxan-4-yl)-1H-indol-3-yl}cyclopropyl)-2,5-dihydro-1,2,4-oxadiazol-5-one (12.0 mg, 32.3% yield). LC-MS: m / z 902.9 (M+H). + .1 H NMR (400MHz, DMSO-d6):δ 11.88(brs, 1H), 11.47(s, 1H), 7.67-7.78(m, 1H), 7.52(d, J=8.0Hz, 1H), 7.33-7.44(m, 1 H), 7.20-7.32(m, 2H), 7.08-7.19(m, 2H), 6.97-7.07(m, 2H), 6.81-6.96(m, 2H), 5.56-5. 70(m, 1H), 3.84-4.02(m, 3H), 3.39-3.51(m, 3H), 2.61-2.91(m, 6H), 2.20(s, 6H), 1.86-1 .98(m, 4H), 1.64-1.78(m, 4H), 1.43-1.58(m, 2H), 1.17-1.36(m, 5H), 0.93-1.05(m, 6H). 19 F NMR (377MHz, DMSO-d6): δ -122.07.

[0661] Example 2 3-(1-{6-[(4S)-3-{3-[4-(diethylphosphoryl)-3-(methylamino)phenyl]-2-oxo-2,3-dihydro-1H-imidazol-1-yl}-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-3-(oxan-4-yl)pyrrolo[1,2-b]pyridazin-7-yl}cyclopropyl)-4,5-dihydro-1,2,4-oxadiazol-5-one (Compound 26) [ka] [ka] [ka] Step A Methyl 1-amino-1H-pyrrole-3-carboxylate [ka] To a stirred solution of methyl 1H-pyrrole-3-carboxylate (10.0 g, 80.0 mmol) in DMF (300 mL) at 0 °C, NaH (60 wt %, dispersed in paraffin liquid) (2.50 g, 104 mmol) was added. After stirring at 0 °C for 20 min, (aminooxy)dip...

Claims

1. Formula I: 【Chemistry 1】 [During the ceremony, X is C and Y is N, or Y is C and X is N, and the dashed line represents 【Chemistry 2】 but 【Chemistry 3】 where bond y is bonded to Y and bond x is bonded to X; 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 selected from halo, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy and C ３－６ optionally substituted with 1 to 5 substituents each independently selected from the group consisting of cycloalkyl; R １ , R ２ and R ３ is H as well as halo, -OH and C １－６ C, optionally substituted with 1 to 6 substituents each independently selected from the group consisting of alkoxy １－６ each independently selected from the group consisting of alkyl; L １ is -C(=O)-, -CH ２ -, -CH(C １－６ Alkyl)- and -S(=O) ２ selected from the group consisting of: Ring B is 【Chemistry 4】 【Chemistry 5】 (In the formula, 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 is alkylene; L ４ is a bond or C １－５ is alkylene; R ８ａ and R ８ｂ are independently H and halo and C ３－１５ C optionally substituted with one or more substituents independently selected from cycloalkyl １－６ selected from alkyl; Or R ８ａ and R ８ｂ Each independently selected 1 to 3 C's, together with the carbon atom to which it is attached, １－６ C optionally substituted with alkyl ３－１５ Form a cycloalkyl ring, wherein the C １－６ Alkyl is 1 to 6 independently selected R ｆ may be substituted with; Or Part-L ３ -C(R ８ａ R ８ｂ )-L ４ -R ９ is substituted with C(=O)OH, and R ｆ phenyl, optionally substituted with 1 to 4 further substituents independently selected from R ９ are C(=O)OH, C(=O)(OC １－６ alkyl), C(=O)NR ９ａ R ９ｂ , (IX-1), (IX-2), (IX-3) and (IX-4): 【Chemistry 6】 selected from the group consisting of: R ９ａ is H or C １－６ is alkyl; R ９ｂ is H, C １－６ Alkyl, C(=O)(C １－６ Alkyl), S(O) ０－２ (C １－６ alkyl) or cyano; R ９ｃ , R ９ｄ , R ９ｅ , R ９ｆ and R ９ｇ is H, 1 to 6 independently selected halo, and C １－６ C optionally substituted with alkoxy １－６ Alkyl and C(=O)(C １－６ alkyl) selected from the group consisting of: Ring C is a 3- to 12-membered heterocyclyl; ３－１５ cycloalkyl and 5- to 10-membered heteroaryl, each of which is selected from the group consisting of 1 to 3 R Ｃａ may be substituted with; Each R Ｃａ is independent, halo, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy and NR ｃ R ｄ or selected from the group consisting of; Or a pair of R on the same or different ring atoms Ｃａ each taken together with the ring atom to which it is attached forms a carbocyclic ring containing 3 to 8 ring atoms; L ２ teeth, 【Chemistry 7】 (In the formula, aa represents the point of attachment to Q; 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 independently represents H and C １－６ alkyl) selected from the group consisting of: Q is C １－１０ Alkyl; C ３－１５ cycloalkyl; 3- to 12-membered heterocyclyl; 5- to 10-membered heteroaryl; and C ６－１０ aryl, where Q is selected from the group consisting of -P(=O)R ａ R ｂ and R Ｑ and optionally substituted with 1 to 6 further substituents independently selected from: Each R Ｑ are independently selected from the following (a) to (n): (a) halo; (b) cyano; (c) OH or oxo; (d)-NR ｃ R ｄ ; (e) -C(=O)NR ｃ R ｄ Or -S(O) ２ N.R. ｃ R ｄ ; (f)-S(=O) ０－２ R ｅ ; (g) 1 to 6 independently selected R ｆ C optionally substituted with １－６ Alkyl; (h) 1 to 6 independently selected R ｆ C optionally substituted with １－６ Alkoxy; (i) 1 to 6 independently selected R ｇ 3- to 12-membered heterocyclyl optionally substituted by (j) 1 to 6 independently selected R ｇ C optionally substituted with ６－１０ Aryl; (k) 1 to 6 independently selected R ｇ 5-10 membered heteroaryl optionally substituted with (l) 1 to 6 independently selected R ｇ C optionally substituted with ３－８ Cycloalkyl; (m)-P(=O)R ａ R ｂ and (n) q1 is 1, 2 or 3 - (CR ｈ R ｈ ) ｑ１ -S(O) ２ -L ｅ -R ｅ ; or selected from the group consisting of Or, Q is C ３－１５ cycloalkyl; 3- to 12-membered heterocyclyl; 5- to 10-membered heteroaryl; or C ６－１０ aryl, each of which is R ＱＡ and R ＱＢ may be substituted with 1 to 6 substituents each independently selected from the group consisting of However, the following (aa) or (bb): (aa) Q is at least one R ＱＢ is replaced by, or (bb) Q is an intracyclic S(O) ２ is a 4-12 membered heterocyclyl or a 7-10 membered bicyclic heteroaryl containing a group; or both, Each R ＱＡ are independently selected from the following (a) to (k): (a) halo; (b) cyano; (c) OH or oxo; (d)-NR ａ R ｂ ; (e)-C(=O)NR ｃ R ｄ ; (f) 1 to 6 independently selected R ｆ C optionally substituted with １－６ Alkyl; (g) 1 to 6 independently selected R ｆ C optionally substituted with １－６ Alkoxy; (h) 1 to 6 independently selected R ｇ 3- to 12-membered heterocyclyl optionally substituted by (i) 1 to 6 independently selected R ｇ C optionally substituted with ６－１０ Aryl; (j) 1 to 6 independently selected R ｇ 5-10 membered heteroaryl optionally substituted with (k) 1 to 6 independently selected R ｇ C optionally substituted with ３－８ Cycloalkyl; selected from the group consisting of: Each R ＱＢ are independently selected from the following (a) to (b): (a)-L ａ -S(O) ２ -L ｂ -R ｅ and (b) 1 to 6 R are independently selected from heterocyclyl or heteroaryl; ｇ each of which is optionally substituted with an S(O) ring ２ 4-12 membered heterocyclyl or 7-10 membered bicyclic heteroaryl containing groups 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 and q2 are independently 0, 1, 2, 3 or 4; However, L ａ -(CR ｈ R ｈ ) ｑ１ -, and when q1 is 0, -L ｂ -R ｅ is unsubstituted C １－３ is other than alkyl; R ａ and R ｂ is independent, C １－６ Alkoxy, C ３－６ C, optionally substituted with 1 to 6 substituents each independently selected from the group consisting of cycloalkyl and halo. １－６ Alkyl; C １－３ C, optionally substituted with 1 to 3 substituents each independently selected from the group consisting of alkyl and halo; ３－６ cycloalkyl; and 1 to 3 independently selected C １－３ C optionally substituted with alkyl ６－１０ aryl; or R ａ and R ｂ each together with the phosphorus atom to which it is attached forms a ring containing 5 to 8 ring atoms, where 0 to 2 ring atoms (R ａ and R ｂ (in addition to the phosphorus bonded to) are heteroatoms each independently selected from the group consisting of O, S and N, wherein the ring is １－６ may be substituted with alkyl; Each R ｃ and R ｄ are independently 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 said C １－６ Alkyl, C(=O)(C １－６ alkyl), C(=O)(C ３－６ cycloalkyl), C(=O)O(C １－６ Alkyl), S(O) １－２ (C １－６ alkyl) and S(O) １－２ (C ３－６ cycloalkyl) are each selected from -OH, halo and C １－６ optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkoxy; R ｅ is H 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 selected from the group consisting of 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 optionally substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy; L ｅ is a bond, NR ｃ or O; Each R ｆ are independently halo, —OH, NR ｃ R ｄ , C １－６ Alkoxy, C １－６ Haloalkoxy and —OH, C １－６ selected from the group consisting of 3- to 12-membered heterocyclyl optionally 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 independent, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, NR ｃ R ｄ , Cyano, Halo, C ３－６ Cycloalkyl and C １－６ Alkyl and C(=O)C １－６ 3- to 12-membered heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R in each case ｈ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ selected from cycloalkyl and halo; or A pair of R on the same or different carbon atoms ｈ C, together with the carbon atom bonded to it, ３－６ cycloalkyl or 4-8 membered heterocyclyl, each of which is selected from halo, cyano, C １－３ Alkyl, C １－３ Haloalkyl, -OH, C １－３ Alkoxy and C １－３ haloalkoxy; or a pharma- ceutically acceptable salt, deuterated analog or solvate thereof.

2. portion 【Chemistry 8】 but 【Chemistry 9】 wherein bond y is bonded to Y and bond x is bonded to X.

2. The compound of claim 1,

3. portion 【Chemistry 10】 but 【Chemistry 11】 wherein bond y is bonded to Y and bond x is bonded to X.

2. The compound of claim 1,

4. Formula II: 【Chemistry 12】 [During the ceremony, Q １ , Q ２ , Q ３ , Q ４ and Q. ５ is (AA) or (BB) below. (AA) Q １ and Q. ５ are independently N, CH and CR ＱＣ selected from the group consisting of: Q ２ , Q ３ and Q. ４ are independently N, CH, CR ＱＣ and C.R. ＱＤ wherein Q is selected from the group consisting of ２ , Q ３ and Q. ４ At least one of the following is CR ＱＤ and each 【Chemistry 13】 is a single bond or a double bond, provided that Q １ ~Q ５ The ring containing is aromatic; (B.B.) Q １ is a bond; Q ２ , Q ３ , Q ４ and Q. ５ are independently O, S, N, NH, NR ｃ , C.H., C.R. ＱＣ and C.R. ＱＤ wherein Q is selected from the group consisting of ２ , Q ３ , Q ４ and Q. ５ At least one of the following is CR ＱＤ and each 【Chemistry 14】 is a single bond or a double bond, provided that Q １ ~Q ５ The ring containing is aromatic; As defined by: R ＱＤ is P(=O)R ａ R ｂ where R ａ and R ｂ is independent, C １－６ Alkoxy, C ３－６ C, optionally substituted with 1 to 6 substituents each independently selected from the group consisting of cycloalkyl and halo. １－６ Alkyl; C １－３ C, optionally substituted with 1 to 3 substituents each independently selected from the group consisting of alkyl and halo; ３－６ cycloalkyl; and 1 to 3 independently selected C １－３ C optionally substituted with alkyl ６－１０ aryl; or R ａ and R ｂ each together with the phosphorus atom to which it is attached forms a ring containing 5 to 8 ring atoms, where 0 to 2 ring atoms (R ａ and R ｂ In addition to the phosphorus atom bonded to １－６ may be substituted with alkyl; Each R ＱＣ are independently: (a) halo; (b) cyano; (c) OH; (d) -NR ｃ R ｄ (e) C(=O)NR ｃ R ｄ (f) S(=O) ０－２ R ｅ (g) 1 to 6 independently selected R ｆ C optionally substituted with １－６ Alkyl; (h) hydroxy, halo and C １－６ C, optionally substituted with 1 to 6 substituents each independently selected from the group consisting of alkoxy １－６ Alkoxy; (i) C １－６ Alkyl and C(=O)(C １－６ (j) 3- to 12-membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of C(═O)(C １－６ C optionally substituted with alkyl ６－１０ aryl; and (k) 1 to 6 independently selected R ｇ or selected from the group consisting of 5-10 membered heteroaryl optionally substituted with Or a pair of R on adjacent carbon atoms ＱＣ each taken together with the atom to which it is attached forms a ring containing 5-8 ring atoms, where 0-2 ring atoms are heteroatoms each independently selected from the group consisting of O, N and S, and where said ring is joined to 1-2 independently selected R ｈ may be substituted with a group; L ２ teeth, 【Chemistry 15】 (In the formula, aa is Q １ ~Q ５ represents a point of attachment to a ring containing 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 independently represents H and C １－６ alkyl) is selected from the group consisting of Ring A is C ６－１０ Aryl, C ５－７ cycloalkyl, 5- to 7-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is selected from halo, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy and C ３－６ optionally substituted with 1 to 5 substituents each independently selected from the group consisting of cycloalkyl; R １ , R ２ and R ３ is H as well as halo, -OH and C １－６ C, optionally substituted with 1 to 6 substituents each independently selected from the group consisting of alkoxy １－６ each independently selected from the group consisting of alkyl; L １ is -C(=O)-, -CH ２ -, -CH(C １－６ Alkyl)- and -S(=O) ２ selected from the group consisting of: Ring B is 【Chemistry 16】 (In the formula, 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 is alkylene; L ４ is a bond or C １－５ is alkylene; R ８ａ and R ８ｂ are independently H and halo and C ３－１５ C, optionally substituted with one or more substituents selected from the group consisting of cycloalkyl １－６ alkyl; or R ８ａ and R ８ｂ Each independently selected 1 to 3 C's, together with the carbon atom to which it is attached, １－６ C optionally substituted with alkyl ３－１５ Form a cycloalkyl ring, wherein the C １－６ Alkyl is one to six independently selected R ｆ may be substituted with; R ９ are C(=O)OH, C(=O)(OC １－６ alkyl), C(=O)NR ９ａ R ９ｂ , (IX-1), (IX-2), (IX-3) and (IX-4): 【Chemistry 17】 selected from the group consisting of: R ９ａ is H or C １－６ is alkyl; R ９ｂ is H, C １－６ Alkyl, C(=O)(C １－６ Alkyl), S(O) ０－２ (C １－６ alkyl) or cyano; R ９ｃ , R ９ｄ , R ９ｅ , R ９ｆ and R ９ｇ is H; 1 to 6 independently selected halo and C １－６ C optionally substituted with alkoxy １－６ alkyl; and C(=O)(C １－６ alkyl) selected from the group consisting of: Ring C is 3- to 12-membered heterocyclyl; ３－１５ cycloalkyl; and 5- to 10-membered heteroaryl, each of which is selected from the group consisting of 1 to 3 R Ｃａ may be substituted with; Each R Ｃａ is independent, halo, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy and NR ｃ R ｄ or selected from the group consisting of; Or a pair of R on the same or different ring atoms 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 ｃ and R ｄ are independently H, C １－６ Alkyl, C(=O)(C １－６ alkyl), C(=O)(C ３－６ cycloalkyl), C(=O)O(C １－６ Alkyl), S(O) １－２ (C １－６ alkyl) and S(O) １－２ (C ３－６ cycloalkyl), wherein said C １－６ Alkyl, C(=O)(C １－６ alkyl), C(=O)(C ３－６ cycloalkyl), C(=O)O(C １－６ Alkyl), S(O) １－２ (C １－６ alkyl) and S(O) １－２ (C ３－６ cycloalkyl) are each selected from -OH, halo and C １－６ optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkoxy; R ｅ is H, C １－６ Alkyl or C １－６ haloalkyl; Each R ｆ are independently halo, —OH, NR ｃ R ｄ , C １－６ Alkoxy, C １－６ Haloalkoxy and —OH, C １－６ selected from the group consisting of 3- to 12-membered heterocyclyl optionally 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 independent, C １－６ Alkyl, C １－６ Alkoxy, NR ｃ R ｄ And C １－６ Alkyl and C(=O)C １－６ 3- to 12-membered heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; Each R ｈ are independently cyano, C １－６ Alkyl, C １－６ Haloalkyl, -OH, NH ２ , NH(C １－３ Alkyl), N(C １－３ Alkyl) ２ , C １－３ Alkoxy and C １－３ haloalkoxy] or a pharma- ceutically acceptable salt or solvate thereof.

5. Formula III: 【Chemistry 18】 [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 selected from the group consisting of R ＱＡ and R ＱＢ may be substituted with 1 to 6 substituents each independently selected from the group consisting of However, (aa) or (bb): (aa) Ring D is 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, with the endocyclic S(O) ２ Groups; or both, Each R ＱＡ are independently selected from the following (a) to (k): (a) halo; (b) cyano; (c) OH or oxo; (d)-NR ａ R ｂ ; (e)-C(=O)NR ｃ R ｄ ; (f) 1 to 6 independently selected R ｆ C optionally substituted with １－６ Alkyl; (g) 1 to 6 independently selected R ｆ C optionally substituted with １－６ Alkoxy; (h) 1 to 6 independently selected R ｇ 3- to 12-membered heterocyclyl optionally substituted by (i) 1 to 6 independently selected R ｇ C optionally substituted with ６－１０ Aryl; (j) 1 to 6 independently selected R ｇ 5-10 membered heteroaryl optionally substituted with (k) 1 to 6 independently selected R ｇ C optionally substituted with ３－８ Cycloalkyl; Each R ＱＢ are independently selected from the following (a) to (b): (a)-L ａ -S(O) ２ -L ｂ -R ｅ and (b) 4- to 12-membered heterocyclyl or 7- to 10-membered bicyclic heteroaryl, each of which is an endocyclic S(O) ２ group, wherein said heterocyclyl or heteroaryl is selected from 1 to 6 independently selected R ｇ Optionally substituted with; 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 and q2 are independently 0, 1, 2, 3 or 4; However, L ａ -(CR ｈ R ｈ ) ｑ１ -, and when q1 is 0, -L ｂ -R ｅ is unsubstituted C １－３ is other than alkyl; L ２ teeth, 【Chemistry 19】 (In the formula, aa represents 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 independently represents H and C １－６ alkyl) selected from the group consisting of: 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 selected from halo, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy and C ３－６ optionally substituted with 1 to 5 substituents each independently selected from the group consisting of cycloalkyl; R １ , R ２ and R ３ is H as well as halo, -OH and C １－６ C, optionally substituted with 1 to 6 substituents each independently selected from the group consisting of alkoxy １－６ each independently selected from the group consisting of alkyl; L １ is -C(=O)-, -CH ２ -, -CH(C １－６ Alkyl)- and -S(=O) ２ selected from the group consisting of: Ring B is 【Chemistry 20】 (In the formula, 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 is alkylene; L ４ is a bond or C １－５ is alkylene; R ８ａ and R ８ｂ are independently H and halo and C ３－１５ C, optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl １－６ alkyl; or R ８ａ and R ８ｂ Each independently selected 1 to 3 C's, together with the carbon atom to which it is attached, １－６ C optionally substituted with alkyl ３－１５ Form a cycloalkyl ring, wherein the C １－６ Alkyl is one to six independently selected R ｆ may be substituted with; R ９ are C(=O)OH, C(=O)(OC １－６ alkyl), C(=O)NR ９ａ R ９ｂ , (IX-1), (IX-2), (IX-3) and (IX-4): 【Chemistry 21】 selected from the group consisting of: R ９ａ is H or C １－６ is alkyl; R ９ｂ is H, C １－６ Alkyl, C(=O)(C １－６ Alkyl), S(O) ０－２ (C １－６ alkyl) or cyano; R ９ｃ , R ９ｄ , R ９ｅ , R ９ｆ and R ９ｇ is H; 1 to 6 independently selected halo and C １－６ C optionally substituted with alkoxy １－６ alkyl; and C(=O)(C １－６ alkyl) selected from the group consisting of: Ring C is 3- to 12-membered heterocyclyl; ３－１５ cycloalkyl; and 5- to 10-membered heteroaryl, each of which is selected from the group consisting of 1 to 3 R Ｃａ may be substituted with; Each R Ｃａ are independently halo, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy and NR ｃ R ｄ or selected from the group consisting of; Or a pair of R on the same or different ring atoms 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 are independently 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 said 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 selected from -OH, halo and C １－６ optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkoxy; Each R ｃ and R ｄ are independently 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 said 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 selected from -OH, halo and C １－６ optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkoxy; R ｅ is H 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 selected from the group consisting of 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 optionally substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy; Each R ｆ are independently halo, —OH, NR ｃ R ｄ , C １－６ Alkoxy, C １－６ Haloalkoxy and —OH, C １－６ selected from the group consisting of 3- to 12-membered heterocyclyl optionally 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 independently １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, NR ｃ R ｄ , Cyano, Halo, C ３－６ Cycloalkyl and C １－６ Alkyl and C(=O)C １－６ 3- to 12-membered heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R in each case ｈ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ is selected from the group consisting of cycloalkyl and halo; or A pair of R on the same or different carbon atoms ｈ C, together with the carbon atom bonded to it, ３－６ cycloalkyl or 4-8 membered heterocyclyl, each of which is selected from halo, cyano, C １－３ Alkyl, C １－３ Haloalkyl, -OH, C １－３ Alkoxy and C １－３ haloalkoxy; or a pharma- ceutically acceptable salt or solvate thereof.

6. Formula IV: 【Chemical 22】 [During the ceremony, 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 selected from halo, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy and C ３－６ optionally substituted with 1 to 5 substituents each independently selected from the group consisting of cycloalkyl; R １ , R ２ and R ３ is H as well as halo, -OH and C １－６ C, optionally substituted with 1 to 6 substituents each independently selected from the group consisting of alkoxy １－６ each independently selected from the group consisting of alkyl; L １ is -C(=O)-, -CH ２ -, -CH(C １－６ Alkyl)- and -S(=O) ２ selected from the group consisting of: Ring B is 【Chemistry 23】 (In the formula, 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 is alkylene; L ４ is a bond or C １－５ is alkylene; R ８ａ and R ８ｂ are independently H and halo and C ３－１５ C, optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl １－６ alkyl; or R ８ａ and R ８ｂ Each independently selected 1 to 3 C's, together with the carbon atom to which it is attached, １－６ C optionally substituted with alkyl ３－１５ Form a cycloalkyl ring, wherein the C １－６ Alkyl is one to six independently selected R ｆ may be substituted with; R ９ are C(=O)OH, C(=O)(OC １－６ alkyl), C(=O)NR ９ａ R ９ｂ , (IX-1), (IX-2), (IX-3) and (IX-4): 【Chemistry 24】 selected from the group consisting of: R ９ａ is H or C １－６ is alkyl; R ９ｂ is H, C １－６ Alkyl, C(=O)(C １－６ Alkyl), S(O) ０－２ (C １－６ alkyl) or cyano; R ９ｃ , R ９ｄ , R ９ｅ , R ９ｆ and R ９ｇ is H; 1 to 6 independently selected halo and C １－６ C optionally substituted with alkoxy １－６ alkyl; and C(=O)(C １－６ alkyl) selected from the group consisting of: Ring C is 3- to 12-membered heterocyclyl; ３－１０ cycloalkyl; and 5- to 10-membered heteroaryl, each of which is selected from the group consisting of 1 to 3 R Ｃａ may be substituted with; Each R Ｃａ is independent, halo, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy and NR ｃ R ｄ or selected from the group consisting of; Or a pair of R on the same or different ring atoms Ｃａ each taken together with the ring atom to which it is attached forms a carbocyclic ring containing 3 to 8 ring atoms; L ２ teeth, 【Chemistry 25】 (In the formula, aa represents the point of attachment to Q; 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 independently represents H and C １－６ alkyl) selected from the group consisting of: Q is C １－１０ Alkyl; 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 1 to 6 independently selected R Ｑ may be substituted with; Each R Ｑ are independently selected from the following (a) to (n): (a) halo; (b) cyano; (c) OH or oxo; (d)-NR ｃ R ｄ ; (e) -C(=O)NR ｃ R ｄ Or -S(O) ２ N.R. ｃ R ｄ ; (f)-S(=O) ０－２ R ｅ ; (g) 1 to 6 independently selected R ｆ C optionally substituted with １－６ Alkyl; (h) 1 to 6 independently selected R ｆ C optionally substituted with １－６ Alkoxy; (i) 1 to 6 independently selected R ｇ 3- to 12-membered heterocyclyl optionally substituted by (j) 1 to 6 independently selected R ｇ C optionally substituted with ６－１０ Aryl; (k) 1 to 6 independently selected R ｇ 5-10 membered heteroaryl optionally substituted with (l) 1 to 6 independently selected R ｇ C optionally substituted with ３－８ Cycloalkyl; (m) P(=O)R ａ R ｂ and (n) q1 is 1, 2 or 3 - (CR ｈ R ｈ ) ｑ１ -S(O) ２ -L ｅ -R ｅ ; selected from the group consisting of: R ａ and R ｂ is independent, C １－６ Alkoxy, C ３－６ C, optionally substituted with 1 to 6 substituents each independently selected from the group consisting of cycloalkyl and halo. １－６ Alkyl; C １－３ C, optionally substituted with 1 to 3 substituents each independently selected from the group consisting of alkyl and halo; ３－６ cycloalkyl; and 1 to 3 independently selected C １－３ C optionally substituted with alkyl ６－１０ aryl; Or, R ａ and R ｂ each together with the phosphorus atom to which it is attached forms a ring containing 5 to 8 ring atoms, where 0 to 2 ring atoms (R ａ and R ｂ In addition to the phosphorus atom bonded to １－６ may be substituted with alkyl; Each R ｃ and R ｄ are independently 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 said C １－６ Alkyl, C(=O)(C １－６ alkyl), C(=O)(C ３－６ cycloalkyl), C(=O)O(C １－６ Alkyl), S(O) １－２ (C １－６ alkyl) and S(O) １－２ (C ３－６ cycloalkyl) are each selected from -OH, halo and C １－６ optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkoxy; R ｅ is H 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 selected from the group consisting of 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 optionally substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy; L ｅ is the bond NR ｃ or O; Each R ｆ are independently halo, —OH, NR ｃ R ｄ , C １－６ Alkoxy, C １－６ Haloalkoxy and —OH, C １－６ selected from the group consisting of 3- to 12-membered heterocyclyl optionally 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 independent, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, NR ｃ R ｄ , Cyano, Halo, C ３－６ Cycloalkyl and C １－６ Alkyl and C(=O)C １－６ 3- to 12-membered heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of alkyl; R in each case ｈ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ is selected from the group consisting of cycloalkyl and halo; or A pair of R on the same or different carbon atoms ｈ C, together with the carbon atom bonded to it, ３－６ cycloalkyl or 4-8 membered heterocyclyl, each of which is selected from halo, cyano, C １－３ Alkyl, C １－３ Haloalkyl, -OH, C １－３ Alkoxy and C １－３ haloalkoxy; or a pharma- ceutically acceptable salt, deuterated analog or solvate thereof.

7. Ring A is halo, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy and C ３－６ C, optionally substituted with 1 to 5 substituents each independently selected from the group consisting of cycloalkyl ６－１０ The compound according to any one of claims 1 to 6, which is aryl.

8. The compound according to any one of claims 1 to 7, wherein Ring A is phenyl optionally substituted with 1 to 3 substituents each independently selected from the group consisting of fluoro, methyl and cyclopropyl.

9. R １ and R ２ The compound according to any one of claims 1 to 8, wherein is H.

10. R ３ C １－６ The compound according to any one of claims 1 to 9, which is alkyl.

11. R ３ The compound according to any one of claims 1 to 10, wherein is methyl.

12. L １ The compound according to any one of claims 1 to 11, wherein is -C(=O)-.

13. Ring B is: 【Chemistry 26】 The compound according to any one of claims 1 to 12,

14. Ring B is: 【Chemistry 27】 The compound according to any one of claims 1 to 12,

15. Ring B is: 【Chemistry 28】 The compound according to any one of claims 1 to 12,

16. Ring B is: 【Chemical 29】 The compound according to any one of claims 1 to 12,

17. R ４ , R ５ , R ６ and R ７ The compound according to any one of claims 1 to 16, wherein is H.

18. L ３ The compound of any one of claims 1 to 17, wherein is a bond.

19. R ８ａ and R ８ｂ Each of these, together with the carbon atom to which it is bonded, is C ３－１５ A compound according to any one of claims 1 to 18 which forms a cycloalkyl.

20. R ８ａ and R ８ｂ The compound according to any one of claims 1 to 19, wherein:

21. R ９ but 【Chemistry 30】 The compound according to any one of claims 1 to 20,

22. R ９ｄ The compound according to any one of claims 1 to 21, wherein is H.

23. The compound of any one of claims 1 to 22, wherein Ring C is a 3- to 12-membered heterocyclyl.

24. The compound according to any one of claims 1 to 23, wherein Ring C is tetrahydropyranyl.

25. L ２ but 【Chemistry 31】 wherein aa represents the point of attachment to Q. The compound according to any one of claims 1 to 24,

26. L ２Ａ The compound of any one of claims 1 to 25, wherein is a bond.

27. Formula IIE: 【Chemistry 32】 [During the ceremony, Ring B is 【Chemical 33】 (In the formula, bb is the attachment point to -C(O)- and xx is X ｂ is a point of attachment to R ４ , R ５ , R ６ and R ７ are independently H, halo and C １－６ alkyl) selected from the group consisting of: R ＡＡ , R ＡＢ and R ＡＣ are each independently hydrogen, halo, C １－３ Alkyl or C ３－６ is cycloalkyl; R ３ is H or C １－３ is alkyl; R ＱＣ is H or halo; R ＱＤ is (a)H; (b)-NH ２ (c) -NH(C １－３ (c) alkyl; (d) halo; (e) C optionally substituted with 1 to 3 independently selected halo. １－３ alkoxy; and (f) C optionally substituted with 1 to 3 independently selected halo. １－３ selected from the group consisting of alkyl; R ａ and R ｂ is C １－４ Alkyl and C ３－６ cycloalkyl; or R ａ and R ｂ each together with the phosphorus atom to which it is attached forms a ring containing 5 to 8 ring atoms, and 0 to 1 ring atom (R ａ and R ｂ (in addition to the phosphorus atom bonded to) is a heteroatom independently selected from the group consisting of O, S and N; R ８ｃ is H or C １－３ is alkyl; X Ｂ is CH or N; Each R Ｃｂ are independently H and C １－３ alkyl] or a pharma- ceutically acceptable salt, deuterated analog or solvate thereof.

28. A compound set forth in Table 1 or a pharma- ceutically acceptable salt, deuterated analog or solvate thereof.

29. 29. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28, or a pharma- ceutically acceptable salt, deuterated analogue or solvate thereof, and a pharma- ceutically acceptable excipient.

30. 30. A method of treating a GLP-1 related disease, disorder, or condition, comprising administering to a patient in need of treatment an effective amount of a compound of any one of claims 1 to 28, or a pharma- ceutically acceptable salt, deuterated analog, or solvate thereof, or a pharmaceutical composition of claim 29.

31. The disease, disorder or illness is type 1 diabetes, type 2 diabetes, juvenile-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of adults (LADA), obesity (including hypothalamic obesity and monogenic obesity), weight gain due to the use of other medications, idiopathic intracranial hypertension, Wolfram syndrome, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia diabetes, 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, interstitial pneumonia, pulmonary hypertension ... Intermittent claudication, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorder, insulin resistance, hepatic insulin resistance, alcohol intake disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerular sclerosis, arthritis, osteoporosis, treatment of addiction, cocaine dependence, bipolar disorder / major 31. The method of claim 30, wherein the disease is selected from depressive disorders, skin and connective tissue disorders, foot ulcers, psoriasis, psychogenic polydipsia, nonalcoholic steatohepatitis (NASH), nonalcoholic 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 disorders, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof.

32. 30. A method of treating type 2 diabetes in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 28 or a pharma- ceutically acceptable salt, deuterated analogue or solvate thereof, or a pharmaceutical composition according to claim 29.

33. 30. A method of regulating insulin levels in a patient in need of treatment, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 28 or a pharma- ceutically acceptable salt, deuterated analogue or solvate thereof, or a pharmaceutical composition according to claim 29.

34. 30. A method of regulating glucose levels in a patient in need of treatment, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 28 or a pharma- ceutically acceptable salt, deuterated analogue or solvate thereof, or a pharmaceutical composition according to claim 29.

35. The method of any one of claims 30 to 34, further comprising administering to the patient an additional treatment or therapeutic agent.

36. 36. The method of claim 35, wherein the additional treatment or therapeutic agent is selected from the group consisting of a non-alcoholic steatohepatitis (NASH) medication, gastric electrical stimulation, dietary monitoring, physical activity, or any combination thereof.

Images