Heterocyclic GLP-1 agonists

Abstract

The present disclosure relates generally to GLP-1 agonists and pharmaceutical compositions comprising GLP-1 agonists for treating GLP-1 associated diseases, disorders or conditions.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to International Application No. PCT / CN2022 / 075604, filed February 9, 2022, which is incorporated herein by reference in its entirety.

[0002] 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. Medications targeting this family of intestinal peptides, such as GLP-1 agonists, have been shown to suppress glucagon production, decrease gastric motility, and increase satiety.

[0004] Diabetes mellitus (DDM) 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 over 90% of diabetes cases. It typically develops in obese or sedentary adults and begins with insulin resistance. While lifestyle modifications are helpful in managing the disease, T2DM patients may require antidiabetic medications, such as dipeptidyl peptidase-4 inhibitors, SGLT2 inhibitors, and sulfonylureas.

[0005] In healthy individuals, the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) simultaneously regulate the insulin secretory response to glucose ingestion. In T2DM, this incretin action is significantly reduced (if present at all), but GLP-1 maintains its insulinotropic action even when the endocrine pancreatic response to GIP is effectively shut down. Therefore, incretin mimetics and other GLP-1-based therapeutics are useful for stimulating insulin production in patients with T2DM. Summary of the Invention

[0006] (summary) The present 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] In one embodiment, a compound of formula I: [ka] [In the formula, X 1 , X 2 and X 5 are independently C or N; X 3 and X 4 is N, NR x , C.R. y independently selected from the group consisting of C(O), O, and S; X 6 is a bond, N, NR x , C.R. y and C(O); [ka] is a single or double bond, provided that X 1 From X 6 at least one of X is independently selected from a heteroatom or a heteroatom group; 1 From X6 At least one of the is C or CR y and X 1 From X 6 The ring containing is aromatic; Each R x are independently selected from the group consisting of hydrogen, (C-C)alkyl, (C-C)haloalkyl, (C-C)cycloalkyl, C(O)(C-C)alkyl, S(O)(C-C)alkyl, and C(O)O(C-C)alkyl; Each R y is independently selected from the group consisting of hydrogen, —OH, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, CN, and halogen; L 0 is a join or #-P 0 -P 1 And, # is X 5 represents the attachment point to; -P 0 is a bond, -NH-, -N(C1-C6 alkyl)-, -O- or S(O) 0-2 and; -P 1 is selected from the group consisting of (C1-C6) alkylene, (C2-C6) alkenylene, (C2-C6) alkynylene, (C3-C8) cycloalkylene, and 4- to 8-membered heterocycloalkylene, each of which optionally contains 1 to 3 R 0 may be substituted with; Each R 0 is independently selected from the group consisting of halogen, CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, and (C1-C6)haloalkoxy; T 1 is C(O)OH or a carboxylic acid bioisostere; or Group-L 0 -T 1 is: -C(O)NH-(C1-C6)alkyl or -C(O)NH-(C3-C6)cycloalkyl; each of the foregoing is selected from 1 to 4 R T optionally substituted with; or a 5- to 6-membered heteroaryl optionally substituted with —C(O)OH, —C(O)O(C1-C6)alkyl, —C(O)NH(C1-C6)alkyl, —C(O)NH—(C3-C6)cycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 6-membered heteroaryl; wherein each of —C(O)O(C1-C6)alkyl, —C(O)NH(C1-C6)alkyl, —C(O)NH—(C3-C6)cycloalkyl, a 3- to 6-membered heterocycloalkyl, and a 6-membered heteroaryl is selected from the group consisting of 1 to 4 R T optionally substituted with; T 2 is: hydrogen, CN, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl or (C1-C6)alkyl; said (C1-C6)alkyl is optionally substituted with (C1-C6)alkoxy, (C1-C6)thioalkoxy, (C1-C6)haloalkoxy, S(O)2(C1-C6 alkyl), —N(C1-C6 alkyl)—S(O)2(C1-C6 alkyl), —NH—S(O)2(C1-C6 alkyl), (C3-C6)cycloalkyl, (C3-C6)cycloalkoxy, 3- to 6-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl, and each of said (C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl is optionally substituted with 1 to 4 R T optionally substituted with; or -NH(C1-C6)alkyl, -NH-(C3-C6)cycloalkyl, -CH2-S(O)2-(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl or 3- to 10-membered heterocycloalkyl; wherein each of -NH(C1-C6)alkyl, -NH-(C3-C6)cycloalkyl, -CH2-S(O)2-(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl or 3- to 10-membered heterocycloalkyl is selected from the group consisting of 1 to 4 R T optionally substituted with; However, the compound is not: [ka] Each R T is independently selected from the group consisting of OH, SH, CN, NO, halogen, ═O, (C-C)alkyl, (C-C)alkenyl, (C-C)alkynyl, (C-C)haloalkyl, (C-C)cyanoalkyl, (C-C)hydroxyalkyl, (C-C)alkoxy, (C-C)haloalkoxy, (C-C)cycloalkyl, amino, (C-C)alkylamino, (C-C)alkylamino(C-Calkyl)-C(O)—C-Calkyl, S(O)(C-Calkyl), and di(C-C)alkylamino; L 1 is a bond or 1 to 3 R L is an optionally substituted (C1-C3) alkylene; L 2 is a bond, -O-, -S(O) 0-2 - or -NH-; Each R L are independently selected from the group consisting of halogen, (C-C) alkyl, and (C-C) haloalkyl; or a pair of R on the same or adjacent carbon atoms L together with the carbon atoms to which they are attached form a (C3-C6)cycloalkyl ring; Ring A is as follows: [ka] (wherein n1 is 0, 1 or 2; W 1 is CR Y1 or N;W 2 is CR Y2 or N); [ka] (In the formula, W 3 is C, CR Y3 or N;L w is (C1-C3) alkylene; [ka] are independently a single bond or a double bond (if valence permits); 1 to 4 R Y phenylene optionally substituted by 1 to 3 R Y an optionally substituted 5- or 6-membered heteroarylene; 1 to 4 R Y (C5-C8)cycloalkylene optionally substituted with 1 to 4 R Y a partially unsaturated monocyclic (C5-C8)cycloalkylene optionally substituted with 1 to 4 R Y and optionally substituted, partially unsaturated monocyclic 5- to 8-membered heterocycloalkylenes, where mm is L 2 represents the point of attachment to ring B; Each R Y is independently selected from the group consisting of halogen, CN, —OH, oxo, (C-C)alkyl, (C-C)haloalkyl, (C-C)alkoxy, and (C-C)haloalkoxy; R Y1 , R Y2 and R Y3are each independently selected from the group consisting of hydrogen, halogen, CN, —OH, (C1-C6) alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy, and (C1-C3) haloalkoxy; or W 1 is CR Y1 and W 2 is CR Y2 If so, R Y1 and R Y2 groups together can form a (C1-C4) alkylene, one of the CH2 units of said (C1-C4) alkylene being selected from O, S, NH and N(C 1-3 ) alkyl, optionally substituted with a heteroatom selected from the group consisting of; Ring B is selected from the group consisting of (BI), (B-II), (B-III), (B-IV), (BV), (B-VI) and (B-VII): [ka] During the ceremony, aa represents the point of attachment to ring A; B 1 , B 2 , B 3 and B 4 Each of the 1 and N; B 5 and B 6 Each of these is N, NR 1 , C, C.R. 1 , O and S, with the proviso that B 5 and B 6 A ring containing is heteroaryl; [ka] In the formula, aa represents the point of attachment to ring A; B 7 and B 8 -O-, -NR N - and -C(R 1 )2- independently selected from the group consisting of; B9 is N or CR aa and; nb is 0 or 1; B 10 , B 11 and B 12 is CR 1 and N; B 13 , B 14 and B 15 are each independently CR 1 and; Each R 1 is hydrogen, halogen, CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C3) alkyl (C3-C6) cycloalkyl, (C1-C3) alkyl (3-5 membered heterocycloalkyl), and -C(O)NR 2 R 3 independently selected from the group consisting of: Each R 2 and R 3 is independently selected from the group consisting of H and (C1-C6)alkyl; Each R N are independently selected from the group consisting of hydrogen, (C-C)alkyl, (C-C)haloalkyl, C(O)(C-C)alkyl, S(O)(C-C)alkyl, and C(O)O(C-C)alkyl; R aa , R ab and R ac are independently selected from the group consisting of H, (C1-C6) alkyl, and (C1-C6) haloalkyl; L 3 is a bond or -Z 1 -Z 2 -* where * represents the point of attachment to Ring C; -Z 1 is a bond, NH, N(C1-C6 alkyl), O or S(O) 0-2 and; -Z 2 is 1 to 2 R c C optionally substituted with 1-3 is alkylene; Each R c is independently selected from the group consisting of halogen, (C1-C6) alkyl, and (C1-C3) haloalkyl; Ring C is phenyl, 5-6 membered heteroaryl, (C3-C6)cycloalkyl, (C5-C 10 ) selected from the group consisting of bicycloalkyl, 5- to 10-membered bicycloheteroaryl, and 3- to 6-membered heterocycloalkyl; Each R b is independently selected from the group consisting of (C-C)alkyl, (C-C)haloalkyl, (C-C)alkoxy, (C-C)haloalkoxy, halogen, (C-C)cycloalkyl, CN, —C(O)NH, or —C(O)OH; and b is an integer selected from 0 to 3; However, there is at least one of the following: 1) At least one R b is —C(O)NH or —C(O)OH; 2) Ring A contains 1 to 4 R Y is an optionally substituted (C5-C8)cycloalkylene; 3) Ring B is [ka] and; 4) Group-L 0 -T 1 is: -C(O)NH-(C1-C6)alkyl or -C(O)NH-(C3-C6)cycloalkyl; each of the foregoing is selected from 1 to 4 R T optionally substituted with; or a 5- to 6-membered heteroaryl optionally substituted with —C(O)OH, —C(O)O(C1-C6)alkyl, —C(O)NH(C1-C6)alkyl, —C(O)NH—(C3-C6)cycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 6-membered heteroaryl; wherein each of —C(O)O(C1-C6)alkyl, —C(O)NH(C1-C6)alkyl, —C(O)NH—(C3-C6)cycloalkyl, a 3- to 6-membered heterocycloalkyl, and a 6-membered heteroaryl is selected from the group consisting of 1 to 4 R T optionally substituted with 5) T 2 is —NH(C1-C6)alkyl, —NH—(C3-C6)cycloalkyl, —CH2—S(O)2—(C3-C6)cycloalkyl, —O—(C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, or 3- to 10-membered heterocycloalkyl; wherein each of —NH(C1-C6)alkyl, —NH—(C3-C6)cycloalkyl, —CH2—S(O)2—(C3-C6)cycloalkyl, —O—(C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, or 3- to 10-membered heterocycloalkyl is selected from the group consisting of 1 to 4 R T and optionally substituted with or a pharmaceutically acceptable salt or solvate thereof.

[0008] The present disclosure also provides pharmaceutical compositions comprising one or more compounds disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0009] Also provided herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0010] Also provided herein is a method for treating type 2 diabetes in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0011] Also provided herein is a method for treating type 2 diabetes in a patient, comprising administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, to a patient identified or diagnosed as having type 2 diabetes.

[0012] Also provided herein is a method for treating diabetes in a patient, the method comprising: determining that the patient has type 2 diabetes; and administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In some embodiments, determining that the patient has type 2 diabetes comprises performing an assay to determine the level of an analyte in a sample from the patient, wherein the analyte is selected from the group consisting of hemoglobin A1c (HbA1c), fasting plasma glucose, postprandial plasma glucose, or any combination thereof. In some embodiments, the level of HbA1c is greater than or about 6.5%. In some embodiments, the level of fasting glucose is greater than or about 126 mg / dL. In some embodiments, the level of postprandial plasma glucose is greater than or about 200 mg / dL.

[0013] In some embodiments, the method further comprises obtaining a sample from the patient. In some embodiments, the sample is a body fluid sample. In some embodiments, the patient is about 40 to about 70 years old and is overweight or obese. In some embodiments, the patient has a body mass index (BMI) of 22 kg / m or less. 2or more or approximately 22 kg / m 2 In one embodiment, the patient has a BMI of 30 kg / m 2 More than or about 30 kg / m 2 It has.

[0014] In certain embodiments, the method of treating type 2 diabetes comprises reducing fasting plasma glucose levels. In certain embodiments, fasting plasma glucose levels are reduced to about 100 mg / dL or below 100 mg / dL.

[0015] In certain embodiments, the method of treating type 2 diabetes comprises reducing HbA1c levels, hi certain embodiments, the HbA1c level is reduced to about 5.7% or below 5.7%.

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

[0017] In certain embodiments, the method of treating type 2 diabetes involves increasing insulin levels.

[0018] In certain embodiments, the method of treating type 2 diabetes includes lowering BMI. In certain embodiments, BMI is about 25 kg / m 2 or 25 kg / m 2 It decreases to the following:

[0019] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or pharmaceutical composition thereof, is administered orally.

[0020] In some embodiments, the method for treating type 2 diabetes further comprises administering to the patient another therapy or therapeutic agent. In some embodiments, the other therapy or therapeutic agent is selected from the group consisting of an antidiabetic agent, an antiobesity agent, a GLP-1 receptor agonist, a nonalcoholic steatohepatitis (NASH) therapeutic agent, an antiemetic agent, gastric electrical stimulation, dietary monitoring, physical activity, or any combination thereof. In some embodiments, the antidiabetic agent is selected from the group consisting of a biguanide, a sulfonylurea, a glitazar, a thiazolidinedione, a dipeptidyl peptidase 4 (DPP-4) inhibitor, a meglitinide, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, a glitazone, a GRP40 agonist, a glucose-dependent insulinotropic polypeptide (GIP), insulin or an insulin analog, an alpha-glucosidase inhibitor, a sodium-glucose cotransporter 1 (SGLT1) inhibitor, or any combination thereof. In some embodiments, the biguanide is metformin. In certain embodiments, the anti-obesity agent is selected from the group consisting of a neuropeptide Y receptor type 2 (NPYR2) agonist, an NPYR1 or NPYR5 antagonist, a human islet peptide precursor (HIP), a cannabinoid receptor type 1 (CB1R) antagonist, a lipase inhibitor, a melanocortin receptor 4 agonist, a farnesoid X receptor (FXR) agonist, phentermine, zonisamide, a norepinephrine / dopamine reuptake inhibitor, a GDF-15 analog, an opioid receptor antagonist, a cholecystokinin agonist, a serotonergic agent, a methionine aminopeptidase 2 (MetAP2) inhibitor, diethylpropion, phendimetrazine, benzphetamine, a fibroblast growth factor receptor (FGFR) modulator, an AMP-activated protein kinase (AMPK) activator, or any combination thereof. In 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 homolog 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, or any combination thereof. In some embodiments, the compound disclosed herein, or its pharmaceutically acceptable salt or solvate, or its pharmaceutical composition, and another therapeutic agent are administered sequentially in any order as separate formulations.

[0021] 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 disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In some embodiments, the modulation results in increased insulin levels.

[0022] 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 disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In some embodiments, the modulation results in a decrease in glucose levels.

[0023] Also provided herein is a method for treating a GLP-1-related disease, disorder, or condition, comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, to a patient in need 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), early-onset atypical diabetes (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of adults (LADA), obesity, weight gain due to the use of other medications, gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, and lipid disorders. Adipocyte dysfunction, sleep apnea syndrome, 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 In some embodiments, the inflammatory bowel disease (IGD) is selected from the group consisting of: diabetes, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, treatment of addiction, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, psychogenic polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof.In certain embodiments, the disease, disorder, or condition is selected from the group consisting of type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat accumulation, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, and the like. In some embodiments, the present invention relates to a condition characterized by a metabolic disorder, a metabolic disorder, anemia, a metabolic disorder, a metabolic disorder characterized by ... In certain embodiments, the disease, disorder, or condition includes, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat accumulation, myocardial infarction, peripheral arterial disease, stroke, transient ischemic attack, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, chronic renal failure, Syndrome X, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, skin and connective tissue disorders, foot ulcers, or any combination thereof.

[0024] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent that the publications, patents, and patent applications incorporated by reference conflict with the disclosure contained herein, the present specification shall take precedence and / or supersede any such conflicting documents. Detailed Description of the Invention

[0025] Before the present compounds and methods are described, it is to be understood that this disclosure is not limited to the methodology, protocols, cell lines, assays, and reagents described, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing embodiments of the present disclosure, and is not intended to limit the scope of the disclosure, which is set forth in the appended claims.

[0026] (definition) It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise.

[0027] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, exemplary methods, devices, and materials are described herein. All publications cited herein are for the purpose of describing and disclosing the methodologies, reagents, and tools reported in the publications that can be used in connection with this disclosure, and are incorporated herein by reference in their entirety.

[0028] Provided herein are heterocyclic GLP-1 agonists for use in the management of T2DM and other conditions where activation of GLP-1 activity is beneficial.

[0029] Where numerical values ​​are stated as ranges, the disclosure will be understood to include disclosure of not only the specific numerical values ​​falling within such ranges, but also all possible subranges within such ranges, whether or not a specific numerical value or specific subrange is explicitly stated.

[0030] 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").

[0031] As used herein, the term "alkyl" means a saturated linear or branched monovalent hydrocarbon radical containing the specified number of carbon atoms. For example, "C 1-6 "Alkyl" refers to a saturated straight or branched chain monovalent hydrocarbon 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.

[0032] As used herein, the term "alkylene" refers to a divalent alkyl containing the specified number of carbon atoms. For example, "(C 1-3 )alkylene" refers to a divalent alkyl having 1 to 3 carbon atoms (e.g., -CH2-, -CH(CH3)-, -CH2CH2-, or -CH2CH2CH2-). Similarly, the terms "cycloalkylene," "heterocyclylene," "arylene," and "heteroarylene" refer to divalent cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, respectively.

[0033] As used herein, the term "alkenyl" refers to a straight or branched monovalent unsaturated hydrocarbon chain containing the specified number of carbon atoms. For example, "(C 2-6")Alkenyl" means a straight or branched monovalent unsaturated hydrocarbon chain of 2 to 6 carbon atoms. Non-limiting examples of alkenyl include ethenyl, propenyl, butenyl, or pentenyl.

[0034] As used herein, the term "alkynyl" refers to a straight or branched divalent unsaturated hydrocarbon chain containing the specified number of carbon atoms. For example, "(C 2-6 ")Alkynyl" means a straight or branched divalent unsaturated hydrocarbon chain containing 2 to 6 carbon atoms. Non-limiting examples of alkynyl include ethynyl, propynyl, butynyl, or pentynyl.

[0035] As used herein, the term "cycloalkyl" means a saturated or partially unsaturated cyclic hydrocarbon containing the specified number of carbon atoms. For example, "(C 3-6") Cycloalkyl" means a saturated or partially unsaturated cyclic hydrocarbon having 3 to 6 ring carbon atoms. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyls may also be partially unsaturated. Non-limiting examples of partially unsaturated cycloalkyls include cyclohexenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl, and the like. Cycloalkyls 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, etc. 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.

[0036] As used herein, the terms "heterocyclyl" and "heterocycloalkyl" refer to a monocyclic, bicyclic, tricyclic, or polycyclic non-aromatic ring group containing the specified 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 monocyclic ring), 1 to 6 heteroatoms (in the case of a bicyclic ring), or 1 to 9 heteroatoms (in the case of a tricyclic or polycyclic ring), wherein the heteroatoms are O, N, S, or S(O). 1-2 (e.g., in the case of monocyclic, bicyclic, or tricyclic rings, each of which contains carbon atoms and 1 to 3, 1 to 6, or 1 to 9 heteroatoms N, O, S, or S(O) 1-2), and 0, 1, 2, or 3 atoms of each ring may be substituted by substituents. Examples of heterocycloalkyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Heterocycloalkyl groups may also be partially unsaturated. Non-limiting examples of partially unsaturated heterocycloalkyls include dihydropyrrolyl, dihydropyridinyl, tetrahydropyridinyl, dihydrofuranyl, dihydropyranyl, and the like. Heterocycloalkyls may include multiple fused and bridged rings. Non-limiting examples of fused / bridged heterocycloalkyls include 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[4.1.0]heptane ...4.1.0]heptane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[4.1.0]heptane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[4.1.0]octane, 5-azabicyclo[2.1.1]hexane, 5-azabicyclo[2.1.1]hexane, 5-azabicyclo[3 Examples include azabicyclo[3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, etc. Heterocycloalkyl also includes spirocycles (e.g., spirocyclic bicycles in which the two rings are joined by only one atom).Non-limiting examples of spirocyclic heterocycloalkyls 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[2.6]nonane, 1,7-dia ... .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.

[0037] As used herein, the term "aryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic hydrocarbon group containing the specified 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.

[0038] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group having a specified number of ring atoms (e.g., 5 to 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 heteroaryls include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and thiazolyl. Benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl Examples include pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chroman, 2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]oxathiin, and isoindoline.

[0039] As used herein, the term "haloalkyl" refers to an alkyl group, as defined herein, in which one or more hydrogen atoms (e.g., 1 to 5 or 1 to 3) are replaced with one or more halogen atoms (e.g., 1 to 5 or 1 to 3). Non-limiting examples include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, chloromethyl, dichloromethyl, chloroethyl, trichloroethyl, bromomethyl, and iodomethyl.

[0040] As used herein, the term "alkoxy" refers to an -O-alkyl group, which means that 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, wherein the group is attached to an 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, wherein the group is attached to an oxygen atom.

[0041] As used herein, the term “amino” refers to a group of the formula —N(R N1 ) 2 amines, and each R N1 is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which can be optionally substituted, for example, by one or more (e.g., 1 to 5 or 1 to 3) substituents (e.g., independently selected from halo, cyano, hydroxy, —NH, —NH(alkyl), —N(alkyl), alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, or haloalkoxy).

[0042] As used herein, the term "compound" includes all stereoisomers, geometric isomers, tautomers, and isotopes of a given structure. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0043] As used herein, when a ring is described as "aromatic," it means that the ring has a contiguous, delocalized π-electron system. Typically, the number of out-of-plane π-electrons corresponds to Hückel's rule (4n+2). Examples of such rings include benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thiazole, isoxazole, isothiazole, and the like. When a ring system containing at least two rings is described as "aromatic," it means that the ring system contains one or more aromatic rings. Therefore, when a ring system containing at least two rings is described as "non-aromatic," it means that none of the constituent rings of the ring system are aromatic.

[0044] As used herein, when a ring is described as "partially unsaturated," it is meant that the ring has one or more additional degrees of unsaturation (e.g., one or more double bonds between constituent ring atoms in addition to the degree of unsaturation due to the ring itself), provided that the ring is not aromatic. Examples of such rings include cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like. When a ring system containing at least two rings is described as "partially unsaturated," it is meant that the ring system contains one or more partially unsaturated rings, provided that none of the constituent rings of the ring system are aromatic.

[0045] As used herein, the term "carboxylic acid bioisostere" refers to a group having chemical and physical similarities that broadly confers similar biological properties to carboxylic acids (see Lipinski, Annual Reports in Medicinal Chemistry, 1986, 21, p. 283 "Bioisosterism in Drug Design"; Yun, Hwahak Sekye, 1993, 33, pages 576-579 "Application of Bioisosterism to New Drug Design"; Zhao, Huaxue Tongbao, 1995, pages 34-38, 25 "Bioisosteric Replacement and Development of Lead Compounds in Drug Design"; Graham, Theochem, 1995, 343, pages 105-109 "Theoretical Studies Applied to Drug Design: ab initio Electronic Distributions in Bioisosteres"). Examples of suitable carboxylic acid bioisosteres include sulfo, phosphono, alkylsulfonylcarbamoyl, tetrazolyl, arylsulfonylcarbamoyl, heteroarylsulfonylcarbamoyl, N-methoxycarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl, or heterocyclic phenols such as 3-hydroxyisoxazolyl and 3-hydroxy-1-methylpyrazolyl.

[0046] As used herein, the term "tautomer" means a compound whose structure differs significantly in the arrangement of atoms, but which readily and rapidly exists in equilibrium; the compounds provided herein may be represented as different tautomers; it is understood that when a compound has tautomeric forms, all tautomeric forms are intended to be within the scope of the present invention, and the name of the compound does not exclude tautomers.

[0047] 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.

[0048] As used herein, the term "GLP-1-related disease" is intended to include, but is not limited to, any disease, disorder, or condition in which modulation of glucagon-like peptide 1 (GLP-1) receptor signaling can alter the pathology and / or symptoms and / or progression of the disease, disorder, or condition.

[0049] As used herein, the term "GLP-1 agonist" or "GLP-1RA" refers to an agonist of the glucagon-like peptide 1 (GLP-1) receptor. GLP-1RA enhances glucose-dependent insulin secretion; suppresses inappropriately elevated glucagon levels in both fasting and postprandial states; and delays gastric emptying (Karla et al., Glucagon-like peptide-1 receptor agonists in the treatment of type 2 diabetes: Past, present and future, Indian J Endocrinol Metab. 2016 Mar-Apr;20(2):254-267. GLP-1RAs have been shown to treat type 2 diabetes). Examples of GLP-1 RAs include, but are not limited to, albiglutide (TANZEUM®), dulaglutide (LY2189265, TRULICITY®), efpeglenatide, exenatide (BYETTA®, BYDUREON®, exendin-4), liraglutide (VICTOZA®, NN2211), lixisenatide (LYXUMIA®), 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.

[0050] As used herein, the term "pharmaceutically acceptable" indicates that a compound or a salt thereof or composition thereof is chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the patient being treated.

[0051] 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 harmful. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and organic acids. Furthermore, when 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 prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional methods for preparing acid addition salts from base compounds. Those skilled in the art will recognize various 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-toluenesulfonic 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, sodium salts, potassium salts, lithium salts, aluminum salts, ammonium salts, calcium salts, magnesium salts, and the like. Salts derived from organic bases include salts of NH3, or primary, secondary, and tertiary amines, e.g., N-containing heterocycles, N-containing heteroaryls, or salts of the formula N(R N ) 3, salts obtained from amines (e.g., HN + (RN)3 or (alkyl)N + (RN)3), where each R Nis independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each optionally substituted with one or more (e.g., 1 or 5, or 1 or 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.

[0052] It is understood that the substituents defined herein are not intended to include impermissible substitution patterns (e.g., methyl substituted with five fluoro groups, or a hydroxy group attached to an ethenyl or acetylene carbon atom). Such impermissible substitution patterns are well known to those of ordinary skill in the art. Similarly, the term "substituted" refers to one or more (e.g., 1-5) chemical groups as disclosed herein (as defined above), which may subsequently be further substituted.

[0053] 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.

[0054] 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 disclosed herein or a pharmaceutically acceptable salt or solvate thereof) to relieve to some extent one or more symptoms of the disease or condition being treated, and may include curing the disease. "Cure" means that the symptoms of active disease are eliminated. 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 can be determined using any suitable technique, such as a dose escalation study. In certain embodiments, a "therapeutically effective amount" of a compound provided herein refers to an amount of the compound that is effective as a monotherapy or combination therapy.

[0055] The term "excipient" or "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In certain embodiments, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and suitable for use in contact with the tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21 sted.;Lippincott Williams & Wilkins:Philadelphia, PA, 2005;Handbook of Pharmaceutical Excipients, 6th ed.;Rowe et al., Eds.;The Pharmaceutical Press and the American Pharmaceutical Association:2009;Handbook of Pharmaceutical Additives, 3rd ed.;Ash and Ash Eds.;Gower Publishing Company:2007;Pharmaceutical Preformulation and Formulation, 2nd ed.;Gibson Ed.;CRC Press LLC: Boca Raton, FL, 2009.

[0056] The term "pharmaceutical composition" refers to a mixture of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, with other chemical components (collectively referred to herein as "excipients"), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or fillers. A pharmaceutical composition facilitates administration of a compound to an organism. Many techniques exist for administering a compound, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0057] The terms "treat," "treating," and "treatment," in the context of treating a disease, disorder, or condition, include alleviating or arresting the disorder, disease, or condition or one or more symptoms associated with the disorder, disease, or condition; or mean slowing the progression, spread, or worsening of the disease, disorder, or condition or one or more symptoms thereof.

[0058] 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 described herein or its symptoms.

[0059] 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.

[0060] The terms "therapeutic regimen" and "dosing regimen" are used interchangeably to refer to the dosage and timing of administration of each therapeutic agent in the combination of the present invention.

[0061] As used herein, the term "pharmaceutical combination" means a pharmaceutical treatment in which more than one active ingredient is mixed or combined, and includes both defined and open-ended combinations of active ingredients.

[0062] As used herein, the term "combination therapy" means a dosing regimen of two different therapeutically active agents (i.e., components of a combination or combination partners), which therapeutically active agents, as defined herein, are administered together or separately in a manner desired by a medical practitioner or in accordance with a regulatory agency.

[0063] As used herein, the term "modulation" means regulation or modulation (e.g., increase or decrease) and can include, for example, agonism, partial agonism, or antagonism.

[0064] (compound) Provided herein are compounds of formula I: [ka] [In the formula, X 1 , X2 and X 5 are independently C or N; X 3 and X 4 is N, NR x , C.R. y independently selected from the group consisting of C(O), O, and S; X 6 is a bond, N, NR x , C.R. y and C(O); [ka] is a single or double bond, provided that X 1 From X 6 at least one of X is independently selected from a heteroatom or a heteroatom group; 1 From X 6 At least one of the is C or CR y and X 1 From X 6 The ring containing is aromatic; Each R x are independently selected from the group consisting of hydrogen, (C-C)alkyl, (C-C)haloalkyl, (C-C)cycloalkyl, C(O)(C-C)alkyl, S(O)(C-C)alkyl, and C(O)O(C-C)alkyl; Each R y is independently selected from the group consisting of hydrogen, —OH, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, CN, and halogen; L 0 is a join or #-P 0 -P 1 And, # is X 5 represents the point of attachment to; -P 0 is a bond, -NH-, -N(C1-C6 alkyl)-, -O- or S(O) 0-2 and; -P 1is selected from the group consisting of (C1-C6) alkylene, (C2-C6) alkenylene, (C2-C6) alkynylene, (C3-C8) cycloalkylene, and 4- to 8-membered heterocycloalkylene, each of which is selected from the group consisting of 1-3 R 0 optionally substituted with; Each R 0 is independently selected from the group consisting of halogen, CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, and (C1-C6)haloalkoxy; T 1 is C(O)OH or a carboxylic acid bioisostere; or Group-L 0 -T 1 is: -C(O)NH-(C1-C6)alkyl or -C(O)NH-(C3-C6)cycloalkyl; each of the foregoing is selected from 1 to 4 R T or a 5- to 6-membered heteroaryl optionally substituted with —C(O)OH, —C(O)O(C1-C6)alkyl, —C(O)NH(C1-C6)alkyl, —C(O)NH—(C3-C6)cycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 6-membered heteroaryl; wherein each of —C(O)O(C1-C6)alkyl, —C(O)NH(C1-C6)alkyl, —C(O)NH—(C3-C6)cycloalkyl, a 3- to 6-membered heterocycloalkyl, and a 6-membered heteroaryl is selected from the group consisting of 1 to 4 R T optionally substituted with; T 2 is: hydrogen, CN, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl or (C1-C6)alkyl; said (C1-C6)alkyl is optionally substituted with (C1-C6)alkoxy, (C1-C6)thioalkoxy, (C1-C6)haloalkoxy, S(O)2(C1-C6 alkyl), —N(C1-C6 alkyl)—S(O)2(C1-C6 alkyl), —NH—S(O)2(C1-C6 alkyl), (C3-C6)cycloalkyl, (C3-C6)cycloalkoxy, 3- to 6-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl, and each of said (C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl is optionally substituted with 1 to 4 R T optionally substituted with; or -NH(C1-C6)alkyl, -NH-(C3-C6)cycloalkyl, -CH2-S(O)2-(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl or 3- to 10-membered heterocycloalkyl; wherein each of -NH(C1-C6)alkyl, -NH-(C3-C6)cycloalkyl, -CH2-S(O)2-(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl or 3- to 10-membered heterocycloalkyl is selected from the group consisting of 1 to 4 R T optionally substituted with; Each R T is independently selected from the group consisting of OH, SH, CN, NO, halogen, ═O, (C-C)alkyl, (C-C)alkenyl, (C-C)alkynyl, (C-C)haloalkyl, (C-C)cyanoalkyl, (C-C)hydroxyalkyl, (C-C)alkoxy, (C-C)haloalkoxy, (C-C)cycloalkyl, amino, (C-C)alkylamino, (C-C)alkylamino(C-Calkyl)-C(O)—C-Calkyl, S(O)(C-Calkyl), and di(C-C)alkylamino; L 1 is a bond or 1 to 3 RL is an optionally substituted (C1-C3) alkylene; L 2 is a bond, -O-, -S(O) 0-2 - or -NH-; Each R L are independently selected from the group consisting of halogen, (C-C) alkyl, and (C-C) haloalkyl; or a pair of R on the same or adjacent carbon atoms L together with the carbon atoms to which they are attached form a (C3-C6)cycloalkyl ring; Ring A is as follows: [ka] (wherein n1 is 0, 1 or 2; W 1 is CR Y1 or N;W 2 is CR Y2 or N); [ka] (In the formula, W 3 is C, CR Y3 or N;L w is (C1-C3) alkylene; [ka] are independently a single bond or a double bond (if valence permits); 1 to 4 R Y phenylene optionally substituted by 1 to 3 R Y an optionally substituted 5- or 6-membered heteroarylene; 1 to 4 R Y (C5-C8)cycloalkylene optionally substituted with 1 to 4 R Y a partially unsaturated monocyclic (C5-C8)cycloalkylene optionally substituted with 1 to 4 RY and optionally substituted, partially unsaturated monocyclic 5- to 8-membered heterocycloalkylenes, where mm is L 2 represents the point of attachment to ring B; Each R Y is independently selected from the group consisting of halogen, CN, —OH, oxo, (C-C)alkyl, (C-C)haloalkyl, (C-C)alkoxy, and (C-C)haloalkoxy; R Y1 , R Y2 and R Y3 are independently selected from the group consisting of hydrogen, halogen, CN, —OH, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; or W 1 is CR Y1 and W 2 is CR Y2 If so, R Y1 and R Y2 groups together can form a (C1-C4) alkylene, one of the CH2 units of said (C1-C4) alkylene being selected from O, S, NH and N(C 1-3 ) alkyl, optionally substituted with a heteroatom selected from the group consisting of; Ring B is selected from the group consisting of (BI), (B-II), (B-III), (B-IV), (BV), (B-VI) and (B-VII): [ka] During the ceremony, aa represents the point of attachment to ring A; B 1 , B 2 , B 3 and B 4 Each of the 1 and N; B 5 and B 6 Each of these is N, NR 1 , C, C.R.1 , O and S, with the proviso that B 5 and B 6 A ring containing is heteroaryl; [ka] During the ceremony, aa represents the point of attachment to ring A; B 7 and B 8 -O-, -NR N - and -C(R 1 )2- independently selected from the group consisting of; B 9 is N or CR aa and; nb is 0 or 1; B 10 , B 11 and B 12 is CR 1 and N; B 13 , B 14 and B 15 are each independently CR 1 and; Each R 1 is hydrogen, halogen, CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C3) alkyl (C3-C6) cycloalkyl, (C1-C3) alkyl (3-5 membered heterocycloalkyl), and -C(O)NR 2 R 3 independently selected from the group consisting of: Each R 2 and R 3 is independently selected from the group consisting of H and (C1-C6)alkyl; Each R N are independently selected from the group consisting of hydrogen, (C-C)alkyl, (C-C)haloalkyl, C(O)(C-C)alkyl, S(O)(C-C)alkyl, and C(O)O(C-C)alkyl; R aa , R ab and R acare independently selected from the group consisting of H, (C1-C6) alkyl, and (C1-C6) haloalkyl; L 3 is a bond or -Z 1 -Z 2 -* where * represents the point of attachment to ring C; -Z 1 is a bond, NH, N(C1-C6 alkyl), O or S(O) 0-2 and; -Z 2 optionally, 1 to 2 R c C optionally substituted with 1-3 is alkylene; Each R c is independently selected from the group consisting of halogen, (C1-C6) alkyl, and (C1-C3) haloalkyl; Ring C is phenyl, 5-6 membered heteroaryl, (C3-C6)cycloalkyl, (C5-C 10 ) selected from the group consisting of bicycloalkyl, 5- to 10-membered bicycloheteroaryl, and 3- to 6-membered heterocycloalkyl; Each R b is independently selected from the group consisting of (C-C)alkyl, (C-C)haloalkyl, (C-C)alkoxy, (C-C)haloalkoxy, halogen, (C-C)cycloalkyl, CN, —C(O)NH, or —C(O)OH; and b is an integer selected from 0 to 3. or a pharmaceutically acceptable salt or solvate thereof.

[0065] In some embodiments, there is at least one of the following: 1) At least one R b is —C(O)NH or —C(O)OH; 2) Ring A contains 1 to 4 R Y is an optionally substituted (C5-C8)cycloalkylene; 3) Ring B is [ka] and; 4) Group-L 0 -T 1 is: -C(O)NH-(C1-C6)alkyl or -C(O)NH-(C3-C6)cycloalkyl; each of the foregoing is selected from 1 to 4 R T optionally substituted with; or a 5- to 6-membered heteroaryl optionally substituted with —C(O)OH, —C(O)O(C1-C6)alkyl, —C(O)NH(C1-C6)alkyl, —C(O)NH—(C3-C6)cycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 6-membered heteroaryl; wherein each of —C(O)O(C1-C6)alkyl, —C(O)NH(C1-C6)alkyl, —C(O)NH—(C3-C6)cycloalkyl, a 3- to 6-membered heterocycloalkyl, and a 6-membered heteroaryl is selected from the group consisting of 1 to 4 R T optionally substituted with 5) T 2 is —NH(C1-C6)alkyl, —NH—(C3-C6)cycloalkyl, —CH2—S(O)2—(C3-C6)cycloalkyl, —O—(C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, or 3- to 10-membered heterocycloalkyl; wherein each of —NH(C1-C6)alkyl, —NH—(C3-C6)cycloalkyl, —CH2—S(O)2—(C3-C6)cycloalkyl, —O—(C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, or 3- to 10-membered heterocycloalkyl is selected from the group consisting of 1 to 4 R T and optionally substituted with

[0066] In certain embodiments, at least one R x is (C3-C6)cycloalkyl.

[0067] In certain embodiments, at least one R y is (C3-C6)cycloalkyl.

[0068] In some embodiments, the compound is not: [ka]

[0069] In some embodiments, provided herein is a compound of formula I: [ka] [In the formula, X 1 , X 2 and X 5 are independently C or N; X 3 and X 4 is N, NR x , C.R. y independently selected from the group consisting of C(O), O, and S; X 6 is a bond, N, NR x , C.R. y and C(O); [ka] is a single or double bond, provided that X 1 From X 6 at least one of X is independently selected from a heteroatom or a heteroatom group; 1 From X 6 At least one of the is C or CR y and X 1 From X 6 The ring containing is aromatic; Each R x are independently selected from the group consisting of hydrogen, (C-C)alkyl, (C-C)haloalkyl, (C-C)cycloalkyl, C(O)(C-C)alkyl, S(O)(C-C)alkyl, and C(O)O(C-C)alkyl; Each R yis independently selected from the group consisting of hydrogen, —OH, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, CN, and halogen; L 0 is a join or #-P 0 -P 1 And, # is X 5 represents the point of attachment to; -P 0 is a bond, -NH-, -N(C1-C6 alkyl)-, -O- or S(O) 0-2 and; -P 1 is selected from the group consisting of (C1-C6) alkylene, (C2-C6) alkenylene, (C2-C6) alkynylene, (C3-C8) cycloalkylene, and 4- to 8-membered heterocycloalkylene, each of which optionally contains 1 to 3 R 0 may be substituted with; Each R 0 is independently selected from the group consisting of halogen, CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, and (C1-C6)haloalkoxy; T 1 is C(O)OH, sulfo, phosphono, alkylsulfonylcarbamoyl, tetrazolyl, arylsulfonylcarbamoyl, heteroarylsulfonylcarbamoyl, N-methoxycarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or a heterocyclic phenol, for example, 3-hydroxyisoxazolyl or 3-hydroxy-1-methylpyrazolyl; or Group-L 0 -T 1 is: -C(O)NH-(C1-C6)alkyl or -C(O)NH-(C3-C6)cycloalkyl; each of the foregoing is selected from 1 to 4 R T optionally substituted with; or a 5- to 6-membered heteroaryl optionally substituted with —C(O)OH, —C(O)O(C1-C6)alkyl, —C(O)NH(C1-C6)alkyl, —C(O)NH—(C3-C6)cycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 6-membered heteroaryl; wherein each of —C(O)O(C1-C6)alkyl, —C(O)NH(C1-C6)alkyl, —C(O)NH—(C3-C6)cycloalkyl, a 3- to 6-membered heterocycloalkyl, and a 6-membered heteroaryl is selected from the group consisting of 1 to 4 R T optionally substituted with; T 2 is: hydrogen, CN, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl or (C1-C6)alkyl; said (C1-C6)alkyl is optionally substituted with (C1-C6)alkoxy, (C1-C6)thioalkoxy, (C1-C6)haloalkoxy, S(O)2(C1-C6 alkyl), —N(C1-C6 alkyl)—S(O)2(C1-C6 alkyl), —NH—S(O)2(C1-C6 alkyl), (C3-C6)cycloalkyl, (C3-C6)cycloalkoxy, 3- to 6-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl, and each of said (C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl is optionally substituted with 1 to 4 R T optionally substituted with; or -NH(C1-C6)alkyl, -NH-(C3-C6)cycloalkyl, -CH2-S(O)2-(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl or 3- to 10-membered heterocycloalkyl; wherein each of -NH(C1-C6)alkyl, -NH-(C3-C6)cycloalkyl, -CH2-S(O)2-(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl or 3- to 10-membered heterocycloalkyl is selected from the group consisting of 1 to 4 R T optionally substituted with; Each R Tis independently selected from the group consisting of OH, SH, CN, NO, halogen, ═O, (C-C)alkyl, (C-C)alkenyl, (C-C)alkynyl, (C-C)haloalkyl, (C-C)cyanoalkyl, (C-C)hydroxyalkyl, (C-C)alkoxy, (C-C)haloalkoxy, (C-C)cycloalkyl, amino, (C-C)alkylamino, (C-C)alkylamino(C-Calkyl)-C(O)—C-Calkyl, S(O)(C-Calkyl), and di(C-C)alkylamino; L 1 is a bond or 1 to 3 R L is an optionally substituted (C1-C3) alkylene; L 2 is a bond, -O-, -S(O) 0-2 - or -NH-; Each R L are independently selected from the group consisting of halogen, (C-C) alkyl, and (C-C) haloalkyl; or a pair of R on the same or adjacent carbon atoms L together with the carbon atoms to which they are attached form a (C3-C6)cycloalkyl ring; Ring A is as follows: [ka] (wherein n1 is 0, 1 or 2; W 1 is CR Y1 or N;W 2 is CR Y2 or N); [ka] (In the formula, W 3 is C, CR Y3 or N;L w is (C1-C3) alkylene, [ka] are independently a single bond or a double bond (if valence permits); 1 to 4 R Y phenylene optionally substituted by 1 to 3 R Y an optionally substituted 5- or 6-membered heteroarylene; 1 to 4 R Y (C5-C8)cycloalkylene optionally substituted with 1 to 4 R Y a partially unsaturated monocyclic (C5-C8)cycloalkylene optionally substituted with 1 to 4 R Y and optionally substituted, partially unsaturated monocyclic 5- to 8-membered heterocycloalkylenes, where mm is L 2 represents the point of attachment to ring B; Each R Y is independently selected from the group consisting of halogen, CN, —OH, oxo, (C-C)alkyl, (C-C)haloalkyl, (C-C)alkoxy, and (C-C)haloalkoxy; R Y1 , R Y2 and R Y3 are independently selected from the group consisting of hydrogen, halogen, CN, —OH, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; or W 1 is CR Y1 and W 2 is CR Y2 If so, R Y1 and R Y2 groups together can form a (C1-C4) alkylene, one of the CH2 units of said (C1-C4) alkylene being selected from O, S, NH and N(C 1-3 ) alkyl, optionally substituted with a heteroatom selected from the group consisting of; Ring B is selected from the group consisting of (BI), (B-II), (B-III), (B-IV), (BV), (B-VI) and (B-VII): [ka] During the ceremony, aa represents the point of attachment to ring A; B 1 , B 2 , B 3 and B 4 Each of the 1 and N; B 5 and B 6 Each of these is N, NR 1 , C, C.R. 1 , O and S, with the proviso that B 5 and B 6 A ring containing is heteroaryl; [ka] During the ceremony, aa represents the point of attachment to ring A; B 7 and B 8 -O-, -NR N - and -C(R 1 )2- independently selected from the group consisting of; B 9 is N or CR aa and; nb is 0 or 1; B 10 , B 11 and B 12 is CR 1 and N; B 13 , B 14 and B 15 are each independently CR 1 and; Each R 1is hydrogen, halogen, CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C3) alkyl (C3-C6) cycloalkyl, (C1-C3) alkyl (3-5 membered heterocycloalkyl), and -C(O)NR 2 R 3 independently selected from the group consisting of: Each R 2 and R 3 is independently selected from the group consisting of H and (C1-C6)alkyl; Each R N are independently selected from the group consisting of hydrogen, (C-C)alkyl, (C-C)haloalkyl, C(O)(C-C)alkyl, S(O)(C-C)alkyl, and C(O)O(C-C)alkyl; R aa , R ab and R ac is independently selected from the group consisting of H, (C1-C6)alkyl, and (C1-C6)haloalkyl; L 3 is a bond or -Z 1 -Z 2 -* where * represents the point of attachment to ring C; -Z 1 is a bond, NH, N(C1-C6 alkyl), O or S(O) 0-2 and; -Z 2 is 1 to 2 R c C optionally substituted with 1-3 is alkylene; Each R c is independently selected from the group consisting of halogen, (C1-C6) alkyl, and (C1-C3) haloalkyl; Ring C is phenyl, 5-6 membered heteroaryl, (C3-C6)cycloalkyl, (C5-C 10 ) selected from the group consisting of bicycloalkyl, 5- to 10-membered bicycloheteroaryl, and 3- to 6-membered heterocycloalkyl; Each R bis independently selected from the group consisting of (C-C)alkyl, (C-C)haloalkyl, (C-C)alkoxy, (C-C)haloalkoxy, halogen, (C-C)cycloalkyl, CN, —C(O)NH, or —C(O)OH; and b is an integer selected from 0 to 3; However, there is at least one of the following: 1) At least one R b is —C(O)NH or —C(O)OH; 2) Ring A contains 1 to 4 R Y is an optionally substituted (C5-C8)cycloalkylene; 3) Ring B is [ka] and; 4) Group-L 0 -T 1 is: -C(O)NH-(C1-C6)alkyl or -C(O)NH-(C3-C6)cycloalkyl; each of the foregoing is selected from 1 to 4 R T optionally substituted with; or a 5- to 6-membered heteroaryl optionally substituted with —C(O)OH, —C(O)O(C1-C6)alkyl, —C(O)NH(C1-C6)alkyl, —C(O)NH—(C3-C6)cycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 6-membered heteroaryl; wherein each of —C(O)O(C1-C6)alkyl, —C(O)NH(C1-C6)alkyl, —C(O)NH—(C3-C6)cycloalkyl, a 3- to 6-membered heterocycloalkyl, and a 6-membered heteroaryl is selected from the group consisting of 1 to 4 R T optionally substituted with 5) T 2is —NH(C1-C6)alkyl, —NH—(C3-C6)cycloalkyl, —CH2—S(O)2—(C3-C6)cycloalkyl, —O—(C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, or 3- to 10-membered heterocycloalkyl; wherein each of —NH(C1-C6)alkyl, —NH—(C3-C6)cycloalkyl, —CH2—S(O)2—(C3-C6)cycloalkyl, —O—(C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, or 3- to 10-membered heterocycloalkyl is selected from the group consisting of 1 to 4 R T and optionally substituted with or a pharmaceutically acceptable salt or solvate thereof.

[0070] In some embodiments, the compound is not: [ka]

[0071] In certain embodiments, each R x is independently selected from the group consisting of hydrogen, (C-C)alkyl, (C-C)haloalkyl, C(O)(C-C)alkyl, S(O)(C-C)alkyl, and C(O)O(C-C)alkyl. In certain embodiments, each R x is independently selected from the group consisting of hydrogen, (C-C) alkyl, (C-C) haloalkyl, and (C-C) cycloalkyl. In certain embodiments, each R x is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, and (C1-C6) haloalkyl.

[0072] In certain embodiments, each R y are independently selected from the group consisting of hydrogen, —OH, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, CN, and halogen.

[0073] In some embodiments, X 3 is N.

[0074] In some embodiments, X 6 is a bond. To avoid any misunderstanding, X 6 If is a bond, then X 1 is X 5 by directly linking (eg, via a single or double bond) to provide a five-membered heteroaromatic ring.

[0075] In some embodiments, X 3 is N; and X 6 is a bond.

[0076] In some embodiments, X 3 and X 4 is N, NR x , C.R. y , O and S.

[0077] In some embodiments, X 6 is a bond, N, NR x and CR y is selected from the group consisting of:

[0078] In some embodiments, X 1 From X 6 The ring containing [ka] In one embodiment, X 2 is C. In some embodiments, X 1 is N. In some embodiments, X 5 is C. In some embodiments, X 4 is CR y In one embodiment, X 4 is CH. In some embodiments, X 4 is N.

[0079] In some embodiments, X 1is N;X 2 is C; and X 5 is C. In some embodiments, X 1 From X 6 The ring containing [ka] where X 1 is N; and X 2 is C. In some embodiments, X 4 is CH. In some embodiments, X 4 is N.

[0080] In some embodiments, X 1 is N;X 2 is C;X 3 is N;X 4 is CR y or N;X 5 is C; and X 6 is a bond. In some embodiments, X 4 is CH or N. In a non-limiting example of the above embodiment, X 1 is N;X 2 is C;X 3 is N;X 4 is CH;X 5 is C; and X 6 is a bond. In another non-limiting example, X 1 is N;X 2 is C;X 3 is N;X 4 is N;X 5 is C; and X 6 is a bond.

[0081] In some embodiments, X 6 is N, NR x , C.R. y and C(O). In some embodiments, X 3 is N; and X 6is N, NR x , C.R. y and C(O).

[0082] In some embodiments, X 1 From X 6 The ring containing [ka] (In the formula, X 6 is N, NR x , C.R. y and C(O) In one embodiment, X 1 is C. In some embodiments, X 2 is C. In some embodiments, X 5 is C. In some embodiments, X 6 is CR y For example, X 6 can be CH. In some embodiments, X 4 is CR y For example, X 4 can be CH.

[0083] In some embodiments, X 1 , X 2 and X 5 is C;X 4 and X 6 are independently N or CR y In one embodiment, X 4 and X 6 is an independent CR y Non-limiting examples of the above embodiment include those in which X 4 and X 6 can be CH.

[0084] In some embodiments, provided herein is a compound of formula II: [ka] [In the formula, L 0 is a bond or -P 0 -P 1 and; -P 0 is a bond, -NH-, -N(C1-C6 alkyl)-, -O- or S(O) 0-2 and; -P 1 is selected from the group consisting of (C1-C6) alkylene, (C2-C6) alkenylene, (C2-C6) alkynylene, (C3-C8) cycloalkylene, and 4- to 8-membered heterocycloalkylene, each of which is selected from the group consisting of 1-3 R 0 optionally substituted with; Each R 0 is independently selected from the group consisting of halogen, CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, and (C1-C6)haloalkoxy; T 1 is C(O)OH or a carboxylic acid bioisostere; or Group-L 0 -T 1 is: -C(O)NH-(C1-C6)alkyl or -C(O)NH-(C3-C6)cycloalkyl; each of the foregoing is selected from 1 to 4 R T optionally substituted with; or a 5- to 6-membered heteroaryl optionally substituted with —C(O)OH, —C(O)O(C1-C6)alkyl, —C(O)NH(C1-C6)alkyl, —C(O)NH—(C3-C6)cycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 6-membered heteroaryl; wherein each of —C(O)O(C1-C6)alkyl, —C(O)NH(C1-C6)alkyl, —C(O)NH—(C3-C6)cycloalkyl, a 3- to 6-membered heterocycloalkyl, and a 6-membered heteroaryl is selected from the group consisting of 1 to 4 R T optionally substituted with; T 2 is: hydrogen, CN, (C-C)haloalkyl, (C-C)hydroxyalkyl or (C-C)alkyl; said (C-C)alkyl is optionally substituted with (C-C)alkoxy, (C-C)thioalkoxy, (C-C)haloalkoxy, S(O)(C-C alkyl), —N(C-C alkyl)—S(O)(C-C alkyl), —NH—S(O)(C-C alkyl), (C-C)cycloalkyl, (C-C)cycloalkoxy, 3- to 6-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl, and each of said (C-C)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl is optionally substituted with 1 to 4 R T optionally substituted with; or -NH(C1-C6)alkyl, -NH-(C3-C6)cycloalkyl, -CH2-S(O)2-(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl or 3- to 10-membered heterocycloalkyl; wherein each of -NH(C1-C6)alkyl, -NH-(C3-C6)cycloalkyl, -CH2-S(O)2-(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl or 3- to 10-membered heterocycloalkyl is selected from the group consisting of 1 to 4 R T optionally substituted with; Each R T is independently selected from the group consisting of OH, SH, CN, NO, halogen, ═O, (C-C)alkyl, (C-C)alkenyl, (C-C)alkynyl, (C-C)haloalkyl, (C-C)cyanoalkyl, (C-C)hydroxyalkyl, (C-C)alkoxy, (C-C)haloalkoxy, (C-C)cycloalkyl, amino, (C-C)alkylamino, (C-C)alkylamino(C-Calkyl)-C(O)—C-Calkyl, S(O)(C-Calkyl), and di(C-C)alkylamino; W 1 is CH or N; Ring B is selected from the group consisting of (BI), (B-II), (B-III), (B-IV), (BV), (B-VI) and (B-VII): [ka] During the ceremony, aa represents the point of attachment to ring A; B 1 , B 2 , B 3 and B 4 Each of the 1 and N; B 5 and B 6 Each of these is N, NR 1 , C, C.R. 1 , O and S, with the proviso that B 5 and B 6 A ring containing is heteroaryl; [ka] During the ceremony, aa represents the point of attachment to ring A; B 7 and B 8 -O-, -NR N - and -C(R 1 )2- independently selected from the group consisting of; B 9 is N or CR aa and; nb is 0 or 1; B 10 , B 11 and B 12 is CR 1 and N; B 13 , B 14 and B 15 are each independently CR 1 and; Each R 1is hydrogen, halogen, CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C3) alkyl (C3-C6) cycloalkyl, (C1-C3) alkyl (3-5 membered heterocycloalkyl), and -C(O)NR 2 R 3 independently selected from the group consisting of: Each R 2 and R 3 is independently selected from the group consisting of H and (C1-C6)alkyl; Each R N are independently selected from the group consisting of hydrogen, (C-C)alkyl, (C-C)haloalkyl, C(O)(C-C)alkyl, S(O)(C-C)alkyl, and C(O)O(C-C)alkyl; R aa , R ab and R ac is independently selected from the group consisting of H, (C1-C6)alkyl, and (C1-C6)haloalkyl; L 3 is a bond or -Z 1 -Z 2 -* where * represents the point of attachment to ring C; -Z 1 is a bond, NH, N(C1-C6 alkyl), O or S(O) 0-2 and; -Z 2 is 1 to 2 R c C optionally substituted with 1-3 is alkylene; Each R c is independently selected from the group consisting of halogen, (C1-C6) alkyl, and (C1-C3) haloalkyl; Ring C is phenyl, 5-6 membered heteroaryl, (C3-C6)cycloalkyl, (C5-C 10 ) selected from the group consisting of bicycloalkyl, 5- to 10-membered bicycloheteroaryl, and 3- to 6-membered heterocycloalkyl; Each R bis independently selected from the group consisting of (C-C)alkyl, (C-C)haloalkyl, (C-C)alkoxy, (C-C)haloalkoxy, halogen, (C-C)cycloalkyl, CN, —C(O)NH, or —C(O)OH; and b is an integer selected from 0 to 3; However, there is at least one of the following: 1) At least one R b is —C(O)NH or —C(O)OH; 2) W 1 is CH; 3) Ring B is [ka] and; 4) Group-L 0 -T 1 is: -C(O)NH-(C1-C6)alkyl or -C(O)NH-(C3-C6)cycloalkyl; each of the foregoing is selected from 1 to 4 R T optionally substituted with; or a 5- to 6-membered heteroaryl optionally substituted with —C(O)OH, —C(O)O(C1-C6)alkyl, —C(O)NH(C1-C6)alkyl, —C(O)NH—(C3-C6)cycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 6-membered heteroaryl; wherein each of —C(O)O(C1-C6)alkyl, —C(O)NH(C1-C6)alkyl, —C(O)NH—(C3-C6)cycloalkyl, a 3- to 6-membered heterocycloalkyl, and a 6-membered heteroaryl is selected from the group consisting of 1 to 4 R T optionally substituted with; or 5) T 2is —NH(C1-C6)alkyl, —NH—(C3-C6)cycloalkyl, —CH2—S(O)2—(C3-C6)cycloalkyl, —O—(C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, or 3- to 10-membered heterocycloalkyl; wherein each of —NH(C1-C6)alkyl, —NH—(C3-C6)cycloalkyl, —CH2—S(O)2—(C3-C6)cycloalkyl, —O—(C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, or 3- to 10-membered heterocycloalkyl, independently, optionally is selected from the group consisting of 1 to 4 R T may be substituted with] or a pharmaceutically acceptable salt or solvate thereof.

[0085] In some embodiments, the compound is not: [ka]

[0086] In some embodiments, L 0 is a bond. In certain embodiments, L 0 is #-P 0 -P 1 And ;P 0 is a bond.

[0087] In certain embodiments, the group -L 0 -T 1 is —C(O)NH—(C1-C6)alkyl or —C(O)NH—(C3-C6)cycloalkyl; each of the foregoing is selected from 1 to 4 R T In certain embodiments, the group -L 0 -T 1 is 1 to 4 R T In certain embodiments, the group -L 0 -T 1 is 1 to 4 R Tis —C(O)NH—(C3-C6)cycloalkyl optionally substituted with

[0088] In some embodiments, the compound of formula IID: [ka] (In the formula, R 6 is -(C1-C6) alkyl or -(C3-C6) cycloalkyl; wherein said -(C1-C6) alkyl or -(C3-C6) cycloalkyl is selected from 1 to 4 R T and optionally substituted with or a pharmaceutically acceptable salt or solvate thereof.

[0089] In some embodiments, R 6 is -(C1-C6 cycloalkyl), and said -(C1-C6) cycloalkyl is selected from 1 to 4 R T In certain embodiments, R 6 is -(C1-C6) alkyl, and said -(C1-C6) alkyl is selected from 1 to 4 R T and optionally substituted with

[0090] In certain embodiments, the compound of Formula I, II, or IID is compound D-1, D-2, D-3, D-4, D-5, D-6, or D-7, as set forth in Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[0091] In certain embodiments, the group -L 0 -T 1is a 5- to 6-membered heteroaryl optionally substituted with —C(O)OH, —C(O)O(C1-C6)alkyl, —C(O)NH(C1-C6)alkyl, —C(O)NH—(C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, or 6-membered heteroaryl; wherein each of —C(O)O(C1-C6)alkyl, —C(O)NH(C1-C6)alkyl, —C(O)NH—(C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, and 6-membered heteroaryl is selected from the group consisting of 1 to 4 R T and optionally substituted with

[0092] In some embodiments, the compound of formula IIE: [ka] (In the formula, Ring D is a 5-6 membered heteroaryl; d is 0 or 1; and R d is —C(O)OH, —C(O)O(C1-C6)alkyl, —C(O)NH(C1-C6)alkyl, —C(O)NH—(C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl or 6-membered heteroaryl; wherein said —C(O)O(C1-C6)alkyl, —C(O)NH(C1-C6)alkyl, —C(O)NH—(C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl or 6-membered heteroaryl is selected from the group consisting of 1 to 4 R T and optionally substituted with or a pharmaceutically acceptable salt or solvate thereof.

[0093] In some embodiments, the compound is not: [ka]

[0094] In some embodiments, d is 0. In some embodiments, d is 1.

[0095] In some embodiments, Ring D is triazolyl, thiazolyl, pyrazolyl, oxadiazolyl, pyridinyl, or thiadiazolyl.

[0096] In certain embodiments, the compound of Formula I, II or IIE is compound E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9, E-10, E-11, E-12, E-13, E-14, E-15, E-16, E-17, E-18 or E-19, as set forth in Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[0097] In one embodiment, L 0 is #-P 0 -P 1 and P 0 is -NH-, -N(C1-C6 alkyl)-, -O- or S(O) 0-2 In one embodiment, P 0 is —O—. In some embodiments, P 0 is -NH-.

[0098] In one embodiment, P 1 is 1 to 3 R 0 In some embodiments, P is (C-C) alkylene optionally substituted with 1 is 1 to 3 R 0 In some embodiments, P is (C1-C3) alkylene optionally substituted with 1 is (C1-C3) alkylene. In some embodiments, P 1 is -CH2CH2-, -CH2-, -CH(Me)- or -C(Me)2-. For example, P 1 can be -CH2CH2-. In another non-limiting example, P 1 can be -CH2-. As a further non-limiting example, P 1 can be -CH(Me)- or -C(Me)2-.

[0099] In one embodiment, P 1is (C2-C6) alkenylene or (C2-C6) alkynylene, each of which is selected from 1 to 3 R 0 In one embodiment, P 1 is 1 to 3 R 0 In certain embodiments, P is (C-C)alkenylene optionally substituted with 1 is 1 to 3 R 0 and optionally substituted (C2-C4) alkenylene (for example, (C2-C3) alkenylene such as C2 alkenylene).

[0100] In one embodiment, P 1 teeth, [ka] where R 0-1 and R 0-2 are independently H or R 0 and ee is T 1 In some embodiments, P 1 teeth, [ka] where R 0-1 and R 0-2 are independently H or R 0 and ee is T 1 In some embodiments, P 1 teeth, [ka] where ee is T 1 In some embodiments, P 1 teeth, [ka] where ee is T 1 For example, P1 teeth, [ka] where ee is T 1 In another non-limiting example, P 1 teeth, [ka] where ee is T 1 In some embodiments, P 1 teeth, [ka] where ee is T 1 For example, P 1 teeth, [ka] where ee is T 1 In another non-limiting example, P 1 teeth, [ka] where ee is T 1 It can be a point of attachment to

[0101] In one embodiment, P 1 teeth, [ka] where np is 1, 2, or 3; ee is T 1 In some embodiments, P 1 teeth, [ka] where ee is the 1 For example, P 1 teeth, [ka] wherein R 0 is (C1-C6)alkoxy or (C1-C6)haloalkoxy; ee is T 1 It is the connection point to

[0102] In one embodiment, P 1 is selected from the group consisting of (C-C)cycloalkylene and 4- to 8-membered heterocycloalkylene, each of which is selected from the group consisting of 1 to 3 R 0 and optionally substituted with

[0103] In one embodiment, P 1 optionally, 1 to 3 R 0 In some embodiments, P is (C-C)cycloalkylene optionally substituted with 1 optionally, 1 to 3 R 0 In some embodiments, P is (C-C)cycloalkylene optionally substituted with 1 is (C3-C4)cycloalkylene. Non-limiting examples of the above embodiment include 1 teeth, [ka] It could be.

[0104] In one embodiment, P 1 optionally, 1 to 3 R 0 In one embodiment, P 1 teeth, [ka] and optionally one to two R 0np is 1, 2, or 3; ee is T 1 In some embodiments, P 1 teeth, [ka] and optionally one to two R 0 where np is 1, 2, or 3; ee is T 1 It is the connection point to

[0105] In one embodiment, L 0 is #-P 0 -P 1 And ;P 0 is a bond;P 1 is 1 to 3 R 0 In some embodiments, P is (C1-C3) alkylene optionally substituted with 1 is (C1-C3) alkylene. For example, P 1 can be CH2CH2. In another embodiment, P 1 can be CH2.

[0106] In one embodiment, L 0 is #-P 0 -P 1 And ;P 0 is -NH-, -N(C1-C3 alkyl) or -O-; P 1 is 1 to 3 R 0 In some embodiments, P is (C1-C3) alkylene optionally substituted with 1 is (C1-C3) alkylene. In a non-limiting example of the above embodiment, P 1 can be CH2, CH(Me) or C(Me)2.

[0107] In one embodiment, L 0 is #-P 0 -P 1 And ;P 0 is a bond;P 1is 1 to 3 R 0 In certain embodiments, P is (C-C)alkenylene optionally substituted with 1 teeth, [ka] where R 0-1 and R 0-2 are independently H or R 0 and ee is T 1 In a non-limiting example of the above embodiment, P 1 teeth, [ka] where ee is T 1 It is the connection point to

[0108] In one embodiment, L 0 is #-P 0 -P 1 And ;P 0 is a bond;P 1 optionally, 1 to 3 R 0 In some embodiments, P is (C-C)cycloalkylene optionally substituted with 1 teeth, [ka] is.

[0109] In one embodiment, L 0 is #-P 0 -P 1 And ;P 0 is a bond;P 1 teeth, [ka] and each of these contains 1 to 2 R 0 where np is 1, 2, or 3; ee is T 1 It is the connection point to

[0110] In one embodiment, T 1 is C(O)OH.

[0111] In one embodiment, T 1 is a carboxylic acid bioisostere.

[0112] In one embodiment, T 1 is tetrazolyl optionally substituted with (C1-C3) alkyl.

[0113] In one embodiment, T 1 is tetrazolyl optionally substituted with 1 to 2 substituents each independently selected from the group consisting of hydroxy, (C1-C6) alkyl, (C1-C6) haloalkyl, and halogen. For example, T 1 teeth, [ka] is selected from the group consisting of:

[0114] In one embodiment, T 1 is triazolyl or oxadiazolyl, which may be optionally substituted with 1 to 2 substituents each independently selected from the group consisting of (C1-C6) alkyl and hydroxy. For example, T 1 teeth, [ka] is.

[0115] In one embodiment, T 1 is triazolyl optionally substituted with 1 to 2 substituents each independently selected from the group consisting of (C1-C6)haloalkyl and CN. For example, T 1 teeth, [ka] is.

[0116] In one embodiment, T 1 is a ring (e.g., a 4- to 6-membered ring, such as a 5-membered ring) containing 0-3 heteroatoms each independently selected from the group consisting of N, O, and S, which is substituted with 1-2 oxo and optionally further substituted with 1-2 substituents each independently selected from the group consisting of hydroxy, (C1-C6) alkyl, (C1-C6) haloalkyl, and halogen. For example, in one embodiment, T 1 teeth, [ka] is.

[0117] In one embodiment, T 1 is (C1-C6) alkyl substituted with 1 to 3 hydroxy and optionally further substituted with 1 to 10 fluoro. 1 is (C1-C6) alkyl substituted with 1 to 3 hydroxy and further substituted with 1 to 10 fluoro. For example, in some embodiments, T 1 teeth, [ka] is.

[0118] In one embodiment, T 1 is C(O)NHS(O)2(C1-C4)alkyl. For example, in some embodiments, T 1 is C(O)NHS(O)Me.

[0119] In one embodiment, T 1 is the following: [ka] is selected from the group consisting of:

[0120] In one embodiment, T2 is hydrogen or (C-C)alkyl optionally substituted with (C-C)alkoxy, (C-C)thioalkoxy, (C-C)haloalkoxy, S(O)(C-C alkyl), (C-C)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, each of said (C-C)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl being selected from the group consisting of 1 to 4 R T and optionally substituted with

[0121] In certain embodiments, each R T are independently selected from the group consisting of OH, SH, CN, NO, halogen, (C-C)alkyl, (C-C)alkenyl, (C-C)alkynyl, (C-C)haloalkyl, (C-C)cyanoalkyl, (C-C)hydroxyalkyl, (C-C)alkoxy, (C-C)haloalkoxy, (C-C)cycloalkyl, amino, (C-C)alkylamino, and di(C-C)alkylamino.

[0122] In one embodiment, T 2 is hydrogen or (C-C)alkyl optionally substituted with (C-C)alkoxy, (C-C)thioalkoxy, (C-C)haloalkoxy, S(O)(C-C alkyl), (C-C)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, each of said (C-C)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl being selected from the group consisting of 1 to 4 R T each R Tare independently selected from the group consisting of OH, SH, CN, NO, halogen, (C-C)alkyl, (C-C)alkenyl, (C-C)alkynyl, (C-C)haloalkyl, (C-C)cyanoalkyl, (C-C)hydroxyalkyl, (C-C)alkoxy, (C-C)haloalkoxy, (C-C)cycloalkyl, amino, (C-C)alkylamino, and di(C-C)alkylamino.

[0123] In one embodiment, T 2 is hydrogen, CN, (C-C)haloalkyl, (C-C)hydroxyalkyl, or (C-C)alkoxy, (C-C)thioalkoxy, (C-C)haloalkoxy, S(O)(C-C alkyl), —N(C-C alkyl)-S(O)(C-C alkyl), —NH—S(O)(C-C alkyl), (C-C)cycloalkyl, (C-C)cycloalkoxy, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, and each of said (C-C)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl may be selected from the group consisting of 1 to 4 R T and optionally substituted with

[0124] In certain embodiments, each R T are independently selected from the group consisting of OH, SH, CN, NO, halogen, ═O, (C-C)alkyl, (C-C)alkenyl, (C-C)alkynyl, (C-C)haloalkyl, (C-C)cyanoalkyl, (C-C)hydroxyalkyl, (C-C)alkoxy, (C-C)haloalkoxy, (C-C)cycloalkyl, amino, (C-C)alkylamino, (C-C)alkylamino(C-Calkyl)-C(O)—C-Calkyl, S(O)(C-Calkyl), and di(C-C)alkylamino.

[0125] In one embodiment, T 2is hydrogen, CN, (C-C)haloalkyl, (C-C)hydroxyalkyl, or (C-C)alkoxy, (C-C)thioalkoxy, (C-C)haloalkoxy, S(O)(C-C alkyl), —N(C-C alkyl)-S(O)(C-C alkyl), —NH—S(O)(C-C alkyl), (C-C)cycloalkyl, (C-C)cycloalkoxy, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, and each of said (C-C)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl may be selected from the group consisting of 1 to 4 R T each R T are independently selected from the group consisting of OH, SH, CN, NO, halogen, ═O, (C-C)alkyl, (C-C)alkenyl, (C-C)alkynyl, (C-C)haloalkyl, (C-C)cyanoalkyl, (C-C)hydroxyalkyl, (C-C)alkoxy, (C-C)haloalkoxy, (C-C)cycloalkyl, amino, (C-C)alkylamino, (C-C)alkylamino(C-Calkyl)-C(O)—C-Calkyl, S(O)(C-Calkyl), and di(C-C)alkylamino.

[0126] In one embodiment, T 2 is hydrogen.

[0127] In one embodiment, T 2 is CN.

[0128] In one embodiment, T 2 is (C1-C6) alkyl. In some embodiments, T 2 is methyl.

[0129] In one embodiment, T 2 is (C1-C6) alkyl substituted with (C1-C6) alkoxy. In some embodiments, T 2is a (C1-C3) alkyl substituted with a (C1-C3) alkoxy. For example, T 2 teeth, [ka] It could be.

[0130] In one embodiment, T 2 is (C1-C6)alkyl substituted with S(O)2(C1-C6 alkyl). In some embodiments, T 2 is (C1-C3) alkyl substituted with S(O)2(C1-C3 alkyl). For example, T 2 teeth, [ka] It could be.

[0131] In one embodiment, T 2 is (C1-C6) alkyl substituted with (C3-C6) cycloalkyl. In some embodiments, T 2 is (C1-C3) alkyl substituted with (C3-C6) cycloalkyl. In some embodiments, T 2 is a (C1-C3) alkyl substituted with cyclobutyl. For example, T 2 teeth, [ka] It could be.

[0132] In one embodiment, T 2 is (C1-C6) alkyl substituted with 3- to 6-membered heterocycloalkyl. 2 is (C1-C3) alkyl substituted with a 3- to 5-membered heterocycloalkyl. 2 is a (C1-C3) alkyl substituted with oxetanyl. For example, T 2 teeth, [ka] where: [ka] The stereocenter in is in the (S)-configuration. 2 is a (C1-C3) alkyl substituted with tetrahydrofuranyl. For example, T 2 teeth, [ka] It could be.

[0133] In one embodiment, T 2 is a (C-C) alkyl substituted with a 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is selected from 1 to 4 R T In some embodiments, T 2 is a (C1-C3) alkyl substituted with a 5-membered heteroaryl, wherein the 5-membered heteroaryl is optionally substituted with 1 to 2 R T In some embodiments, T 2 is (C1-C3) alkyl substituted with imidazolyl, said imidazolyl optionally being R T For example, T 2 teeth, [ka] In another non-limiting example, T 2 teeth, [ka] It could be.

[0134] In one embodiment, T 2 is a (C1-C6) alkyl substituted with a (C3-C6) cycloalkoxy.

[0135] In one embodiment, T 2is a (C-C) alkyl substituted with a 3- to 6-membered heterocycloalkyl, wherein the 3- to 6-membered heterocycloalkyl is substituted with 1 to 4 R T In any of these embodiments, R T is S(O)2(C1-C6 alkyl).

[0136] In one embodiment, T 2 is (C1-C6) alkyl substituted with -N(C1-C6 alkyl)-S(O)2(C1-C6 alkyl).

[0137] In one embodiment, T 2 is (C1-C6) alkyl substituted with -NH-S(O)2(C1-C6 alkyl).

[0138] In one embodiment, T 2 is (C1-C6) hydroxyalkyl.

[0139] In one embodiment, T 2 is (C1-C6)haloalkyl.

[0140] In one embodiment, T 2 is —NH(C1-C6)alkyl, —NH—(C3-C6)cycloalkyl, —CH2—S(O)2—(C3-C6)cycloalkyl, —O—(C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl or 3- to 10-membered heterocycloalkyl; each of said —NH(C1-C6)alkyl, —NH—(C3-C6)cycloalkyl, —CH2—S(O)2—(C3-C6)cycloalkyl, —O—(C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl or 3- to 10-membered heterocycloalkyl may be selected from the group consisting of 1 to 4 R T and optionally substituted with

[0141] In one embodiment, T 2is —NH(C1-C6)alkyl, —NH—(C3-C6)cycloalkyl, —CH2—S(O)2—(C3-C6)cycloalkyl, —O—(C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl or 3-10 membered nitrogen-containing heterocycloalkyl; each of said —NH(C1-C6)alkyl, —NH—(C3-C6)cycloalkyl, —CH2—S(O)2—(C3-C6)cycloalkyl, —O—(C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl or 3-10 membered nitrogen-containing heterocycloalkyl may be selected from 1 to 4 R T and optionally substituted with

[0142] In one embodiment, T 2 is a (C3-C6)cycloalkyl or a 3- to 10-membered heterocycloalkyl; each of said (C3-C6)cycloalkyl or 3- to 10-membered heterocycloalkyl is selected from 1 to 4 R T In some embodiments, T 2 is a (C3-C6)cycloalkyl or a 3- to 10-membered nitrogen-containing heterocycloalkyl; each of said (C3-C6)cycloalkyl or 3- to 10-membered nitrogen-containing heterocycloalkyl is selected from 1 to 4 R T and optionally substituted with

[0143] In one embodiment, T 2 is 1 to 4 R T In certain embodiments, T is (C-C)cycloalkyl optionally substituted with 2 is 1 to 4 R T In one embodiment, T 2 is 1 to 4 R T and optionally substituted 3-10 membered nitrogen-containing heterocycloalkyl.

[0144] In certain embodiments, a compound of formula IIF: [ka] [In the formula, L 4 is a bond, —NH—, —CH—S(O) or —O—; and R 7 is (C1-C6) alkyl, (C3-C6) cycloalkyl or 3- to 10-membered heterocycloalkyl, each of said (C1-C6) alkyl, (C3-C6) cycloalkyl or 3- to 10-membered heterocycloalkyl being selected from 1 to 4 R T and optionally substituted with 4 If is a bond, R 7 is a substituted or unsubstituted (C3-C6)cycloalkyl or a substituted or unsubstituted 3- to 10-membered heterocycloalkyl. or a pharmaceutically acceptable salt or solvate thereof.

[0145] In some embodiments, the compound is [ka] isn't it.

[0146] In some embodiments, R 7 is a (C3-C6)cycloalkyl or a 3- to 10-membered heterocycloalkyl, each of said (C3-C6)cycloalkyl or 3- to 10-membered heterocycloalkyl being selected from 1 to 4 R T In certain embodiments, R 7 is 1 to 4 R T In certain embodiments, R 7 is 1 to 4 R T In one embodiment, R 7 is 1 to 4 R T and optionally substituted 3-10 membered nitrogen-containing heterocycloalkyl.

[0147] In one embodiment, L 4 is a bond, -NH-, -CH2-S(O)2 or -O-; R 7 is (C1-C6) alkyl, (C3-C6) cycloalkyl or 3-10 membered nitrogen-containing heterocycloalkyl, and said (C1-C6) alkyl, (C3-C6) cycloalkyl or 3-10 membered nitrogen-containing heterocycloalkyl is selected from the group consisting of 1 to 4 R T and optionally substituted with 4 If is a bond, R 7 is a substituted or unsubstituted (C3-C6)cycloalkyl or a substituted or unsubstituted 3- to 10-membered nitrogen-containing heterocycloalkyl.

[0148] In certain embodiments, the compound of Formula I, II or IIF is compound F-1, F-2, F-3, F-4, F-5, F-6, F-7, F-8, F-9, F-10, F-11, F-12, F-13, F-14, F-15, F-16, F-17, F-18, F-19 or F-20 as set forth in Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[0149] In one embodiment, L 2 is a bond.

[0150] In one embodiment, L 1 is CH2. In certain embodiments, L 1 is a bond.

[0151] In one embodiment, L 2 is a bond; L 1 is CH2.

[0152] In one embodiment, L 1 is a bond; L 2 is a bond.

[0153] In certain embodiments, ring A is [ka] In one embodiment, W 1 is N. In some embodiments, W 2 is CR Y2 In some embodiments, R Y2 is hydrogen. In some embodiments, W 2 is N. In some embodiments, n1 is 0. For example, ring A is [ka] As another non-limiting example, ring A can be: [ka] In some embodiments, n1 is 1. For example, ring A can be [ka] It could be.

[0154] In certain embodiments, ring A is [ka] In some embodiments, ring A is [ka] In one embodiment, L W is CH2. In some embodiments, W 3 is N. As a non-limiting example of the above embodiment, ring A is [ka] It could be.

[0155] In some embodiments, L 2 is a bond; L 1 is CH; ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] is.

[0156] In one embodiment, L 2 is a bond; L 1 is a bond; ring A is [ka] In some embodiments, ring A is [ka] is.

[0157] In certain embodiments, ring A is selected from the group consisting of 1 to 4 R Y In some embodiments, ring A is (C5-C8)cycloalkylene optionally substituted with [ka] is.

[0158] In some embodiments, a compound of formula IIB: [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0159] In certain embodiments, the compound of Formula I, II, or IIB is Compound B-1, as set forth in Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[0160] In certain embodiments, ring B is [ka] In one embodiment, B 4 is CR 1 For example, B 4 can be CH. In some embodiments, B 1 is CR 1 For example, B 1 can be CH. In some embodiments, B 3 is CR 1 For example, B 3 can be CH. In some embodiments, B 2 is N. In some embodiments, ring B is [ka] For example, ring B is [ka] It could be.

[0161] In certain embodiments, ring B is [ka] In one embodiment, B 4 and B 3 is an independent CR 1 Non-limiting examples of the above embodiment include B 4 and B 3 can be CH. In some embodiments, B 1 is CR 1 For example, B 1 can be CH. In some embodiments, B 2 is N. In some embodiments, ring B is [ka] For example, ring B is [ka] It could be.

[0162] In certain embodiments, ring B is [ka] In one embodiment, B 9 is CR aa In some embodiments, R aa is H. In certain embodiments, R aa is (C1-C6) alkyl. In certain embodiments, R aa is (C1-C3) alkyl. For example, R aa may be methyl. In some embodiments, nb is 0. In some embodiments, nb is 1. In some embodiments, B 9 is CR aa If B 8 and R aa The carbon atoms to which both B are attached have the (R)-configuration. 9 is CR aa If B 8 and R aa The carbon atoms to which both are attached have the (S)-configuration.

[0163] In certain embodiments, ring B is [ka] In one embodiment, B 7 is —O—. In some embodiments, B 8 is —O—. In some embodiments, B 7 is -O-; and B 8 is —O—. In certain embodiments, R aa is H. In certain embodiments, R aais (C1-C6) alkyl. In certain embodiments, R aa is (C1-C3) alkyl. For example, R aa can be methyl. In certain embodiments, R ab is H. In certain embodiments, R ac is H. In certain embodiments, R aa , R ab and R ac are each H. In certain embodiments, R aa is (C-C) alkyl; and R ab and R ac is H. In some embodiments, B 10 is CR 1 For example, B 10 can be CH. In some embodiments, B 11 is CR 1 For example, B 11 can be CH. In some embodiments, B 12 is CR 1 For example, B 12 can be CH. In some embodiments, B 10 , B 11 and B 12 are each independently 1 In one embodiment, B 10 , B 11 and B 12 is CH. In some embodiments, B 8 and R aa The carbon atoms to which both B are attached have the (R)-configuration. 8 and R aa The carbon atoms to which both are attached have the (S)-configuration.

[0164] In certain embodiments, B is [ka] In one embodiment, B 7 is —O—. In some embodiments, B8 is —O—. In some embodiments, B 7 is -O-;B 8 is —O—. In certain embodiments, R aa is H. In certain embodiments, R aa is (C1-C6) alkyl. In certain embodiments, R aa is (C1-C3) alkyl. For example, R aa may be methyl. In some embodiments, B 10 is CR 1 For example, B 10 can be CH. In some embodiments, B 11 is CR 1 For example, B 11 can be CH. In some embodiments, B 12 is CR 1 For example, B 12 can be CH. In some embodiments, B 10 , B 11 and B 12 is an independent CR 1 In one embodiment, B 10 , B 11 and B 12 is CH. In some embodiments, B 8 and R aa The carbon atoms to which both B are attached have the (R)-configuration. 8 and R aa The carbon atoms to which both are attached have the (S)-configuration.

[0165] In certain embodiments, ring B is [ka] and;B 7 and B 8 is -O-;R aa is H or (C1-C3) alkyl, e.g., H or methyl. In certain embodiments, R ab and R acis H. In certain embodiments, R aa is H. In certain embodiments, R aa is (C1-C3) alkyl, e.g., methyl. In some embodiments, B 10 , B 11 and B 12 is CR 1 In one embodiment, B 10 , B 11 and B 12 is CH. In some embodiments, B 8 and R aa The carbon atoms to which both B are attached have the (R)-configuration. 8 and R aa The carbon atoms to which both are attached have the (S)-configuration.

[0166] In certain embodiments, ring B is [ka] and;B 7 and B 8 is -O-;R aa is H or (C1-C3) alkyl. In certain embodiments, R aa is H. In certain embodiments, R aa is (C1-C3) alkyl, e.g., methyl. In some embodiments, B 10 , B 11 and B 12 is CR 1 In one embodiment, B 10 , B 11 and B 12 is CH. In some embodiments, B 8 and R aa The carbon atoms to which both B are attached have the (R)-configuration. 8 and R aa The carbon atoms to which both are attached have the (S)-configuration.

[0167] In certain embodiments, ring B is [ka] and the carbon atom marked with ** has the (R)-configuration.

[0168] In certain embodiments, ring B is [ka] and the carbon atom marked with ** has the (S)-configuration.

[0169] In certain embodiments, ring B is [ka] and the carbon atom marked with ** has the (R)-configuration.

[0170] In certain embodiments, ring B is [ka] and the carbon atom marked with ** has the (S)-configuration. In certain embodiments, R aa is (C1-C3) alkyl. For example, R aa For example, ring B can be [ka] It could be.

[0171] In certain embodiments, ring B is [ka] and the carbon atom marked with ** has the (R)-configuration. In some embodiments, R aa is (C1-C3) alkyl. For example, R aa For example, ring B can be [ka] It could be.

[0172] In certain embodiments, ring B is [ka] In some embodiments, ring B is [ka] is.

[0173] In some embodiments, a compound of formula IIC: [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0174] In certain embodiments, the compound of Formula I, II, or IIC is compound AC-1, as set forth in Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[0175] In some embodiments, L 3 In some embodiments, ring B is selected from the group consisting of (BV) and (B-VI); 3 is a bond. In some embodiments, ring B is (BV) (e.g., ring B is as defined in one or more embodiments, supra); L 3 is a bond.

[0176] In some embodiments, L 3 -Z 1 -Z 2 -*, where * represents the point of attachment to ring C. In some embodiments, ring B is selected from the group consisting of (BI), (B-II), (B-III) and (B-IV), and L 3 -Z 1 -Z 2-*, where * represents the point of attachment to ring C. For example, ring B is (BI) or (B-II); 3 -Z 1 -Z 2 -*.

[0177] In some embodiments, Z 1 is -O-.

[0178] In some embodiments, Z 2 is 1 to 2 R c In certain embodiments, Z is —CH—, optionally substituted with 2 is -CH2-.

[0179] In some embodiments, L 3 is -O-CH2-*, where * represents the point of attachment to ring C.

[0180] In some embodiments, Ring C is selected from the group consisting of phenyl, 5- to 6-membered heteroaryl, and 5- to 10-membered bicycloheteroaryl. In some embodiments, Ring C is selected from the group consisting of phenyl and 6-membered heteroaryl (e.g., pyridyl).

[0181] In some embodiments, b is 1 to 3. In some embodiments, b is 2. In some embodiments, b is 1. In some embodiments, b is 0.

[0182] In some embodiments, ring C is phenyl. In some embodiments, ring C is phenyl; and b is 2. [ka] teeth, [ka] In some embodiments, ring C is phenyl; and b is 1. [ka] teeth, [ka] In some embodiments, ring C is phenyl;

[0183] In certain embodiments, each R b is independently selected from the group consisting of (C-C) alkyl, (C-C) haloalkyl, (C-C) alkoxy, (C-C) haloalkoxy, halogen, and CN. b are independently selected from the group consisting of -F, -Cl, CF3 and CN.

[0184] In certain embodiments, at least one R b is —C(O)NH or —C(O)OH. In certain embodiments, at least one R b is —C(O)NH or —C(O)OH; the remaining R b is independently selected from the group consisting of (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, halogen, and CN.

[0185] In some embodiments, a compound of formula IIA: [ka] (In the formula, R 5 is —OH or —NH, and each remaining variable is independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0186] In certain embodiments, the compound of Formula I, II, or IIA is compound A-1 or A-3, as set forth in Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[0187] In some embodiments, the compound has formula (I-A1): [ka] (In the formula, R cA and R cB is H and R c (independently selected from the group consisting of or a pharmaceutically acceptable salt thereof.

[0188] In certain embodiments of Formula (I-A1), B 1 , B 2 , B 3 and B 4 The ring containing [ka] In one embodiment, B 1 , B 2 , B 3 and B 4 The ring containing [ka] It could be.

[0189] In some embodiments, the compound has formula (I-A2): [ka] (In the formula, R cA and R cB is H and R c (independently selected from the group consisting of or a pharmaceutically acceptable salt thereof.

[0190] In certain embodiments of Formula (I-A2), B 1 , B 2 , B 3 and B 4 The ring containing [ka] In one embodiment, B 1 , B 2 , B 3 and B 4 The ring containing [ka] It could be.

[0191] In certain embodiments of formula (I-A1) or (I-A2), Z 1 is —O—. In certain embodiments of Formula (I-A1) or (I-A2), R cA is H. In certain embodiments of formula (I-A1) or (I-A2), R cB is H.

[0192] In some embodiments, the compound has formula (I-A3): [ka] or a pharmaceutically acceptable salt thereof.

[0193] In certain embodiments of Formula (I-A3), R ab and R ac is H.

[0194] In some embodiments, the compound has formula (I-A4): [ka] or a pharmaceutically acceptable salt thereof.

[0195] In certain embodiments of Formula (I-A4), B 7 is -O-; B 8 is -O-.

[0196] In some embodiments of Formula (I-A3) or (I-A4), R aa is H. In certain embodiments, R aais (C1-C3) alkyl. For example, R aa can be methyl.

[0197] In some embodiments of formula (I-A3) or (I-A4), B 10 , B 11 and B 12 is independently 1 In one embodiment, B 10 , B 11 and B 12 is CH.

[0198] In some embodiments of formula (I-A1), (I-A2), (I-A3), or (I-A4), X 1 is N.

[0199] In some embodiments of formula (I-A1), (I-A2), (I-A3), or (I-A4), X 2 is C.

[0200] In some embodiments of formula (I-A1), (I-A2), (I-A3), or (I-A4), X 5 is C.

[0201] In some embodiments of formula (I-A1), (I-A2), (I-A3), or (I-A4), X 4 is N. In certain embodiments of formula (I-A1), (I-A2), (I-A3) or (I-A4), X 4 is CR y (e.g., CH).

[0202] In some embodiments of Formula (I-A1), (I-A2), (I-A3) or (I-A4), [ka] teeth, [ka] In one embodiment, X4 is N. In some embodiments, X 4 is CR y For example, X 4 can be CH.

[0203] In some embodiments, the compound has Formula (I-B1): [ka] (In the formula, X 6 is N, NR x , C.R. y and C(O); and R cA and R cB is H and R c (independently selected from the group consisting of or a pharmaceutically acceptable salt thereof.

[0204] In certain embodiments of Formula (I-B1), X 1 is C. In certain embodiments of Formula (I-B1), X 2 and X 5 is C. In certain embodiments of Formula (I-B1), X 4 and X 6 is CR y For example, X 4 and X 6 can be CH.

[0205] In certain embodiments of Formula (I-B1), [ka] teeth, [ka] In some embodiments, each R y is H.

[0206] In certain embodiments of Formula (I-B1), L0 is #-P 0 -P 1 is.

[0207] In certain embodiments of Formula (I-B1), Z 1 is —O—. In certain embodiments of Formula (I-B1), R cA is H;R cB is H.

[0208] In certain embodiments of formula (I-A1), (I-A2), (I-A3), (I-A4), or (I-B1), P 0 is a bond;P 1 is 1 to 3 R 0 In some embodiments, P is (C1-C3) alkylene optionally substituted with 1 is (C1-C3) alkylene. For example, P 1 can be -CH2CH2-.

[0209] In certain embodiments of formula (I-A1), (I-A2), (I-A3), (I-A4), or (I-B1), P 0 is -NH-, -N(C1-C3 alkyl) or -O-; P 1 optionally, 1 to 3 R 0 In some embodiments, P is (C1-C3) alkylene optionally substituted with 1 is (C1-C3) alkylene. For example, P 1 can be CH2, CH(Me) or C(Me)2.

[0210] In certain embodiments of formula (I-A1), (I-A2), (I-A3), (I-A4), or (I-B1), P 0 is a bond;P 1 is 1 to 3 R 0 In certain embodiments, P is (C-C)alkenylene optionally substituted with 1 teeth, [ka] where R 0-1 and R 0-2 are independently H or R 0 and ee is T 1 In some embodiments, P 1 teeth, [ka] where ee is T 1 It is the connection point to

[0211] In certain embodiments of formula (I-A1), (I-A2), (I-A3), (I-A4), or (I-B1), P 0 is a bond;P 1 is 1 to 3 R 0 In certain embodiments, P is (C-C)cycloalkylene optionally substituted with 1 teeth, [ka] is.

[0212] In certain embodiments of formula (I-A1), (I-A2), (I-A3), (I-A4), or (I-B1), P 0 is a bond;P 1 teeth, [ka] and each of these is one to two R 0 np is 1, 2, or 3; ee is T 1 It is the connection point to

[0213] In some embodiments of formula (I-A1), (I-A2), (I-A3), (I-A4), or (I-B1), T 1 is C(O)OH.

[0214] In some embodiments of formula (I-A1), (I-A2), (I-A3), (I-A4), or (I-B1), T2 is H or (C1-C3) alkyl.

[0215] In some embodiments of formula (I-A1), (I-A2), (I-A3), (I-A4), or (I-B1), T 2 is a (C1-C3) alkyl substituted with a (C1-C3) alkoxy. For example, T 2 teeth, [ka] It could be.

[0216] In some embodiments of formula (I-A1), (I-A2), (I-A3), (I-A4), or (I-B1), T 2 is (C1-C3) alkyl substituted with S(O)2(C1-C3 alkyl). For example, T 2 teeth, [ka] It could be.

[0217] In some embodiments of formula (I-A1), (I-A2), (I-A3), (I-A4), or (I-B1), T 2 is a (C1-C3) alkyl substituted with a (C3-C6) cycloalkyl. For example, T 2 teeth, [ka] It could be.

[0218] In some embodiments of formula (I-A1), (I-A2), (I-A3), (I-A4), or (I-B1), T 2 is (C1-C3) alkyl substituted with a 3- to 5-membered heterocycloalkyl. 2 is a (C1-C3) alkyl substituted with oxetanyl. For example, T 2 teeth, [ka] It may be possible, as appropriate [ka] The stereocenter in may have the (S)-configuration. 2 is (C1-C3) alkyl substituted with tetrahydrofuranyl. In certain embodiments, T 2 teeth, [ka] is.

[0219] In some embodiments of formula (I-A1), (I-A2), (I-A3), (I-A4), or (I-B1), T 2 is a (C1-C3) alkyl substituted with a 5-membered heteroaryl, wherein the 5-membered heteroaryl is substituted with 1 to 2 R T In some embodiments, T 2 is a (C-C) alkyl substituted with an imidazolyl, wherein the imidazolyl is R T For example, T 2 teeth, [ka] In another non-limiting example, T 2 teeth, [ka] It could be.

[0220] In certain embodiments of formula (I-A1), (I-A2), (I-A3), (I-A4), or (I-B1), L 1 is CH; ring A is [ka] is.

[0221] In certain embodiments of formula (I-A1), (I-A2), (I-A3), (I-A4), or (I-B1), L 1 is CH; ring A is [ka] is.

[0222] In certain embodiments of formula (I-A1), (I-A2), (I-A3), (I-A4), or (I-B1), L 1 is CH; ring A is [ka] is.

[0223] In certain embodiments of formula (I-A1), (I-A2), (I-A3), (I-A4), or (I-B1), L 1 is a bond; ring A is [ka] In some embodiments, ring A is [ka] is.

[0224] In some embodiments of Formula (I-A1), (I-A2), (I-A3), (I-A4), or (I-B1), Ring C is selected from the group consisting of phenyl and 6-membered heteroaryl (e.g., pyridyl, such as 2-pyridyl, 3-pyridyl, or 4-pyridyl).

[0225] In some embodiments of Formula (I-A1), (I-A2), (I-A3), (I-A4) or (I-B1), [ka] teeth, [ka] is.

[0226] In some embodiments of Formula (I-A1), (I-A2), (I-A3), (I-A4) or (I-B1), [ka] teeth, [ka] is.

[0227] In certain embodiments of formula (I-A1), (I-A2), (I-A3), (I-A4), or (I-B1), each R b is independently selected from the group consisting of (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, halogen, and CN.

[0228] In some embodiments of formula (I-A1), (I-A2), (I-A3), (I-A4), or (I-B1), R b are independently selected from the group consisting of -F, -Cl, CF3 and CN.

[0229] In some embodiments, the compound of Formula (I) has the formula (I-A4-1): [ka] [In the formula, [ka] is a single or double bond; R 0-1 is selected from the group consisting of hydrogen and (C1-C3) alkyl; X 4 are N and CR y selected from the group consisting of: T 2is (C1-C3)alkyl substituted with a substituent selected from the group consisting of (C1-C3)alkoxy, S(O)2(C1-C3 alkyl), (C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, wherein said phenyl or 5- to 6-membered heteroaryl are each optionally substituted with halogen or (C1-C3)alkyl; R aa is selected from the group consisting of hydrogen and (C1-C3) alkyl; Ring C is selected from the group consisting of phenyl and 6-membered heteroaryl; b is 0, 1 or 2; and Each R b are independently selected from the group consisting of (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, halogen, and CN. or a pharmaceutically acceptable salt thereof.

[0230] In some embodiments of Formula (I-A4-1), [ka] is a double bond.

[0231] In some embodiments of Formula (I-A4-1), [ka] is a single bond.

[0232] In certain embodiments of Formula (I-A4-1), R 0-1 is hydrogen.

[0233] In certain embodiments of Formula (I-A4-1), R 0-1 is (C1-C3) alkyl. For example, R 0-1 can be methyl.

[0234] In some embodiments of Formula (I-A4-1), [ka] is a double bond; R 0-1 is hydrogen.

[0235] In some embodiments of Formula (I-A4-1), [ka] is a double bond; R 0-1 is methyl.

[0236] In some embodiments of Formula (I-A4-1), [ka] is a single bond; and R 0-1 is hydrogen.

[0237] In some embodiments of Formula (I-A4-1), X 4 is CH.

[0238] In some embodiments of Formula (I-A4-1), X 4 is N.

[0239] In some embodiments of Formula (I-A4-1), T 2 is (C1-C3) alkyl substituted with a 3- to 6-membered heterocycloalkyl. 2 is a (C1-C3) alkyl substituted with oxetanyl. For example, T 2 teeth, [ka] (e.g., T 2 The stereocenter in T may be in the (S)-configuration. 2 is a (C1-C3) alkyl substituted with tetrahydrofuranyl. For example, T 2 teeth, [ka] (e.g., T 2 The stereocenter in can have the (S)-configuration).

[0240] In some embodiments of Formula (I-A4-1), T 2 is (C1-C3) alkyl substituted with a 5-membered heteroaryl, said 5-membered heteroaryl being optionally substituted with (C1-C3) alkyl. In certain embodiments, T 2 is (C1-C3) alkyl substituted with imidazolyl, said imidazolyl being optionally substituted with (C1-C3) alkyl. For example, T 2 teeth, [ka] In another non-limiting example, T 2 teeth, [ka] It could be.

[0241] In some embodiments of Formula (I-A4-1), T 2 is a (C1-C3) alkyl substituted with a (C1-C3) alkoxy. For example, T 2 teeth, [ka] It could be.

[0242] In certain embodiments of Formula (I-A4-1), R aa is (C1-C3) alkyl. For example, R aa is methyl.

[0243] In certain embodiments of Formula (I-A4-1), R aa is hydrogen.

[0244] In some embodiments of Formula (I-A4-1), R aa The carbon attached to both the ring C and the ring B may have the (S)-configuration.

[0245] In some embodiments of Formula (I-A4-1), R aa is (C1-C3) alkyl; R aa and ring C have the (S)-configuration. aa is methyl.

[0246] In some embodiments of Formula (I-A4-1), Ring C is phenyl.

[0247] In some embodiments of Formula (I-A4-1), b is 1 or 2.

[0248] In some embodiments of Formula (I-A4-1), [ka] teeth, [ka] (for example, [ka] )

[0249] In some embodiments of Formula (I-A4-1), [ka] teeth, [ka] (for example, [ka] )

[0250] In certain embodiments of Formula (I-A4-1), each R b is independently selected from the group consisting of -F, -Cl, and -CN. b is independently selected from the group consisting of -F and -Cl. For example, each R b can independently be —F or —Cl.

[0251] In some embodiments of Formula (I-A4-1), R 0-1 is hydrogen or methyl; X 4 is N or CH; T 2 teeth, [ka] selected from the group consisting of: R aa is (C1-C3) alkyl, and the R aa and ring C have the (S)-configuration; ring C is phenyl; and b is 1 or 2.

[0252] In some embodiments, R aa is methyl. In certain embodiments, X 4 is CH. In some embodiments, X 4 is N. In certain embodiments, each R b are independently -F or -Cl.

[0253] In some embodiments, the compound has formula (I-A1): [ka] (In the formula, R cA and R cB is H and R c (independently selected from the group consisting of or a pharmaceutically acceptable salt thereof.

[0254] In certain embodiments of Formula (I-A5), B 1 , B 2 , B 3 and B 4 The ring containing [ka] For example, B 1 , B 2 , B 3 and B 4 The ring containing [ka] It could be.

[0255] In some embodiments, the compound has formula (I-A2): [ka] (In the formula, R cA and R cB is H and R c (independently selected from the group consisting of or a pharmaceutically acceptable salt thereof.

[0256] In some embodiments of Formula (I-A6), B 1 , B 2 , B 3 and B 4 The ring containing [ka] For example, B 1 , B 2 , B 3 and B 4 The ring containing [ka] It could be.

[0257] In certain embodiments of formula (I-A1) or (I-A2), Z 1 is —O—. In certain embodiments of Formula (I-A1) or (I-A2), R cA is H. In certain embodiments of formula (I-A1) or (I-A2), R cB is H.

[0258] In some embodiments, the compound has formula (I-A7): [ka] or a pharmaceutically acceptable salt thereof.

[0259] In certain embodiments of Formula (I-A7), R ab and R ac is H.

[0260] In some embodiments, the compound has formula (I-A8): [ka] or a pharmaceutically acceptable salt thereof.

[0261] In certain embodiments of Formula (I-A8), B 7 is -O-;B 8 is -O-.

[0262] In some embodiments of Formula (I-A7) or (I-A8), R aa is H. In certain embodiments, R aa is (C1-C3) alkyl. For example, R aa can be methyl.

[0263] In some embodiments of formula (I-A7) or (I-A8), B 10 , B 11 and B 12 is independently 1 In one embodiment, B10 , B 11 and B 12 is CH.

[0264] In some embodiments of formula (I-A5), (I-A6), (I-A7), or (I-A8), X 1 is N.

[0265] In some embodiments of formula (I-A5), (I-A6), (I-A7), or (I-A8), X 2 is C.

[0266] In some embodiments of formula (I-A5), (I-A6), (I-A7), or (I-A8), X 5 is C.

[0267] In some embodiments of formula (I-A5), (I-A6), (I-A7), or (I-A8), X 4 is N. In certain embodiments of formula (I-A5), (I-A6), (I-A7) or (I-A8), X 4 is CR y (e.g., CH).

[0268] In some embodiments of Formula (I-A5), (I-A6), (I-A7), or (I-A8), [ka] teeth, [ka] In one embodiment, X 4 is N. In some embodiments, X 4 is CR y For example, X 4 can be CH.

[0269] In some embodiments, the compound has Formula (I-B2): [ka] (In the formula, X 6 is N, NR x , C.R. y and C(O); and R cA and R cB is H and R c (independently selected from the group consisting of or a pharmaceutically acceptable salt thereof.

[0270] In certain embodiments of Formula (I-B2), X 1 is C. In certain embodiments of Formula (I-B2), X 2 and X 5 is C. In certain embodiments of Formula (I-B2), X 4 and X 6 is independently y For example, X 4 and X 6 can be CH.

[0271] In certain embodiments of Formula (I-B2), [ka] teeth, [ka] In some embodiments, each R y is H.

[0272] In certain embodiments of Formula (I-B2), L 0 is #-P 0 -P 1 is.

[0273] In certain embodiments of Formula (I-B2), Z 1 is —O—. In certain embodiments of Formula (I-B2), R cA is H;RcB is H.

[0274] In some embodiments of formula (I-A5), (I-A6), (I-A7), (I-A8), or (I-B2), T 1 is C(O)OH.

[0275] In some embodiments of formula (I-A5), (I-A6), (I-A7), (I-A8), or (I-B2), T 1 is a carboxylic acid bioisostere (eg, tetrazolyl, optionally substituted triazolyl).

[0276] In some embodiments of formula (I-A5), (I-A6), (I-A7), (I-A8), or (I-B2), T 2 is H or (C1-C3) alkyl.

[0277] In some embodiments of formula (I-A5), (I-A6), (I-A7), (I-A8), or (I-B2), T 2 is a (C1-C3) alkyl substituted with a (C1-C3) alkoxy. For example, T 2 teeth, [ka] It could be.

[0278] In some embodiments of formula (I-A5), (I-A6), (I-A7), (I-A8), or (I-B2), T 2 is (C1-C3) alkyl substituted with S(O)2(C1-C3 alkyl). For example, T 2 teeth, [ka] It could be.

[0279] In some embodiments of formula (I-A5), (I-A6), (I-A7), (I-A8), or (I-B2), T 2is a (C1-C3) alkyl substituted with a (C3-C6) cycloalkyl. For example, T 2 teeth, [ka] It could be.

[0280] In some embodiments of formula (I-A5), (I-A6), (I-A7), (I-A8), or (I-B2), T 2 is (C1-C3) alkyl substituted with a 3- to 5-membered heterocycloalkyl. 2 is a (C1-C3) alkyl substituted with oxetanyl. For example, T 2 teeth, [ka] It may be, as appropriate, [ka] The stereocenter in may have the (S)-configuration. In certain embodiments, T 2 is (C1-C3) alkyl substituted with tetrahydrofuranyl. In certain embodiments, T 2 teeth, [ka] is.

[0281] In some embodiments of formula (I-A5), (I-A6), (I-A7), (I-A8), or (I-B2), T 2 is a (C1-C3) alkyl substituted with a 5-membered heteroaryl, wherein the 5-membered heteroaryl is substituted with 1 to 2 R T In some embodiments, T 2 is a (C-C) alkyl substituted with an imidazolyl, wherein the imidazolyl is R T For example, T 2 teeth, [ka] In another non-limiting example, T 2 teeth, [ka] It could be.

[0282] In some embodiments of formula (I-A5), (I-A6), (I-A7), (I-A8), or (I-B2), L 1 is CH; ring A is [ka] is.

[0283] In some embodiments of formula (I-A5), (I-A6), (I-A7), (I-A8), or (I-B2), L 1 is CH2; Ring A is [ka] is.

[0284] In some embodiments of formula (I-A5), (I-A6), (I-A7), (I-A8), or (I-B2), L 1 is CH2; Ring A is [ka] is.

[0285] In some embodiments of formula (I-A5), (I-A6), (I-A7), (I-A8), or (I-B2), L 1 is a bond; ring A is [ka] In some embodiments, ring A is [ka] is.

[0286] In some embodiments of Formula (I-A5), (I-A6), (I-A7), (I-A8), or (I-B2), Ring C is selected from the group consisting of phenyl and 6-membered heteroaryl (e.g., pyridyl, such as 2-pyridyl, 3-pyridyl, or 4-pyridyl).

[0287] In some embodiments of Formula (I-A5), (I-A6), (I-A7), (I-A8), or (I-B2), [ka] teeth, [ka] is.

[0288] In some embodiments of Formula (I-A5), (I-A6), (I-A7), (I-A8), or (I-B2), [ka] teeth, [ka] is.

[0289] In certain embodiments of formula (I-A5), (I-A6), (I-A7), (I-A8), or (I-B2), each R b is independently selected from the group consisting of (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, halogen, and CN.

[0290] In some embodiments of formula (I-A5), (I-A6), (I-A7), (I-A8), or (I-B2), R b are independently selected from the group consisting of -F, -Cl, CF3 and CN.

[0291] In certain embodiments, a compound selected from Table 1, or a pharmaceutically acceptable salt or solvate thereof, is provided. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13]

[0292] In certain embodiments, a compound selected from Table 2, or a pharmaceutically acceptable salt or solvate thereof, is provided. [Table 14]

Table 15

Table 17

Table 19

[0293] The compounds disclosed herein include pharmaceutically acceptable salts thereof. Additionally, the compounds disclosed herein also include other salts of the compounds, which are not necessarily pharmaceutically acceptable salts and may be useful as intermediate compounds for preparing and / or purifying the compounds disclosed herein and / or separating the enantiomers of the compounds disclosed herein. Non-limiting examples of pharmaceutically acceptable salts of the compounds disclosed herein include trifluoroacetic acid salts.

[0294] Furthermore, the compounds disclosed herein or their salts may be isolated in the form of a solvate, and therefore, it is understood that any solvate is included within the scope of the present invention. "Solvate" refers to an association or complex of one or more solvent molecules with a compound of the present disclosure. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine. For example, the compounds disclosed herein and their salts can exist in unsolvated and solvated forms with pharmaceutically acceptable solvents (e.g., water, ethanol, etc.).

[0295] Pharmaceutical Compositions and Administration When used as a pharmaceutical composition, the compounds disclosed herein (e.g., a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof) can be administered in the form of a pharmaceutical composition. These compositions can be prepared by methods well known in the pharmaceutical arts 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., inhalation or insufflation of powders or aerosols (including nebulizers); 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, via 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.

[0296] Also provided herein is a pharmaceutical composition comprising the compound disclosed herein or its pharmaceutically acceptable salt or solvate as an active ingredient in combination with one or more pharmaceutically acceptable excipients (carriers).For example, a pharmaceutical composition prepared using the compound disclosed herein or its pharmaceutically acceptable salt or solvate.In some embodiments, the composition is suitable for topical administration.When preparing the compositions provided herein, the active ingredient is usually mixed with an excipient, diluted by the excipient, or contained in the carrier, for example, in the form of a capsule, sachet, paper or other container.When an excipient is used as a diluent, it can be a solid, semi-solid or liquid substance that acts as a vehicle, carrier or medium for the active ingredient. Thus, composition can be in the form of tablets, pills, powder, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments (e.g., containing 10% by weight of active compound), soft and hard gelatin capsules, suppositories, sterile injection solutions and sterile packaged powders.In some embodiments, composition is formulated for oral administration.In some embodiments, composition is a solid oral formulation.In some embodiments, composition is formulated as tablets or capsules.

[0297] Further provided herein is a pharmaceutical composition comprising the compound disclosed herein or its pharmaceutically acceptable salt or solvate together with a pharmaceutically acceptable excipient.The pharmaceutical composition comprising the compound disclosed herein or its pharmaceutically acceptable salt or solvate as an active ingredient can be prepared by thoroughly mixing the compound disclosed herein or its pharmaceutically acceptable salt or solvate with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.The carrier can be in a wide variety of forms depending on the desired route of administration (for example, oral, parenteral).In some embodiments, the composition is a solid oral composition.

[0298] Suitable pharmaceutically acceptable carriers are well known in the art, and a description of some of these pharmaceutically acceptable carriers is provided in The Handbook of Pharmaceutical Excipients (published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain).

[0299] 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.

[0300] In some embodiments, compound or pharmaceutical compositions 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 Tweens, poloxamer or other similar polymer delivery matrices, serum proteins, such as human serum albumin, buffer substances, such as phosphate, Tris, glycine, sorbic acid, potassium sorbate, saturated vegetable fatty acid partial glyceride mixture, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene polyoxypropylene block polymer and wool fat. Cyclodextrins, such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives, such as hydroxyalkylcyclodextrins (including 2- and 3-hydroxypropyl-β-cyclodextrin) or other solubilized derivatives, can be used to enhance delivery of the compounds described herein. Dosage forms or compositions containing the chemical entities described herein in the range of 0.005% to 100%, with the balance composed of non-toxic excipients, can be prepared. The desired 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).

[0301] In certain embodiments, the compounds and pharmaceutical compositions described herein or pharmaceutical compositions thereof can be administered to a patient in need thereof by any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, intracervical, endosinusial, intratracheal, intraintestinal, epidural, intrainterstitial, intraabdominal, intraarterial, intrabronchial, intracystic, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrarespiratory, intrathecal, intrasynovial, intratesticular, intrathecal, intraductal, intratumoral, intrauterine, intravascular, intravenous, intranasal (e.g., intranasal), nasogastric, oral, parenteral, transdermal, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and vaginal. In certain embodiments, the route of administration is parenteral (eg, intratumoral).

[0302] In some embodiments, the compound described herein, or its pharmaceutically acceptable salt or solvate, or their pharmaceutical compositions can be formulated for parenteral administration, for example, can be formulated for injection by intraarterial, intrasternal, intracerebral, intravenous, intramuscular, subcutaneous or intraperitoneal route.For example, such compositions can be prepared as injectable liquid solution or suspension; can also be prepared as a solid form suitable for preparing solution or suspension by adding liquid before injection; and this preparation can also be emulsified.The preparation of such preparations is known to those skilled in the art from the present disclosure.In some embodiments, a device is used for parenteral administration.For example, such device can include needle injector, microneedle injector, needle-free injector and injection technology.

[0303] In some embodiments, the pharmaceutical forms suitable for injection include sterile aqueous solution or dispersion; formulations containing sesame oil, peanut oil or propylene glycol solution; and sterile powders for the immediate preparation of sterile injectable solution or dispersion.In some embodiments, the form must be sterilized and fluid enough to be easily squirted.In some embodiments, the form must be stable under the conditions of manufacture and storage, and must be prevented from the contamination of microorganisms, such as bacteria and fungi.

[0304] 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), suitable mixtures thereof, and vegetable oils. In some embodiments, proper fluidity can be maintained, for example, by using a coating such as lecithin, maintaining the required particle size during dispersion, and using surfactants. In some embodiments, the action of microorganisms can be prevented by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In some embodiments, isotonic agents (e.g., sugars or sodium chloride) are included. In some embodiments, prolonged absorption of the injectable composition can be achieved by using agents that delay absorption, such as aluminum monostearate and gelatin, in the composition.

[0305] In some embodiments, sterile injectable solution is prepared by incorporating the compound disclosed herein or its pharmaceutically acceptable salt or solvate in the required amount in a suitable solvent with various other components as listed above, and then optionally sterile filtered.In some embodiments, dispersion is prepared by incorporating various sterilized active ingredients into a sterile medium containing a basic dispersion medium and other required components from those listed above.In some embodiments, sterile powder is used to prepare sterile injectable solution.In some embodiments, the preparation method is vacuum drying and freeze-drying technology to obtain powder of active ingredient and additional desired components from the solution previously sterile filtered.

[0306] 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 of various molecular weights and fatty acid esters of polyethylene glycol, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, 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.

[0307] In some embodiments, suppositories can be prepared by mixing the compounds disclosed herein, or their pharmaceutically acceptable salts or solvates, or pharmaceutical compositions disclosed herein, with suitable non-irritating excipients or carriers (e.g., cocoa butter, polyethylene glycol, or suppository wax) that are solid at ambient temperature but liquid at body temperature, so that they melt in the rectum and release the active compound. In some embodiments, the composition for rectal administration is in the form of an enema.

[0308] In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions thereof, are formulated for local delivery to the gastrointestinal or GI tract by oral administration (e.g., solid or liquid formulations).

[0309] In some embodiments, the solid formulation for oral administration includes capsules, tablets, pills, powders, and granules.In some embodiments, the compound disclosed herein or its pharmaceutically acceptable salt or solvate is mixed with one or more pharmaceutically acceptable excipients (for example, sodium citrate or dicalcium phosphate) and / or the following: 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. In some embodiments, the formulation may contain additives such as sorbitol, PEG, PEG-100, PEG-120, PEG-140, PEG-150 PEG-160, PEG-170 PEG-180, PEG-190, PEG-200 PEG-210, PEG-220, PEG-230, PEG-240, PEG-250 PEG-260, PEG-270, PEG-280, PEG-290, PEG-300 PEG-310, PEG-320, PEG-330, PEG-340, PEG-350, PEG-360, PEG-370, PEG-380, PEG-390, PEG-400, PEG-410, PEG-420, PEG-430, PEG-440, PEG-450, PEG-460, PEG-470, PEG-480, PEG-49 ...

[0310] In some embodiments, the pharmaceutical composition is in the form of a unit dosage form such as a pill or tablet, and thus the composition may contain a diluent, such as lactose, sucrose, dicalcium phosphate, etc.; a lubricant, such as magnesium stearate; and a binder, such as starch, gum arabic, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, etc., together with the compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a separate solid formulation, powder, marume solution, or suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglyceride) is encapsulated in a capsule (gelatin or cellulose-based capsule). In some embodiments, unit dosage forms in which one or more compounds of the present application and the pharmaceutical composition or additional active agent are physically separated, such as a granule capsule and each agent in a granule (or tablet in a capsule); a bilayer tablet; a two-compartment gel capsule, etc. In some embodiments, enteric-coated or sustained-release oral formulations are also included.

[0311] 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.

[0312] 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 additives such as tablets and capsules, sterilization is not required. For example, United States Pharmacopeia / National Formulary (USP / NF) standards may be sufficient.

[0313] In some embodiments, the compound disclosed herein, or its pharmaceutically acceptable salt or solvate, or its pharmaceutical composition, is formulated for ophthalmic use.In some embodiments, the ophthalmic composition can 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, EDTA, SofZia (boric acid, propylene glycol, sorbitol and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloroisothiazolinone complex; Allergan, Inc.)).

[0314] In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts or solvates, or pharmaceutical compositions thereof, are formulated for topical administration to the skin or mucosa (e.g., dermal or transdermal). In some embodiments, topical compositions can include ointments and creams. In some embodiments, ointments are typically semi-solid preparations based on petrolatum or other petroleum derivatives. In some embodiments, creams containing 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 certain embodiments, the ointment base, as well as other carriers or vehicles, should be inert, stable, non-irritating, and non-sensitizing.

[0315] In any of the above embodiments, the pharmaceutical compositions described herein may comprise one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[0316] The amount of the compound in a pharmaceutical composition or formulation can vary within the range used by those skilled in the art. Typically, the formulation contains, on a weight percent (wt%) basis, about 0.01 to 99.99 wt% of the compound of the present disclosure based on the total formulation, with the remainder being one or more suitable pharmaceutical excipients. In one embodiment, the compound is present at a level of about 1 to 80 wt%. Representative pharmaceutical formulations are described below.

[0317] Formulation Example 1 - Tablets The following ingredients were first mixed and pressed into a single scored tablet: [Table 29]

[0318] Formulation example 2 - Capsule formulation The following ingredients were first mixed and filled into hard-shell gelatin capsules: [Table 30]

[0319] Formulation Example 3 - Suspension Formulation The following ingredients were mixed to form a suspension for oral administration: [Table 31]

[0320] Formulation Example 4 - Injectable formulation The following ingredients were mixed to form an injectable formulation: [Table 32]

[0321] Formulation Example 5 - Suppositories Suppositories with a total weight of 2.5 g were prepared by mixing the claimed compounds with Witepsol® H-15 (triglycerides of saturated vegetable fatty acids; Riches-Nelson, Inc., New York) to have the following composition: [Table 33]

[0322] In some embodiments, the dosage of the compound disclosed herein or its pharmaceutically acceptable salt or solvate is determined based on many factors, including but not limited to, patient type, age, weight, sex, medical condition, the severity of patient's medical condition, route of administration and the activity of compound or its pharmaceutically acceptable salt or solvate.In some embodiments, the appropriate dosage for specific circumstances can be determined by those skilled in the medical field.In some embodiments, the total daily dosage can be divided and administered in portions throughout the day or administered by the method of providing sustained delivery.

[0323] In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of about 0.01 to about 1000 mg. For example, about 0.1 to about 30 mg, about 10 to about 80 mg, about 0.5 to about 15 mg, about 50 mg to about 200 mg, about 100 mg to about 300 mg, about 200 to about 400 mg, about 300 mg to about 500 mg, about 400 mg to about 600 mg, about 500 mg to about 800 mg, about 600 mg to about 900 mg, or about 700 mg to about 1000 mg. In some embodiments, the dose is a therapeutically effective amount.

[0324] In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts or solvates thereof, are administered in a concentration of from about 0.0002 mg / Kg to about 100 mg / Kg (e.g., from about 0.0002 mg / Kg to about 50 mg / Kg; from about 0.0002 mg / Kg to about 25 mg / Kg; from about 0.0002 mg / Kg to about 10 mg / Kg; from about 0.0002 mg / Kg to about 5 mg / Kg; from about 0.0002 mg / Kg to about 1 mg / Kg; from about 0.0002 mg / Kg to about 0.5 mg / Kg; from about 0.0002 mg / Kg to about 0.1 mg / Kg; from about 0.001 mg / Kg to about 50 mg / Kg; from about 0.001 mg / Kg to about 25 mg / Kg; from about 0.001 mg / Kg to about 10 mg / Kg; from about 0.001 mg / Kg to about 0.001 mg / Kg to about 10 mg / Kg; mg / Kg~about 5 mg / Kg;about 0.001 mg / Kg~about 1 mg / Kg;about 0.001 mg / Kg~about 0.5 mg / Kg;about 0.001 mg / Kg~about 0.1 mg / Kg;about 0.01 mg / Kg~about 50 mg / Kg;about 0.01 mg / Kg~about 25 mg / Kg;about 0.01 mg / Kg~about 10 mg / Kg;about 0.01 mg / Kg~about 5 mg / Kg;about 0.01 mg / Kg~about 1 mg / Kg;about 0.01 mg / Kg~about 0.5 mg / Kg;about 0.01 mg / Kg~about 0.1 mg / Kg;about 0.1 mg / Kg~about 50 mg / Kg;about 0.1 mg / Kg~about 25 mg / Kg; approx. 0.1 mg / Kg ~ approx. 10 In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts or solvates thereof, are administered at a dose of about 100 mg / Kg.

[0325] In certain embodiments, the dosage of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, can be administered on a daily basis (e.g., as a single dose or two or more divided doses) or off-daily (e.g., every day, every other day, every third day, once a week, twice a week, once every two weeks, once a month).

[0326] In certain embodiments, the administration period of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more. In some embodiments, the period of time during which administration is discontinued is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, is administered to a patient for a period of time, followed by a discontinuation period during which administration of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, is discontinued. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, is administered for a first period, followed by a second period after the first period, during which administration is discontinued, followed by a third period during which administration of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, is initiated, followed by a fourth period after the third period during which administration is discontinued. For example, the period during which a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, is administered, 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.

[0327] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, is orally administered to a patient one or more times daily (e.g., once daily, twice daily, three times daily, four times daily, or once daily dose).

[0328] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, is parenterally administered to a patient one or more times daily (e.g., 1 to 4 times daily, 2 times daily, 3 times daily, 4 times daily, or a single daily dose).

[0329] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, is parenterally administered to a patient once a week.

[0330] Treatment method In certain embodiments, the disclosure features methods of treating a patient (e.g., a human) having a disease, disorder, or condition in which modulation of GLP-1R (e.g., inhibition or impairment, and / or increase or attenuation of GLP-1R) is beneficial in treating the underlying pathology and / or symptoms and / or progression of the disease, disorder, or condition. In certain embodiments, the methods described herein can include, or can further include, one or more conditions associated with, or resulting in sequelae of, any one or more of the conditions described herein.

[0331] Provided herein is a method for treating a GLP-1 related disease, disorder, or condition, comprising administering to a patient in need thereof an effective amount of a present compound, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as disclosed herein.

[0332] In certain embodiments, the disease, disorder, or condition includes, but is not limited to, type 1 diabetes, type 2 diabetes, juvenile-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of adults (LADA), obesity (e.g., hypothalamic obesity and monogenic obesity), weight gain due to the use of other medications, idiopathic intracerebral hypertension, Wolfram syndrome, gout, Excessive sugar intake, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, renal disease, adipocyte dysfunction, sleep apnea, visceral fat accumulation, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, vascular restenosis, Thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis , osteoporosis, treatment of addiction, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, and polycystic ovarian syndrome (PCOS).

[0333] In certain embodiments, the disease, disorder, or condition includes, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, gestational diabetes, renal disease (e.g., acute kidney injury, renal tubular dysfunction, inflammatory changes in the proximal tubule), adipocyte dysfunction, sleep apnea, visceral fat accumulation, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, hyperglycemia, postprandial lipemia, metabolic syndrome, and the like. Includes acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS) or any combination thereof.

[0334] In certain embodiments, the disease, disorder, or condition includes, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, idiopathic intracerebral hypertension, Wolfram syndrome, weight gain due to the use of other medications, gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat accumulation, myocardial infarction, peripheral arterial disease, stroke, transient ischemic attack, hyperglycemia, postprandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, dysglycemia, 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.

[0335] In some embodiments, the compounds and pharmaceutical compositions and patient treatment methods described herein induce one or more of the following: blood glucose level reduction (e.g., lowering blood glucose level), blood hemoglobin A1c (HbA1c) level reduction, insulin synthesis promotion, insulin secretion stimulation, beta cell mass increase, gastric acid secretion regulation, gastric emptying regulation, body mass index (BMI) reduction, and / or glucagon production (e.g., level reduction).In some embodiments, the compounds and pharmaceutical compositions and patient treatment methods described herein include lowering blood glucose concentration, lowering blood hemoglobin A1c (HbA1c) concentration, promoting insulin synthesis, stimulating insulin secretion, increasing beta cell mass, regulating gastric acid secretion, regulating gastric emptying, reducing body mass index (BMI), reducing glucagon production (e.g., level reduction), or combinations 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 concentration and serum insulin concentration). Also provided herein is a method for regulating glucose or insulin levels in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein.

[0336] 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 disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as disclosed 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 with type 2 diabetes (T2D). In certain embodiments, the patient is an adult with heart disease. In certain embodiments, the patient has type 2 diabetes (T2D) and heart disease.

[0337] Indications Obesity In some embodiments, the condition, disease or disorder is obesity, and conditions, diseases or disorders 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).

[0338] In some embodiments, the condition, disease or disorder is related to obesity.Examples of such condition, disease or disorder include, but are not limited to, impaired glucose tolerance, diabetes (for example, type 2 diabetes, obesity diabetes), dyslipidemia, hyperlipidemia, hypertension, heart failure, hyperuricemia, gout, fatty liver (including non-alcoholic steatohepatitis (NASH)), coronary heart disease (for example, myocardial infarction, angina pectoris), cerebral infarction (for example, cerebral thrombosis, transient ischemic attack), bone or joint disease (for example, knee osteoarthritis, hip osteoarthritis, spondylitis osteoarthritis, lower back pain), sleep apnea syndrome, obesity hypoventilation syndrome (Pickwickian syndrome), menstrual disorders (for example, abnormal menstrual cycle, menstrual bleeding and cycle abnormalities, amenorrhea, abnormal menstrual symptoms), visceral obesity syndrome and metabolic syndrome.In some embodiments, the compounds and pharmaceutical compositions described herein can be used to treat patients who show both symptoms of obesity and insulin deficiency.

[0339] diabetes In some embodiments, the condition, disease or disorder is diabetes.Non-limiting examples of diabetes include type 1 diabetes, type 2 diabetes (for example, diet-treated type 2 diabetes, sulfonylurea-treated type 2 diabetes, extreme type 2 diabetes, long-term insulin-treated type 2 diabetes), diabetes (for example, non-insulin-dependent diabetes, insulin-dependent diabetes), gestational diabetes, obesity-related diabetes, autoimmune diabetes and borderline diabetes.In some embodiments, the condition, disease or disorder is type 2 diabetes (for example, diet-treated type 2 diabetes, sulfonylurea-treated type 2 diabetes, extreme type 2 diabetes, long-term insulin-treated type 2 diabetes).

[0340] Provided herein is a method 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 disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as disclosed herein.

[0341] Provided herein is a method for treating type 2 diabetes in a patient, comprising administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as disclosed herein, to a patient identified or diagnosed as having type 2 diabetes.

[0342] Also provided herein is a method for treating type 2 diabetes in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as disclosed herein.

[0343] In certain embodiments, the compounds, pharmaceutical compositions, and methods for treating patients with conditions, diseases, or disorders (e.g., type 2 diabetes) described herein reduce fasting plasma glucose levels. In certain embodiments, the compounds, pharmaceutical compositions, and methods for treating patients with conditions, diseases, or disorders (e.g., type 2 diabetes) described herein reduce non-fasting plasma glucose levels. In certain embodiments, the compounds, pharmaceutical compositions, and methods for treating patients with conditions, diseases, or disorders (e.g., type 2 diabetes) described herein reduce HbA1c levels. In certain embodiments, the compounds, pharmaceutical compositions, and methods for treating patients with conditions, diseases, or disorders (e.g., type 2 diabetes) described herein reduce glucagon levels. In certain embodiments, the compounds, pharmaceutical compositions, and methods for treating patients with conditions, diseases, or disorders (e.g., type 2 diabetes) described herein increase insulin levels. In certain embodiments, the compounds, pharmaceutical compositions, and methods for treating patients with conditions, diseases, or disorders (e.g., type 2 diabetes) described herein reduce BMI.

[0344] In certain embodiments, a reduction in fasting plasma glucose levels of about 5% to about 95% is shown with treatment of type 2 diabetes. A reduction in fasting plasma glucose levels of about 15% to about 80% is shown with treatment of type 2 diabetes. A reduction in fasting plasma glucose levels of about 25% to about 60% is shown with treatment of type 2 diabetes. In certain embodiments, a reduction in fasting plasma glucose levels to 126 mg / dL or less, to about 110 mg / dL or less, or to about 90 mg / dL or less is shown with treatment of type 2 diabetes.

[0345] In certain embodiments, a reduction in non-fasting plasma glucose levels of about 5% to about 95% is demonstrated with treatment of type 2 diabetes. A reduction in non-fasting plasma glucose levels of about 15% to about 80% is demonstrated with treatment of type 2 diabetes. A reduction in non-fasting plasma glucose levels of about 25% to about 60% is demonstrated with treatment of type 2 diabetes. In certain embodiments, a reduction in non-fasting plasma glucose levels to about 200 mg / dL or less, about 150 mg / dL or less, or about 130 mg / dL or less is demonstrated with treatment of type 2 diabetes.

[0346] In certain embodiments, treatment of type 2 diabetes mellitus results in a reduction in HbA1c levels of about 5% to about 95%. Treatment of type 2 diabetes mellitus results in a reduction in HbA1c levels of about 15% to about 80%. Treatment of type 2 diabetes mellitus results in a reduction in HbA1c levels of about 25% to about 60%. In certain embodiments, treatment of type 2 diabetes mellitus results in a reduction in HbA1c levels of about 6.5% or less, about 6.0% or less, or about 5.0% or less.

[0347] 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.

[0348] 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.

[0349] In some embodiments, the condition, disease or disorder is related to diabetes (for example, diabetic complications).Non-limiting examples of the disorder related to diabetes include obesity, obesity-related disorder, metabolic syndrome, neuropathy, nephropathy (for example, diabetic nephropathy), retinopathy, diabetic cardiomyopathy, cataract, macroangiopathy, osteopenia, hyperosmolar diabetic coma, infectious diseases (for example, respiratory infection, urinary tract infection, gastrointestinal infection, skin and soft tissue infection, lower limb infection), diabetic gangrene, xerostomia, hearing impairment, cerebrovascular disease, diabetic cachexia, delayed wound healing, diabetic dyslipidemia, peripheral blood circulation disorder, cardiovascular risk factors (for example, coronary artery disease, peripheral artery disease, cerebrovascular disease, hypertension and risk factors related to uncontrolled cholesterol and / or lipid level and / or inflammation), NASH, fracture and cognitive dysfunction.

[0350] 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.

[0351] In certain embodiments, the condition, disease, or disorder is diabetes and obesity (diabetic obesity). In certain embodiments, the compounds described herein are useful for improving the therapeutic effectiveness of metformin.

[0352] Diseases of metabolically important tissues In certain embodiments, the condition, disease, or disorder is a disease of a metabolically important tissue. Non-limiting examples of metabolically important tissues are the liver, adipose tissue, pancreas, kidney, and digestive tract.

[0353] In some embodiments, the condition, disease or disorder is fatty liver disease.Fatty liver disease includes, but is 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.

[0354] Nonalcoholic fatty liver disease (NAFLD) refers to a group of diseases that occur in the absence of alcohol abuse and is typically characterized by the presence of fatty liver (fat in the liver). NAFLD is thought to be associated with various conditions, such as metabolic syndrome (including obesity, diabetes, and hypertriglyceridemia) and insulin resistance. This can cause liver disease in adults and children, eventually leading to cirrhosis (Skelly et al., J Hepatol 2001; 35: 195-9; Chitturi et al., Hepatology 2002; 35(2):373-9). The severity of NAFLD ranges from relatively benign, mainly isolated macrovesicular fatty liver (i.e., nonalcoholic fatty liver or NAFL) to nonalcoholic steatohepatitis (NASH) (Angulo et al., J Gastroenterol Hepatol 2002; 17 Suppl:S186-90).

[0355] Other non-limiting examples of disorders of metabolically important tissues include arthropathy (e.g., osteoarthritis, secondary osteoarthritis), fatty liver (e.g., intrahepatic), fibrosis (e.g., intrahepatic), cirrhosis (e.g., intrahepatic), gallstones, gallbladder disease, gastroesophageal reflux, sleep apnea, hepatitis, fatty liver, bone disorders characterized by altered bone metabolism, e.g., osteoporosis (including postmenopausal osteoporosis), decreased bone strength, osteopenia, Paget's disease, osteolytic metastases in cancer patients, and osteodystrophy in liver disease. and bone metabolism changes 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 syndrome. In some embodiments, the compounds and pharmaceutical compositions described herein can be used to treat surgical trauma by improving post-surgical recovery and / or preventing catabolic reactions that may be caused by surgical trauma.

[0356] Cardiovascular and vascular diseases In some embodiments, the condition, disease or disorder is cardiovascular disease.Non-limiting examples of cardiovascular disease include congestive heart failure, atherosclerosis, arteriosclerosis, coronary heart disease, coronary artery disease, congestive heart failure, coronary heart disease, hypertension, heart failure, cerebrovascular disease (e.g., cerebral infarction), vascular insufficiency, myocardial infarction, elevated blood pressure (e.g., 130 / 85 mm Hg or higher) and prothrombotic conditions (e.g., elevated blood fibrinogen or plasminogen activator inhibitor).

[0357] In some embodiments, the condition, disease or disorder is related to 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.

[0358] Neurological disorders In certain embodiments, the condition, disease, or disorder is a neurological disorder (e.g., a neurodegenerative disorder) or a psychiatric disorder. Non-limiting examples of neurological disorders include idiopathic intracranial hypertension (IIH), brain insulin resistance, mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), anxiety disorders, dementia (e.g., senile dementia), traumatic brain injury, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, Morbus Parkinson's disease, Steele-Richard syndrome, Down's syndrome, myasthenia gravis, neurotrauma, brain trauma, vascular amyloidosis, cerebral hemorrhage with amyloidosis, encephalitis, Friedreich's ataxia, acute confusional disorder, amyotrophic lateral sclerosis (ALS), glaucoma, and apoptosis-mediated degenerative diseases of the central nervous system (e.g., Creutzfeldt-Jakob disease, bovine spongiform encephalopathy (mad cow disease), and chronic wasting syndrome). See, for example, US Publication 20060275288A1 A1.

[0359] In some embodiments, the condition, disease, or disorder is idiopathic intracranial hypertension. Idiopathic intracranial hypertension is characterized by elevated intracranial pressure and papilledema. See, for example, Virdee et al., Ophthalmol Ther. 2020;9(4):767-781. In some embodiments, the compounds, pharmaceutical compositions, and methods described herein reduce cerebrospinal fluid secretion in patients with idiopathic intracranial hypertension. In some embodiments, the compounds, pharmaceutical compositions, and methods described herein reduce intracranial pressure in patients with idiopathic intracranial hypertension. In some embodiments, the compounds, pharmaceutical compositions, and methods described herein alleviate 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 certain embodiments, the patient with idiopathic intracranial hypertension is about 20 to about 30 years old. In certain embodiments, the patient with idiopathic intracranial hypertension is obese.

[0360] In some embodiments, the condition, disease, or disorder is Wolfram syndrome. Wolfram syndrome is caused by a digenic mutation 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 experience 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 olivary nucleus of the patient. 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 alleviate one or more symptoms (eg, any of the symptoms described herein) in patients with Wolfram Syndrome.

[0361] 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 a given addictive substance.See, for example, US Publication 20120021979A1.

[0362] In certain embodiments, the compounds and pharmaceutical compositions described herein are useful for improving learning and memory by enhancing neuroplasticity and promoting cell differentiation, as well as preserving dopamine neuron and motor function in Morbus Parkinson's disease.

[0363] Insulin-Related Conditions and Diseases In certain embodiments, the condition, disease or disorder is impaired fasting glucose (IFG), fasting hyperglycemia (IFG), hyperglycemia, insulin resistance (impaired glucose homeostasis), hyperinsulinemia, increased 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, hyperprolactinemia, hypoglycemia (e.g., nocturnal hypoglycemia), and insulin-related concomitant comatose endpoint.

[0364] In certain embodiments, the compounds and pharmaceutical compositions described herein can reduce or delay the progression of borderline impaired fasting glucose or impaired fasting glucose to diabetes.

[0365] autoimmune disease In some embodiments, condition, disease or disorder is 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 Publication 20120148586A1.

[0366] Gastrointestinal disorders In some embodiments, the condition, disease, or disorder is a stomach or intestinal disorder. Non-limiting examples of these disorders include ulcers of any etiology (e.g., gastric ulcer, Zollinger-Ellison syndrome, drug-induced ulcer, ulcer associated with infection or other pathogens), gastrointestinal diseases, 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).

[0367] 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 or poor food intake, or may be due to concomitant use of a drug (e.g., an insulin sensitizer with PPARγ agonist-like activity, such as troglitazone, rosiglitazone, englitazone, ciglitazone, pioglitazone, etc.). In some embodiments, the weight gain may be pre-obese or may be in an obese patient. In some embodiments, the weight gain may be drug-induced weight gain or weight gain after smoking cessation. In some embodiments, the weight gain may be induced by the use of a steroid or an antipsychotic drug.

[0368] In certain embodiments, the condition, disease, or disorder is an eating disorder (e.g., overeating, binge eating, bulimia, or compulsive overeating) or syndromic obesity (e.g., Prader-Willi syndrome and Bardet-Biedl syndrome).

[0369] Inflammatory diseases In some embodiments, the condition, disease or disorder is inflammatory disease.Non-limiting examples of inflammatory disease include rheumatoid arthritis, spondylitis deformans, osteoarthritis, lower back pain, gout, post-operative or post-traumatic inflammation, abdominal distension, neuralgia, pharyngitis, cystitis, pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory bowel disease), and the inflammation and pro-inflammatory state (for example, the level of inflammatory markers such as pro-inflammatory cytokine C or reactive protein in blood) of metabolically important tissues (including liver, fat, pancreas, kidney and intestine) is increased.

[0370] cancer In some embodiments, the condition, disease, or disorder is cancer. Suitable examples of cancer include breast cancer (e.g., invasive ductal carcinoma, ductal carcinoma in situ, inflammatory breast cancer), prostate cancer (e.g., hormone-dependent prostate cancer, hormone-independent prostate cancer), pancreatic cancer (e.g., pancreatic ductal carcinoma), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), lung cancer (e.g., non-small cell lung cancer, small cell lung carcinoma, malignant mesothelioma), colon cancer (e.g., gastrointestinal stromal tumor), rectal cancer (e.g., gastrointestinal stromal tumor), and rectal cancer (e.g., gastrointestinal stromal tumor). 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 tumor, childhood solid tumors (e.g., Wilms' tumor, childhood kidney tumor), Kaposi's sarcoma, Kaposi's sarcoma caused by AIDS, maxillary sinus tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia).

[0371] Hypothalamic-pituitary disorders In some embodiments, the condition, disease or disorder is related to the hypothalamic pituitary gonadal axis. For example, the condition, disease or disorder is related to the hypothalamic-pituitary ovarian axis. In another example, the condition, disease or disorder is related to the hypothalamic pituitary testis axis. Diseases of the hypothalamic pituitary gonadal axis include, but are not limited to, hypogonadism, polycystic ovarian syndrome, hypothyroidism, hypopituitarism, sexual dysfunction and Cushing's disease.

[0372] In certain embodiments, the diabetes-related condition, disease or disorder is related to the hypothalamic pituitary gonadal axis.

[0373] Pulmonary disease In certain embodiments, the condition, disease, or disorder is associated with a pulmonary disease, including, but not limited to, asthma, idiopathic pulmonary fibrosis, pulmonary hypertension, obstructive sleep apnea, and chronic obstructive pulmonary disease (COPD) (e.g., emphysema, chronic bronchitis, and refractory (irreversible) asthma).

[0374] In certain embodiments, the diabetes-related condition, disease or disorder is a pulmonary disease.

[0375] Combination therapy In certain embodiments, the present invention is intended to include both monotherapy and combination therapy regimens.

[0376] In certain embodiments, the methods described herein can further include administering one or more additional therapies (e.g., one or more additional therapeutic agents and / or one or more treatment regimens) in combination with the administration of the compound of the present application.

[0377] In some embodiments, the methods described herein include administering a compound of the present application 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.

[0378] In certain embodiments, the compounds of the present application, or pharmaceutically acceptable salts or solvates thereof, can be administered in combination with one or more additional therapeutic agents.

[0379] Representative additional therapeutic agents include, but are not limited to, anti-obesity agents, therapeutic agents for diabetes, therapeutic agents for diabetic complications, therapeutic agents for hyperlipidemia, antihypertensive agents, diuretics, chemotherapeutic agents, immunotherapeutic agents, anti-inflammatory agents, antithrombotic agents, antioxidants, therapeutic agents for osteoporosis, vitamins, therapeutic agents for dementia, therapeutic agents for erectile dysfunction, therapeutic agents for urinary frequency or urinary incontinence, therapeutic agents for NAFLD, therapeutic agents for NASH, therapeutic agents for dysuria, and antiemetics.

[0380] 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), GABA receptor agonists (e.g., gabapentin, pregabalin), neuropeptide Y antagonists (e.g., velneperit), peptide YY or analogs thereof, cannabinoid receptor antagonists (e.g., rimonabant, taranabant), and the like. ant), ghrelin antagonists, ghrelin receptor antagonists, ghrelin acylation enzyme inhibitors, opioid receptor antagonists (e.g., GSK-1521498, naltrexone), orexin receptor antagonists, melanocortin 4 receptor agonists, 11β-hydroxysteroid dehydrogenase inhibitors (e.g., AZD-4017, BVT-3498, INCB-13739), pancreatic lipase inhibitors (e.g., orlistat, cetilistat), β3 agonists (e.g., N-5984), diacylglycerol acyltransferase 1 (DGAT1) inhibitors, acetyl-CoA carboxylase (ACC) inhibitors (e.g., International Publication No. WO 2020 / 234726, WO 2020 / 044266 and compounds described in U.S. Patent 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-1 inhibitors, MCR-4 agonists, monoamine reuptake inhibitors, melanocyte-stimulating hormone analogs, 5HT2cagonists, galanin antagonists, eating disorder agents (e.g., bombesin agonists), thyroid hormone mimetics, dehydroepiandrosterone or analogs thereof, human agouti-related protein (AGRP) inhibitors, neuromedin U agonists, NFK inhibitors (e.g., HE-3286), PPAR agonists (e.g., GFT-505, DRF-11605, gemfibrozil, fenofibrate, balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone, CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767, and SB-21 9994), phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate, trodascumine), GPR119 agonists (e.g., PSN-821, MBX-2982, APD597, compounds described in International Publication Nos. WO 2010 / 140092, WO 2010 / 128425, WO 2010 / 128414, WO 2010 / 106457), glucokinase activators (e.g., pyragliatin, AZD-1656, AZD6370, TTP-355, TTP-399, TTP547, ARRY403, MK-0599, TAK-329, AZD5658 or GKM-001, compounds described in International Publication Nos. WO 2010 / 103437, WO 2010 / 103438, WO 2010 / 013161, WO 2007 / 122482, WO 2006 / 112549, WO 2007 / 028135, WO 2008 / 047821, WO 2008 / 050821, WO 2008 / 136428 and WO2008 / 156757), leptin, leptin derivatives (e.g., metreleptin), leptin resistance improving agents, CNTF (ciliary neurotrophic factor), BDNF (brain-derived neurotrophic factor), cholecystokinin agonists, amylin preparations (e.g., pramlintide, AC-2307), neuropeptide Y agonists (e.g., PYY3-36, PYY3-36 derivatives, obinineptide, TM-30339, TM-30335), oxyntomodulin (OXM) preparations, appetite suppressants (e.g., ephedrine), FGF21 preparations (e.g., animal FGF21 preparations extracted from bovine or porcine spleens, preparations; human FGF21 preparations genetically synthesized using E. coli or yeast; fragments or derivatives of FGF21), appetite suppressants (e.g., P-57), human proislet peptide (HIP), melanocortin receptor 4 agonists (e.g., cetamelanoides), melanin-concentrating hormone receptor 1 antagonists, serotonin drugs (e.g., sibutramine, lorcaserin), farnesoid X receptor (FXR) agonists (e.g., obeticholic acid, tropifexor, cilofexor, LY2562175, Met409, TERN-101, EDP305, International Publication No. WO 2020 / 234726 and U.S. Patent No. 2020 / 044266), phentermine, zonisamide, norepinephrine / dopamine reuptake inhibitors (e.g., bupropion), GDF-15 analogs, methionine aminopeptidase 2 (MetAP2) inhibitors (e.g., beloranib or ZGN-1061), diethylpropion, phendimetrazine, benzphetamine, fibroblast growth factor receptor (FGFR) modulators, biotin, MAS receptor modulators, glucagon receptor agonists, CCKa agonists (e.g., compounds described in International Publication No. WO 2005 / 116034 and U.S. Publication No. 2005 / 0287100), and AMP-activated protein kinase (AMPK) activators.

[0381] In some embodiments, one or more additional therapeutic agents include, for example, the agent useful as an antidiabetic agent.Non-limiting examples include insulin and insulin preparations (for example, 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 (for example, INS-1), oral insulin preparations, synthetic human insulin), insulin sensitizers (for example, pioglitazone or its salt), biguanides (for example, metformin, buformin or its salts (for example, hydrochloride, fumarate, succinate)), glucagon analogs (for example, WO 2010 / 011439), drugs that antagonize the action of glucagon or decrease the secretion of glucagon, sulfonylurea drugs (e.g., chlorpropamide, tolazamide, glimepiride, tolbutamide, glibenclamide, gliclazide, acetohexamide, glyclopyramide, glybuzole, glyburide, glipizide), thiazolidinediones (e.g., rosiglitazone, lobeglitazone, troglitazone, balaglitazone, lobeglitazone, or pioglitazone), glitazars ( for example, aleglitazar, tiglitazar, saroglitazar, muraglitazar, tesaglitazar), SGLT2 inhibitors (for example, JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, THR1474, TS-071, ISIS388626, LX4211, remogliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, cerigliflozin etabonate, remogliflozin etabonate, ertugliflozin, WO2010 / 023594), GPR40 agonists (e.g., FFAR1 / FFA1 agonists, e.g., fasiglifam), α-glucosidase inhibitors (e.g., adiposine, camiglibose, pradimicin-Q, salbostatin, voglibose, acarbose, miglitol, emiglitate), insulin secretagogues, e.g., prandial glucose regulators (sometimes referred to as "short-acting secretagogues"), e.g., meglitinides (e.g., repaglinide and nateglinide), cholinesterase inhibitors (e.g., donepezil, galantamine, rivastigmine, tacrine), NMDA receptor antagonists, dual GLP-1 / GIP receptor agonists (e.g., LBT-2000, ZPD1-70), GLP-1R These include agonists (e.g., exenatide, liraglutide, albiglutide, taspoglutide, lixisenatide, semaglutide, AVE-0010, S4P, and Boc5) and dipeptidyl peptidase IV (DPP-4) inhibitors (e.g., vildagliptin, dutogliptin, gemigliptin, alogliptin, saxagliptin, sitagliptin, linagliptin, berberine, adogliptin, anagliptin (SK-0403), teneligliptin, omarigliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, ALS2-0426, TA-6666, TS-021, KRP-104, trelagliptin).

[0382] In certain embodiments, the one or more additional therapeutic agents include, for example, agents useful in the treatment of NAFL and NASH. Non-limiting examples include FXR agonists (e.g., obeticholic acid), PF-05221304, PPARα / δ agonists (e.g., elafibranor), synthetic fatty acid bile conjugates (e.g., aranchol), anti-lysyl oxidase homolog 2 (LOXL2) monoclonal antibodies (e.g., simtuzumab), caspase inhibitors (e.g., emricasan), MAPK5 inhibitors, galectin 3 inhibitors (e.g., GR-MD-02), fibroblast growth factor 21 (FGF21) (e.g., BMS-986036), niacin analogs (e.g., ARJ 3037MO), leukotriene D4 (LTD4) receptor antagonists (e.g., tipekast), acetyl-CoA carboxylase (ACC) inhibitors (e.g., NDI 010976 and International Publication No. WO 2009 / 144554, WO 2003 / 072197, WO 2009 / 144555 and WO 2008 / 065508), ketohexokinase (KHK) inhibitors (e.g., compounds described in WO 2020 / 234726), apoptosis signal-regulating kinase 1 (ASK1) inhibitors (selonsertib), 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., WO No. 2020 / 234726 and U.S. Publication No. 20180051012), CB1 receptor antagonists, anti-CB1R antibodies, glycyrrhizin, scilla extract, ascorbic acid, glutathione, silymarin, lipoic acid and d-alpha-tocopherol, ascorbic acid, glutathione, vitamin B complex, glitazones / thiazolidinediones (e.g., troglitazone, rosiglitazone, pioglitazone, balaglitazone, rivoglitazone, lobeglitazone), metformin, cysteamine, sulfonylureas, alpha-glucosidase inhibitors, meglitinides, vitamin E, tetrahydrolipstatin, milk thistle proteins, antivirals, and antioxidants.

[0383] In some embodiments, the one or more additional therapeutic agents include, for example, agents useful for treating diabetic complications. Non-limiting examples include aldose reductase inhibitors (e.g., tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat, lidrestat), neurotrophic factors and growth factors (e.g., NGF, NT-3, BDNF, neurotrophic production / secretion promoting agents described in WO2001 / 14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxyl)propyl]oxazole, a compound described in WO2004 / 039365), PKC inhibitors (e.g., ruthenium, erythrocyte sedimentation inhibitors ... Examples of such anti-inflammatory drugs include benzodiazepines (e.g., benzodiazepine mesylate), AGE inhibitors (e.g., ALT946, N-phenacylthiazolium bromide (ALT766), EXO-226, pyridoline, pyridoxamine), serotonin and noradrenaline reuptake inhibitors (e.g., duloxetine), sodium channel inhibitors (e.g., lacosamide), reactive oxygen scavengers (e.g., thioctic acid), cerebral vasodilators (e.g., tiapride, mexiletine), somatostatin receptor agonists (e.g., BIM23190), and apoptosis signal-regulating kinase 1 (ASK-1) inhibitors.

[0384] In some embodiments, the one or more additional therapeutic agents include, for example, agents useful for treating hyperlipidemia. Non-limiting examples include HMG-COA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin, or salts thereof (e.g., sodium salts, calcium salts)), squalene synthase inhibitors (e.g., compounds described in WO97 / 10224, such as N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetate, and the like. [1-methyl]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).

[0385] 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, fusinopril, enalapril, ceranopril, cirazopril, delapril, pentopril, quinapril, ramipril, lisinopril), angiotensin II antagonists (e.g., candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, telmisartan, irbesartan, val ... Non-limiting examples of antihypertensive agents include diuretics (e.g., acetaminophen, benzodiazepine, benzocaine ... (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methychlorothiazide, trichloromethiazide, polythiazide, benzthiazide, triclinafen ethacrynate, chlorthalidone, torsemide, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone), alpha adrenergic blockers, beta adrenergic blockers, calcium channel blockers, channel blockers (e.g., diltiazem, verapamil, nifedipine, and amlodipine), vasodilators (e.g., hydrazine), renin inhibitors, AT-1 receptor antagonists (e.g., losartan, irbesartan, and valsartan), ET receptor antagonists (e.g., sitaxsentan, atorsentan, and compounds described in U.S. Patent Nos. 5,612,359 and 6,043,265), dual ET / AII antagonists (e.g., compounds described in WO 2000 / 01389), neutral endopeptidase (NEP) inhibitors, and when the channel blocker is ivabradine, vasopeptidase inhibitors (dual NEP-ACE inhibitors) (e.g., gemopatrilat and nitrate) are included.

[0386] In some embodiments, one or more additional therapeutic agents include, for example, the agent useful as a diuretic.Non-limiting examples include xanthine derivatives (for example, theobromine sodium salicylate, theobromine calcium salicylate), thiazides (for example, ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penfluthiazide, polythiazide, methyclothiazide), antialdosterone agents (for example, spironolactone, triamterene), carbonic anhydrase inhibitors (for example, acetazolamide) and chlorobenzenesulfonamides (for example, chlorthalidone, mefruside, indapamide).

[0387] 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., interferon, interleukin (IL), e.g., IL-1, IL-2, IL-12) and colony-stimulating factors (e.g., granulocyte colony-stimulating factor, erythropoietin).

[0388] In some embodiments, the one or more additional therapeutic agents include, for example, an agent useful as an antithrombotic agent.Non-limiting examples include heparin (e.g., heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarin (e.g., warfarin potassium), antithrombin agents (e.g., argatroban, dabigatran, boroarginine derivatives, boropeptides, heparin, hirudin, and melagatran), FXa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, betrixaban, YM150, compounds described in WO02 / 06234, WO2004 / 048363, WO2005 / 030740, WO2005 / 058823, and WO2005 / 113504), Thrombolytic agents (e.g., anistreplase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), urokinase, tisokinase, alteplase, nateplase, monteplase, pamiteplase, factor VIIa inhibitors, PAI-1 inhibitors, α2-antiplasmin inhibitors, and anisoylated plasminogen streptokinase activator complex) and platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cilostazol, ethyl icosapentate, beraprost sodium, and sarpogrelate hydrochloride) are included.

[0389] In some embodiments, one or more additional therapeutic agents include, for example, drugs useful for treating osteoporosis.Non-limiting examples include alpha calcidol, 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 erectile dysfunction therapeutic agents include apomorphine and sildenafil citrate.Suitable examples of frequent urination or urinary incontinence therapeutic agents include flavoxate hydrochloride, oxybutynin hydrochloride and propiverine hydrochloride.Suitable examples of therapeutic agents for urination disorders include acetylcholinesterase inhibitors (e.g., distigmine).Suitable examples of anti-inflammatory agents include nonsteroidal anti-inflammatory agents, such as aspirin, acetaminophen, and indomethacin.

[0390] 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, anti-dyslipidemic agents, such as HMG-CoA reductase inhibitors (statins, e.g., rosuvastatin), pravastatin, pitavastatin, lovastatin, atorvastatin , simvastatin, fluvastatin, itavastatin, ZD-4522), HMG-CoA synthesis inhibitors, cholesterol-lowering agents, bile acid sequestrants (e.g., cholestyramine, questran, colestipol, and colesveram), cholesterol absorption inhibitors (e.g., plant sterols such as phytosterols), cholesteryl ester transfer protein (CETP) inhibitors, inhibitors of the ileal bile acid transport system (IBAT inhibitors), diacylglyceryl acyltransferase 1 (DGAT1) inhibitors (e.g., AZD7687, LCQ908, compounds described in WO2009 / 016462, WO2010 / 086820), monoacylglycerol O-acyltransferase inhibitors, α-amylase inhibitors (e.g., tendamistat, trestatin, AL-3688), α-glucoside hydrolase inhibitors, SIRT-1 activators, c-Jun N-terminal kinase (JNK) inhibitors, VPAC2 receptor agonists, TGR5 receptor modulators (e.g., the described compounds), GPBAR1 receptor modulators, GPR120 modulators, high affinity nicotinic acid receptor (HM74A) activators, carnitine palmitoyltransferase inhibitors, mineralocorticoid receptor inhibitors, TORC2 inhibitors, fatty acid synthase inhibitors, serine palmitoyltransferase inhibitors, GPR81 modulators, GPR39 modulators, GPR43 modulators, GPR41 modulators, GPR105 modulators, Kv1. 3 modulators, retinol binding protein 4 modulators, somatostatin receptor modulators, PDHK2 modulators,PDHK4 modulators, MAP4K4 inhibitors, IL1 family modulators (e.g., ILIβ modulators), ACAT inhibitors, MTP inhibitors (e.g., diliotapide, mitratapide, and impitapide), lipoxygenase inhibitors, PCSK9 modulators (e.g., alirocumab and evolocumab), RXRα modulators, cysteamine, RNA antisense constructs inhibiting protein tyrosine phosphatase PTPRU, vitamin B complex, pentraxin proteins, protein tyrosine phosphatase-1 B (PTP-1 B) inhibitors (e.g., trodasquemine, hiruthiosal extract, and Zhang, et. al. (Drug Discovery Today. 2007, 12(9-10): 373-381), editinbe, betaine, pentoxifylline, αδ-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 including adrenergic receptor antagonists, e.g., beta-blockers (e.g., atenolol), α-blockers (e.g., doxazosin) and mixed α / β-blockers (e.g., labetalol), adrenergic receptor agonists including α2 agonists (e.g., clonidine), angiotensin-converting enzyme (ACE) inhibitors (e.g., lisinopril), calcium channel blockers such as dihydropyridines (e.g., nifedipine), phenylalkylamines (e.g., verapamil) and benzothiazepines (e.g., diltiazem), angiotensin II receptor antagonists (e.g., candesartan), aldosterone receptor antagonists (e.g., eplerenone, spironolactone), centrally acting adrenergic agents, for example, central alpha agonists (e.g., clonidine), diuretics (e.g., furosemide), torsemide, bemethanide, ethacrynic acid, thiazide diuretics (e.g., chlorothiazide, hydrochlorothiazide, benzthiazide, hydroflumethiazide, bendroflumethiazide, methychlorthiazide, polythiazide, trichlormethiazide, indapamide),Phthalimidine diuretics (e.g., chlorthalidone, metolazone), quinazoline diuretics (e.g., quinethazone), potassium-sparing diuretics (e.g., triamterene and amiloride), thyroid receptor agonists (e.g., compounds described in WO2020 / 117987), hemostasis modulating agents including antithrombotic agents (e.g., activators of fibrinolysis), thrombin antagonists, factor VIIa inhibitors, anticoagulants (e.g., vitamin K antagonists such as warfarin), heparin and and their low molecular weight analogs, factor Xa inhibitors, and direct thrombin inhibitors (e.g., argatroban), antiplatelet agents (e.g., cyclooxygenase inhibitors (e.g., aspirin), nonsteroidal anti-inflammatory drugs (NSAIDS), thromboxane-A2-receptor antagonists (e.g., ifetroban), thromboxane-A2-synthetase inhibitors, PDE inhibitors (e.g., pletal, dipyridamole), purinergic receptor antagonists (e.g., P2Y1 and P2Y 12), adenosine diphosphate (ADP) receptor inhibitors (e.g., clopidogrel), phosphodiesterase inhibitors (e.g., cilostazol), glycoprotein IIB / IIA inhibitors (e.g., tirofiban, eptifibatide, and abciximab), adenosine reuptake inhibitors (e.g., dipyridamole), noradrenergic agonists (e.g., phentermine), serotonergic agents (e.g., sibutramine, lorcaserin), diacylglycerol acyltransferases ferase (DGAT) inhibitors, feeding behavior regulators, pyruvate dehydrogenase kinase (PDK) regulators, serotonin receptor modulators, monoamine transmission modulators such as selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine), noradrenaline reuptake inhibitors (NARIs), noradrenaline serotonin reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs) (e.g., toloxatone and amifluramine), WO 2007 / 013694, WO 2007 / 018314, WO 2008 / 093639 and WO 2008 / 099794, GPR40 agonists (e.g., fasiglifam or a hydrate thereof, WO 2004 / 041266, WO 2004 / 106276, WO 2005 / 063729, WO 2005 / 063725, WO 2005 / 087710,compounds described in WO 2005 / 095338, WO 2007 / 013689 and WO 2008 / 001931), SGLT1 inhibitors, adiponectin or its agonists, IKK inhibitors (e.g., AS-2868), somatostatin receptor agonists, ACC2 inhibitors, anti-cachexia agents, for example, cyclooxygenase inhibitors (e.g., indomethacin), progesterone derivatives (e.g., megestrol acetate), glucocorticoids (e.g., dexamethasone), metoclopramide agents, tetrahydrocannabinol agents, fat substitutes metabolic improvers (e.g., eicosapentaenoic acid), growth hormone, IGF-1, antibodies against cachexia-inducing factors TNF-α, LIF, IL-6, and oncostatin M, metabolic improvers such as glucokinase (GK), glucokinase regulatory protein (GKRP), uncoupling proteins 2 and 3 (UCP2 and UCP3), peroxisome proliferator-activated receptor α (PPARα), MC4r agonists, insulin receptor agonists, PDE 5 inhibitors, glycation inhibitors (e.g., ALT-711), neuroregeneration promoters (e.g., Y-128, VX853, prosaptide), antidepressants (e.g., desipramine, amitriptyline, imipramine), antiepileptics (e.g., lamotrigine, trileptal, keppra, zonegran, pregabalin, halcoceride, carbamazepine), antiarrhythmics (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), topical analgesics (e.g., capsaicin), anxiolytics (e.g., benzothiazepines), phosphodiesterase inhibitors (e.g., sildenafil), dopamine receptor agonists (e.g., apomorphine), cytotoxic antibodies (e.g., T cell receptor-specific antibodies, IL-2 receptor-specific antibodies), B cell depletion therapies (e.g., anti-CD20 antibodies such as Rituxan, i-BLyS antibodies), agents affecting T cell migration (e.g., anti-integrin α4 / β1 antibodies (e.g., Tysabri), ), drugs acting on immunophilins (e.g., cyclosporine, tacrolimus, sirolimus, rapamycin), interferons (e.g., IFN-β), immunomodulators (e.g., glatiramer), TNF-binding proteins (e.g., circulating receptors), immunosuppressants (e.g., mycophenolate), metaglidazen, AMG-131, balaglitazone, MBX-2044, rivoglitazone, aleglitazar, tiglitazar, saroglitazar, muraglitazone Examples of such agents include tetracycline, 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).

[0391] In some embodiments, the one or more additional therapeutic agents include, for example, those useful as antiemetic agents. As used herein, an "antiemetic" agent refers to any agent that neutralizes (e.g., reduces or eliminates) nausea or emesis (vomiting). Without being bound by theory, it is believed that administering one or more antiemetic agents in combination with the compounds described herein may result in a rapid response to treatment, for example, by allowing patients to consume a normal diet, thereby allowing for higher doses of the compounds.

[0392] Non-limiting examples of antiemetic agents include 5HT3-receptor antagonists (serotonin receptor antagonists), neuroleptics / antipsychotics, antihistamines, anticholinergics, steroids (e.g., corticosteroids), NK1 receptor antagonists (e.g., neurokinin 1 substance P receptor antagonists), antidopaminergics / dopamine receptor antagonists, benzodiazepines, and cannabinoids.

[0393] For example, the antiemetic agent is selected from the group consisting of neuroleptics, antihistamines, anticholinergics, steroids, 5HT-3-receptor antagonists, NK1-receptor antagonists, antidopaminergics / dopamine receptor antagonists, benzodiazepines and non-psychoactive cannabinoids.

[0394] In some embodiments, the antiemetic agent is a 5HT3-receptor antagonist (serotonin receptor antagonist). Non-limiting examples of 5HT3-receptor antagonists (serotonin receptor antagonists) include granisetron (Kytril), dolasetron, ondansetron (Zofran), tropisetron, ramosetron, palonosetron, alosetron, azasetron, bemesetron, zatisetron, batanopride, MDL-73147EF; metoclopramide, N-3389 (endo-3,9-dimethyl-3,9-diazabicyclo[3,3,1]non-7-yl-1H-indazole-3-carboxamide dihydrochloride), Y-25130 hydrochloride, MDL 72222, tropanyl-3,5-dimethylbenzoate, 3-(4-allylpiperazin-1-yl)-2-quinoxalinecarbonitrile maleate, zacopride hydrochloride, and mitrazepine. Other non-limiting examples of 5HT3-receptor antagonists (serotonin receptor antagonists) include cilansetron, clozapine, cyproheptadine, dazopride, hydroxyzine, lerisetron, metoclopramide, mianserin, olanzapine, palonosetron (plus netupitant), quetiapine, camosetron, ramosetron, licasetron, risperidone, ziprasidone, and zatosterone.

[0395] In certain embodiments, the 5HT-3-receptor antagonist is granisetron, dolasetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemesetron, zatisetron, batanopride, MDL-73147EF, metoclopramide, N-3389, Y-25130 hydrochloride, MDL 72222, tropanyl-3,5-dimethylbenzoate 3-(4-allyl-piperazin-1-yl)-2-quinoxalinecarbonitrile maleate, zacopride hydrochloride, and mirtazepine.

[0396] In certain embodiments, the 5HT-3-receptor antagonist is granisetron, dolasetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemesetron, and zatisetron.

[0397] In certain embodiments, the 5HT-3-receptor antagonist is granisetron, dolasetron, or ondansetron.

[0398] In certain embodiments, the 5HT-3-receptor antagonist is granisetron.

[0399] In certain embodiments, the 5HT-3-receptor antagonist is ondansetron.

[0400] In some embodiments, the antiemetic agent is an antihistamine. Non-limiting examples of antihistamines include piperazine derivatives (e.g., cyclizine, meclizine, and cinnarizine); promethazine; dimenhydrinate (Dramamine, Gravol); diphenhydramine; hydroxyzine; buclizine; and meclizine hydrochloride (Bonine, Antivert), doxylamine, and mitrazepine.

[0401] In some embodiments, the antiemetic agent is an anticholinergic (an inhibitor of acetylcholine receptors). Non-limiting examples of anticholinergic agents include atropine, scopolamine, glycopyrone, hyoscine, Artane (trihexy-5-trihexyphenidyl hydrochloride), Contin (benztropine mesylate), Akineton (biperiden hydrochloride), Dizipar (Norflex: orphenadrine citrate), diphenhydramine, hydroxyzine, hyoscyamine, and Chemadrin (procyclidine hydrochloride).

[0402] In some embodiments, the antiemetic agent comprises a steroid (e.g., a corticosteroid). Non-limiting examples of steroids include betamethasone, dexamethasone, methylprednisolone, Prednisone®, and trimethobenzamide (Tigan).

[0403] In certain embodiments, the antiemetic agent is an NK1-receptor antagonist (e.g., a neurokinin 1 substance P receptor antagonist). Non-limiting examples of NK1-receptor antagonists include aprepitant, casopitant, ezlopitant, fosaprepitant, maropitant, netupitant, rolapitant, and vestipitant.

[0404] Other non-limiting examples of NK1-receptor antagonists include: MPC-4505, GW597599, MPC-4505, GR205171, L-759274, SR 140333, CP-96,345, BIIF 1149, NKP 608C, NKP 608A, CGP 60829, SR 140333 (norpitantium besylate / chloride), LY 303870 (lanepitant), MDL-105172A, MDL-103896, MEN-11149, MEN-11467, DNK 333A, 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-11974, benserazide and carbidopa, TAK-637 [(aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazotino[2,1-g][1,7]naphthyridine-6,13-dione], PD 154075, ([(2-benzofuran)-CHOCO]-(R)-α-MeTrp-(S)-NHCH(CH)Ph), FK888, and (D-Pro, D-Trp, Phe)SP.

[0405] In some embodiments, the antiemetic agent is an antidopaminergic / dopamine receptor antagonist (e.g., a dopamine receptor antagonist, e.g., a D2 or D3 antagonist). Non-limiting examples include phenothiazines (e.g., promethazine, chlorpromazine, prochlorperazine, perphenazine, hydroxyzine, thiethylperazine, metopimazine); benzamides (e.g., metoclopramide, domperidone), butyrophenones (e.g., haloperidol, droperidol); alizapride, bromopride, clebopride, domperidone, itopride, metoclopramide, trimethobenzamide, and amisulpride.

[0406] In some embodiments, antiemetic agents include non-psychoactive cannabinoids (e.g., cannabidiol (CBD), cannabidiol dimethylheptyl (CBD-DMH), tetra-hydro-cannabinol (THC), cannabinoid agonists such as WIN 55-212 (CB1 and CB2 receptor agonist), dronabinol (Marinol®), and nabilone (Cesamet)).

[0407] Other examples of antiemetics include: c-9280 (Merck); benzodiazepines (diazepam, midazolam, lorazepam); neuroleptic / antipsychotics (e.g., dixyrazine, haloperidol, and prochlorperazine (Compazine®)); cerium oxalate; propofol; sodium citrate; dextrose; fructose (Nauzene); orthophosphate; fructose; glucose (Emetrol); bismuth subsalicylate (Pepto Bismol); ephedrine; vitamin B6; peppermint, lavender, and lemon essential oils; and ginger.

[0408] Further examples of antiemetic agents include those described in US 20120101089A1; US ​​10,071,088 B2; US 6,673,792 B1; US ​​6,197,329 B1; US ​​10,828,297 B2; US 10,322,106 B2; US 10,525,033 B2; WO 2009080351 A1; WO 2019203753 A2; WO 2002020001 A2; US 8,119,697 B2; US 5,039,528; US20090305964A1; and WO 2006 / 111169, each of which is incorporated herein by reference in its entirety.

[0409] 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).

[0410] 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 the pharmaceutical composition.In one example, the additional therapeutic agent or regimen and the compound and the pharmaceutical composition are simultaneously provided to the patient in the same formulation.In another example, the additional therapeutic agent or regimen and the compound and the pharmaceutical composition are simultaneously provided to the patient in separate formulations.

[0411] Patient selection In certain embodiments, the methods described herein further include identifying a patient (e.g., subject) in need of said treatment (e.g., by blood assay, body mass index, or other conventional methods known in the art).

[0412] In certain embodiments, the methods described herein further include a step of identifying a patient (e.g., a subject) having a disease, disorder, or condition provided herein (e.g., a GLP-1-related disease, disorder, or condition).

[0413] In certain embodiments, the methods described herein further include identifying a patient (e.g., a patient) with type 2 diabetes. In certain embodiments, determining whether a patient has type 2 diabetes includes performing an assay to determine hemoglobin A1c (HbA1c) levels, fasting plasma glucose levels, non-fasting plasma glucose levels, 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.

[0414] In some embodiments, fasting plasma glucose levels are from about 120 mg / dL or greater to about 750 mg / dL or greater. In some embodiments, fasting plasma glucose levels are from about 200 mg / dL or greater to about 500 mg / dL or greater. In some embodiments, fasting plasma glucose levels are from about 300 mg / dL or greater to about 700 mg / dL or greater.

[0415] In some embodiments, non-fasting plasma glucose levels are from about 190 mg / dL or greater to about 750 mg / dL or greater. In some embodiments, non-fasting plasma glucose levels are from about 250 mg / dL or greater to about 450 mg / dL or greater. In some embodiments, non-fasting plasma glucose levels are from about 400 mg / dL or greater to about 700 mg / dL or greater.

[0416] In some embodiments, determining whether a patient has type 2 diabetes further includes determining the patient's BMI. In some embodiments, the patient's BMI is about 22 kg / m 2 or greater to about 100 mg / dL or greater. In some embodiments, the patient's BMI is about 30 kg / m 2 or greater to about 90 mg / dL or greater. In some embodiments, the patient's BMI is about 40 kg / m 2 or greater to about 80 mg / dL or greater. In some embodiments, the patient's BMI is about 50 kg / m 2 or higher to about 70 mg / dL or higher.

[0417] In some 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 some embodiments, the patient is about 10 years old or older. In some embodiments, the patient is about 15 years old or older. In some embodiments, the patient is about 20 years old or older. In some embodiments, the patient is about 25 years old or older. In some embodiments, the patient is about 30 years old or older. In some embodiments, the patient is about 35 years old or older. In some embodiments, the patient is about 40 years old or older. In some embodiments, the patient is about 42 years old or older. In some embodiments, the patient is about 44 years old or older. In some embodiments, the patient is about 46 years old or older. In some embodiments, the patient is about 48 years old or older. In some embodiments, the patient is about 50 years old or older. In some embodiments, the patient is about 52 years old or older. In some embodiments, the patient is about 54 years old or older. In some embodiments, the patient is about 56 years old or older. In some embodiments, the patient is about 58 years old or older. In some embodiments, the patient is about 60 years old or older. In some embodiments, the patient is about 62 years old or older. In some embodiments, the patient is about 64 years old or older. In some embodiments, the patient is about 66 years old or older. In some embodiments, the patient is about 68 years old or older. In some embodiments, the patient is about 70 years old or older. In some embodiments, the patient is about 72 years old or older. In some embodiments, the patient is about 74 years old or older. In some embodiments, the patient is about 76 years old or older. In some embodiments, the patient is about 78 years old 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 can be African American, American Indian or Alaska Native, Asian American, Hispanic or Latino American, or Native Hawaiian or Pacific Islander.

[0418] In some embodiments, the patient is a pediatric patient.The term "pediatric patient" used herein refers to patients who are under 21 years old at the time of diagnosis or treatment.The term "child" can be further divided into various subgroups, including neonates (from birth to 1 month); infants (from 1 month to 2 years); children (from 2 to 12 years); and adolescents (from 12 to 21 years (up to but not including their 22nd birthday)).Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: 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 between birth and 28 days of age, between 29 days of age and less than 2 years of age, between 2 and less than 12 years of age, or between 12 and 21 years of age (up to but not including the 22nd birthday). In certain embodiments, the pediatric patient is between birth and 28 days of age, between 29 days of age and less than 1 year of age, between 1 month and less than 4 months of age, between 3 months and less than 7 months of age, between 6 months and less than 1 year of age, between 1 year and less than 2 years of age, between 2 years and less than 3 years of age, between 2 years and less than 7 years of age, between 3 years and less than 5 years of age, between 5 years and less than 10 years of age, between 6 years and less than 13 years of age, between 10 years and less than 15 years of age, or between 15 years and less than 22 years of age. In certain embodiments, the patient is an adult patient.

[0419] General synthesis method The compounds of the present disclosure can be prepared, for example, from readily available starting materials using the following general methods and procedures. Where specific process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it will be 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.

[0420] Furthermore, 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 specific 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.

[0421] Additionally, compounds of the present disclosure may contain one or more chiral centers. Thus, if desired, the compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of the present disclosure, unless otherwise specified. Pure stereoisomers (or enriched mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of the compounds can be separated, for example, using chiral column chromatography, chiral resolving agents, etc.

[0422] 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), Bachem (Torrance, CA USA), EMKA-Chemie Gmbh & Co. KG (Eching Germany) or Millipore Sigma (Burlington, MA USA). Others can be prepared by methods 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 modifications thereof.

[0423] Scheme I illustrates a general method that may be used for the synthesis of compounds described herein, wherein Ring A, Ring B, Ring C, mm, nn, b, T 1 , T 2 , L 0 , L 1 , L 2 , L 3 , R b , X 1 , X 2 , X 3 , X 4 , X 5 and X6 are each as defined herein, and LG is a leaving group such as halo (e.g., Cl, Br, or I), or -L 1 -L 2 together to form oxo. [ka]

[0424] Compounds of formula I can be provided by coupling compound I-1 with compound I-2 under suitable coupling reaction conditions. Exemplary suitable reaction conditions include, but are not limited to, a polar aprotic solvent (e.g., acetonitrile), optionally in the presence of a base (e.g., potassium carbonate), or under reductive amination conditions.

[0425] It should be understood that for the compounds shown in Scheme I, a variety of derivatives may be provided by interconversion of functional groups at any stage. For example, -L 0 -T 1 or T 1 can be used to provide a variety of compounds of formula I by functional group interconversion using methods known to those skilled in the art. Similarly, a variety of compounds of formula I can be provided by R b is a leaving group (e.g., a halo such as Cl, Br, or I, or a pseudohalide such as a triflate, sulfonate, or phosphate) with a compound of formula R b-B, where B is an appropriate functional group, such as, but not limited to, boronic acid or a derivative thereof (e.g., a boronic ester), a zinc or magnesium halide (e.g., tributylstannane or trimethylstannane), a fluorosulfonyl ester, tin, sodium, or hydrogen. The reaction is commonly utilized for aromatic functionalization and typically involves the use of a suitable catalyst (e.g., [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, Pd(OAc)2, Pd(PPh3)4, PdCl2(PPh3)2, or tris(dibenzylideneacetone). The reaction is carried out in the presence of a palladium catalyst, such as dipalladium(0), or a copper catalyst, such as CuCl or CuI, optionally using a suitable solvent / solvent mixture, employing a suitable mediator, co-catalyst, and / or base known to those skilled in the art. After completion of the reaction, the compound of Formula I can be recovered by conventional techniques, such as neutralization, extraction, precipitation, chromatography, or filtration. In certain embodiments, where control of stereochemistry is desired, the formation of various stereoisomers can be determined or maintained, at least in part, by appropriate control of reaction conditions and selection of reagent substituents.

[0426] In certain embodiments, various substituents (e.g., ring A, ring B, ring C, mm, nn, b, T) of formula I-1, I-2, or I-3 are 1 , T 2 , L 0 , L 1 , L 2 , L 3 , R b , X 1 , X 2 , X 3 , X 4 , X 5 and X 6) are as defined herein. However, various compounds of Formula I can be obtained by derivatizing compound I, I-1, or I-2 prior to reaction in any step and / or by further derivatizing the resulting reaction product. Suitable starting materials and reagents can be purchased or prepared by methods known to those skilled in the art. Suitable starting materials and reagents can be purchased or prepared by methods known to those skilled in the art. Upon completion of each reaction, each intermediate or final compound can be recovered and, if desired, purified by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, and the like. Other modifications to arrive at compounds of the present disclosure are within the skill of those skilled in the art. [Example]

[0427] General information: All evaporations were performed in vacuo using a rotary evaporator. Thin-layer chromatography (TLC) was performed on silica gel plates, and spots were visualized with UV light (214 and 254 nm). Column and flash chromatographic purifications were performed using silica gel (100-200 mesh). Solvent systems are listed as volumetric mixtures. NMR spectra were recorded on a Bruker 400 or Varian (400 MHz) spectrometer. 1H chemical shifts are reported in δ values ​​in ppm using deuterated solvents as internal standards. Data are as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constant (Hz), and integration. LCMS spectra were obtained on a SHIMADZU LC20-MS2020 or Agilent 1260 series 6125B mass spectrometer, Agilent 1200 series 6110 or 6120 mass spectrometer equipped with an electrospray ionizer unless otherwise stated.

[0428] The present disclosure will be further understood by reference to the following examples, which are intended to be purely exemplary of the present disclosure. The present disclosure is not limited in scope by the exemplified embodiments, which are intended only as illustrations of one aspect of the present disclosure. Any methods that are functionally equivalent are within the scope of the present disclosure. Various modifications of the present disclosure, in addition to those described herein, will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to be encompassed by the appended claims.

[0429] Method 1: (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridine (F-6) [ka]

[0430] Step A: (Z)-5-Bromo-N'-hydroxy-6-methylnicotinimidamide A mixture of 5-bromo-6-methylnicotinonitrile (60 mg, 0.31 mmol) and 50% aqueous NHOH (202 mg, 3.1 mmol) in EtOH (3 mL) was stirred at 90 °C for 1 h. The mixture was concentrated to give (Z)-5-bromo-N'-hydroxy-6-methylnicotinimidamide (60 mg, 87% yield). MS calculated: 229.0; MS found: 230.0 [M+H] +

[0431] Step B: 3-(5-bromo-6-methylpyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole To a solution of (Z)-5-bromo-N'-hydroxy-6-methylnicotinimidamide (60 mg, 0.26 mmol) in THF (3 mL) was added dropwise TFAA (550 mg, 2.6 mmol) at 0 °C. The mixture was warmed to rt and stirred for 16 h. Aqueous NaHCO3 and EtOAc were added to the mixture to adjust the pH to 7 or higher, the organic phase was washed with brine, dried over Na2SO4, and the solvent was concentrated to dryness to give a residue that was purified by prep-TLC to give 3-(5-bromo-6-methylpyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (80 mg). MS calculated: 307.0; MS found: 307.9 [M+H] +

[0432] Step C: 3-(5-(3,6-dihydro-2H-pyran-4-yl)-6-methylpyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole A mixture of 3-(5-bromo-6-methylpyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (80 mg, 0.26 mmol) in dioxane / HO (4 mL / 1 mL) was added to 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (101 mg, 0.52 mmol) and Pd(dppf)Cl (21 mg, 0.03 mmol) under N. The mixture was stirred at 90 °C for 8 h. Water and EtOAc were added to the mixture, the organic phase was washed with brine, dried over Na2SO4, and the residue was purified by prep-TLC to give 3-(5-(3,6-dihydro-2H-pyran-4-yl)-6-methylpyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (11 mg, yield: 13.5%). MS calculated: 311.1; MS found: 312.1 [M+H] + .

[0433] Step D: 3-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridine A mixture of 3-(5-(3,6-dihydro-2H-pyran-4-yl)-6-methylpyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (21 mg, 0.068 mmol) and 85% aqueous NH2NH2·H2O (0.2 mL) in EtOH (0.5 mL) was stirred at 70 °C for 1 h. The crude product was obtained by lyophilization together with the solvent. The crude product was purified by prep-TLC to give 3-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridine (16 mg, yield: 76.5%). MS calculated: 310.1; MS found: 311.1 [M+H] +

[0434] Step E: 2-methyl-3-(tetrahydro-2H-pyran-4-yl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridine A mixture of 3-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridine (16 mg, 0.052 mmol) in EtOAc / MeOH (5 mL / 0.5 mL) was added to Pd / C 10 wt% (10 mg) under a H balloon at room temperature with stirring for 16 hours. The mixture was purified by prep-TLC to give 2-methyl-3-(tetrahydro-2H-pyran-4-yl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridine (14 mg, yield: 86.9%). MS calculated: 312.1; MS found: 313.0 [M+H] + .

[0435] Step F: 5-(tetrahydro-2H-pyran-4-yl)-3-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)picolinaldehyde To a mixture of 2-methyl-3-(tetrahydro-2H-pyran-4-yl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridine (14 mg, 0.045 mmol) in dioxane (3 mL) was added SeO (50 mg, 0.448 mmol) with stirring at 80 °C for 16 h. The mixture was filtered, and the filtrate was concentrated to give 5-(tetrahydro-2H-pyran-4-yl)-3-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)picolinaldehyde (13 mg, yield: 89%), which was used directly without further purification. MS calculated: 326.1; MS found: 327.1 [M+H] + .

[0436] Step G: (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridine (F-6) A mixture of (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine (21 mg, 0.041 mmol), TEA (0.028 mL, 0.20 mmol) in DCM (4 mL) was stirred at 0 °C for 30 min. Then, a mixture of 5-(tetrahydro-2H-pyran-4-yl)-3-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)picolinaldehyde (13 mg, 0.040 mmol) and NaBH(OAc) (34 mg, 0.16 mol) was added slowly with stirring at 0 °C for 15 min. The mixture was then allowed to warm to rt with stirring for 3 h. Water and DCM were added to the mixture, and the organic phase was washed with brine and dried over Na SO . The solvent was concentrated to dryness. The residue was purified by pre-HPLC (0.1% NH H O) to give (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridine (1.0 mg, yield: 3.8%). MS calculated: 657.2; MS found: 658.0 [M+H] + . 1H NMR (400 MHz, MeOD-d4):δ 9.09 (s, 1 H), 8.45 (s, 1 H), 7.63 - 7.58 (t, J = 16.4 Hz, 1 H), 7.29 (dd, J = 2.0 Hz / J = 10.8Hz, 2 H), 7.22 (dd, J = 2.0 Hz / J = 8.4 Hz, 1 H), 6.82 - 6.75 (m, 3 H), 4.58 (s, 2 H), 4.12 - 4.09 (dd, J =3.2 Hz / J = 11.2 Hz, 2 H), 3.67 (s, 1 H), 3.64 - 3.61(dd, J = 1.6 Hz / J = 12 Hz, 1 H), 3.48 (m, 1H), 3.30 (m, 1 H), 3.13 (m, 1 H), 2.05 - 1.93 (m, 2 H),1.83 - 1.79 (m, 2 H), 1.33 - 1.29 (m, 6). 19 F NMR (377 MHz, MeOD-d4):δ 65.01, -112.37.

[0437] Method 2: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(tetrahydro-2H-pyran-3-yl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridine (F-10) [ka] Step A: 5-(3,4-dihydro-2H-pyran-5-yl)-6-methylnicotinonitrile To a mixture of 2-(3,4-dihydro-2H-pyran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (200 mg, 0.95 mmol) in dioxane / HO (4 mL / 1 mL) was added 5-bromo-6-methylnicotinonitrile (186 mg, 0.95 mmol), Pd(dppf)Cl (70 mg, 0.01 mmol), and KCO (393 mg, 2.8 mmol) under N. The mixture was stirred at 90 °C for 8 h. Water and EtOAc were added to the mixture, the organic phase was washed with brine, dried over NaSO, and the residue was purified by prep-TLC to give 5-(3,4-dihydro-2H-pyran-5-yl)-6-methylnicotinonitrile (60 mg, yield: 31.6%). MS calculated: 200.0; MS found: 201.0 [M+H] + .

[0438] Step B: (Z)-5-(3,4-dihydro-2H-pyran-5-yl)-N'-hydroxy-6-methylnicotinimidamide A mixture of 5-(3,4-dihydro-2H-pyran-5-yl)-6-methylnicotinonitrile (60 mg, 0.3 mmol) and 50% aqueous NHOH (198 mg, 3 mmol) in EtOH (3 mL) was stirred at 90 °C for 1 h. The mixture was concentrated to give (Z)-5-(3,4-dihydro-2H-pyran-5-yl)-N'-hydroxy-6-methylnicotinimidamide (70 mg). MS calculated: 233.0; MS found: 234.1 [M+H] +

[0439] Step C: 3-(5-(3,4-dihydro-2H-pyran-5-yl)-6-methylpyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole To a solution of (Z)-5-(3,4-dihydro-2H-pyran-5-yl)-N'-hydroxy-6-methylnicotinimidamide (70 mg, 0.3 mmol) in THF (3 mL) was added dropwise TFAA (500 mg, 2.4 mmol) at 0 °C. The mixture was allowed to warm to rt with stirring for 16 h. Aqueous NaHCO and EtOAc were added to the mixture to adjust the pH to 7 or higher. The organic phase was washed with brine, dried over NaSO, and the solvent was concentrated to dryness to give a residue that was purified by prep-TLC to give 3-(5-(3,4-dihydro-2H-pyran-5-yl)-6-methylpyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (80 mg, yield: 86%). MS calculated: 311.2; MS found: 312.2 [M+H] +

[0440] Step D: 3-(3-(3,4-dihydro-2H-pyran-5-yl)-4-methylphenyl)-5-(trifluoromethyl)-4H-1,2,4-triazole A mixture of 3-(5-(3,4-dihydro-2H-pyran-5-yl)-6-methylpyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (80 mg, 0.26 mmol) and 85% aqueous NH2NH2·H2O (0.2 mL) in EtOH (0.5 mL) was stirred at 70 °C for 1 h. The crude product was obtained by lyophilization together with the solvent. The crude product was purified by prep-TLC to give 3-(3-(3,4-dihydro-2H-pyran-5-yl)-4-methylphenyl)-5-(trifluoromethyl)-4H-1,2,4-triazole (30 mg, yield: 37.5%). MS calculated: 310.10; MS found: 311.1 [M+H] +

[0441] Step E: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(tetrahydro-2H-pyran-3-yl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridine 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(tetrahydro-2H-pyran-3-yl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridine (13 mg) was obtained using a method similar to that described in Example 1. MS calculated: 657.2; MS found: 658.2 [M+H] + . 1 H NMR (400 MHz, MeOD-d4):δ 8.95 (d, J = 1.6 Hz, 1 H), 8.29 (d, J = 2.0 Hz, 1 H), 7.58 - 7.52 (m, 2 H), 7.35 - 7.31 (m, 1 H), 6.80 - 6.78 (m, 2 H), 6.70 (dd, J1= 4.0 Hz, J2= 8.8 Hz, 1 H), 3.99 - 3.82 (m, 4 H), 3.49 - 3.40 (m, 3 H), 2.93 - 2.91 (m, 2 H), 2.68 - 2.64 (m, 1 H), 2.33 - 2.26 (m, 2 H), 2.04 - 1.97 (m, 5 H), 1.75 - 1.67 (m, 6 H). 19 F NMR (377 MHz, MeOD-d4):δ 65.01, -112.37.

[0442] Method 3: (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(oxetan-3-yl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridine (F-19) [ka] Step A: 2-methyl-3-(oxetan-3-yl)-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridine A mixture of 3-bromo-2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridine (105 mg, 0.24 mmol), trifluoro(oxetan-3-yl)borate (118 mg, 0.72 mmol), Pd(dppf)Cl (18 mg, 0.02 mmol), KCO (133 mg, 0.96 mmol), water (0.5 ml) and t-butanol (1 ml) in toluene (10 mL) was stirred at 100 °C for 16 h in a microwave apparatus. The mixture was poured into water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the residue was purified by prep-TLC (PE:EA=4:1) to give 2-methyl-3-(oxetan-3-yl)-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridine (22 mg, yield: 22.2). MS calculated: 414.2; MS found: 415.3 [M+H] +

[0443] Step B: 3-(oxetan-3-yl)-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)picolinaldehyde A mixture of 2-methyl-3-(oxetan-3-yl)-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridine (22 mg, 0.05 mmol) and SeO (59 mg, 0.53 mmol) in 1,4-dioxane (2 mL) was stirred at 80 °C for 16 h. The mixture was filtered and the residue was concentrated to give 3-(oxetan-3-yl)-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)picolinaldehyde (35 mg). MS calculated: 428.1; MS found: 429.0 [M+H] +

[0444] Step C: (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(oxetan-3-yl)-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridine A mixture of (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine 4-methylbenzenesulfonate (47 mg, 0.09 mmol) and TEA (42 mg, 0.42 mmol) in DCM (5 mL) was stirred at room temperature for 0.5 h. To the mixture was added 3-(oxetan-3-yl)-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)picolinaldehyde (35 mg, 0.08 mmol), and the mixture was stirred for 2 h. To the mixture was added NaBH(OAC) (69 mg, 0.33 mmol), and the mixture was stirred at room temperature for 16 h. The mixture was poured into water (30 mL) and extracted with DCM (2 x 30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the residue was concentrated to give (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(oxetan-3-yl)-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridine (70 mg). MS calculated: 759.3; MS found: 760.3 [M+H] + .

[0445] Step D: (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(oxetan-3-yl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridine A mixture of (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(oxetan-3-yl)-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridine (70 mg, 0.09 mmol) and TABF (1 M in THF, 2 mL) in THF (1 mL) was stirred at 60° C. for 6 h. The mixture was purified by prep-HPLC to give (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(oxetan-3-yl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridine (0.9 mg, yield: 1.6%). MS calculated: 629.2; MS found: 630.2 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ 8.97 (s, 1 H), 8.24 (s, 1 H), 7.61 (t, J = 7.4 Hz, 1 H), 7.25 (dd, J = 6.8 Hz / J = 23.6 Hz, 2 H), 6.84 - 6.74 (m, 3 H), 3.67 - 3.52 (m, 11 H), 3.07 - 2.91 (m, 1 H), 2.26 - 2.20 (m, 7 H). 19 F NMR (377 MHz, CD3OD):δ -73.9), -75.85, -112.05.

[0446] Method 4: 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(cyclopentyloxy)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridine (F-12) [ka] Step A: 5-Bromo-3-(cyclopentyloxy)picolinonitrile A mixture of 5-bromo-3-fluoropicolinonitrile (2.0 g, 9.9 mmol), cyclopentanol (943 mg, 10.9 mmol), and CsCO (9.7 g, 29.8 mmol) in ACN (20 mL) was stirred at 70 °C for 13 h. The reaction mixture was cooled to room temperature. The mixture was extracted with HO (100 mL) and EA (3 × 200 mL). The combined organic layers were washed with brine (150 mL). The organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (5 / 1) to give 5-bromo-3-(cyclopentyloxy)picolinonitrile (2.0 g, yield: 76.2%). MS calculated: 266.0; MS found: 267.0 [M+H] + .

[0447] Step B: 5-Bromo-3-(cyclopentyloxy)picolinaldehyde Under nitrogen, DIBAH (1.0 M in THF, 5.6 mL) was added dropwise to a stirred solution of 5-bromo-3-(cyclopentyloxy)picolinonitrile (1.0 g, 3.7 mmol) in dry THF (10 mL) at −78 °C. The reaction mixture was stirred at −60 °C for 1 h. The mixture was diluted with saturated sodium potassium tartrate solution (100 mL) and extracted with EA (3 × 200 mL). The combined organic layers were washed with brine (150 mL). The organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3 / 1) to give 5-bromo-3-(cyclopentyloxy)picolinaldehyde (390 mg, yield: 38.5%). MS calculated: 269.01; MS found: 269.9 [M+H].

[0448] Step C: 5-bromo-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(cyclopentyloxy)pyridine To a mixture of 5-bromo-3-(cyclopentyloxy)picolinaldehyde (390 mg, 1.44 mmol), 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine (502 mg, 1.44 mmol) in DCM (4 mL) was added NaBH(OAc) (916 mg, 4.32 mmol). The reaction mixture was stirred at rt for 2 h. The mixture was diluted with HO (50 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (150 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (50 / 1) to give 5-bromo-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(cyclopentyloxy)pyridine (650 mg, yield: 75.0%). MS calculated: 600.1; MS found: 602.9 [M+H+2] + .

[0449] Step D: 6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(cyclopentyloxy)nicotinonitrile A mixture of 5-bromo-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(cyclopentyloxy)pyridine (200 mg, 0.33 mmol), Zn(CN) (117 mg, 1.00 mmol), and Pd(PPh) (34 mg, 0.03 mmol) in DMF (2 mL) was stirred under N and irradiated in a microwave oven at 160 °C for 2 h. The mixture was diluted with HO (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (150 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (30 / 1) to give 6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(cyclopentyloxy)nicotinonitrile (114 mg, yield: 63.6%). MS calculated: 547.20; MS found: 548.1 [M+H] + .

[0450] Step E: (E)-6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(cyclopentyloxy)-N'-hydroxynicotinimidamide A mixture of 6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(cyclopentyloxy)nicotinonitrile (144 mg, 0.21 mmol), TEA (210 mg, 2.08 mmol), and NH2OH HCl (87 mg, 1.25 mmol) in EtOH (2 mL). The reaction mixture was stirred at 90 °C for 2 h. The mixture was diluted with HO (50 mL) and extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (150 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (10 / 1) to give (E)-6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(cyclopentyloxy)-N'-hydroxynicotinimidamide (115 mg, yield: 95.2%). MS calculated: 580.23; MS found: 581.0 [M+H] + .

[0451] Step F: 3-(6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(cyclopentyloxy)pyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole A mixture of (E)-6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(cyclopentyloxy)-N'-hydroxynicotinimidamide (115 mg, 0.20 mmol), TFAA (166 mg, 0.79 mmol) in THF (2 mL). The reaction mixture was stirred at room temperature for 4 h. The mixture was diluted with HO (50 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (150 mL). The organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (10 / 1) to give 3-(6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(cyclopentyloxy)pyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (130 mg, yield: 98.6%). MS calculated: 658.20; MS found: 659.0 [M+H] + .

[0452] Step G: 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(cyclopentyloxy)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridine (F-12) A mixture of 3-(6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(cyclopentyloxy)pyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (130 mg, 0.20 mmol) and NH2NH2·H2O (29.6 mg, 0.59 mmol) in EtOH (3 mL) was stirred at 80 °C for 16 h. After completion of the reaction, the reaction mixture was purified by Prep-HPLC to give 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(cyclopentyloxy)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridine (14.9 mg, yield: 11.3%). MS calculated: 657.2; MS found: 658.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6):8.76 (d, J=1.6 Hz, 1 H), 7.94 (s, J=1.2 Hz, 1 H), 7.53-7.59 (m, 2 H), 7.34 (dd, J=8.4 Hz, 1.6 Hz, 1 H), 6.79-6.80 (m, 2 H), 6.71-6.75 (m, 1 H), 5.04-5.05 (m, 1 H), 3.91 (s, 2 H), 3.16-3.18 (m, 2 H), 2.67-2.71 (m, 1 H), 2.55-2.61 (m, 2 H), 1.89-2.02 (m, 5H), 1.65-1.83 (m, 10 H).

[0453] Method 5: 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-N-(2-methoxyethyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-amine (F-4) [ka]

[0454] Step A: 5-amino-6-methylnicotinonitrile A mixture of 5-bromo-2-methylpyridin-3-amine (8.0 g, 42.8 mmol), Zn(CN) (15.0 g, 128.2 mmol), and Pd(PPh) (2.48 g, 2.15 mmol) in DMF (20 mL) was stirred under Ar with microwave irradiation at 100 °C for 2 h. The reaction mixture was filtered, the filter cake was washed with a small amount of DMF, and the filtrate was purified by flash reverse-phase chromatography and concentrated in vacuo to give 5-amino-6-methylnicotinonitrile (3.0 g, 52.8% yield).

[0455] Step B: 5-Bromo-6-methylnicotinonitrile To a solution of 5-amino-6-methylnicotinonitrile (3.0 g, 21.9 mmol) and isopentyl nitrate (15.5 g, 87.6 mmol) in ACN (50 mL) was added the mixture, which was stirred at room temperature for 2 hours, then heated to 60°C and stirred for 2 hours. HBr / water (48% in water, 140 mL) and CuBr (4.7 g, 32.8 mmol) were added, and the mixture was stirred at 60°C under Ar for 2 hours. The mixture was poured into aqueous NaHCO3 (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (PE:EA = 20:1) to give 5-bromo-6-methylnicotinonitrile (2.8 g, yield: 65.1%). MS calculated: 196.0; MS found: 197.2 [M+H] +

[0456] Step C: 5-Bromo-N'-hydroxy-6-methylnicotinimidamide A mixture of 5-bromo-6-methylnicotinonitrile (2.8 g, 14.3 mmol) and aqueous NHOH (50%) (9.1 g, 142.9 mmol) in EtOH (30 mL) was stirred at 90° C. for 1 h. The mixture was concentrated to give 5-bromo-N′-hydroxy-6-methylnicotinimidamide (3.0 g, crude). MS calculated: 229.0; MS found: 230.0 [M+H] + .

[0457] Step D: 3-(5-bromo-6-methylpyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole To a solution of 5-bromo-N'-hydroxy-6-methylnicotinimidamide (3.0 g, crude) in THF (10 mL) was added TFAA (25.7 g, 131.0 mmol) in THF (20 mL) dropwise at 0 °C. The mixture was stirred at room temperature for 16 hours. The mixture was poured into sodium bicarbonate solution (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated to give 3-(5-bromo-6-methylpyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (4.0 g). MS calculated: 307.0; MS found: 308.1 [M+H] +

[0458] Step E: 3-Bromo-2-methyl-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridine A mixture of 3-(5-bromo-6-methylpyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (4.0 g, 13.0 mmol) and NHNH·HO (6 ml) in EtOH (30 mL) was stirred at 70 °C for 1 h. The mixture was purified by prep-HPLC to give 3-bromo-2-methyl-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridine (4.5 g, crude). MS calculated: 306.0; MS found: 307.1 [M+H] +

[0459] Step F: 3-Bromo-2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridine To a solution of 3-bromo-2-methyl-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridine (4.5 g, 14.7 mmol) in THF (150 mL) was then added NaH (60%, w / w 2.4 g, 58.8 mmol), and the mixture was stirred at 50° C. for 0.5 h. Then, SEMCl (7.4 g, 44.10 mmol) was added, and the mixture was stirred at 50° C. for 16 h. The mixture was poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (PE:EA=8:1) to give 3-bromo-2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridine (4.3 g, yield: 67.5%). MS calculated: 436.0; MS found: 437.1 [M+H] +

[0460] Several positional isomers may exist, and we choose A-1 as a representative structure. [ka]

[0461] Step G: N-(2-methoxyethyl)-2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-amine A mixture of 3-bromo-2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridine (60 mg, 0.14 mmol), 2-methoxyethan-1-amine (20 mg, 0.28 mmol), Pd(OAc) (3 mg, 0.01 mmol), Xphos (13 mg, 0.03 mmol), and CsCO (134 mg, 0.41 mmol) in toluene (5 mL) was stirred at 90 °C under argon for 16 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by prep-TLC (PE:EA=2:1) ​​to give N-(2-methoxyethyl)-2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-amine (32 mg, yield: 53.0%). MS calculated: 431.2; MS found: 432.2 [M+H] +

[0462] Step H: 3-((2-methoxyethyl)amino)-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)picolinaldehyde A mixture of N-(2-methoxyethyl)-2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-amine (32 mg, 0.07 mmol) and SeO (82 mg, 0.74 mmol) in 1,4-dioxane (2 mL) was stirred at 80 °C for 16 h. The mixture was filtered, and the filtrate was concentrated to give 3-((2-methoxyethyl)amino)-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)picolinaldehyde (33 mg, crude). MS calculated: 445.2; MS found: 446.3 [M+H] +

[0463] Step I: (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-N-(2-methoxyethyl)-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-amine

[0464] A mixture of (R)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine (43 mg, 0.08 mmol) and TEA (38 mg, 0.38 mmol) in DCM (5 mL) was stirred at room temperature for 0.5 h. 3-((2-Methoxyethyl)amino)-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)picolinaldehyde (33 mg, 0.07 mmol) was added, and the mixture was stirred for 2 h. NaBH(OAc)3 (63 mg, 0.30 mmol) was added, and the mixture was stirred at room temperature for 16 h. The mixture was poured into water (30 mL) and extracted with DCM (2 x 30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated to give (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-N-(2-methoxyethyl)-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-amine (50 mg, yield: 92.0%). MS calculated: 776.3; MS found: 777.4 [M+H] +

[0465] Step J: 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-N-(2-methoxyethyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-amine (F-4) A mixture of (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-N-(2-methoxyethyl)-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-amine (50 mg, 0.06 mmol) and TABF (1M, 2 mL) in THF (1 mL) was stirred at 60° C. for 6 hours. The mixture was purified by prep-HPLC to give 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-N-(2-methoxyethyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-amine (F-4) (5.3 mg, yield: 13.8%). MS calculated: 646.2; MS found: 647.3 [M+H] + 1 H NMR (400 MHz, CD3OD):δ 8.37 (s, 1 H), 7.63 - 7.55 (m, 2 H), 7.34 - 7.17 (m, 2 H), 6.83 - 6.67 (m, 3 H), 3.86 (s, 2 H), 3.77 - 3.68 (m, 2 H), 3.50 - 3.37 (m, 6 H), 3.08 - 2.97 (m, 2 H), 2.83 - 2.70 (m, 1 H), 2.40 - 2.25 (m, 2 H), 2.03 (s, 3 H), 1.99 -1.80 (m, 4 H). 19 F-NMR (377 MHz, CD3OD):δ -66.36, -112.28.

[0466] Method 6: (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-N-cyclopentyl-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-amine (F-11) [ka]

[0467] Step A: N-cyclopentyl-2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-amine A mixture of 3-bromo-2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridine (60 mg, 0.14 mmol), cyclopentanamine (23 mg, 0.28 mmol), Pd(OAc) (3 mg, 0.014 mmol), XPhos (13 mg, 0.027 mmol), and CsCO (134 mg, 0.41 mmol) in toluene (5 mL). The mixture was stirred at 90 °C under argon for 16 h. The mixture was poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the residue was concentrated. The residue was removed of volatiles in vacuo and purified by prep-TLC to give N-cyclopentyl-2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-amine (32 mg, 52.5% yield). MS calculated: 441.2; MS found: 442.2 [M+H] +

[0468] Step B: (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-N-cyclopentyl-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-amine (F-11) (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-N-cyclopentyl-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-amine (2.3 mg) was obtained in a similar manner to Method 5. MS calculated: 656.2; MS found: 659.5 [M+H] + 1 H NMR (400 MHz, CD3OD):δ 8.33 (s, 1 H), 7.63 - 7.55 (m, 2 H), 7.31 - 7.18 (m, 2 H), 6.80 - 6.74 (m, 1 H), 6.71 - 6.66 (m, 2 H), 3.96 - 3.91 (m, 1 H), 3.84 - 3.79 (m, 2 H), 3.06 - 2.95 (m, 2 H), 2.76 - 2.65 (m, 1 H), 2.33 - 2.24 (m, 2 H), 2.16- 2.04 (m,2 H), 2.04 (s, 3 H), 1.92 - 1.57 (m, 10 H). 19 F NMR (377 MHz, CD3OD):δ -66.22, -112.06.

[0469] Method 7: 4-[2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]morpholine (F-1) [ka] Step A: 4-(2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)morpholine A mixture of 3-bromo-2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridine (50 mg, 0.11 mmol), morpholine (20 mg, 0.23 mmol), Pd(OAc) (3 mg, 0.01 mmol), Xphos (11 mg, 0.02 mmol), and CsCO (112 mg, 0.34 mmol) in toluene (8 mL) was stirred at 90 °C under argon for 16 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by prep-TLC (PE:EA=2:1) ​​to give 4-(2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)morpholine (40 mg, yield: 78.7%). MS calculated: 443.2; MS found: 444.6 [M+H] +

[0470] Step B: 4-[2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]morpholine (F-1) 4-[2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]morpholine (F-1) (5.0 mg) was obtained in a similar manner to Method 5. MS calculated: 658.2; MS found: 659.3 [M+H] + 1H NMR (400 MHz, CD3OD):δ 9.05 (d, J = 1.6 Hz, 1 H), 8.29 (d, J = 1.6 Hz, 1 H), 7.62 (t, J = 8.4 Hz, 1 H), 7.33 - 7.20 (m, 2 H), 6.89 - 6.73 (m, 3 H), 4.61 (s, 2 H), 3.91 (t, J = 4.4 Hz, 4 H), 3.70 - 3.60 (m, 2 H), 3.30 - 3.21 (m, 2 H), 3.09 - 3.00 (m, 5 H), 2.35 - 2.05 (m, 4 H), 2.08 (s, 3 H). 19 F-NMR (377 MHz, CD3OD):δ -65.47, -112.21.

[0471] Method 8: 5-[2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]-2-oxa-5-azabicyclo[2.2.1]heptane (F-5) [ka] Step A: 5-(2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-2-oxa-5-azabicyclo[2.2.1]heptane A mixture of 3-bromo-2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridine (50 mg, 0.11 mmol), 2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (15 mg, 0.11 mmol), Pd(OAc) (3 mg, 0.01 mmol), Xphos (11 mg, 0.02 mmol), and CsCO (150 mg, 0.46 mmol) in toluene (8 mL) was stirred at 90 °C under argon for 16 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by prep-TLC (PE:EA=2:1) ​​to give 5-(2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (46 mg, yield: 88.2%). MS calculated: 455.2; MS found: 456.3 [M+H] +

[0472] Step B: 5-[2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]-2-oxa-5-azabicyclo[2.2.1]heptane (F-5) 5-[2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]-2-oxa-5-azabicyclo[2.2.1]heptane (F-5) (1.0 mg) was obtained in a similar manner to Method 5. MS calculated: 670.2; MS found: 671.4 [M+H] + . 1H NMR (400 MHz, CD3OD):δ 8.82 (s, 1 H), 8.00 (s, 1 H), 7.62 (t, J = 8.4 Hz, 1 H), 7.34 - 7.18 (m, 2 H), 6.88 - 6.72 (m, 3 H), 4.67 (s, 1 H), 4.60 - 4.49 (m, 1 H), 4.44 (s, 1 H), 4.39 - 4.30 (m, 1 H), 4.11 (d, J = 8 Hz, 1 H), 3.90 (d, J = 8 Hz, 1H), 3.73 - 3.50 (m, 4 H), 3.30 - 3.15 (m, 2 H), 3.08 - 2.98 (m, 1 H), 2.35 - 2.13 (m, 2 H), 2.13 - 1.98 (m, 7 H). 19 F-NMR (377 MHz, CD3OD):δ -64.99, -112.25.

[0473] Method 9: (S)-4-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)piperazin-2-one (F-9) [ka] Step A: 4-(2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)piperazin-2-one A mixture of 3-bromo-2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridine (50 mg, 0.115 mmol), tert-butyl 2-oxopiperazine-1-carboxylate (23 mg, 0.115 mmol), and Pd(dba) (11 mg, 0.011 mmol) in toluene (5 mL) was stirred with Xantphos (13 mg, 0.023 mmol) and CsCO (112 mg, 0.344 mmol) at 110 °C for 16 h under argon. The mixture was poured into water (50 mL) and extracted with EA (2 × 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the residue was concentrated. The residue was purified by TLC gel to give 4-(2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)piperazin-2-one (50 mg, yield: 78.1%). MS calculated: 456.2; MS found: 457.3 [M+H] +

[0474] Step D: (S)-4-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)piperazin-2-one (S)-4-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)piperazin-2-one (0.5 mg) was obtained in a similar manner to Method 5. MS calculated: 671.2; MS found: 672.3 [M+H] +

[0475] 1H NMR (400 MHz, CD3OD):δ 9.06 (s, 1 H), 8.34 (s, 1 H), 7.65 - 7.59 (m, 1 H), 7.30 - 7.21 (m, 2 H), 6.84 - 6.73 (m, 3 H), 4.54 (s, 2 H), 3.73 (s, 2 H), 3.58 - 3.48 (m, 2 H), 3.43 - 3.41 (m, 2 H), 3.07 - 3.03 (m, 4 H), 3.01 (s, 1 H), 2.28 - 2.13 (m, 2 H), 2.02 - 2.00 (m, 5 H). 19 F NMR (377 MHz, CD3OD-d4):δ -64.96, -112.31.

[0476] Method 10: (S)-1-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-methylazetidine-3-carbonitrile (F-18) [ka] Step A: 3-methyl-1-(2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)azetidine-3-carbonitrile A mixture of 3-bromo-2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridine (40 mg, 0.09 mmol), 3-methylazetidine-3-carbonitrile hydrochloride (24 mg, 0.18 mmol), Pd(OAC) (2 mg, 0.01 mmol), Xphos (9 mg, 0.02 mmol), and CsCO (120 mg, 0.37 mmol) in toluene (5 mL) was stirred at 90 °C for 16 h under argon. The mixture was filtered, and the residue was concentrated. The residue was purified by prep-TLC to give 3-methyl-1-(2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)azetidine-3-carbonitrile (40 mg, yield: 96.5%). MS calculated: 452.2; MS found: 453.3 [M+H] +

[0477] Step B: (S)-1-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-methylazetidine-3-carbonitrile (F-18) (S)-1-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-methylazetidine-3-carbonitrile (13 mg) was obtained in a similar manner to Method 5. MS calculated: 667.2; MS found: 668.4 [M+H] + 1H NMR (400 MHz, CD3OD):δ 8.80 (d, J = 1.6 Hz, 1 H), 7.67 - 7.59 (m, 2 H), 7.33 - 7.20 (m, 2 H), 6.89 - 6.74 (m, 3 H), 4.53 (s, 2 H), 4.46 (d, J = 7.2 Hz, 2 H), 4.10 (d, J = 7.2 Hz, 2 H), 3.79 (d, J = 10.0 Hz, 2 H), 3.40 - 3.32 (m, 2 H), 3.16 - 3.14 (m, 1 H), 2.39 - 2.27 (m, 2 H), 2.21 - 2.01 (m, 2 H), 2.06 (s, 3H), 1.79 (s, 3H). 19 F NMR (377 MHz, CD3OD):δ -66.74, -77.13, -112.22.

[0478] Method 11: 1-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-methylpyrrolidine-3-carbonitrile (F-13) [ka] Step A: 3-Methylpyrrolidine-3-carbonitrile hydrochloride A mixture of tert-butyl 3-cyano-3-methylpyrrolidine-1-carboxylate (150 mg, 0.71 mmol) and HCl·dioxane (1.5 mL) in DCM (4 mL) was stirred at room temperature for 1 h. The mixture was concentrated to give 3-methylpyrrolidine-3-carbonitrile hydrochloride (79 mg, 96.8% yield). MS calculated: 110.1; MS found: 111.3 [M+H]. +

[0479] Step B: 3-methyl-1-(2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)pyrrolidine-3-carbonitrile A mixture of 3-bromo-2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridine (40 mg, 0.092 mmol), 3-methylpyrrolidine-3-carbonitrile hydrochloride (79 mg, 0.46 mmol), and Pd(dba) (8 mg, 0.009 mmol) in toluene (5 mL) with BINAP (11 mg, 0.018 mmol) and t-BuOK (31 mg, 0.27 mmol) was stirred at 120 °C for 16 h under argon. The mixture was poured into water (50 mL) and extracted with EA (2 × 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the residue was concentrated. The residue was purified by pre-TLC gel to give 3-methyl-1-(2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)pyrrolidine-3-carbonitrile (33 mg, yield: 76.7%). MS calculated: 466.2; MS found: 467.4 [M+H] +

[0480] Step C: 1-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-methylpyrrolidine-3-carbonitrile 1-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-methylpyrrolidine-3-carbonitrile (10.7 mg) was obtained in a similar manner to Method 5. MS calculated: 681.2; MS found: 682.4 [M+H] + . 1 H NMR (400 MHz, CD3OD-d4):δ 8.88 (s, 1 H), 8.09 (s, 1 H), 7.61 (t, J = 8.4 Hz, 1 H), 7.29 (d, J = 11.2 Hz, 1 H), 7.22 (d, J = 9.6 Hz, 1 H), 6.83 - 6.76 (m, 3 H), 4.52 - 4.48 (m, 2 H), 3.78 - 3.61 (m, 4 H), 3.39 - 3.37 (m, 1 H), 3.24 - 3.15 (m, 2 H), 3.04 - 2.98 (m, 1 H), 2.58 - 2.50 (m, 1 H), 2.21 - 2.05 (m, 9 H), 1.62 (s, 3 H). 19 F NMR (377 MHz, CD3OD-d4):δ:(-65.22), (-112.23).

[0481] Method 12: 1-[2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]pyrrolidin-3-ol (F-7) [ka] Step A: 1-(2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)pyrrolidin-3-ol A mixture of 3-bromo-2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridine (20.00 mg, 0.459 mmol), pyrrolidin-3-ol (14.00 mg, 0.115 mmol), and Pd(dba) (4 mg, 0.005 mmol) in toluene (5 mL) was stirred with BINAP (6 mg, 0.009 mmol) and t-BuOK (15 mg, 0.138 mmol) at 120 °C for 16 h under argon. The mixture was poured into water (50 mL) and extracted with DCM (2 × 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by TLC gel to give 1-(2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)pyrrolidin-3-ol (24 mg, yield: 82.3%). MS calculated: 443.2; MS found: 444.0 [M+H] +

[0482] Step B: 1-[2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]pyrrolidin-3-ol (F-7) 1-[2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]pyrrolidin-3-ol (F-7) (0.8 mg) was obtained in a similar manner to Method 5. MS calculated: 658.2; MS found: 659.0 [M+H] + 1H NMR (400 MHz, CD3OD) :δ 8.80 (s, 1 H), 8.48 (s, 1 H), 7.99 (s, 1 H), 7.65 - 7.60 (m, 1 H), 7.30 (dd, J = 1.2 Hz / J = 10.0 Hz, 1 H), 7.22 (dd, J = 2.4 Hz / J = 4.8 Hz, 1 H), 6.86 - 6.75 (m, 3 H), 5.37 - 5.32 (m, 1 H), 4.57 - 4.53 (m, 4 H), 3.70 - 3.55 (m, 4 H), 3.23 -3.20 (m, 2 H), 3.08 - 2.99 (m, 1H), 2.38 - 2.17 (m, 2 H), 2.17 - 1.99 (m, 7 H). 19 F-NMR (377 MHz, CD3OD):δ -65.28, -112.25.

[0483] Method 13: 3-[2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]-1,3-oxazolidin-2-one (F-2) [ka] Step A: 3-(2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)oxazolidin-2-one A mixture of 3-bromo-2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridine (40 mg, 0.09 mmol), oxazolidin-2-one (40 mg, 0.46 mmol), Pd(OAc) (2 mg, 0.01 mmol), Xphos (9 mg, 0.01 mmol), and CsCO (89 mg, 0.27 mmol) in toluene (5 mL) was stirred at 90 °C under argon for 16 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by prep-TLC (DCM:MeOH=30:1) to give 3-(2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)oxazolidin-2-one (35 mg, yield: 87.8%). MS calculated: 443.2; MS found: 444.3 [M+H] +

[0484] Step B: 3-[2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]-1,3-oxazolidin-2-one (F-2) 3-[2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]-1,3-oxazolidin-2-one (F-2) (7.1 mg) was obtained in a similar manner to Method 5. MS calculated: 658.2; MS found: 659.4 [M+H] + 1H NMR (400 MHz, CD3OD):δ 9.26 (s, 1 H), 8.51 (s, 1 H), 7.62 (t, J = 8.2 Hz, 1 H), 7.29 (d, J = 10.8 Hz, 1 H), 7.23 (d, J = 8.0 Hz, 1 H), 6.89 - 6.74 (m, 3 H), 4.67 (t, J = 8.0 Hz, 2 H), 4.58 (s, 2 H), 4.24 (t, J = 7.8 Hz, 2 H), 3.78-3.68 (m, 2 H), 3.15 - 3.01 (m, 2 H), 2.40 - 2.05 (m, 8 H). 19 F-NMR (377 MHz, CD3OD):δ -66.18, -112.43.

[0485] Method 14: 4-(3-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridazin-4-yl)-2-methylmorpholine (F-17) [ka] Step A: 5-chloro-6-methylpyridazine-3-carbonitrile A mixture of 4,6-dichloro-3-methylpyridazine (1.89 g, 11.6 mmol), zinc cyanide (0.68 g, 5.8 mmol), Pd(dba) (0.53 g, 0.58 mmol), and dppf (0.51 g, 0.9 mmol) in DMF (20 mL) was stirred at 90 °C for 3 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature. The mixture was diluted with water (40 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to give 5-chloro-6-methylpyridazine-3-carbonitrile (1.59 g, yield: 89.3%).

[0486] Step B: 6-methyl-5-(2-methylmorpholino)pyridazine-3-carbonitrile A mixture of 5-chloro-6-methylpyridazine-3-carbonitrile (300 mg, 1.96 mmol), 2-methylmorpholine (238 mg, 2.35 mmol), and DIEA (379 mg, 2.94 mmol) in DMF (5 mL) was stirred at 80 °C for 1 h under a N atmosphere. The reaction mixture was cooled to room temperature. The mixture was quenched with HO (10 mL) and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (10 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 1) to give 6-methyl-5-(2-methylmorpholino)pyridazine-3-carbonitrile (440 mg, yield: 92.7%, 90% purity). MS calculated: 218.1; MS found: 219.1 [M+H] + .

[0487] Step C: 6-formyl-5-(2-methylmorpholino)pyridazine-3-carbonitrile A mixture of 6-methyl-5-(2-methylmorpholino)pyridazine-3-carbonitrile (400 mg, 1.83 mmol) and SeO (407 mg, 3.67 mmol) in dioxane (6 mL) was stirred at 80 °C for 3 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, quenched with HO (10 mL), and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (10 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 1) to give 6-formyl-5-(2-methylmorpholino)pyridazine-3-carbonitrile (330 mg, yield: 66%, 85% purity). MS calculated: 232.1; MS found: 233.1 [M+H] + .

[0488] Step D: 6-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(2-methylmorpholino)pyridazine-3-carbonitrile To a solution of 6-formyl-5-(2-methylmorpholino)pyridazine-3-carbonitrile (330 mg, 1.4 mmol) and (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine (740 mg, 1.4 mmol, TsOH salt) in MeOH (8 mL) was added sodium cyanoborohydride (268 mg, 4.3 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with HO (20 mL) and extracted with EA (3 x 40 mL). The combined organic layers were washed with brine (20 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (PE / EA=5 / 1) to give 6-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(2-methylmorpholino)pyridazine-3-carbonitrile (110 mg, yield: 13.7%). MS calculated: 563.2; MS found: 564.2 [M+H] + .

[0489] Step E: (Z)-6-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-N'-hydroxy-5-(2-methylmorpholino)pyridazine-3-carboximidamide To a solution of 6-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(2-methylmorpholino)pyridazine-3-carbonitrile (110 mg, 0.19 mmol) in ethyl alcohol (3 mL) was added hydroxylamine hydrochloride (27 mg, 0.39 mmol) and TEA (59 mg, 0.58 mmol). The resulting mixture was stirred at 70 °C for 1 h. The reaction mixture was diluted with EA (20 mL) and washed with HO (10 mL). The organic layer was dried over NaSO and purified. The filtrate was concentrated under reduced pressure to give (Z)-6-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-N'-hydroxy-5-(2-methylmorpholino)pyridazine-3-carboximidamide (110 mg, yield: 94%). The crude product was used directly in the next step without further purification. MS calculated: 596.2; MS found: 597.2 [M+H] + .

[0490] Step F: 4-(3-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridazin-4-yl)-2-methylmorpholine To a solution of (Z)-6-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-N'-hydroxy-5-(2-methylmorpholino)pyridazine-3-carboximidamide (110 mg, 0.18 mmol) in THF (4 mL) was added TFAA (155 mg, 0.74 mmol) at room temperature. The resulting mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 mL) and then extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (PE / EA=2 / 1) to give 4-(3-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridazin-4-yl)-2-methylmorpholine (80 mg, yield: 64%). MS calculated: 674.2; MS found: 675.2 [M+H] + .

[0491] Step G: 4-(3-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridazin-4-yl)-2-methylmorpholine (F-17) To a solution of 4-(3-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridazin-4-yl)-2-methylmorpholine (80 mg, 0.12 mmol) in DMF (1.5 mL) was added hydrazine hydrate (24 mg, 0.47 mmol). The resulting mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo. The residue was purified by prep-HPLC to give 4-(3-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridazin-4-yl)-2-methylmorpholine (20.4 mg, yield: 25%). MS calculated: 673.2; MS found: 674.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6):δ 10.27 (brs, 1 H), 7.77 (s, 1 H), 7.57-7.65 (m, 2 H), 7.35 (dd, J=8.4 Hz, 2.0 Hz, 1 H), 6.84-6.92 (m, 2 H), 6.73-6.80 (m, 1 H), 4.71-4.89 (m, 2 H), 3.93-3.96 (m, 1 H), 3.73-3.85 (m, 2 H), 3.53-3.68 (m, 2 H), 3.28-3.45 (m, 4 H), 2.93-3.13 (m, 2 H), 2.74-2.84 (m, 1 H), 2.10-2.26 (m, 2 H), 1.92-2.05 (m, 5 H), 1.19 (d, J=6.4 Hz, 3 H). 19 F NMR (377 MHz, DMSO-d6):δ -63.72, -110.51.

[0492] Method 15: (S)-7-(3-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridazin-4-yl)-4-oxa-7-azaspiro[2.5]octane (F-8) [ka] Step A: 6-methyl-5-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyridazine-3-carbonitrile A mixture of 5-chloro-6-methylpyridazine-3-carbonitrile (450 mg, 2.94 mmol), 4-oxa-7-azaspiro[2.5]octane HCl salt (657 mg, 4.41 mmol), and DIEA (1.1 g, 8.8 mmol) in DMF (7.0 mL) was stirred at 90 °C for 1 h. After the reaction was completed, the mixture was diluted with HO (40 mL) and extracted with EA (30 mL × 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography (EA / PE = 1 / 2) to give 6-methyl-5-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyridazine-3-carbonitrile (535 mg, yield: 79%). MS calculated: 230.1 MS observed: 231.2 [M+H] + .

[0493] Step B: (S)-7-(3-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridazin-4-yl)-4-oxa-7-azaspiro[2.5]octane (S)-7-(3-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridazin-4-yl)-4-oxa-7-azaspiro[2.5]octane (11 mg) was obtained by a method similar to Method 14. MS calculated: 685.2; MS found: 686.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6):δ 7.51-7.61 (m, 3 H), 7.33 (d, J=10.0 Hz, 1 H), 6.75-6.81 (m, 2 H), 6.68-6.75 (m, 1 H), 3.85-3.92 (m, 2 H), 3.81 (s, 2 H), 3.61-3.70 (m, 2 H), 3.51-3.57 (m, 2 H), 2.93-3.04 (m, 2 H), 2.60-2.71 (m, 1 H), 2.20-2.35 (m, 2 H), 2.01 (s, 3 H), 1.64-1.78 (m, 4H), 0.71-0.78 (m, 2 H), 0.58-0.66 (m, 2 H). 19 F NMR(377 MHz, DMSO-d6):δ -62.95, -110.74.

[0494] Method 16: 4-[3-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridazin-4-yl]-3-methylmorpholine (F-3) [ka]

[0495] Step A: 6-methyl-5-(3-methylmorpholino)pyridazine-3-carbonitrile A mixture of 5-chloro-6-methylpyridazine-3-carbonitrile (300 mg, 1.96 mmol), 3-methylmorpholine (397 mg, 3.92 mmol), and DIEA (379 mg, 2.94 mmol) in DMF (6.0 mL) was stirred at 90° C. for 1 hour. After the reaction was completed, the mixture was diluted with HO (40 mL) and extracted with EA (30 mL × 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography (EA / PE=1 / 1) to give 6-methyl-5-(3-methylmorpholino)pyridazine-3-carbonitrile (128 mg, yield: 30%). MS calculated: 218.1 MS observed: 219.1 [M+H] + .

[0496] Step B: 4-[3-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridazin-4-yl]-3-methylmorpholine (F-3) 4-[3-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridazin-4-yl]-3-methylmorpholine (47.5 mg) was obtained using a similar method disclosed herein. MS calculated: 673.22; MS found: 674.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6):δ 7.51-7.63 (m, 3 H), 7.30-7.37 (m, 1 H), 6.69-6.82 (m, 3 H), 4.24-4.38 (m, 1 H), 3.79-4.02 (m, 4 H), 3.53-3.72 (m, 3 H), 3.13-3.21 (m, 1 H), 3.00-3.08 (m, 1 H), 2.89-2.98 (m, 1 H), 2.60-2.71 (m, 1 H), 2.20-2.35 (m, 2 H), 2.01 (d, J=1.6 Hz, 3 H), 1.66-1.85 (m, 4 H), 1.07 (d, J=6.0 Hz, 3 H). 19 F NMR(377 MHz, DMSO-d6):δ -63.41, -110.77, -110.78.

[0497] Method 17: 1-(3-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridazin-4-yl)pyrrolidin-3-ol (F-15) [ka]

[0498] Step A: 5-(3-hydroxypyrrolidin-1-yl)-6-methylpyridazine-3-carbonitrile A mixture of 5-chloro-6-methylpyridazine-3-carbonitrile (400 mg, 2.6 mmol), pyrrolidin-3-ol (454 mL, 5.2 mmol), and DIEA (1.7 g, 13.0 mmol) in DMF (5 mL) was stirred at 90 °C under a nitrogen atmosphere for 2 h. The mixture was cooled to room temperature. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE to give 5-(3-hydroxypyrrolidin-1-yl)-6-methylpyridazine-3-carbonitrile (300 mg, yield: 56.4%). MS calculated: 204.10; MS found: 205.2 [M+H].

[0499] Step B: 1-(3-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridazin-4-yl)pyrrolidin-3-ol (F-15) 1-(3-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridazin-4-yl)pyrrolidin-3-ol (75.0 mg) was obtained using a method similar to Method 14. MS calculated: 659.20; MS found: 660.1 [M+H] + .

[0500] 1H NMR (400 MHz, DMSO-d6):δ 7.51-7.61 (m, 2 H), 7.33 (d, J=8.4 Hz, 1 H), 7.13 (s, 1 H), 6.69-6.80 (m, 3 H), 4.39-4.51 (m, 1 H), 3.69-4.06 (m, 7 H), 2.89-3.00 (m, 2 H), 2.65-2.72 (m, 1 H), 2.14-2.25 (m, 2 H), 1.92-2.05 (m, 5 H), 1.65-1.79 (m, 4 H). 19 F NMR (377 MHz, DMSO-d6):δ -63.18, -110.82.

[0501] Method 18: 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-methoxy-5-(1H-tetrazol-5-yl)pyridine (F-20) [ka]

[0502] Step A: 5-Bromo-3-methoxypicolinonitrile To a solution of 5-bromo-3-fluoropicolinonitrile (10.0 g, 49.7 mmol) in THF (100 mL) was added MeONa (3.2 g, 59.7 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with water (200 mL) and extracted with EA (200 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated, and the residue was purified by column chromatography on silica gel (PE:EA = 4:1) to give 5-bromo-3-methoxypicolinonitrile (9.7 g, 91.5% yield). MS calculated: 212.0; MS found: 212.9 [M+H] + .

[0503] Step B: 5-Bromo-3-methoxypicolinic acid To a solution of 5-bromo-3-methoxypicolinonitrile (200 mg, 0.94 mmol) in MeOH (5 mL) and HO (2 mL) was added KOH (2.5 g, 47 mmol) at room temperature. The mixture was heated to 80 °C and stirred for 3 h. The mixture was poured onto ice and adjusted to pH = 7 with 1 N HCl. The aqueous layer was extracted with EA (50 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated to give 5-bromo-3-methoxypicolinic acid (170 mg, 74% yield). MS calculated: 230.9; MS found: 231.9 [M+H] + .

[0504] Step C: (5-bromo-3-methoxypyridin-2-yl)methanol To a solution of 5-bromo-3-methoxypicolinic acid (800 mg, 3.5 mmol) in THF (8 mL) was added BH3 / THF (7 mL, 7.0 mmol, 1M in THF) at room temperature, and the mixture was stirred for 12 hours. After the reaction was complete, the mixture was quenched with MeOH (4 mL), diluted with EA (50 mL), and washed with brine (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA=1 / 1) to give (5-bromo-3-methoxypyridin-2-yl)methanol (400 mg, 52.6% yield). MS calculated: 216.97; MS found: 218.0 [M+H] + .

[0505] Step D: 5-Bromo-3-methoxypicolinaldehyde A mixture of (5-bromo-3-methoxypyridin-2-yl)methanol (400 mg, 1.8 mmol) and MnO (1.6 g, 18.3 mmol) in DCM (10 mL) was stirred at room temperature overnight. The mixture was filtered and concentrated to give 5-bromo-3-methoxypicolinaldehyde (401 mg, crude).

[0506] Step E: 5-bromo-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-methoxypyridine To a solution of 5-bromo-3-methoxypicolinaldehyde (300 mg, 1.4 mmol) and 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine HCl (483 mg, 1.4 mmol) in DCM (10 mL) was added NaBH(OAc) (884 mg, 4.17 mmol) at room temperature and stirred for 2 h. The resulting mixture was diluted with EA (40 mL) and washed with water (30 mL × 2). The organic layer was dried over Na2SO4, filtered, concentrated, and the residue was purified by silica gel column chromatography (PE:EA=1:1) to give 5-bromo-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-methoxypyridine (400 mg, 52.7% yield). MS calculated: 546.1; MS found: 547.1 [M+H] + .

[0507] Step F: 6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methoxynicotinonitrile A mixture of 5-bromo-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-methoxypyridine (400 mg, 0.73 mmol), Zn(CN) (250 mg, 2.19 mmol), and Pd(PPh) (80 mg, 0.07 mmol) in DMF (5 mL) was stirred at 160 °C for 2 h under microwave irradiation. After the reaction was complete, the mixture was diluted with EA (70 mL) and washed with HO (40 mL × 3). The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography (PE / EA=1 / 1) to give 6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methoxynicotinonitrile (120 mg, 33.1% yield). MS calculated: 493.2; MS found: 494.2 [M+H] + .

[0508] Step G: 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-methoxy-5-(1H-tetrazol-5-yl)pyridine A mixture of 6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methoxynicotinonitrile (60 mg, 0.12 mmol), BuSnO (89 mg, 0.36 mmol), and TMSN3 (70 mg, 0.60 mmol) in dioxane (1 mL) was stirred at 100° C. for 6 hours. After the reaction was completed, the mixture was filtered, and the filtrate was purified by Prep-HPLC to give 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-methoxy-5-(1H-tetrazol-5-yl)pyridine (16.3 mg, yield: 24.0%). MS calculated: 536.2; MS found: 537.2 [M+ H] + . 1 H NMR (400 MHz, DMSO-d6):δ 8.91 (d, J=1.2 Hz, 1 H), 8.07 (d, J=1.6 Hz, 1 H), 7.68 (t, J=8.4 Hz, 1 H), 7.57 (dd, J=11.2 Hz, 2.0 Hz, 1 H), 7.40 (dd. 2 H), 2.96-3.03 (m, 1 H), 1.97-2.18 (m, 7 H). 19 F NMR (377 MHz, DMSO-d6): δ -110.45.

[0509] Method 19: 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-cyclopropyl-5-(1H-tetrazol-5-yl)pyridine (F-14) [ka] Step A: 6-chloro-5-cyclopropylnicotinonitrile A mixture of 5-bromo-6-chloronicotinonitrile (200 mg, 0.92 mmol), cyclopropylboronic acid (119 mg, 1.38 mmol), Pd(dppf)Cl (50 mg, 0.07 mmol), and KCO (381 mg, 2.76 mmol) in 1,4-dioxane (2 mL) was stirred at 90 °C for 12 h under argon. The mixture was poured into water (30 mL) and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the residue was concentrated. The residue was purified by column chromatography on silica gel to give 6-chloro-5-cyclopropylnicotinonitrile (90 mg, 55% yield). MS calculated: 178.0; MS found: 179.1 [M+H]. + .

[0510] Step B: 5-Cyclopropyl-6-methylnicotinonitrile A mixture of 6-chloro-5-cyclopropylnicotinonitrile (90 mg, 0.51 mmol), a toluene solution of MeZn (1.01 mL, 1 M, 1.01 mmol), and Pd(PPh) (58 mg, 0.05 mmol) in THF (6 mL) was stirred at 80 °C for 16 h under argon. The mixture was poured into water (30 mL) and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the residue was concentrated. The residue was purified by column chromatography on silica gel to give 5-cyclopropyl-6-methylnicotinonitrile (60 mg, 75.1% yield). MS calculated: 158.1; MS found: 159.2 [M+H]. + .

[0511] Step C: 6-(Bromomethyl)-5-cyclopropylnicotinonitrile A mixture of 5-cyclopropyl-6-methylnicotinonitrile (60 mg, 0.38 mmol), NBS (74 mg, 0.42 mmol), and AIBN (13 mg, 0.08 mmol) in CCl4 (5 mL) was stirred at 80 °C for 16 h. The mixture was poured into water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the residue was concentrated. The residue was purified by column chromatography on silica gel to give 6-(bromomethyl)-5-cyclopropylnicotinonitrile (25 mg, yield: 27.9%). MS calculated: 236.0; MS found: 239.0 [M+H] + .

[0512] Step D: 6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-cyclopropylnicotinonitrile A mixture of 6-(bromomethyl)-5-cyclopropylnicotinonitrile (25 mg, 0.11 mmol), 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine hydrochloride (41 mg, 0.11 mmol), and K2CO3 (44 mg, 0.32 mmol) in DMSO (3 mL) was stirred at 60 °C for 3 h. The mixture was poured into water (30 mL) and extracted with EtOAc (2 x 30 mL), the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the residue was concentrated. The residue was purified by column chromatography on silica gel to give 6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-cyclopropylnicotinonitrile (25 mg, yield: 47.2%). MS calculated: 503.2; MS found: 504.1 [M+H] + .

[0513] Step F: 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-cyclopropyl-5-(1H-tetrazol-5-yl)pyridine (F-14) A mixture of 6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-cyclopropylnicotinonitrile (25 mg, 0.05 mmol), NaN (5 mg, 0.077 mmol), and NHCl (4 mg, 0.077 mmol) in DMF (1 mL) was stirred in a sealed tube at 110 °C for 16 h. The mixture was filtered, and the residue was purified by prep-HPLC to give 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-cyclopropyl-5-(1H-tetrazol-5-yl)pyridine (4.4 mg, yield: 16.3%). MS calculated: 546.2; MS found: 547.1 [M+H] + 1 H NMR (400 MHz, CD3OD):δ 9.08 (s, 1 H), 8.12 (s, 1 H), 7.62 (t, J = 8.4 Hz, 1 H), 7.31 - 7.22 (m, 2 H), 6.83 - 6.75 (m, 3 H), 4.61 - 4.50 (m, 2 H), 3.66 - 3.58 (m, 2 H), 3.11 - 2.97 (m, 2 H), 2.23 - 2.13 (m, 3 H), 2.05 (s, 5 H), 1.14 - 1.12 (m, 2 H), 0.87 - 0.86 (m, 2 H). 19 F-NMR (377 MHz, CD3OD):δ -112.25.

[0514] The compounds in Table 1 can be synthesized according to the general syntheses or procedures described herein using the appropriate starting materials. [Table 34] [Table 35] [Table 36] [Table 37] [Table 38] [Table 39] [Table 40] [Table 41] [Table 42] [Table 43] [Table 44] [Table 45] [Table 46]

[0515] Biological Examples Biological Example 1: cAMP Assay Activation of the GLP-1 receptor is mediated by the G protein heterotrimer G αS It is known to stimulate the production of cyclic AMP (cAMP) in cells that exhibit initial binding to the G subunit.αS These results suggest that inducible cAMP-stimulated signaling provides the desired pharmacological response for insulin release from pancreatic β-cells.

[0516] G αS To optimize functional activity for binding, the HEK293 / CRE-Luc cell line developed by HDB, which stably expresses the GLP-1 receptor, was used. A 200x compound working solution (Agilent Technologies Bravo) was prepared in a 1 / 2 log serial dilution in a 384-well Echo LDV plate (Labcyte, Cat# LP-0200). 50 nL / well of the 200x compound working solution was transferred to a 384-well white low-volume plate (Greiner, Cat# 784075) using a Labcyte ECHO550. 1x10 5 Cells / mL of HEK293 / GLP1R / CRE-LUC (HD Biosciences) cell suspension was prepared in assay buffer (DPBS containing 0.5 mM IBMX (Sigma, Cat#I5879) and 0.1% BSA (GENVIEW, Cat#FA016-100g)). 10 μL of cell suspension was added to each well of the pre-made assay plate containing 50 nL of compound at 200× concentration using ThermoFisher Multidrop Combi (1000 cells / well). The plate was sealed and incubated at 37°C under 5% CO2 for 30 minutes.

[0517] After incubation, the cAMP assay signal was developed using the cAMP dynamic 2 Kit (Cisbio). Five microliters of a working solution of cAMP-d2 was added to each well, followed by 5 μL of an anti-cAMP antibody-cryptate working solution using a ThermoFisher Multidrop Combi. The plates were incubated for 1 hour at room temperature in the dark. Luminescence was read at 665 nm and 615 nm using a PerkinElmer EnVision reader. % Activity = 100% x (mean RLU of test sample - mean RLU of vehicle control) / (Average RLU of MAX control - Average RLU of medium control)

[0518] Table 3 shows the biological activity of compounds in the GLP-1R agonist cAMP stimulation assay (EC 50 The activity of the test compounds is shown in Table 3 below: +++=EC 50 <1 nM;++=EC 50 1–100 nM; +=EC ...

Claims

1. Formula I: 【Chemistry 1】 [In the formula, X 1 , X 2 and X 5 are independently C or N; X 3 and X 4 is N, NR x , C.R. y independently selected from the group consisting of C(O), O, and S; X 6 is a bond, N, NR x , C.R. y and C(O); 【Chemistry 2】 is a single or double bond, provided that X 1 From X 6 at least one of X is independently selected from a heteroatom or a heteroatom group; 1 From X 6 At least one of the is C or CR y and X 1 From X 6 The ring containing is aromatic; Each R x is hydrogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, C(O)(C 1 -C 6 ) alkyl, S(O) 2 (C 1 -C 6 ) alkyl and C(O)O(C 1 -C 6 ) alkyl; Each R y is hydrogen, -OH, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) independently selected from the group consisting of haloalkoxy, CN, and halogen; L 0 is a join or #-P 0 -P 1 And, # is X 5 represents the point of attachment to -P 0 is a bond, -NH-, -N(C 1 -C 6 alkyl)-, -O- or S(O) 0-2 and -P 1 is (C 1 -C 6 ) alkylene, (C 2 -C 6 ) alkenylene, (C 2 -C 6 ) alkynylene, (C 3 -C 8 ) cycloalkylene and 4- to 8-membered heterocycloalkylene, each of which optionally contains 1 to 3 R 0 optionally substituted with; Each R 0 are halogens, CN, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy and (C 1 -C 6 ) haloalkoxy; T 1 is C(O)OH or a carboxylic acid bioisostere; or Group-L 0 -T 1 is the following: -C(O)NH-(C 1 -C 6 ) alkyl or -C(O)NH-(C 3 -C 6 ) cycloalkyl; each of the foregoing is selected from 1 to 4 R T or -C(O)OH, -C(O)O(C 1 -C 6 ) alkyl, -C(O)NH(C 1 -C 6 ) alkyl, -C(O)NH-(C 3 -C 6 ) cycloalkyl, 5- to 6-membered heteroaryl optionally substituted with 3- to 6-membered heterocycloalkyl or 6-membered heteroaryl; 1 -C 6 ) alkyl, -C(O)NH(C 1 -C 6 ) alkyl, -C(O)NH-(C 3 -C 6 ) Each of the cycloalkyl, 3- to 6-membered heterocycloalkyl, and 6-membered heteroaryl is selected from 1 to 4 R T optionally substituted with; T 2 is the following: Hydrogen, CN, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) hydroxyalkyl or (C 1 -C 6 ) alkyl; 1 -C 6 ) alkyl is (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) thioalkoxy, (C 1 -C 6 ) haloalkoxy, S(O) 2 (C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl)-S(O) 2 (C 1 -C 6 alkyl), -NH-S(O) 2 (C 1 -C 6 alkyl), (C 3 -C 6 ) cycloalkyl, (C 3 -C 6 ) cycloalkoxy, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, and 3 -C 6 ) Each of cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl is selected from 1 to 4 R T optionally substituted with; or -NH(C 1 -C 6 ) alkyl, -NH-(C 3 -C 6 ) cycloalkyl, -CH 2 -S(O) 2 -(C 3 -C 6 ) cycloalkyl, -O-(C 3 -C 6 ) cycloalkyl, (C 1 -C 6 ) alkoxy, (C 3 -C 6 )cycloalkyl or 3- to 10-membered heterocycloalkyl; 1 -C 6 ) alkyl, -NH-(C 3 -C 6 ) cycloalkyl, -CH 2 -S(O) 2 -(C 3 -C 6 ) cycloalkyl, -O-(C 3 -C 6 ) cycloalkyl, (C 1 -C 6 ) alkoxy, (C 3 -C 6 ) Each cycloalkyl or 3- to 10-membered heterocycloalkyl is selected from 1 to 4 R T optionally substituted with; Each R T OH, SH, CN, NO 2 , halogen, =O, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) cyanoalkyl, (C 1 -C 6 ) hydroxyalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, (C 3 -C 6 ) cycloalkyl, amino, (C 1 -C 6 ) alkylamino, (C 1 -C 6 ) Alkylamino(C 1 -C 6 alkyl)-C(O)-C 1 -C 6 Alkyl, S(O) 2 (C 1 -C 6 alkyl) and di(C 1 -C 6 ) alkylamino; L 1 is a bond or 1 to 3 R L (C 1 -C 3 ) alkylene; L 2 is a bond, -O-, -S(O) 0-2 - or -NH-; Each R L is a halogen, (C 1 -C 3 ) alkyl and (C 1 -C 3 ) haloalkyl; or a pair of R on the same or adjacent carbon atoms. L together with the carbon atoms to which they are attached, (C 3 -C 6 ) forming a cycloalkyl ring; Ring A is as follows: 【Transformation 3】 (wherein n1 is 0, 1 or 2; W 1 is CR Y1 or N; W 2 is CR Y2 or N), 【Chemistry 4】 (In the formula, W 3 is C, CR Y3 or N; L w is (C 1 -C 3 ) alkylene; 【Transformation 5】 are independently a single bond or a double bond (where valence permits); 1 to 4 R Y phenylene optionally substituted with 1 to 3 R Y an optionally substituted 5- to 6-membered heteroarylene; 1 to 4 R Y (C 5 -C 8 ) cycloalkylene; 1 to 4 R Y a partially unsaturated monocyclic ring optionally substituted with (C 5 -C 8 ) cycloalkylene; and 1 to 4 R Y partially unsaturated monocyclic 5-8 membered heterocycloalkylene optionally substituted with where mm is L 2 represents the point of attachment to ring B; Each R Y is halogen, CN, -OH, oxo, (C 1 -C 6 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 3 ) alkoxy and (C 1 -C 3 ) haloalkoxy; R Y1 , R Y2 and R Y3 are hydrogen, halogens, CN, -OH, (C 1 -C 6 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 3 ) alkoxy and (C 1 -C 3 ) haloalkoxy; or W 1 is CR Y1 and W 2 is CR Y2 If so, R Y1 and R Y2 The bases of (C 1 -C 4 ) alkylene, 1 -C 4 ) alkylene CH 2 One of the units is O, S, NH and N(C 1-3 ) alkyl, optionally substituted with a heteroatom selected from the group consisting of; Ring B is selected from the group consisting of (BI), (B-II), (B-III), (B-IV), (BV), (B-VI) and (B-VII): 【Transformation 6】 During the ceremony, aa represents the point of attachment to ring A; B 1 , B 2 , B 3 and B 4 Each of the 1 and N; B 5 and B 6 Each of these is N, NR 1 , C, C.R. 1 , O and S, with the proviso that B 5 and B 6 A ring containing is heteroaryl; 【Transformation 7】 During the ceremony, aa represents the point of attachment to ring A; B 7 and B 8 -O-, -NR N - and -C(R 1 ) 2 - independently selected from the group consisting of; B 9 is N or CR aa and nb is 0 or 1; B 10 , B 11 and B 12 is CR 1 and N; B 13 , B 14 and B 15 are each independently CR 1 and Each R 1 is hydrogen, halogen, CN, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 3 ) Alkyl(C 3 -C 6 ) cycloalkyl, (C 1 -C 3 ) alkyl(3- to 5-membered heterocycloalkyl) and —C(O)NR 2 R 3 are independently selected from the group consisting of: Each R 2 and R 3 is H and (C 1 -C 6 ) alkyl; Each R N is hydrogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, C(O)(C 1 -C 6 ) alkyl, S(O) 2 (C 1 -C 6 ) alkyl and C(O)O(C 1 -C 6 ) alkyl; R aa , R ab and R ac is H, (C 1 -C 6 ) alkyl and (C 1 -C 6 ) haloalkyl; L 3 is a bond or -Z 1 -Z 2 -* where * represents the point of attachment to ring C; -Z 1 is a bond, NH, N(C 1 -C 6 alkyl), O or S(O) 0-2 and -Z 2 is 1 to 2 R c C optionally substituted with 1-3 alkylene; Each R c is a halogen, (C 1 -C 6 ) alkyl and (C 1 -C 3 ) haloalkyl; Ring C is phenyl, 5- to 6-membered heteroaryl, (C 3 -C 6 ) cycloalkyl, (C 5 -C 10 ) selected from the group consisting of bicycloalkyl, 5- to 10-membered bicycloheteroaryl, and 3- to 6-membered heterocycloalkyl; Each R b is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, halogen, (C 3 -C 6 )Cycloalkyl, CN, -C(O)NH 2 or —C(O)OH; and b is an integer selected from 0 to 3; provided that at least one of the following is present: 1) At least one R b is -C(O)NH 2 or -C(O)OH; 2) Ring A is 1 to 4 R Y (C 5 -C 8 ) cycloalkylene; 3) Ring B is 【Transformation 8】 and 4) Group-L 0 -T 1 is the following: -C(O)NH-(C 1 -C 6 ) alkyl or -C(O)NH-(C 3 -C 6 ) cycloalkyl; each of the foregoing is selected from 1 to 4 R T or -C(O)OH, -C(O)O(C 1 -C 6 ) alkyl, -C(O)NH(C 1 -C 6 ) alkyl, -C(O)NH-(C 3 -C 6 ) cycloalkyl, 5- to 6-membered heteroaryl optionally substituted with 3- to 6-membered heterocycloalkyl or 6-membered heteroaryl; 1 -C 6 ) alkyl, -C(O)NH(C 1 -C 6 ) alkyl, -C(O)NH-(C 3 -C 6 ) Each of the cycloalkyl, 3- to 6-membered heterocycloalkyl, and 6-membered heteroaryl is selected from 1 to 4 R T or 5) T 2 is -NH(C 1 -C 6 ) alkyl, -NH-(C 3 -C 6 ) cycloalkyl, -CH 2 -S(O) 2 -(C 3 -C 6 ) cycloalkyl, -O-(C 3 -C 6 ) cycloalkyl, (C 1 -C 6 ) alkoxy, (C 3 -C 6 )cycloalkyl or 3- to 10-membered heterocycloalkyl; 1 -C 6 ) alkyl, -NH-(C 3 -C 6 ) cycloalkyl, -CH 2 -S(O) 2 -(C 3 -C 6 ) cycloalkyl, -O-(C 3 -C 6 ) cycloalkyl, (C 1 -C 6 ) alkoxy, (C 3 -C 6 ) Each cycloalkyl or 3- to 10-membered heterocycloalkyl is selected from 1 to 4 R T optionally substituted with; The compound is not: 【Chemistry 9】 ] or a pharmaceutically acceptable salt or solvate thereof.

2. Formula II: 【Chemistry 10】 [In the formula, L 0 is a bond or -P 0 -P 1 and -P 0 is a bond, -NH-, -N(C 1 -C 6 alkyl)-, -O- or S(O) 0-2 and -P 1 is (C 1 -C 6 ) alkylene, (C 2 -C 6 ) alkenylene, (C 2 -C 6 ) alkynylene, (C 3 -C 8 ) cycloalkylene and 4- to 8-membered heterocycloalkylene, each of which optionally contains 1 to 3 R 0 optionally substituted with; Each R 0 are halogens, CN, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy and (C 1 -C 6 ) haloalkoxy; T 1 is C(O)OH or a carboxylic acid bioisostere; or Group-L 0 -T 1 is the following: -C(O)NH-(C 1 -C 6 ) alkyl or -C(O)NH-(C 3 -C 6 ) cycloalkyl; each of the foregoing is selected from 1 to 4 R T or -C(O)OH, -C(O)O(C 1 -C 6 ) alkyl, -C(O)NH(C 1 -C 6 ) alkyl, -C(O)NH-(C 3 -C 6 ) cycloalkyl, 5- to 6-membered heteroaryl optionally substituted with 3- to 6-membered heterocycloalkyl or 6-membered heteroaryl; 1 -C 6 ) alkyl, -C(O)NH(C 1 -C 6 ) alkyl, -C(O)NH-(C 3 -C 6 ) Each of the cycloalkyl, 3- to 6-membered heterocycloalkyl, and 6-membered heteroaryl is selected from 1 to 4 R T optionally substituted with; T 2 is the following: Hydrogen, CN, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) hydroxyalkyl or (C 1 -C 6 ) alkyl; 1 -C 6 ) alkyl is (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) thioalkoxy, (C 1 -C 6 ) haloalkoxy, S(O) 2 (C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl)-S(O) 2 (C 1 -C 6 alkyl), -NH-S(O) 2 (C 1 -C 6 alkyl), (C 3 -C 6 ) cycloalkyl, (C 3 -C 6 ) cycloalkoxy, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, and 3 -C 6 ) Each of cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl is selected from 1 to 4 R T optionally substituted with; or -NH(C 1 -C 6 ) alkyl, -NH-(C 3 -C 6 ) cycloalkyl, -CH 2 -S(O) 2 -(C 3 -C 6 ) cycloalkyl, -O-(C 3 -C 6 ) cycloalkyl, (C 1 -C 6 ) alkoxy, (C 3 -C 6 )cycloalkyl or 3- to 10-membered heterocycloalkyl; 1 -C 6 ) alkyl, -NH-(C 3 -C 6 ) cycloalkyl, -CH 2 -S(O) 2 -(C 3 -C 6 ) cycloalkyl, -O-(C 3 -C 6 ) cycloalkyl, (C 1 -C 6 ) alkoxy, (C 3 -C 6 ) Each cycloalkyl or 3- to 10-membered heterocycloalkyl is selected from 1 to 4 R T optionally substituted with; Each R T OH, SH, CN, NO 2 , halogen, =O, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) cyanoalkyl, (C 1 -C 6 ) hydroxyalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, (C 3 -C 6 ) cycloalkyl, amino, (C 1 -C 6 ) alkylamino, (C 1 -C 6 ) Alkylamino(C 1 -C 6 alkyl)-C(O)-C 1 -C 6 Alkyl, S(O) 2 (C 1 -C 6 alkyl) and di(C 1 -C 6 ) alkylamino; W 1 is CH or N; Ring B is selected from the group consisting of (BI), (B-II), (B-III), (B-IV), (BV), (B-VI) and (B-VII): 【Chemistry 11】 During the ceremony, aa represents the point of attachment to ring A; B 1 , B 2 , B 3 and B 4 Each of the 1 and N; B 5 and B 6 Each of these is N, NR 1 , C, C.R. 1 , O and S, with the proviso that B 5 and B 6 A ring containing is heteroaryl; 【Chemistry 12】 During the ceremony, aa represents the point of attachment to ring A; B 7 and B 8 -O-, -NR N - and -C(R 1 ) 2 - independently selected from the group consisting of; B 9 is N or CR aa and nb is 0 or 1; B 10 , B 11 and B 12 is CR 1 and N; B 13 , B 14 and B 15 are each independently CR 1 and Each R 1 is hydrogen, halogen, CN, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 3 ) Alkyl(C 3 -C 6 ) cycloalkyl, (C 1 -C 3 ) alkyl(3- to 5-membered heterocycloalkyl) and —C(O)NR 2 R 3 are independently selected from the group consisting of: Each R 2 and R 3 is H and (C 1 -C 6 ) alkyl; Each R N is hydrogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, C(O)(C 1 -C 6 ) alkyl, S(O) 2 (C 1 -C 6 ) alkyl and C(O)O(C 1 -C 6 ) alkyl; R aa , R ab and R ac is H, (C 1 -C 6 ) alkyl and (C 1 -C 6 ) haloalkyl; L 3 is a bond or -Z 1 -Z 2 -* where * represents the point of attachment to ring C; -Z 1 is a bond, NH, N(C 1 -C 6 alkyl), O or S(O) 0-2 and -Z 2 is 1 to 2 R c C optionally substituted with 1-3 alkylene; Each R c is a halogen, (C 1 -C 6 ) alkyl and (C 1 -C 3 ) haloalkyl; Ring C is phenyl, 5- to 6-membered heteroaryl, (C 3 -C 6 ) cycloalkyl, (C 5 -C 10 ) selected from the group consisting of bicycloalkyl, 5- to 10-membered bicycloheteroaryl, and 3- to 6-membered heterocycloalkyl; Each R b is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, halogen, (C 3 -C 6 )Cycloalkyl, CN, -C(O)NH 2 or —C(O)OH; and b is an integer selected from 0 to 3; provided that at least one of the following is present: 1) At least one R b is -C(O)NH 2 or -C(O)OH; 2) W 1 is CH; 3) Ring B is 【Chemistry 13】 and 4) Group-L 0 -T 1 is the following: -C(O)NH-(C 1 -C 6 ) alkyl or -C(O)NH-(C 3 -C 6 ) cycloalkyl; each of the foregoing is selected from 1 to 4 R T or -C(O)OH, -C(O)O(C 1 -C 6 ) alkyl, -C(O)NH(C 1 -C 6 ) alkyl, -C(O)NH-(C 3 -C 6 ) cycloalkyl, 5- to 6-membered heteroaryl optionally substituted with 3- to 6-membered heterocycloalkyl or 6-membered heteroaryl; 1 -C 6 ) alkyl, -C(O)NH(C 1 -C 6 ) alkyl, -C(O)NH-(C 3 -C 6 ) Each of the cycloalkyl, 3- to 6-membered heterocycloalkyl, and 6-membered heteroaryl is selected from 1 to 4 R T or 5) T 2 is -NH(C 1 -C 6 ) alkyl, -NH-(C 3 -C 6 ) cycloalkyl, -CH 2 -S(O) 2 -(C 3 -C 6 ) cycloalkyl, -O-(C 3 -C 6 ) cycloalkyl, (C 1 -C 6 ) alkoxy, (C 3 -C 6 )cycloalkyl or 3- to 10-membered heterocycloalkyl; 1 -C 6 ) alkyl, -NH-(C 3 -C 6 ) cycloalkyl, -CH 2 -S(O) 2 -(C 3 -C 6 ) cycloalkyl, -O-(C 3 -C 6 ) cycloalkyl, (C 1 -C 6 ) alkoxy, (C 3 -C 6 ) Each cycloalkyl or 3- to 10-membered heterocycloalkyl is selected from 1 to 4 R T optionally substituted with; The compound is not: 【Chemistry 14】 ] or a pharmaceutically acceptable salt or solvate thereof.

3. At least one R b But -C(O)NH 2 or -C(O)OH.

4. Formula IIA: 【Chemistry 15】 (In the formula, R 5 is -OH or -NH 2 is) 3. The compound of claim 2, represented by: or a pharmaceutically acceptable salt or solvate thereof.

5. The following structure: Table 1 5. The compound of claim 4, having the formula: or a pharmaceutically acceptable salt or solvate thereof.

6. Ring A is a ring having 1 to 4 R Y (C 5 -C 8 ) cycloalkylene.

7. Formula IIB: 【Chemistry 16】 3. The compound of claim 2, represented by: or a pharmaceutically acceptable salt or solvate thereof.

8. The following structure: Table 2 8. The compound of claim 7, having the formula: or a pharmaceutically acceptable salt or solvate thereof.

9. Ring B is 【Chemistry 17】 2. The compound of claim 1, wherein:

10. Formula IIC: [Chemistry 18] 3. The compound of claim 2, represented by: or a pharmaceutically acceptable salt or solvate thereof.

11. The following structure: Table 3 11. The compound of claim 10, having the formula: or a pharmaceutically acceptable salt or solvate thereof.

12. Group-L 0 -T 1 is -C(O)NH-(C 1 -C 6 ) alkyl or -C(O)NH-(C 3 -C 6 ) cycloalkyl; each of the foregoing is selected from 1 to 4 R T 10. The compound of claim 1, optionally substituted with

13. Formula IID: 【Chemistry 19】 (In the formula, R 6 is -(C 1 -C 6 ) alkyl or -(C 3 -C 6 )cycloalkyl; 1 -C 6 ) alkyl or -(C 3 -C 6 ) Cycloalkyl is one to four R T and optionally substituted with 3. The compound of claim 2, represented by: or a pharmaceutically acceptable salt or solvate thereof.

14. The following structure: Table 4 Table 5 14. The compound of claim 13, having the formula: or a pharmaceutically acceptable salt or solvate thereof.

15. Group-L 0 -T 1 -C(O)OH, -C(O)O(C 1 -C 6 ) alkyl, -C(O)NH(C 1 -C 6 ) alkyl, -C(O)NH-(C 3 -C 6 ) cycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heteroaryl optionally substituted with 6-membered heteroaryl; 1 -C 6 ) alkyl, -C(O)O(C 1 -C 6 ) alkyl, -C(O)NH-(C 3 -C 6 ) Each of the cycloalkyl, 3- to 6-membered heterocycloalkyl, and 6-membered heteroaryl is selected from 1 to 4 R T 10. The compound of claim 1, optionally substituted with

16. Formula IIE: 【Chemistry 20】 wherein ring D is a 5-6 membered heteroaryl; d is 0 or 1; and R d -C(O)OH, -C(O)O(C 1 -C 6 ) alkyl, -C(O)NH(C 1 -C 6 ) alkyl, -C(O)NH-(C 3 -C 6 )cycloalkyl, 3- to 6-membered heterocycloalkyl, or 6-membered heteroaryl; 1 -C 6 ) alkyl, -C(O)NH(C 1 -C 6 ) alkyl, -C(O)NH-(C 3 -C 6 ) Cycloalkyl, 3- to 6-membered heterocycloalkyl, or 6-membered heteroaryl is 1 to 4 R T and optionally substituted with 3. The compound of claim 2, represented by: or a pharmaceutically acceptable salt or solvate thereof.

17. The following structure: Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 17. The compound of claim 16, or a pharmaceutically acceptable salt or solvate thereof, having the formula:

18. T 2 But -NH(C 1 -C 6 ) alkyl, -NH-(C 3 -C 6 ) cycloalkyl, -CH 2 -S(O) 2 -(C 3 -C 6 ) cycloalkyl, -O-(C 3 -C 6 ) cycloalkyl, (C 1 -C 6 ) alkoxy, (C 3 -C 6 )cycloalkyl or 3- to 10-membered heterocycloalkyl; 1 -C 6 ) alkyl, -NH-(C 3 -C 6 ) cycloalkyl, -CH 2 -S(O) 2 -(C 3 -C 6 ) cycloalkyl, -O-(C 3 -C 6 ) cycloalkyl, (C 1 -C 6 ) alkoxy, (C 3 -C 6 ) Each cycloalkyl or 3- to 10-membered heterocycloalkyl is selected from 1 to 4 R T 10. The compound of claim 1, optionally substituted with

19. Formula IIF: 【Chemistry 21】 (In the formula, L 4 is a bond, -NH-, -CH 2 -S(O) 2 or -O-; and R 7 is (C 1 -C 6 ) alkyl, (C 3 -C 6 )cycloalkyl or 3- to 10-membered heterocycloalkyl, 1 -C 6 ) alkyl, (C 3 -C 6 ) Each cycloalkyl or 3- to 10-membered heterocycloalkyl is selected from 1 to 4 R T with the proviso that L 4 If is a bond, then R 7 is a substituted or unsubstituted (C 3 -C 6 ) cycloalkyl or substituted or unsubstituted 3- to 10-membered heterocycloalkyl 3. The compound of claim 2, represented by: or a pharmaceutically acceptable salt or solvate thereof.

20. The following structure: Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 20. The compound of claim 19, having the formula: or a pharmaceutically acceptable salt or solvate thereof.

21. A compound having the following structure: Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 Table 26 Table 27 Table 28 Table 29 Table 30 or a pharmaceutically acceptable salt or solvate thereof.

22. 22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

23. 23. The pharmaceutical composition of claim 22 for treating a GLP-1 related disease, disorder or condition.

24. The disease, disorder or condition is type 1 diabetes, type 2 diabetes, young-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), young-onset atypical diabetes (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of adults (LADA), obesity, weight gain due to use of other medications, gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, kidney disease, adipocyte dysfunction, or sleep apnea. Group, 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 lipemia, metabolic acidosis, keto 24. The pharmaceutical composition of claim 23, wherein the therapeutic agent is selected from the group consisting of: diabetes mellitus, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, treatment of addiction, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, polycystic ovary syndrome (PCOS), or a combination thereof.

25. The pharmaceutical composition of claim 22 for treating type 2 diabetes.

26. The pharmaceutical composition of claim 22 for regulating insulin levels in a patient.

27. The pharmaceutical composition of claim 22 for regulating glucose levels in a patient.

28. 23. The pharmaceutical composition of claim 22, administered in combination with another therapeutic method or agent.

29. 29. The pharmaceutical composition of claim 28, wherein the additional therapeutic method or agent is selected from the group consisting of an antidiabetic agent, an antiobesity agent, a GLP-1 receptor agonist, an antiemetic agent, a nonalcoholic steatohepatitis (NASH) therapeutic agent, gastric electrical stimulation, dietary monitoring, physical activity, or a combination thereof.

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