Heterocyclic GLP-1 agonists

Abstract

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

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of International Patent Application No. PCT / CN2022 / 075604, filed on February 9, 2022, which is incorporated herein by reference in its entirety. Technical Field

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

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

[0004] Diabetes refers to a group of metabolic disorders characterized by persistent hyperglycemia. The most common form, type 2 diabetes (T2DM), is an acquired condition that accounts for more than 90% of diabetes cases. Typical attacks occur in obese adults or otherwise sedentary adults and insulin resistance begins to occur. Although lifestyle changes can be used to effectively manage this disorder, T2DM patients may need to take antidiabetic drugs, especially dipeptidyl peptidase-4 inhibitors, SGLT2 inhibitors and sulfonylureas.

[0005] In healthy individuals, the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like 1 (GLP-1) provide tandem regulation of the insulin secretory response to glucose ingestion. Although this incretin effect is significantly diminished (if present at all) in cases of T2DM, GLP-1 retains insulinotropic properties even though the endocrine pancreatic response to GIP is effectively terminated. Therefore, incretin mimetics and other GLP-1-based therapies can help stimulate insulin production in patients with T2DM. Summary of the invention

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

[0007] In one aspect, compounds of Formula I are provided: or a pharmaceutically acceptable salt or solvate thereof, wherein: X 1 , X 2 and X 5 independently C or N; X 3 and X 4 Independently selected from: N, NR x , CR y , C(O), O and S; X 6 Selected from: bond, N, NR x , CR y and C(O); Each is a single bond or a double bond, provided that X 1 -X 6 At least one of X is an independently selected heteroatom or heteroatom group; 1 -X 6 At least one of them is C or CR y ; and contains X 1 -X 6 The ring is aromatic; Each R x independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, C(O)(C1-C6)alkyl, S(O)2(C1-C6)alkyl and C(O)O(C1-C6)alkyl; Each R y 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 Yes key or #-P 0 -P 1 , where # indicates that the 5 Attachment point; -P 0 is a bond, -NH-, -N(C1-C6 alkyl)-, -O- or S(O) 0-2 ; -P 1 is selected from: (C1-C6)alkylene, (C2-C6)alkenylene, (C2-C6)alkynylene, (C3-C8)cycloalkylene and 4- to 8-membered heterocycloalkylene, each of which is optionally substituted by 1-3 R 0 replace; Each R 0 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 a C(O)OH or carboxylic acid bioisostere; or Part-L 0 -T1 yes: -C(O)NH-(C1-C6)alkyl or -C(O)NH-(C3-C6)cycloalkyl; each of which is optionally substituted by 1 to 4 R T replace; or -5 to 6 membered heteroaryl, -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 optionally substituted with -C(O)OH; wherein -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 are each optionally substituted with 1 to 4 R T replace; T 2 yes: hydrogen, CN, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, or (C1-C6)alkyl optionally substituted by (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)cycloalkyloxy, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein each of said (C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted by 1-4 R T replace; 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 3-10 membered heterocycloalkyl; wherein -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 heterocycloalkyl are each optionally substituted by 1 to 4 R T replace; Provided that the compound is not: Each R Tindependently selected from OH, SH, CN, NO2, halogen, =O, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C1-C6)cyanoalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C3-C6)cycloalkyl, amino, (C1-C6)alkylamino, (C1-C6)alkylamino(C1-C6alkyl)-C(O)-C1-C6alkyl, S(O)2(C1-C6alkyl) and di(C1-C6)alkylamino; L 1 is a bond or optionally 1-3 R L Substituted (C1-C3) alkylene; L 2 is a bond, -O-, -S(O) 0-2 - or -NH-; Each R L independently selected from: halogen, (C1-C3) alkyl and (C1-C3) haloalkyl; or a pair of R located on the same carbon atom or adjacent carbon atoms L Together with the atom or atoms to which they are attached, they form a (C3-C6)cycloalkyl ring; Ring A is selected from: Where n1 is 0, 1 or 2, W 1 Yes CR Y1 or N, and W 2 Yes CR Y2 or N; Where W 3 Yes C, CR Y3 or N, L w is (C1-C3)alkylene, and as valence permits, each are independently a single bond or a double bond; Optionally 1-4 R Y Substituted phenylene; Optionally 1-3 R Y substituted 5- to 6-membered heteroarylene; Optionally 1-4 R Y Substituted (C5-C8)cycloalkylene; Optionally 1-4 R Y Substituted partially unsaturated monocyclic (C5-C8) cycloalkylene; and Optionally 1-4 R Y substituted partially unsaturated monocyclic 5- to 8-membered heterocycloalkylene; Where mm represents L 2, and nn represents the attachment point to ring B; Each occurrence of R Y independently selected from halogen, CN, -OH, oxo, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy and (C1-C3)haloalkoxy; R Y1 , R Y2 and R Y3 are each independently selected from hydrogen, halogen, CN, -OH, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy and (C1-C3)haloalkoxy; or When W 1 Yes CR Y1 And W 2 Yes CR Y2 When R Y1 and R Y2 The groups can together form a (C1-C4)alkylene group, wherein one of the CH2 units of the (C1-C4)alkylene group is optionally selected from O, S, NH and N(C 1-3 ) heteroatom substitution of an alkyl group; Ring B is selected from: (BI), (B-II), (B-III), (B-IV), (BV), (B-VI) and (B-VII): where aa represents the point of attachment to ring A; B 1 , B 2 , B 3 and B 4 Each of which is independently selected from CR 1 and N; B 5 and B 6 Each of which is independently selected from N, NR 1 , C, CR 1 , O and S, provided that B is contained 5 and B 6 The ring of is heteroaryl; where aa represents the point of attachment to ring A; B 7 and B 8 Independently selected from: -O-, -NR N -and-C(R 1 )2-; B 9 Is N or CR aa ; nb is 0 or 1; B 10 , B 11 and B 12 Independently selected from CR 1 and N; B 13 , B 14 and B 15 Each is independently CR 1 ; Each R 1 independently selected from hydrogen, halogen, CN, (C1-C6)alkyl, (C1-C6)haloalkyl; (C1-C3)alkyl (C3-C6)cycloalkyl, (C1-C3)alkyl (3 to 5 membered heterocycloalkyl) and -C(O)NR 2 R 3 ; R 2 and R 3 Each independently selected from H and (C1-C6) alkyl; Each R N independently selected from hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, C(O)(C1-C6)alkyl, S(O)2(C1-C6)alkyl and C(O)O(C1-C6)alkyl; R aa , R ab and R ac Each is independently selected from H, (C1-C6)alkyl and (C1-C6)haloalkyl; L 3 Yes key or -Z 1 -Z 2 -*, where * indicates the point of attachment to ring C; -Z 1 is a bond, NH, N(C1-C6 alkyl), O or S(O) 0-2 ; -Z 2 is optionally replaced by 1-2 R c Substituted C 1-3 Alkylene; Each R c independently selected from halogen, (C1-C6)alkyl and (C1-C3)haloalkyl; Ring C is selected from phenyl, 5- to 6-membered heteroaryl, (C3-C6)cycloalkyl, (C5-C 10 ) bicycloalkyl, 5- to 10-membered bicycloheteroaryl, and 3- to 6-membered heterocycloalkyl; Each R bis independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C3-C6)cycloalkyl, CN, -C(O)NH2 or -C(O)OH; and b is an integer selected from 0-3; The condition is that at least one of the following occurs: 1) At least one R b is -C(O)NH2 or -C(O)OH; 2) Ring A is optionally substituted with 1-4 R Y Substituted (C5-C8)cycloalkylene; 3) Ring B is 4) Part-L 0 -T 1 yes: -C(O)NH-(C1-C6)alkyl or -C(O)NH-(C3-C6)cycloalkyl; each of which is optionally substituted by 1 to 4 R T replace; or · 5- to 6-membered heteroaryl optionally substituted by -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 -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 are each optionally substituted with 1-4 R T replace; or 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 3-10 membered heterocycloalkyl; wherein -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 heterocycloalkyl are each optionally substituted by 1-4 R T replace.

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

[0009] Also provided herein are pharmaceutical compositions 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 to a patient identified or diagnosed as having type 2 diabetes a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0012] Also provided herein is a method for treating diabetes in a patient, the method comprising determining that the patient suffers from type 2 diabetes; and administering to the patient a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In some embodiments, the step of determining that the patient suffers from type 2 diabetes comprises performing an assay to determine the level of an analyte in a sample from the patient, wherein the analyte is selected from hemoglobin A1c (HbA1c), fasting plasma glucose, non-fasting 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 plasma glucose is greater than or about 126 mg / dL. In some embodiments, the level of non-fasting 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) greater than or about 22 kg / m 2 In some embodiments, the patient's BMI is greater than or about 30 kg / m 2 .

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

[0015] In some embodiments, treatment of type 2 diabetes comprises lowering HbA1c levels. In some embodiments, HbA1c levels are lowered to about or below 5.7%.

[0016] In some embodiments, the method for treating type 2 diabetes comprises lowering glucagon levels.

[0017] In some embodiments, the method for treating type 2 diabetes comprises increasing insulin levels.

[0018] In some embodiments, the method for treating type 2 diabetes comprises reducing BMI. In some embodiments, the BMI is reduced to about or below 25 kg / m 2 .

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

[0020] In some embodiments, the method for treating type 2 diabetes further includes applying another therapy or therapeutic agent to the patient. In some embodiments, the other therapy or therapeutic agent is selected from antidiabetic agents, anti-obesity agents, GLP-1 receptor agonists, agents for treating non-alcoholic steatohepatitis (NASH), antiemetics, gastric electrical stimulation, dietary monitoring, physical activity or any combination thereof. In some embodiments, the antidiabetic agent is selected from biguanides, sulfonylureas, glitazar, thiazolidinediones, dipeptidyl peptidase 4 (DPP-4) inhibitors, meglitinides, sodium-glucose cotransporter 2 (SGLT2) inhibitors, glitazones, GRP40 agonists, glucose-dependent insulinotropic peptides (GIP), insulin or insulin analogs, alpha glucosidase inhibitors, sodium-glucose cotransporter 1 (SGLT1) inhibitors or any combination thereof. In some embodiments, the biguanide is metformin. In some embodiments, the anti-obesity agent is selected from a neuropeptide Y receptor type 2 (NPYR2) agonist, an NPYR1 or NPYR5 antagonist, a human proislet peptide (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 some embodiments, the GLP-1 receptor agonist is selected from liraglutide, exenatide, dulaglutide, albiglutide, taspoglutide, lixisenatide, semaglutide, or any combination thereof. In some embodiments, the agent for treating NASH is selected from 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, nicotinic acid analogs, leukotriene D4 (LTD4) receptor antagonists, acetyl-CoA carboxylase (ACC) inhibitors, hexokinases (KHK) inhibitors, ileal bile acid transporter (IBAT) inhibitors, apoptosis signal-regulating kinase 1 (ASK1) inhibitors, or any combination thereof. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, and the additional therapeutic agent are administered sequentially in any order as separate doses.

[0021] Also provided herein is a method for regulating insulin levels in a patient in need of such regulation, 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 thereof. In some embodiments, the regulation results in an increase in insulin levels.

[0022] Also provided herein is a method for regulating the glucose level of a patient in need of such regulation, 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 thereof. In some embodiments, the regulation results in a decrease in glucose levels.

[0023] Also provided herein are methods for treating a GLP-1 related disease, disorder or condition, comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In some embodiments, the disease, disorder or condition is selected from type 1 diabetes, type 2 diabetes, early onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of adults (LADA), obesity, weight gain caused by the use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient 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 lipidosis, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, addiction treatment, 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 any combination thereof.In some embodiments, the disease, disorder or condition is selected from type 2 diabetes, early onset type 2 diabetes, obesity, weight gain caused by the use of other agents, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, hyperglycemia, postprandial lipidosis, metabolic acidosis, ketosis , hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, primary polydipsia, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS), or any combination thereof. In some embodiments, the disease, disorder, or condition includes but is not limited to type 2 diabetes, early onset type 2 diabetes, obesity, weight gain due to use of other medications, gout, sugar cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat deposition, myocardial infarction, peripheral arterial disease, stroke, transient ischemic attack, hyperglycemia, postprandial lipidosis, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, chronic renal failure, syndrome X, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, skin and connective tissue disorders, foot ulcers, or any combination thereof.

[0024] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent that publications and patents or patent applications incorporated by reference conflict with the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such conflicting material. DETAILED DESCRIPTION

[0025] Before describing the compounds and methods of the present invention, it should be understood that the present disclosure is not limited to the described methods, protocols, cell lines, assays and reagents, as these may vary. It should also be understood that the terms used herein are intended to describe embodiments of the present disclosure and are by no means intended to limit the scope of the present disclosure as set forth in the appended claims. definition

[0026] It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents 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 those of ordinary skill in the art to which the present disclosure belongs. Although methods and materials similar or equivalent to any methods and materials described herein can be used in the practice and testing of the present disclosure, exemplary methods, devices and materials are now described. All publications cited herein are incorporated herein by reference in their entirety for the purpose of describing and disclosing the methods, reagents and tools reported in the publications that may be used in conjunction with the present disclosure.

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

[0029] When values ​​are described as a range, it should be understood that such disclosure includes disclosure of all possible sub-ranges within such range, as well as specific values ​​falling within such range, regardless of whether a specific value or a specific sub-range is explicitly stated.

[0030] As used herein, the term "halo" or "halogen" refers to -F (sometimes referred to herein as "fluoro" or "fluoros"), -Cl (sometimes referred to herein as "chloro" or "chloros"), -Br (sometimes referred to herein as "bromo" or "bromos"), and -I (sometimes referred to herein as "iodo" or "iodos").

[0031] As used herein, the term "alkyl" refers to a saturated straight or branched chain monovalent hydrocarbon radical containing the indicated number of carbon atoms. For example, "(C 1-6 The term "alkyl" refers to a saturated straight or branched monovalent hydrocarbon radical having one to six carbon atoms. Non-limiting examples of alkyl include methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, 2-methyl-2-propyl, pentyl, neopentyl, and hexyl.

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

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

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

[0035] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon containing the indicated number of carbon atoms. For example, "(C 3-6 ") Cycloalkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon having three to six ring carbon atoms. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl may be partially unsaturated. Non-limiting examples of partially unsaturated cycloalkyl include cyclohexenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl, and the like. The cycloalkyl may include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyl include bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, and the like. [3.5]nonane, spiral [4.4]nonane, spiral [2.6]nonane, spiral [4.5]decane, spiral [3.6]decane, spiral [5.5]undecane, etc.

[0036] As used herein, the terms "heterocyclyl" and "heterocycloalkyl" refer to a monocyclic, bicyclic, tricyclic or polycyclic non-aromatic ring system containing the indicated number of ring atoms (e.g., a 3-8 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, the heteroatoms being selected from O, N, S or S(O). 1-2 (e.g., carbon atoms, and 1-3, 1-6, or 1-9 N, O, S, or S(O) in the case of a monocyclic, bicyclic, or tricyclic ring, respectively) 1-2) wherein 0, 1, 2 or 3 atoms of each ring may be substituted with a substituent. Examples of heterocycloalkyl include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, etc. Heterocycloalkyl may be partially unsaturated. Non-limiting examples of partially unsaturated heterocycloalkyl include dihydropyrrolyl, dihydropyridyl, tetrahydropyridyl, dihydrofuranyl, dihydropyranyl, etc. Heterocycloalkyl may include multiple fused rings and bridged rings. Non-limiting examples of fused / bridged heterocycloalkyl groups include: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 1 .0]octane, 2-oxabicyclo[1 .1 .0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1 .1 .1]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, etc. Heterocycloalkyl also includes spirocycles (e.g., spirobicycles in which the two rings are connected via 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-oxo[4.5] ... Spiro[2.2]pentane, 4-oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane, and the like.

[0037] As used herein, the term "aryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic hydrocarbon group containing the indicated number of carbon atoms, wherein at least one ring in the system is aromatic (e.g., C6 monocyclic, C 10 Bicyclic or C 14 A tricyclic aromatic ring system). Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

[0038] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group having the indicated number of ring atoms (e.g., 5-6 ring atoms; e.g., 5, 6, 9, 10, or 14 ring atoms); wherein at least one ring in the system is aromatic (but not necessarily a heteroatom-containing ring, e.g., tetrahydroisoquinolyl, e.g., tetrahydroquinolyl), and at least one ring in the system contains one or more heteroatoms independently selected from N, O, and S. Heteroaryl groups may be unsubstituted or substituted with one or more substituents. Examples of heteroaryl groups include thienyl, pyridyl, furanyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolylbenzothiophenyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-d]pyrimidinyl, b]pyridyl, quinazolinyl, quinolyl, thieno[2,3-c]pyridyl, pyrazolo[3,4-b]pyridyl, pyrazolo[3,4-c]pyridyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridyl, tetrazolyl, chromane, 2,3-dihydrobenzo[b][1,4]dioxin, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]oxathiin, isoindoline, etc.

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

[0040] As used herein, the term "alkoxy" refers to an -O-alkyl group, wherein the group is on the oxygen atom. For example, "C 1-6 "Alkoxy" refers to -O-(C 1-6The term "haloalkoxy" as used herein refers to an -O-haloalkyl group, wherein the group is on the oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy. Thus, as used herein, the term "haloalkoxy" refers to an -O-haloalkyl group, wherein the group is on the oxygen atom.

[0041] As used herein, the term "amino" refers to a group of the formula -N(R N1 )2, wherein each R N1 is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each of which is optionally substituted, such as by one or more (e.g., 1 to 5 or 1 to 3) substituents (e.g., independently selected from halo, cyano, hydroxy, -NH2, -NH(alkyl), -N(alkyl)2, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy or haloalkoxy).

[0042] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structure. Unless otherwise stated, a compound identified herein as one particular tautomeric form by name or structure is intended to include the other tautomeric forms.

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

[0044] As used herein, when a ring is described as "partially unsaturated", this means that the ring has one or more additional unsaturations (in addition to the unsaturation attributed to the ring itself; for example, one or more double bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, etc. When a ring system comprising at least two rings is described as "partially unsaturated", this means that the ring system comprises 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" means a group that has chemical and physical similarities that result in biological properties broadly similar to carboxylic acids (see Lipinski, Annual Reports in Medicinal Chemistry, 1986, 21, p283 "Bioisosterism In Drug Design"; Yun, Hwahak Sekye, 1993, 33, pp. 576-579 "Application Of Bioisosterism To New Drug Design"; Zhao, Huaxue Tongbao, 1995, pp. 34-38, 25 "Bioisosteric Replacement And Development Of Lead Compounds In Drug Design"; Graham, Theochem, 1995, 343, pp. 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" refers to compounds whose structures differ significantly in the arrangement of atoms but exist in a readily and rapidly equilibrium manner, and it is understood that the compounds provided herein may be depicted as different tautomers, and when compounds have tautomeric forms, all tautomeric forms are intended to fall within the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer.

[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 chains, complementary sequences, peptides, polypeptides, proteins, homologs, 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, all diseases, disorders or conditions in which modulation of glucagon-like peptide-1 (GLP-1) receptor signaling can alter the pathology and / or symptoms and / or progression of the disease, disorder or condition.

[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 the fasting and postprandial states; and slows gastric emptying. Karla et al., Glucagon-like peptide-1 receptor agonists in the treatment of type 2 diabetes: Past, present, and future, Indian J Endocrinol Metab. 2016 Mar-Apr; 20(2): 254-267. GLP-1RA has been shown to treat type 2 diabetes. Examples of GLP-1RA include, but are not limited to, albiglutide Dulaglutide (LY2189265, ), efpeglenatide, exenatide Exendin-4), liraglutide ( NN2211), lixisenatide Semaglutide Tirzepatide, ZP2929, NNC0113-0987, BPI-3016, and TT401. See also, for example, additional GLP-1 receptor agonists described in the following 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 the compound or salt thereof or composition is chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the patient to be treated therewith.

[0051] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of a given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts formed with inorganic acids and salts formed with organic acids. In addition, if the compounds described herein are obtained as acid addition salts, the free base can be obtained by alkalizing a solution of the acid salt. On the contrary, if the product is a free base, an addition salt (particularly a pharmaceutically acceptable addition salt) can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures 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 acids 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, etc. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic bases and organic bases. For example only, salts derived from inorganic bases include sodium salts, potassium salts, lithium salts, aluminum salts, ammonium salts, calcium salts, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of NH3 or primary amines, secondary amines, tertiary amines, such as those derived from N-containing heterocycles, N-containing heteroaryls, or derived from formula N(R N )3(For example, HN + (R N )3 or (alkyl) N + (R N )3) wherein each R N is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each of which is optionally substituted, such as by 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(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0052] It should be understood that substituents as defined herein are not intended to include impermissible substitution patterns (e.g., a methyl group substituted with 5 fluoro groups, or a hydroxyl group attached to an olefinic or acetylenic carbon atom). Such impermissible substitution patterns are well known to the skilled artisan. Likewise, the term "substituted" refers to one or more (e.g., one to five) chemical moieties as disclosed herein (such as those defined above), which may then be further substituted.

[0053] The term "administration" or "administering" refers to a method of giving a dose of a compound or pharmaceutical composition to a vertebrate or invertebrate (including a mammal, bird, fish or amphibian). The method of administration may vary depending on various factors, such as the components of the pharmaceutical composition, the site of the disease, and the severity of the disease.

[0054] As used herein, the term "effective amount" or "effective dose" or "pharmaceutically effective amount" or "therapeutically effective amount" refers to the amount of a sufficient chemical entity (e.g., a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof) administered that will alleviate one or more symptoms of the disease or condition being treated to some extent, and may include curing the disease. "Cure" means that the symptoms of active disease are eliminated. Results include reduction and / or alleviation of signs, symptoms or causes of the disease or any other desired changes in the biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound as disclosed herein required to provide a clinically significant reduction in disease symptoms. The appropriate "effective" amount in any individual case is determined using any suitable technique, such as a dose escalation study. In some embodiments, a "therapeutically effective amount" of a compound as provided herein refers to the amount of a compound that is effective as a monotherapy or combination therapy.

[0055] The term "excipient" or "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, carrier, solvent or encapsulating material. In some embodiments, each component is "pharmaceutically acceptable" in the sense that it is compatible with the other ingredients of the pharmaceutical formulation and is 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, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash, eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson, ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0056] The term "pharmaceutical composition" refers to a mixture of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof as described herein with other chemical components (collectively referred to herein as "excipients") such as carriers, stabilizers, diluents, dispersants, suspending agents and / or thickening agents. Pharmaceutical compositions facilitate administration of the compound to an organism. There are a variety of techniques for administering compounds in the art, 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 are intended to include alleviating or eradicating the disorder, disease, or condition, or one or more symptoms associated with the disorder, disease, or condition; or slowing the progression, spread, or worsening of the disease, disorder, or condition, or one or more symptoms thereof.

[0058] As used herein, the term "preventing" or "preventing" is the complete or partial prevention of the onset, recurrence, or spread of a disease or disorder as described herein, or symptoms thereof.

[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, cattle, sheep, horses, primates, and humans. In some embodiments, the terms refer to a subject, particularly a mammalian subject, for whom diagnosis, prognosis, or therapy is desired or required. In some embodiments, the patient is a human. In some embodiments, the subject has experienced and / or exhibits 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 disclosure.

[0061] As used herein, the term "pharmaceutical combination" refers to a medical therapy that results from the admixture or combination of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.

[0062] As used herein, the term "combination therapy" refers to a dosing regimen of two different therapeutically active agents (ie, components of the combination or combination partners) wherein the therapeutically active agents are administered together or separately in a manner prescribed by a healthcare practitioner or according to a regulatory regime as defined herein.

[0063] As used herein, the term "modulate" means to regulate or adjust (eg, increase or decrease), and may include, for example, agonism, partial agonism, or antagonism. Compound

[0064] Provided herein are compounds of Formula I: or a pharmaceutically acceptable salt or solvate thereof, wherein: X 1 , X 2 and X 5 independently C or N; X 3 and X 4 Independently selected from: N, NR x , CR y , C(O), O and S; X 6 Selected from: bond, N, NR x , CR y and C(O); Each is a single bond or a double bond, provided that X 1 -X 6 At least one of X is an independently selected heteroatom or heteroatom group; 1 -X6 At least one of them is C or CR y ; and contains X 1 -X 6 The ring is aromatic; Each R x independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, C(O)(C1-C6)alkyl, S(O)2(C1-C6)alkyl and C(O)O(C1-C6)alkyl; Each R y L 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; 0 Yes key or #-P 0 -P 1 , where # indicates that the 5 Attachment point; -P 0 is a bond, -NH-, -N(C1-C6 alkyl)-, -O- or S(O) 0-2 ; -P 1 is selected from: (C1-C6)alkylene, (C2-C6)alkenylene, (C2-C6)alkynylene, (C3-C8)cycloalkylene and 4- to 8-membered heterocycloalkylene, each of which is optionally substituted by 1-3 R 0 replace; Each R 0 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 a C(O)OH or carboxylic acid bioisostere; or Part-L 0 -T 1 yes: -C(O)NH-(C1-C6)alkyl or -C(O)NH-(C3-C6)cycloalkyl; each of which is optionally substituted by 1 to 4 R T replace; or · 5- to 6-membered heteroaryl optionally substituted by -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 -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 are each optionally substituted with 1-4 R T replace; T 2 yes: Hydrogen, CN, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl or (C1-C6) optionally substituted Alkyl: (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) cycloalkyloxy, 3- to 6-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl, wherein each of the (C3-C6) cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl is optionally substituted by 1-4 R T replace; 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 3-10 membered heterocycloalkyl; Among them -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 heterocycloalkyl are each optionally substituted by 1-4 R T replace; Each R T independently selected from OH, SH, CN, NO2, halogen, =O, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C1-C6)cyanoalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C3-C6)cycloalkyl, amino, (C1-C6)alkylamino, (C1-C6)alkylamino(C1-C6alkyl)-C(O)-C1-C6alkyl, S(O)2(C1-C6alkyl) and di(C1-C6)alkylamino; L 1 is a bond or optionally 1-3 R L Substituted (C1-C3) alkylene; L 2 is a bond, -O-, -S(O) 0-2 - or -NH-; Each R L independently selected from: halogen, (C1-C3) alkyl and (C1-C3) haloalkyl; or a pair of R located on the same carbon atom or adjacent carbon atoms L Together with the atom or atoms to which they are attached, they form a (C3-C6)cycloalkyl ring; Ring A is selected from: Where n1 is 0, 1 or 2, W 1 Yes CR Y1 or N, and W 2 Yes CR Y2 or N; Where W 3 Yes C, CR Y3 or N, L w is (C1-C3)alkylene, and as valence permits, each are independently a single bond or a double bond; Optionally 1-4 R Y Substituted phenylene; Optionally 1-3 R Y substituted 5- to 6-membered heteroarylene; Optionally 1-4 R Y Substituted (C5-C8)cycloalkylene; Optionally 1-4 R Y Substituted partially unsaturated monocyclic (C5-C8) cycloalkylene; and Optionally 1-4 R Y substituted partially unsaturated monocyclic 5- to 8-membered heterocycloalkylene; Where mm represents L 2 , and nn represents the attachment point to ring B; Each occurrence of R Y independently selected from halogen, CN, -OH, oxo, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy and (C1-C3)haloalkoxy; R Y1 , R Y2 and R Y3 are each independently selected from hydrogen, halogen, CN, -OH, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy and (C1-C3)haloalkoxy; or When W 1 Yes CR Y1 And W 2 Yes CR Y2 When R Y1 and RY2 The groups can together form a (C1-C4)alkylene group, wherein one of the CH2 units of the (C1-C4)alkylene group is optionally selected from O, S, NH and N(C 1-3 ) heteroatom substitution of an alkyl group; Ring B is selected from: (BI), (B-II), (B-III), (B-IV), (BV), (B-VI) and (B-VII): where aa represents the point of attachment to ring A; B 1 , B 2 , B 3 and B 4 Each of which is independently selected from CR 1 and N; B 5 and B 6 Each of which is independently selected from N, NR 1 , C, CR 1 , O and S, provided that B is contained 5 and B 6 The ring of is heteroaryl; where aa represents the point of attachment to ring A; B 7 and B 8 Independently selected from: -O-, -NR N -and-C(R 1 )2-; B 9 Is N or CR aa ; nb is 0 or 1; B 10 , B 11 and B 12 Independently selected from CR 1 and N; B 13 , B 14 and B 15 Each is independently CR 1 ; Each R 1 independently selected from hydrogen, halogen, CN, (C1-C6)alkyl, (C1-C6)haloalkyl; (C1-C3)alkyl (C3-C6)cycloalkyl, (C1-C3)alkyl (3 to 5 membered heterocycloalkyl) and -C(O)NR 2 R 3 ; R 2 and R 3Each independently selected from H and (C1-C6) alkyl; Each R N independently selected from hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, C(O)(C1-C6)alkyl, S(O)2(C1-C6)alkyl and C(O)O(C1-C6)alkyl; R aa , R ab and R ac Each is independently selected from H, (C1-C6)alkyl and (C1-C6)haloalkyl; L 3 Yes key or -Z 1 -Z 2 -*, where * indicates the point of attachment to ring C; -Z 1 is a bond, NH, N(C1-C6 alkyl), O or S(O) 0-2 ; -Z 2 is optionally replaced by 1-2 R c Substituted C 1-3 Alkylene; Each R c independently selected from halogen, (C1-C6)alkyl and (C1-C3)haloalkyl; Ring C is selected from phenyl, 5- to 6-membered heteroaryl, (C3-C6)cycloalkyl, (C5-C 10 ) bicycloalkyl, 5- to 10-membered bicycloheteroaryl, and 3- to 6-membered heterocycloalkyl; Each R b is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C3-C6)cycloalkyl, CN, -C(O)NH2 or -C(O)OH; and b is an integer selected from 0-3.

[0065] In some embodiments, at least one of the following occurs: 1) At least one R b is -C(O)NH2 or -C(O)OH; 2) Ring A is optionally substituted with 1-4 R Y Substituted (C5-C8)cycloalkylene; 3) Ring B is 4) Part-L 0 -T 1 yes: -C(O)NH-(C1-C6)alkyl or -C(O)NH-(C3-C6)cycloalkyl; each of which is optionally substituted by 1 to 4 RT replace; or · 5- to 6-membered heteroaryl optionally substituted by -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 -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 are each optionally substituted with 1-4 R T replace; or 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 3-10 membered heterocycloalkyl; wherein -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 heterocycloalkyl are each optionally substituted by 1-4 R T replace.

[0066] In some embodiments, at least one R x It is a (C3-C6) cycloalkyl group.

[0067] In some embodiments, at least one R y It is a (C3-C6) cycloalkyl group.

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

[0069] In some embodiments, provided herein are compounds of Formula I: or a pharmaceutically acceptable salt or solvate thereof, wherein: X 1 , X 2 and X 5 independently C or N; X 3 and X 4 Independently selected from: N, NR x , CR y , C(O), O and S; X 6 Selected from: bond, N, NRx , CR y and C(O); Each is a single bond or a double bond, provided that X 1 -X 6 At least one of X is an independently selected heteroatom or heteroatom group; 1 -X 6 At least one of them is C or CR y ; and contains X 1 -X 6 The ring is aromatic; Each R x independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, C(O)(C1-C6)alkyl, S(O)2(C1-C6)alkyl and C(O)O(C1-C6)alkyl; Each R y L 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; 0 Yes key or #-P 0 -P 1 , where # indicates that the 5 Attachment point; -P 0 is a bond, -NH-, -N(C1-C6 alkyl)-, -O- or S(O) 0-2 ; -P 1 is selected from: (C1-C6)alkylene, (C2-C6)alkenylene, (C2-C6)alkynylene, (C3-C8)cycloalkylene and 4- to 8-membered heterocycloalkylene, each of which is optionally substituted by 1-3 R 0 replace; Each R 0 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 such as 3-hydroxyisoxazolyl or 3-hydroxy-1-methylpyrazolyl; or Part-L 0 -T 1 yes: -C(O)NH-(C1-C6)alkyl or -C(O)NH-(C3-C6)cycloalkyl; each of which is optionally substituted by 1 to 4 R T replace; or -5 to 6 membered heteroaryl, -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 optionally substituted with -C(O)OH; wherein -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 are each optionally substituted with 1 to 4 R T replace; T 2 yes: hydrogen, CN, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, or (C1-C6)alkyl optionally substituted by (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)cycloalkyloxy, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein each of said (C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted by 1-4 R T replace; 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 3-10 membered heterocycloalkyl; wherein -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 heterocycloalkyl are each optionally substituted by 1 to 4 R T replace; Each R Tindependently selected from OH, SH, CN, NO2, halogen, =O, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C1-C6)cyanoalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C3-C6)cycloalkyl, amino, (C1-C6)alkylamino, (C1-C6)alkylamino(C1-C6alkyl)-C(O)-C1-C6alkyl, S(O)2(C1-C6alkyl) and di(C1-C6)alkylamino; L 1 is a bond or optionally 1-3 R L Substituted (C1-C3) alkylene; L 2 is a bond, -O-, -S(O) 0-2 - or -NH-; Each R L independently selected from: halogen, (C1-C3) alkyl and (C1-C3) haloalkyl; or a pair of R located on the same carbon atom or adjacent carbon atoms L Together with the atom or atoms to which they are attached, they form a (C3-C6)cycloalkyl ring; Ring A is selected from: Where n1 is 0, 1 or 2, W 1 Yes CR Y1 or N, and W 2 Yes CR Y2 or N; Where W 3 Yes C, CR Y3 or N, L w is (C1-C3)alkylene, and as valence permits, each are independently a single bond or a double bond; Optionally 1-4 R Y Substituted phenylene; Optionally 1-3 R Y substituted 5- to 6-membered heteroarylene; Optionally 1-4 R Y Substituted (C5-C8)cycloalkylene; Optionally 1-4 R Y Substituted partially unsaturated monocyclic (C5-C8) cycloalkylene; and Optionally 1-4 R Y substituted partially unsaturated monocyclic 5- to 8-membered heterocycloalkylene; Where mm represents L 2, and nn represents the attachment point to ring B; Each occurrence of R Y independently selected from halogen, CN, -OH, oxo, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy and (C1-C3)haloalkoxy; R Y1 , R Y2 and R Y3 are each independently selected from hydrogen, halogen, CN, -OH, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy and (C1-C3)haloalkoxy; or When W 1 Yes CR Y1 And W 2 Yes CR Y2 When R Y1 and R Y2 The groups can together form a (C1-C4)alkylene group, wherein one of the CH2 units of the (C1-C4)alkylene group is optionally selected from O, S, NH and N(C 1-3 ) heteroatom substitution of an alkyl group; Ring B is selected from: (BI), (B-II), (B-III), (B-IV), (BV), (B-VI) and (B-VII): where aa represents the point of attachment to ring A; B 1 , B 2 , B 3 and B 4 Each of which is independently selected from CR 1 and N; B 5 and B 6 Each of which is independently selected from N, NR 1 , C, CR 1 , O and S, provided that B is contained 5 and B 6 The ring of is heteroaryl; where aa represents the point of attachment to ring A; B 7 and B 8 Independently selected from: -O-, -NR N -and-C(R 1 )2-; B 9 Is N or CR aa ; nb is 0 or 1; B 10 , B 11 and B 12 Independently selected from CR 1 and N; B 13 , B 14 and B 15 Each is independently CR 1 ; Each R 1 independently selected from hydrogen, halogen, CN, (C1-C6)alkyl, (C1-C6)haloalkyl; (C1-C3)alkyl (C3-C6)cycloalkyl, (C1-C3)alkyl (3 to 5 membered heterocycloalkyl) and -C(O)NR 2 R 3 ; R 2 and R 3 Each independently selected from H and (C1-C6) alkyl; Each R N independently selected from hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, C(O)(C1-C6)alkyl, S(O)2(C1-C6)alkyl and C(O)O(C1-C6)alkyl; R aa , R ab and R ac Each is independently selected from H, (C1-C6)alkyl and (C1-C6)haloalkyl; L 3 Yes key or -Z 1 -Z 2 -*, where * indicates the point of attachment to ring C; -Z 1 is a bond, NH, N(C1-C6 alkyl), O or S(O) 0-2 ; -Z 2 is optionally replaced by 1-2 R c Substituted C 1-3 Alkylene; Each R c independently selected from halogen, (C1-C6)alkyl and (C1-C3)haloalkyl; Ring C is selected from phenyl, 5- to 6-membered heteroaryl, (C3-C6)cycloalkyl, (C5-C 10 ) bicycloalkyl, 5- to 10-membered bicycloheteroaryl, and 3- to 6-membered heterocycloalkyl; Each R bis independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C3-C6)cycloalkyl, CN, -C(O)NH2 or -C(O)OH; and b is an integer selected from 0-3; The condition is that at least one of the following occurs: 1) At least one R b is -C(O)NH2 or -C(O)OH; 2) Ring A is optionally substituted with 1-4 R Y Substituted (C5-C8)cycloalkylene; 3) Ring B is 4) Part-L 0 -T 1 yes: -C(O)NH-(C1-C6)alkyl or -C(O)NH-(C3-C6)cycloalkyl; each of which is optionally substituted by 1 to 4 R T replace; or -5 to 6 membered heteroaryl, -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 optionally substituted with -C(O)OH; wherein -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 are each optionally substituted with 1 to 4 R T replace; or 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 3-10 membered heterocycloalkyl; wherein -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 heterocycloalkyl are each optionally substituted by 1-4 R T replace.

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

[0071] In some embodiments, each R xis independently selected from hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, C(O)(C1-C6)alkyl, S(O)2(C1-C6)alkyl, and C(O)O(C1-C6)alkyl. x is independently selected from hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, and (C3-C6)cycloalkyl. x Independently selected from hydrogen, (C1-C6)alkyl and (C1-C6)haloalkyl.

[0072] In some embodiments, each R y Independently selected from hydrogen, -OH, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, CN and halogen.

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

[0074] In some embodiments, X 6 is a key. For the avoidance of doubt, when X 6 When it is a key, X 1 Attach directly to X 5 (eg, via a single bond or a double bond), thereby providing a 5-membered heteroaromatic ring.

[0075] In some embodiments, X 3 is N; and X 6 is the key.

[0076] In some embodiments, X 3 and X 4 Independently selected from: N, NR x , CR y , O and S.

[0077] In some embodiments, X 6 Selected from: bond, N, NR x and CR y .

[0078] In some embodiments, comprising X 1 -X 6 The ring is: In some embodiments, X 2 is C. In some embodiments, X 1 is N. In some embodiments, X 5 is C. In some embodiments, X 4 Yes CR y In some embodiments, X 4 is CH. In some embodiments, X4 It is N.

[0079] In some embodiments, X 1 Yes N; X 2 is C; and X 5 is C. In some embodiments, comprising X 1 -X 6 The ring is Where X 1 is N; and X 2 is C. In some embodiments, X 4 is CH. In some embodiments, X 4 It is N.

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

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

[0082] In some embodiments, comprising X 1 -X 6 The ring is: Where X 6 Selected from: N, NR x , CR y In some embodiments, X1 is C. In some embodiments, X 2 is C. In some embodiments, X 5 is C. In some embodiments, X 6 Yes CR y For example, X 6 Can be CH. In some embodiments, X 4 Yes CR y For example, X 4 It can be CH.

[0083] In some embodiments, X 1 , X 2 and X 5 It is C; X 4 and X 6 Independently N or CR y In some embodiments, X 4 and X 6 is independently selected CR y As a non-limiting example of the foregoing embodiment, X 4 and X 6 It can be CH.

[0084] In some embodiments, provided herein is a compound of Formula II: in: or a pharmaceutically acceptable salt or solvate thereof, wherein: L 0 Yes key or -P 0 -P 1 ; -P 0 is a bond, -NH-, -N(C1-C6 alkyl)-, -O- or S(O) 0-2 ; -P 1 is selected from: (C1-C6)alkylene, (C2-C6)alkenylene, (C2-C6)alkynylene, (C3-C8)cycloalkylene and 4- to 8-membered heterocycloalkylene, each of which is optionally substituted by 1-3 R 0 replace; Each R 0 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 a C(O)OH or carboxylic acid bioisostere; or Part-L 0 -T 1 yes: -C(O)NH-(C1-C6)alkyl or -C(O)NH-(C3-C6)cycloalkyl; each of which is optionally substituted by 1 to 4 R T replace; or · 5- to 6-membered heteroaryl optionally substituted by -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 -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 are each optionally substituted with 1-4 R T replace; T 2 yes: hydrogen, CN, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, or (C1-C6)alkyl optionally substituted by (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)cycloalkyloxy, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein each of (C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted by 1-4 R T replace; 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 3-10 membered heterocycloalkyl; wherein -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 heterocycloalkyl are each optionally substituted by 1-4 R T replace; Each R Tindependently selected from OH, SH, CN, NO2, halogen, =O, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C1-C6)cyanoalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C3-C6)cycloalkyl, amino, (C1-C6)alkylamino, (C1-C6)alkylamino(C1-C6alkyl)-C(O)-C1-C6alkyl, S(O)2(C1-C6alkyl) and di(C1-C6)alkylamino; W 1 is CH or N; Ring B is selected from: (BI), (B-II), (B-III), (B-IV), (BV), (B-VI) and (B-VII): where aa represents the point of attachment to ring A; B 1 , B 2 , B 3 and B 4 Each of which is independently selected from CR 1 and N; B 5 and B 6 Each of which is independently selected from N, NR 1 , C, CR 1 , O and S, provided that B is contained 5 and B 6 The ring of is heteroaryl; where aa represents the point of attachment to ring A; B 7 and B 8 Independently selected from: -O-, -NR N -and-C(R 1 )2-; B 9 Is N or CR aa ; nb is 0 or 1; B 10 , B 11 and B 12 Independently selected from CR 1 and N; B 13 , B 14 and B 15 Each is independently CR 1 ; Each R 1independently selected from hydrogen, halogen, CN, (C1-C6)alkyl, (C1-C6)haloalkyl; (C1-C3)alkyl (C3-C6)cycloalkyl, (C1-C3)alkyl (3 to 5 membered heterocycloalkyl) and -C(O)NR 2 R 3 ; R 2 and R 3 Each independently selected from H and (C1-C6) alkyl; Each R N independently selected from hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, C(O)(C1-C6)alkyl, S(O)2(C1-C6)alkyl and C(O)O(C1-C6)alkyl; R aa , R ab and R ac Each is independently selected from H, (C1-C6)alkyl and (C1-C6)haloalkyl; L 3 Yes key or -Z 1 -Z 2 -*, where * indicates the point of attachment to ring C; -Z 1 is a bond, NH, N(C1-C6 alkyl), O or S(O) 0-2 ; -Z 2 is optionally replaced by 1-2 R c Substituted C 1-3 Alkylene; Each R c independently selected from halogen, (C1-C6)alkyl and (C1-C3)haloalkyl; Ring C is selected from phenyl, 5- to 6-membered heteroaryl, (C3-C6)cycloalkyl, (C5-C 10 ) bicycloalkyl, 5- to 10-membered bicycloheteroaryl, and 3- to 6-membered heterocycloalkyl; Each R b is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C3-C6)cycloalkyl, CN, -C(O)NH2 or -C(O)OH; and b is an integer selected from 0-3; The condition is that at least one of the following occurs: 1) At least one R b is -C(O)NH2 or -C(O)OH; 2)W 1 It is CH; 3) Ring B is 4) Part-L 0 -T 1 yes: -C(O)NH-(C1-C6)alkyl or -C(O)NH-(C3-C6)cycloalkyl; each of which is optionally substituted by 1 to 4 R T replace; or · 5- to 6-membered heteroaryl optionally substituted by -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 -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 are each optionally substituted with 1-4 R T replace; or 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 3-10 membered heterocycloalkyl; wherein -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 heterocycloalkyl are each optionally substituted by 1-4 R T replace.

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

[0086] In some embodiments, L 0 is a bond. In some embodiments, L 0 Yes#-P 0 -P 1 ; and P 0 is the key.

[0087] In some embodiments, the moiety -L 0 -T 1 is -C(O)NH-(C1-C6)alkyl or -C(O)NH-(C3-C6)cycloalkyl; wherein each is optionally substituted by 1-4 R T In some embodiments, the moiety -L 0 -T 1 is optionally replaced by 1-4 RT Substituted -C(O)NH-(C1-C6)alkyl. In some embodiments, the portion -L 0 -T 1 is optionally replaced by 1-4 R T Substituted -C(O)NH-(C3-C6)cycloalkyl.

[0088] In some embodiments, a compound of Formula IID is provided: or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is -(C1-C6)alkyl or -(C3-C6)cycloalkyl; and wherein -(C1-C6)alkyl or -(C3-C6)cycloalkyl is optionally substituted by 1-4 R T replace.

[0089] In some embodiments, R 6 is -(C1-C6)cycloalkyl, wherein -(C1-C6)cycloalkyl is optionally substituted by 1 to 4 R T In some embodiments, R 6 is -(C1-C6)alkyl, wherein -(C1-C6)alkyl is optionally substituted by 1 to 4 R T replace.

[0090] In some 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 depicted in Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[0091] In some embodiments, the moiety -L 0 -T 1 is a 5- to 6-membered heteroaryl, -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 optionally substituted with -C(O)OH; wherein -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 are each optionally substituted with 1-4 R T replace.

[0092] In some embodiments, a compound of Formula IIE is provided: or a pharmaceutically acceptable salt or solvate thereof, wherein: Ring D is a 5- to 6-membered heteroaryl group; 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 optionally substituted by 1-4 R T replace.

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

[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 some 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 depicted in Table 1, or a pharmaceutically acceptable salt or solvate thereof.

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

[0098] In some embodiments, P 1 is optionally replaced by 1-3 R 0 In some embodiments, P 1 is optionally replaced by 1-3 R 0 In some embodiments, P 1 is (C1-C3) alkylene. 1 is -CH2CH2-, -CH2-, -CH(Me)- or -C(Me)2-. For example, P 1Can be -CH2CH2-. As another non-limiting example, P 1 Can be -CH2-. As another non-limiting example, P 1 It can be -CH(Me)- or -C(Me)2-.

[0099] In some embodiments, P 1 is (C2-C6)alkenylene or (C2-C6)alkynylene, each of which is optionally substituted by 1 to 3 R 0 In some embodiments, P 1 is optionally replaced by 1-3 R 0 In some embodiments, P 1 is optionally replaced by 1-3 R 0 Substituted (C2-C4)alkenylene (eg, (C2-C3)alkenylene, such as C2 alkenylene).

[0100] In some embodiments, P 1 yes Where R 0-1 and R 0-2 independently H or R 0 ; and ee is the same as T 1 In some embodiments, P 1 yes Where R 0-1 and R 0-2 independently H or R 0 ; and ee is the same as T 1 In some embodiments, P 1 yes Where ee is the same as T 1 In some embodiments, P 1 yes Where ee is the same as T 1 For example, P 1 Can be Where ee is the same as T 1 As another non-limiting example, P 1 Can be Where ee is the same as T 1 In some embodiments, P 1 yes Where ee is the same as T 1 For example, P 1 Can be Where ee is the same as T 1 As another non-limiting example, P 1 Can be Where ee is the same as T 1 attachment point.

[0101] In some embodiments, P 1 yes where np is 1, 2, or 3; and ee is the same as T 1 In some embodiments, P 1 yes Where ee is the same as T 1 For example, P 1 Can be Where R 0 is (C1-C6)alkoxy or (C1-C6)haloalkoxy; and ee is the same as T 1 attachment point.

[0102] In some embodiments, P 1 Selected from: (C3-C8) cycloalkylene and 4 to 8 membered heterocycloalkylene, each of which is optionally substituted by 1 to 3 R 0 replace.

[0103] In some embodiments, P 1 is optionally replaced by 1-3 R 0 In some embodiments, P 1 is optionally replaced by 1-3 R 0 In some embodiments, P 1 is (C3-C4) cycloalkylene. As a non-limiting example of the foregoing embodiment, P 1 Can be

[0104] In some embodiments, P 1 is optionally replaced by 1-3 R 0 In some embodiments, P 1 is optionally replaced by 1-2 R 0 Replaced where np is 1, 2, or 3; and ee is the same as T 1 In some embodiments, P 1 is optionally replaced by 1-2 R 0 Replaced where np is 1, 2, or 3; and ee is the same as T 1 attachment point.

[0105] In some embodiments, L 0 Yes#-P 0 -P 1 ;P 0 is a key; and P1 is optionally replaced by 1-3 R 0 In some embodiments, P 1 is (C1-C3) alkylene. For example, P 1 It can be CH2CH2. As another example, P 1 It can be CH2.

[0106] In some embodiments, L 0 Yes#-P 0 -P 1 ;P 0 is -NH-, -N(C1-C3 alkyl) or -O-; and P 1 is optionally replaced by 1-3 R 0 In some embodiments, P 1 As a non-limiting example of the foregoing embodiment, P 1 It can be CH2, CH(Me) or C(Me)2.

[0107] In some embodiments, L 0 Yes#-P 0 -P 1 ;P 0 is a key; and P 1 is optionally replaced by 1-3 R 0 In some embodiments, P 1 yes Where R 0-1 and R 0-2 independently H or R 0 ; and ee is the same as T 1 As a non-limiting example of the foregoing embodiment, P 1 Can be Where ee is the same as T 1 attachment point.

[0109] In some embodiments, L 0 Yes#-P 0 -P 1 ;P 0 is a key; and P 1 is optionally replaced by 1-3 R 0 In some embodiments, P 1 yes

[0110] In some embodiments, L 0 Yes#-P 0-P 1 ;P 0 is a key; and P 1 yes Each of which is optionally replaced by 1-2 R 0 substituted, wherein np is 1, 2 or 3; and ee is 1 attachment point.

[0111] In some embodiments, T 1 It is C(O)OH.

[0112] In some embodiments, T 1 It is a carboxylic acid bioisostere.

[0113] In some embodiments, T 1 is tetrazolyl optionally substituted by (C1-C3)alkyl.

[0114] In some embodiments, T 1 is a tetrazolyl group optionally substituted by 1-2 substituents, each of which is independently selected from hydroxyl, (C1-C6) alkyl, (C1-C6) haloalkyl, and halogen. 1 Selected from

[0115] In some embodiments, T 1 is a triazolyl or oxadiazolyl group optionally substituted by 1-2 substituents, each of which is independently selected from (C1-C6) alkyl and hydroxyl. 1 yes

[0116] In some embodiments, T 1 is a triazolyl group optionally substituted by 1-2 substituents, each of which is independently selected from (C1-C6)haloalkyl, CN. 1 yes

[0117] In some embodiments, T 1 is a ring containing 0-3 heteroatoms (e.g., 4-6 membered rings, e.g., 5 membered rings), each of which is independently selected from N, O, and S, wherein the ring is substituted with 1-2 oxo groups and further optionally substituted with 1-2 substituents, each of which is independently selected from hydroxyl, (C1-C6) alkyl, (C1-C6) haloalkyl, and halogen. For example, in some embodiments, T 1 yes

[0118] In some embodiments, T 1 is (C1-C6)alkyl substituted by 1-3 hydroxyl groups and further optionally substituted by 1-10 fluorine groups. 1 is (C1-C6)alkyl substituted by 1-3 hydroxyl groups and further substituted by 1-10 fluorine groups. For example, in some embodiments, T 1 yes

[0119] In some embodiments, T 1 is C(O)NHS(O)2(C1-C4)alkyl. For example, in some embodiments, T 1 It is C(O)NHS(O)2Me.

[0120] In some embodiments, T 1 Select from the following:

[0121]

[0122] In some embodiments, T 2 is hydrogen or (C1-C6)alkyl optionally substituted by (C1-C6)alkoxy, (C1-C6)thioalkoxy, (C1-C6)haloalkoxy, S(O)2(C1-C6alkyl), (C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl, wherein each of said (C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl is optionally substituted by 1-4 R T replace.

[0123] In some embodiments, each R T Independently selected from OH, SH, CN, NO2, halogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl, (C1-C6) cyanoalkyl, (C1-C6) hydroxyalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, (C3-C6) cycloalkyl, amino, (C1-C6) alkylamino and di(C1-C6) alkylamino.

[0124] In some embodiments, T 2 is hydrogen or (C1-C6)alkyl optionally substituted by (C1-C6)alkoxy, (C1-C6)thioalkoxy, (C1-C6)haloalkoxy, S(O)2(C1-C6alkyl), (C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl, wherein each of said (C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl is optionally substituted by 1-4 RT Replace; and each R T Independently selected from OH, SH, CN, NO2, halogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl, (C1-C6) cyanoalkyl, (C1-C6) hydroxyalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, (C3-C6) cycloalkyl, amino, (C1-C6) alkylamino and di(C1-C6) alkylamino.

[0125] In some embodiments, T 2 is hydrogen, CN, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, or (C1-C6)alkyl optionally substituted by (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)cycloalkyloxy, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein each of said (C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted by 1-4 R T replace.

[0126] In some embodiments, each R T Independently selected from OH, SH, CN, NO2, halogen, =O, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C1-C6)cyanoalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C3-C6)cycloalkyl, amino, (C1-C6)alkylamino, (C1-C6)alkylamino(C1-C6 alkyl)-C(O)-C1-C6 alkyl, S(O)2(C1-C6 alkyl) and di(C1-C6)alkylamino.

[0127] In some embodiments, T 2is hydrogen, CN, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, or (C1-C6)alkyl optionally substituted by (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)cycloalkyloxy, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein each of said (C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted by 1-4 R T Replace; and each R T Independently selected from OH, SH, CN, NO2, halogen, =O, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C1-C6)cyanoalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C3-C6)cycloalkyl, amino, (C1-C6)alkylamino, (C1-C6)alkylamino(C1-C6 alkyl)-C(O)-C1-C6 alkyl, S(O)2(C1-C6 alkyl) and di(C1-C6)alkylamino.

[0128] In some embodiments, T 2 It's hydrogen.

[0129] In some embodiments, T 2 It is CN.

[0130] In some embodiments, T 2 is (C1-C6)alkyl. 2 It's methyl.

[0131] In some embodiments, T 2 is (C1-C6)alkyl substituted by (C1-C6)alkoxy. 2 is a (C1-C3)alkyl group substituted with a (C1-C3)alkoxy group. 2 Can be

[0132] In some embodiments, T 2 is (C1-C6)alkyl substituted with S(O)2(C1-C6alkyl). 2 is (C1-C3)alkyl substituted by S(O)2(C1-C3alkyl). For example, T 2 Can be

[0133] In some embodiments, T 2 is (C1-C6)alkyl substituted by (C3-C6)cycloalkyl. 2 is (C1-C3)alkyl substituted by (C3-C6)cycloalkyl. 2 is a (C1-C3)alkyl group substituted with a cyclobutyl group. For example, T 2 Can be

[0134] In some embodiments, T 2 is (C1-C6)alkyl substituted by 3 to 6 membered heterocycloalkyl. 2 is (C1-C3)alkyl substituted with 3 to 5 membered heterocycloalkyl. 2 is a (C1-C3)alkyl substituted with an oxetane group. For example, T 2 Can be Optionally The stereocenter in has the (S)-configuration. In some embodiments, T 2 is a (C1-C3)alkyl group substituted with a tetrahydrofuranyl group. 2 Can be

[0135] In some embodiments, T 2 is (C1-C6)alkyl substituted by 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally substituted by 1-4 R T In some embodiments, T 2 is (C1-C3)alkyl substituted with 5-membered heteroaryl, wherein the 5-membered heteroaryl is optionally substituted with 1-2 R T In some embodiments, T 2 is (C1-C3)alkyl substituted by imidazolyl, wherein the imidazolyl is optionally substituted by R T For example, T 2 Can be As another non-limiting example, T 2 Can be

[0136] In some embodiments, T 2 It is a (C1-C6)alkyl group substituted by a (C3-C6)cycloalkyloxy group.

[0137] In some embodiments, T 2 is (C1-C6)alkyl substituted by 3 to 6 membered heterocycloalkyl, wherein the 3 to 6 membered heterocycloalkyl is optionally substituted by 1 to 4 R TIn certain of these embodiments, R T It is S(O)2(C1-C6 alkyl).

[0138] In some embodiments, T 2 It is a (C1-C6)alkyl group substituted by -N(C1-C6alkyl)-S(O)2(C1-C6alkyl).

[0139] In some embodiments, T 2 It is a (C1-C6)alkyl group substituted by -NH-S(O)2(C1-C6alkyl).

[0140] In some embodiments, T 2 It is a (C1-C6) hydroxyalkyl group.

[0141] In some embodiments, T 2 It is a (C1-C6) haloalkyl group.

[0142] In some embodiments, 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 3-10 membered heterocycloalkyl; wherein -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 heterocycloalkyl are each optionally substituted by 1-4 R T replace.

[0143] In some embodiments, 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 3-10 membered nitrogen-containing heterocycloalkyl; wherein -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 are each optionally substituted by 1-4 R T replace.

[0144] In some embodiments, T 2 is (C3-C6) cycloalkyl or 3-10 membered heterocycloalkyl; wherein (C3-C6) cycloalkyl or 3-10 membered heterocycloalkyl are each optionally substituted by 1-4 R TIn some embodiments, T 2 is (C3-C6) cycloalkyl or 3-10 membered nitrogen-containing heterocycloalkyl; wherein (C3-C6) cycloalkyl or 3-10 membered nitrogen-containing heterocycloalkyl are each optionally substituted by 1-4 R T replace.

[0145] In some embodiments, T 2 is optionally replaced by 1-4 R T In some embodiments, T 2 is optionally replaced by 1-4 R T In some embodiments, T 2 is optionally replaced by 1-4 R T Substituted 3-10 membered nitrogen-containing heterocycloalkyl.

[0146] In some embodiments, a compound of Formula IIF is provided: or a pharmaceutically acceptable salt or solvate thereof, wherein: L 4 is a bond, -NH-, -CH2-S(O)2, or -O-; and R 7 is (C1-C6)alkyl, (C3-C6)cycloalkyl or 3-10 membered heterocycloalkyl, wherein each of the (C1-C6)alkyl, (C3-C6)cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted by 1 to 4 R T Replacement; the condition is that when L 4 When it is a key, then R 7 It is a substituted or unsubstituted (C3-C6)cycloalkyl group, or a substituted or unsubstituted 3-10 membered heterocycloalkyl group.

[0147] In some embodiments, the compound is not:

[0148] In some embodiments, R 7 is (C3-C6) cycloalkyl or 3-10 membered heterocycloalkyl, wherein each of the (C3-C6) cycloalkyl and 3-10 membered heterocycloalkyl groups is optionally substituted by 1 to 4 R T In some embodiments, R 7 is optionally replaced by 1-4 R T In some embodiments, R 7 is optionally replaced by 1-4 R T In some embodiments, R 7is optionally replaced by 1-4 R T Substituted 3-10 membered nitrogen-containing heterocycloalkyl.

[0149] In some embodiments, L 4 is a bond, -NH-, -CH2-S(O)2, or -O-; and R 7 is (C1-C6)alkyl, (C3-C6)cycloalkyl or 3-10 membered nitrogen-containing heterocycloalkyl, wherein (C1-C6)alkyl, (C3-C6)cycloalkyl or 3-10 membered nitrogen-containing heterocycloalkyl is optionally replaced by 1-4 R T Replacement; the condition is that when L 4 When it is a key, then R 7 It is a substituted or unsubstituted (C3-C6) cycloalkyl group, or a substituted or unsubstituted 3-10 membered nitrogen-containing heterocycloalkyl group.

[0150] In some 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 depicted in Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[0151] In some embodiments, L 2 is the key.

[0152] In some embodiments, L 1 is CH2. In some embodiments, L 1 is the key.

[0153] In some embodiments, L 2 is a key; and L 1 It is CH2.

[0154] In some embodiments, L 1 is a key; and L 2 is the key.

[0155] In some embodiments, Ring A is In some embodiments, W 1 is N. In some embodiments, W 2 Yes 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 can be As another non-limiting example, Ring A can be In some embodiments, n1 is 1. For example, ring A can be

[0156] In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, L W is CH2. In some embodiments, W 3 is N. As a non-limiting example of the foregoing embodiment, ring A can be

[0157] In some embodiments, L 2 Yes key; L 1 is CH2; and Ring A is In some embodiments, Ring A is In some embodiments, Ring A is

[0158] In some embodiments, L 2 Yes key; L 1 is a bond; and ring A is In some embodiments, Ring A is

[0159] In some embodiments, Ring A is optionally substituted with 1-4 R Y Substituted (C5-C8)cycloalkylene. In some embodiments, Ring A is

[0160] In some embodiments, a compound of Formula IIB is provided: or a pharmaceutically acceptable salt or solvate thereof.

[0161] In some embodiments, the compound of Formula I, II, or IIB is Compound Bl as depicted in Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[0162] In some embodiments, Ring B is In some embodiments, B 4 Yes CR 1 For example, B 4 It may be CH. In some embodiments, B 1 Yes CR 1 For example, B 1 It may be CH. In some embodiments, B 3 Yes CR 1 For example, B 3 It may be CH. In some embodiments, B 2is N. In some embodiments, Ring B is For example, ring B can be

[0164] In some embodiments, Ring B is In some embodiments, B 4 and B 3 is independently selected CR 1 As a non-limiting example of the foregoing embodiment, B 4 and B 3 It may be CH. In some embodiments, B 1 Yes CR 1 For example, B 1 It may be CH. In some embodiments, B 2 is N. In some embodiments, Ring B is For example, ring B can be

[0165] In some embodiments, Ring B is In some embodiments, B 9 Yes CR aa In some embodiments, R aa is H. In some embodiments, R aa is (C1-C6)alkyl. aa is (C1-C3) alkyl. For example, R aa In some embodiments, nb is 0. In some embodiments, nb is 1. In some embodiments, when B 9 Yes CR aa When B 8 and R aa The carbon atoms to which both are attached have the (R)-configuration. 9 Yes CR aa When B 8 and R aa The carbon atoms to which both are attached have the (S)-configuration.

[0166] In some embodiments, Ring B is In some embodiments, B 7 In some embodiments, B 8 In some embodiments, B 7 is -O-; and B 8 In some embodiments, R aa is H. In some embodiments, R aa is (C1-C6)alkyl.aa is (C1-C3) alkyl. For example, R aa It may be methyl. In some embodiments, R ab is H. In some embodiments, R ac is H. In some embodiments, R aa , R ab and R ac Each is H. In some embodiments, R aa is (C1-C3)alkyl; and R ab and R ac is H. In some embodiments, B 10 Yes CR 1 For example, B 10 It may be CH. In some embodiments, B 11 Yes CR 1 For example, B 11 It may be CH. In some embodiments, B 12 Yes CR 1 For example, B 12 It may be CH. In some embodiments, B 10 , B 11 and B 12 Each is independently selected CR 1 In some embodiments, B 10 , B 11 and B 12 is CH. In some embodiments, B 8 and R aa The carbon atoms to which both are attached have the (R)-configuration. 8 and R aa The carbon atoms to which both are attached have the (S)-configuration.

[0167] In some embodiments, B is In some embodiments, B 7 In some embodiments, B 8 In some embodiments, B 7 is -O-; and B 8 In some embodiments, R aa is H. In some embodiments, R aa is (C1-C6)alkyl. aa is (C1-C3) alkyl. For example, R aa It may be methyl. In some embodiments, B 10 Yes CR 1 For example, B 10It may be CH. In some embodiments, B 11 Yes CR 1 For example, B 11 It may be CH. In some embodiments, B 12 Yes CR 1 For example, B 12 It may be CH. In some embodiments, B 10 , B 11 and B 12 Each is independently selected CR 1 In some embodiments, B 10 , B 11 and B 12 is CH. In some embodiments, B 8 and R aa The carbon atoms to which both are attached have the (R)-configuration. 8 and R aa The carbon atoms to which both are attached have the (S)-configuration.

[0168] In some embodiments, Ring B is B 7 and B 8 is -O-; and R aa is H or (C1-C3) alkyl, such as H or methyl. In some embodiments, R ab and R ac is H. In some embodiments, R aa is H. In some embodiments, R aa is (C1-C3)alkyl, such as methyl. 10 , B 11 and B 12 Each is independently selected CR 1 In some embodiments, B 10 , B 11 and B 12 is CH. In some embodiments, B 8 and R aa The carbon atoms to which both are attached have the (R)-configuration. 8 and R aa The carbon atoms to which both are attached have the (S)-configuration.

[0169] In some embodiments, Ring B is B 7 and B 8 is -O-; and R aa is H or (C1-C3) alkyl. aais H. In some embodiments, R aa is (C1-C3)alkyl, such as methyl. 10 , B 11 and B 12 Each is independently selected CR 1 In some embodiments, B 10 , B 11 and B 12 is CH. In some embodiments, B 8 and R aa The carbon atoms to which both are attached have the (R)-configuration. 8 and R aa The carbon atoms to which both are attached have the (S)-configuration.

[0170] In some embodiments, Ring B is And use ** The labeled carbon atoms have the (R)-configuration.

[0171] In some embodiments, Ring B is And use ** The labeled carbon atoms have the (S)-configuration.

[0172] In some embodiments, Ring B is And the carbon atom marked with ** has the (R)-configuration.

[0173] In some embodiments, Ring B is And use ** The carbon atom labeled has the (S)-configuration. aa is (C1-C3) alkyl. For example, R aa can be methyl. For example, ring B can be

[0174] In some embodiments, Ring B is And use ** The carbon atom labeled has the (R)-configuration. aa is (C1-C3) alkyl. For example, R aa can be methyl. For example, ring B can be

[0175] In some embodiments, Ring B is In some embodiments, Ring B is

[0176] In some embodiments, a compound of Formula IIC is provided: or a pharmaceutically acceptable salt or solvate thereof.

[0177] In some embodiments, the compound of Formula I, II, or IIC is Compound AC-1 as depicted in Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[0178] In some embodiments, L 3 is a bond. In some embodiments, Ring B is selected from (BV) and (B-VI); and L 3 is a bond. In some embodiments, Ring B is (BV) (eg, Ring B is as defined in one or more embodiments, as above); and L 3 is the key.

[0179] In some embodiments, L 3 Yes-Z 1 -Z 2 -*, wherein * represents the point of attachment to ring C. In some embodiments, ring B is selected from (BI), (B-II), (B-III) and (B-IV), L 3 Yes-Z 1 -Z 2 -*, wherein * indicates the point of attachment to ring C. For example, ring B is (BI) or (B-II); and L 3 Yes-Z 1 -Z 2 -*.

[0180] In some embodiments, Z 1 Yes -O-.

[0181] In some embodiments, Z 2 is optionally replaced by 1-2 R c In some embodiments, Z 2 It is -CH2-.

[0182] In some embodiments, L 3 It is -O-CH2-*, where * indicates the point of attachment to ring C.

[0183] In some embodiments, ring C is selected from: phenyl, 5- to 6-membered heteroaryl, and 5- to 10-membered bicyclic heteroaryl. In some embodiments, ring C is selected from phenyl and 6-membered heteroaryl (eg, pyridinyl).

[0184] In some embodiments, b is 1-3. In some embodiments, b is 2. In some embodiments, b is 1. In some embodiments, b is 0.

[0185] In some embodiments, Ring C is phenyl. In some embodiments, Ring C is phenyl; and b is 2. In some embodiments, yes In some embodiments, Ring C is phenyl; and b is 1. In some embodiments, yes In some embodiments, Ring C is phenyl; and b is 0.

[0186] In some embodiments, each occurrence of 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. b Independently selected from -F, -Cl, CF3 and CN.

[0187] In some embodiments, at least one R b is -C(O)NH2 or -C(O)OH. In some embodiments, at least one R b is -C(O)NH2 or -C(O)OH; and the remaining R b Independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen and CN.

[0188] In some embodiments, a compound of Formula IIA is provided: or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is -OH or -NH 2 , and each of the remaining variables is independently as defined herein.

[0189] In some embodiments, the compound of Formula I, II, or IIA is Compound A-1 or A-3 as depicted in Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[0190] In some embodiments, the compound is a compound of formula (I-A1) or a pharmaceutically acceptable salt thereof: Where R cA and R cB Independently selected from H and R c .

[0191] In some embodiments of Formula (I-A1), containing B 1 , B 2 , B 3 and B 4 The ring is In some embodiments, the 1 , B 2 , B 3 and B 4 The ring can be

[0192] In some embodiments, the compound is a compound of formula (I-A2) or a pharmaceutically acceptable salt thereof: Where R cA and R cB Independently selected from H and R c .

[0193] In some embodiments of Formula (I-A2), containing B 1 , B 2 , B 3 and B 4 The ring is In some embodiments, the 1 , B 2 , B 3 and B 4 The ring can be

[0194] In some embodiments of Formula (I-A1) or (I-A2), Z 1 In some embodiments of Formula (I-A1) or (I-A2), R cA is H. In some embodiments of Formula (I-A1) or (I-A2), R cB It's H.

[0195] In some embodiments, the compound is a compound of formula (I-A3): or a pharmaceutically acceptable salt thereof.

[0196] In some embodiments of Formula (I-A3), R ab and R ac It's H.

[0197] In some embodiments, the compound is a compound of formula (I-A4): or a pharmaceutically acceptable salt thereof.

[0198] In some embodiments of Formula (I-A4), B 7 is -O-; and B 8 Yes -O-.

[0199] In some embodiments of Formula (I-A3) or (I-A4), R aa is H. In some embodiments, R aa is (C1-C3) alkyl. For example, R aa It may be methyl.

[0200] In some embodiments of Formula (I-A3) or (I-A4), B 10 , B 11 and B 12 is independently selected CR 1 In some embodiments, B 10 , B 11 and B 12 It is CH.

[0201] In some embodiments of Formula (I-A1), (I-A2), (I-A3) or (I-A4), X 1 It is N.

[0202] In some embodiments of Formula (I-A1), (I-A2), (I-A3) or (I-A4), X 2 It is C.

[0203] In some embodiments of Formula (I-A1), (I-A2), (I-A3) or (I-A4), X 5 It is C.

[0204] In some embodiments of Formula (I-A1), (I-A2), (I-A3) or (I-A4), X 4 is N. In some embodiments of Formula (I-A1), (I-A2), (I-A3) or (I-A4), X 4 Yes CR y , such as CH.

[0205] In some embodiments of Formula (I-A1), (I-A2), (I-A3) or (I-A4), Part is In some embodiments, X 4 is N. In some embodiments, X 4 Yes CR y For example, X 4 It can be CH.

[0206] In some embodiments, the compound is a compound of formula (I-B1) or a pharmaceutically acceptable salt thereof: Where X 6 Selected from: N, NR x, CR y and C(O); and R cA and R cB Independently selected from H and R c .

[0207] In some embodiments of Formula (I-B1), X 1 is C. In some embodiments of Formula (I-B1), X 2 and X 5 is C. In some embodiments of Formula (I-B1), X 4 and X 6 is independently selected CR y For example, X 4 and X 6 It can be CH.

[0208] In some embodiments of Formula (I-B1), Part is In some embodiments, each R y It's H.

[0209] In some embodiments of Formula (I-B1), L 0 Yes#-P 0 -P 1 .

[0210] In some embodiments of Formula (I-B1), Z 1 In some embodiments of Formula (I-B1), R cA is H; and R cB It's H.

[0211] In some embodiments of Formula (I-A1), (I-A2), (I-A3), (I-A4) or (I-B1), P 0 is a key; and P 1 is optionally replaced by 1-3 R 0 In some embodiments, P 1 is (C1-C3) alkylene. For example, P 1 It can be -CH2CH2-.

[0212] In some embodiments of Formula (I-A1), (I-A2), (I-A3), (I-A4) or (I-B1), P 0 is -NH-, -N(C1-C3 alkyl) or -O-; and P 1 is optionally replaced by 1-3 R 0 In some embodiments, P 1is (C1-C3) alkylene. For example, P 1 It can be CH2, CH(Me) or C(Me)2.

[0213] In some embodiments of Formula (I-A1), (I-A2), (I-A3), (I-A4) or (I-B1), P 0 is a key; and P 1 is optionally replaced by 1-3 R 0 In some embodiments, P 1 yes Where R 0-1 and R 0-2 independently H or R 0 ; and ee is the same as T 1 In some embodiments, P 1 yes Where ee is the same as T 1 attachment point.

[0214] In some embodiments of Formula (I-A1), (I-A2), (I-A3), (I-A4) or (I-B1), P 0 is a key; and P 1 is optionally replaced by 1-3 R 0 In some embodiments, P 1 yes

[0215] In some embodiments of Formula (I-A1), (I-A2), (I-A3), (I-A4) or (I-B1), P 0 is a key; and P 1 yes Each of which is optionally replaced by 1-2 R 0 substituted, wherein np is 1, 2 or 3; and ee is 1 attachment point.

[0216] In some embodiments of Formula (I-A1), (I-A2), (I-A3), (I-A4) or (I-B1), T 1 It is C(O)OH.

[0217] In some embodiments of Formula (I-A1), (I-A2), (I-A3), (I-A4) or (I-B1), T 2 It is H or (C1-C3) alkyl.

[0218] In some embodiments of Formula (I-A1), (I-A2), (I-A3), (I-A4) or (I-B1), T2 is a (C1-C3)alkyl group substituted with a (C1-C3)alkoxy group. 2 Can be

[0219] In some embodiments of Formula (I-A1), (I-A2), (I-A3), (I-A4) or (I-B1), T 2 is (C1-C3)alkyl substituted by S(O)2(C1-C3alkyl). For example, T 2 Can be

[0220] In some embodiments of Formula (I-A1), (I-A2), (I-A3), (I-A4) or (I-B1), T 2 is a (C1-C3)alkyl group substituted with a (C3-C6)cycloalkyl group. 2 Can be

[0221] In some embodiments of Formula (I-A1), (I-A2), (I-A3), (I-A4) or (I-B1), T 2 is (C1-C3)alkyl substituted with 3 to 5 membered heterocycloalkyl. 2 is a (C1-C3)alkyl substituted with an oxetane group. For example, T 2 Can be Optionally The stereocenter in has the (S)-configuration. In some embodiments, T 2 is (C1-C3)alkyl substituted with tetrahydrofuranyl. 2 yes

[0222] In some embodiments of Formula (I-A1), (I-A2), (I-A3), (I-A4) or (I-B1), T 2 is (C1-C3)alkyl substituted with 5-membered heteroaryl, wherein the 5-membered heteroaryl is optionally substituted with 1-2 R T In some embodiments, T 2 is (C1-C3)alkyl substituted by imidazolyl, wherein the imidazolyl is optionally substituted by R T Replace. For example, T 2 Can be As another non-limiting example, T 2 Can be

[0223] In some embodiments of Formula (I-A1), (I-A2), (I-A3), (I-A4) or (I-B1), L 1 is CH2; and Ring A is

[0224] In some embodiments of Formula (I-A1), (I-A2), (I-A3), (I-A4) or (I-B1), L 1 is CH2; and Ring A is

[0225] In some embodiments of Formula (I-A1), (I-A2), (I-A3), (I-A4) or (I-B1), L 1 is CH2; and Ring A is

[0226] In some embodiments of Formula (I-A1), (I-A2), (I-A3), (I-A4) or (I-B1), L 1 is a bond; and ring A is In some embodiments, Ring A is

[0227] In some embodiments of Formula (I-A1), (I-A2), (I-A3), (I-A4) or (I-B1), Ring C is selected from: phenyl and 6-membered heteroaryl (e.g., pyridinyl, such as 2-pyridinyl, 3-pyridinyl or 4-pyridinyl).

[0228] In some embodiments of Formula (I-A1), (I-A2), (I-A3), (I-A4) or (I-B1), yes

[0229] In some embodiments of Formula (I-A1), (I-A2), (I-A3), (I-A4) or (I-B1), yes

[0230] In some embodiments of Formula (I-A1), (I-A2), (I-A3), (I-A4) or (I-B1), each occurrence of R b Independently selected from: (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen and CN.

[0231] In some embodiments of Formula (I-A1), (I-A2), (I-A3), (I-A4) or (I-B1), R b Independently selected from -F, -Cl, CF3 and CN.

[0232] In some embodiments, the compound of formula (I) is a compound of formula (I-A4-1) or a pharmaceutically acceptable salt thereof: in: is a single bond or a double bond; R 0-1 is selected from hydrogen and (C1-C3)alkyl; X 4 Selected from N and CR y ; T 2 is (C1-C3)alkyl substituted by 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 the phenyl or 5- to 6-membered heteroaryl are each optionally substituted by halogen or (C1-C3)alkyl; R aa is selected from hydrogen and (C1-C3)alkyl; Ring C is selected from: phenyl and 6-membered heteroaryl; b is 0, 1, or 2; and Each occurrence of R b Independently selected from: (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen and CN.

[0233] In some embodiments of Formula (I-A4-1), It's a double bond.

[0234] In some embodiments of Formula (I-A4-1), It is a single bond.

[0235] In some embodiments of Formula (I-A4-1), R 0-1 It's hydrogen.

[0236] In some embodiments of Formula (I-A4-1), R 0-1 is (C1-C3) alkyl. For example, R 0-1 It may be methyl.

[0237] In some embodiments of Formula (I-A4-1), is a double bond; and R 0-1 It's hydrogen.

[0238] In some embodiments of Formula (I-A4-1), is a double bond; and R 0-1 It's methyl.

[0239] In some embodiments of Formula (I-A4-1), single bond; and R 0-1 It's hydrogen.

[0240] In some embodiments of Formula (I-A4-1), X 4 It is CH.

[0241] In some embodiments of Formula (I-A4-1), X 4 It is N.

[0242] In some embodiments of Formula (I-A4-1), T 2 is (C1-C3)alkyl substituted with 3 to 6 membered heterocycloalkyl. 2 is a (C1-C3)alkyl substituted with an oxetane group. For example, T 2 Can be (For example, T 2 The stereocenter in may have the (S)-configuration). In some embodiments, T 2 is a (C1-C3)alkyl group substituted with a tetrahydrofuranyl group. 2 Can be (For example, T 2 The stereocenter in may have the (S)-configuration).

[0243] In some embodiments of Formula (I-A4-1), T 2 is (C1-C3)alkyl substituted with 5-membered heteroaryl, wherein the 5-membered heteroaryl is optionally substituted with (C1-C3)alkyl. 2 is a (C1-C3)alkyl group substituted by an imidazolyl group, wherein the imidazolyl group is optionally substituted by a (C1-C3)alkyl group. 2 Can be As another non-limiting example, T 2 Can be

[0244] In some embodiments of Formula (I-A4-1), T 2 is a (C1-C3)alkyl group substituted with a (C1-C3)alkoxy group. 2 Can be

[0245] In some embodiments of Formula (I-A4-1), R aa is (C1-C3) alkyl. For example, R aa It's methyl.

[0246] In some embodiments of Formula (I-A4-1), R aa It's hydrogen.

[0247] In some embodiments of Formula (I-A4-1), R aa The carbon to which both and ring C are attached has the (S)-configuration.

[0248] In some embodiments of Formula (I-A4-1), R aa is (C1-C3)alkyl; and R aa The carbon to which both R and ring C are attached has the (S)-configuration. aa It's methyl.

[0249] In some embodiments of Formula (I-A4-1), Ring C is phenyl.

[0250] In some embodiments of Formula (I-A4-1), b is 1 or 2.

[0251] In some embodiments of Formula (I-A4-1), yes (For example, ).

[0252] In some embodiments of Formula (I-A4-1), yes (For example, ).

[0253] In some embodiments of Formula (I-A4-1), each R b In some embodiments, each R b Independently selected from: -F and -Cl. For example, each R b may independently be -F or -Cl.

[0254] In some embodiments of Formula (I-A4-1): R 0-1 is hydrogen or methyl; X 4 is N or CH; T 2 Selected from: R aa is (C1-C3)alkyl, wherein R aa and the carbon to which ring C is both attached has the (S)-configuration; Ring C is phenyl; and b is 1 or 2.

[0255] In some embodiments, Raa In some embodiments, X 4 is CH. In some embodiments, X 4 is N. In some embodiments, each R b is independently -F or -Cl.

[0256] In some embodiments, the compound is a compound of formula (I-A1) or a pharmaceutically acceptable salt thereof: Where R cA and R cB Independently selected from H and R c .

[0257] In some embodiments of Formula (I-A5), containing B 1 , B 2 , B 3 and B 4 The ring is For example, containing B 1 , B 2 , B 3 and B 4 The ring can be

[0258] In some embodiments, the compound is a compound of formula (I-A2) or a pharmaceutically acceptable salt thereof: Where R cA and R cB Independently selected from H and R c .

[0259] In some embodiments of Formula (I-A6), containing B 1 , B 2 , B 3 and B 4 The ring is For example, containing B 1 , B 2 , B 3 and B 4 The ring can be

[0260] In some embodiments of Formula (I-A1) or (I-A2), Z 1 In some embodiments of Formula (I-A1) or (I-A2), R cA is H. In some embodiments of Formula (I-A1) or (I-A2), R cB It's H.

[0261] In some embodiments, the compound is a compound of formula (I-A7): or a pharmaceutically acceptable salt thereof.

[0262] In some embodiments of Formula (I-A7), R ab and R ac It's H.

[0263] In some embodiments, the compound is a compound of formula (I-A8): or a pharmaceutically acceptable salt thereof.

[0264] In some embodiments of Formula (I-A8), B 7 is -O-; and B 8 Yes -O-.

[0265] In some embodiments of Formula (I-A7) or (I-A8), R aa is H. In some embodiments, R aa is (C1-C3) alkyl. For example, R aa It may be methyl.

[0266] In some embodiments of Formula (I-A7) or (I-A8), B 10 , B 11 and B 12 is independently selected CR 1 In some embodiments, B 10 , B 11 and B 12 It is CH.

[0267] In some embodiments of Formula (I-A5), (I-A6), (I-A7) or (I-A8), X 1 It is N.

[0268] In some embodiments of Formula (I-A5), (I-A6), (I-A7) or (I-A8), X 2 It is C.

[0269] In some embodiments of Formula (I-A5), (I-A6), (I-A7) or (I-A8), X 5 It is C.

[0270] In some embodiments of Formula (I-A5), (I-A6), (I-A7) or (I-A8), X 4 is N. In some embodiments of Formula (I-A5), (I-A6), (I-A7) or (I-A8), X4 Yes CR y , such as CH.

[0271] In some embodiments of Formula (I-A5), (I-A6), (I-A7) or (I-A8), Part is In some embodiments, X 4 is N. In some embodiments, X 4 Yes CR y For example, X 4 It can be CH.

[0272] In some embodiments, the compound is a compound of formula (I-B2) or a pharmaceutically acceptable salt thereof: Where X 6 Selected from: N, NR x , CR y and C(O); and R cA and R cB Independently selected from H and R c .

[0273] In some embodiments of Formula (I-B2), X 1 is C. In some embodiments of Formula (I-B2), X 2 and X 5 is C. In some embodiments of Formula (I-B2), X 4 and X 6 is independently selected CR y For example, X 4 and X 6 It can be CH.

[0274] In some embodiments of Formula (I-B2), Part is In some embodiments, each R y It's H.

[0275] In some embodiments of Formula (I-B2), L 0 Yes#-P 0 -P 1 .

[0276] In some embodiments of Formula (I-B2), Z 1 In some embodiments of Formula (I-B2), R cA is H; and R cB It's H.

[0277] In some embodiments of Formula (I-A5), (I-A6), (I-A7), (I-A8) or (I-B2), T 1 It is C(O)OH.

[0278] 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).

[0279] In some embodiments of Formula (I-A5), (I-A6), (I-A7), (I-A8) or (I-B2), T 2 It is H or (C1-C3) alkyl.

[0280] In some embodiments of Formula (I-A5), (I-A6), (I-A7), (I-A8) or (I-B2), T 2 is a (C1-C3)alkyl group substituted with a (C1-C3)alkoxy group. 2 Can be

[0281] In some embodiments of Formula (I-A5), (I-A6), (I-A7), (I-A8) or (I-B2), T 2 is (C1-C3)alkyl substituted by S(O)2(C1-C3alkyl). For example, T 2 Can be

[0282] In some embodiments of Formula (I-A5), (I-A6), (I-A7), (I-A8) or (I-B2), T 2 is a (C1-C3)alkyl group substituted with a (C3-C6)cycloalkyl group. 2 Can be

[0283] In some embodiments of Formula (I-A5), (I-A6), (I-A7), (I-A8) or (I-B2), T 2 is (C1-C3)alkyl substituted with 3 to 5 membered heterocycloalkyl. 2 is a (C1-C3)alkyl substituted with an oxetane group. For example, T 2 Can be Optionally The stereocenter in has the (S)-configuration. In some embodiments, T 2 is (C1-C3)alkyl substituted with tetrahydrofuranyl. 2 yes

[0284] In some embodiments of Formula (I-A5), (I-A6), (I-A7), (I-A8) or (I-B2), T 2 is (C1-C3)alkyl substituted with 5-membered heteroaryl, wherein the 5-membered heteroaryl is optionally substituted with 1-2 R T In some embodiments, T 2 is (C1-C3)alkyl substituted by imidazolyl, wherein the imidazolyl is optionally substituted by R T Replace. For example, T 2 Can be As another non-limiting example, T 2 Can be

[0285] In some embodiments of Formula (I-A5), (I-A6), (I-A7), (I-A8) or (I-B2), L 1 is CH2; and Ring A is

[0286] In some embodiments of Formula (I-A5), (I-A6), (I-A7), (I-A8) or (I-B2), L 1 is CH2; and Ring A is

[0287] In some embodiments of Formula (I-A5), (I-A6), (I-A7), (I-A8) or (I-B2), L 1 is CH2; and Ring A is

[0288] In some embodiments of Formula (I-A5), (I-A6), (I-A7), (I-A8) or (I-B2), L 1 is a bond; and ring A is In some embodiments, Ring A is

[0289] In some embodiments of Formula (I-A5), (I-A6), (I-A7), (I-A8) or (I-B2), Ring C is selected from: phenyl and 6-membered heteroaryl (e.g., pyridinyl, such as 2-pyridinyl, 3-pyridinyl or 4-pyridinyl).

[0290] In some embodiments of Formula (I-A5), (I-A6), (I-A7), (I-A8) or (I-B2), yes

[0291] In some embodiments of Formula (I-A5), (I-A6), (I-A7), (I-A8) or (I-B2), yes

[0292] In some embodiments of Formula (I-A5), (I-A6), (I-A7), (I-A8) or (I-B2), each occurrence of R b Independently selected from: (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen and CN.

[0293] In some embodiments of Formula (I-A5), (I-A6), (I-A7), (I-A8) or (I-B2), R b Independently selected from -F, -Cl, CF3 and CN.

[0294] In some embodiments, a compound selected from Table 1 or a pharmaceutically acceptable salt or solvate thereof is provided. Table 1

[0295] In some embodiments, a compound selected from Table 2 or a pharmaceutically acceptable salt or solvate thereof is provided. Table 2

[0296] The compounds disclosed herein include pharmaceutically acceptable salts thereof. In addition, the compounds disclosed herein also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts and can be used as intermediates for preparing and / or purifying the compounds disclosed herein and / or for separating the enantiomers of the compounds disclosed herein. Non-limiting examples of pharmaceutically acceptable salts of the compounds disclosed herein include trifluoroacetate.

[0297] It is further understood that the compounds disclosed herein or their salts can be separated in the form of solvates, and accordingly, any such solvates are included within the scope of the present disclosure. "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 form as well as solvated form with pharmaceutically acceptable solvents (such as water, ethanol, etc.). Pharmaceutical compositions and administration

[0298] When used as a drug, a compound as described 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 in a manner well known in the pharmaceutical field and can be administered by various routes, depending on whether local treatment or systemic treatment is desired and the area to be treated. Administration can be topical (including transdermal, epidermal, ocular and mucosal, including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powder or aerosol, including by a nebulizer; intratracheal or intranasal), oral or parenteral. Oral administration can include a dosage form formulated for once daily or twice daily (BID) administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or injection or infusion; or intracranial (e.g., intrathecal or intraventricular) administration. Parenteral administration can be in the form of a single bolus dose or can be, for example, by a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

[0299] Also provided herein is a pharmaceutical composition, which contains a combination of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof as an active ingredient and one or more pharmaceutically acceptable excipients (carriers). For example, a pharmaceutical composition prepared using a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the composition is suitable for topical administration. In the manufacture of the composition provided herein, the active ingredient is typically mixed with an excipient, diluted with an excipient or encapsulated in such a carrier, which is in the form of, for example, a capsule, a sachet, paper or other container. When an excipient is used as a diluent, it can be a solid, semisolid or liquid material, which serves as a vehicle, carrier or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In some embodiments, the composition is formulated for oral administration. In some embodiments, the composition is a solid oral formulation. In some embodiments, the composition is formulated as a tablet or capsule.

[0300] Further provided herein is a pharmaceutical composition containing a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient. A pharmaceutical composition containing a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof as an active ingredient can be prepared by closely mixing a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof with a pharmaceutical carrier according to conventional drug compounding techniques. The carrier can take many forms, depending on the desired route of administration (e.g., oral, parenteral, etc.). In some embodiments, the composition is a solid oral composition.

[0301] Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

[0302] Methods of formulating pharmaceutical compositions have been described in numerous publications, such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al.; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al.; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al. and published by Marcel Dekker, Inc.

[0303] In some embodiments, the compound or pharmaceutical composition can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; self-emulsifying drug delivery systems (SEDDS), such as d-α-tocopheryl polyethylene glycol 1000 succinate; surfactants used in pharmaceutical dosage forms, such as Tween, poloxamer or other similar polymer delivery matrices; serum proteins, such as human serum albumin; buffer substances, such as phosphate, tris, glycine, sorbic acid, potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride; zinc salts; colloidal silicon dioxide; magnesium trisilicate; polyvinyl pyrrolidone; cellulose-based substances; polyethylene glycol; sodium carboxymethyl cellulose; polyacrylates; waxes; polyethylene-polyoxypropylene block copolymers; and lanolin. Cyclodextrins (such as α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin) or chemically modified derivatives such as hydroxyalkylcyclodextrin (including 2- and 3-hydroxypropyl-β-cyclodextrin) or other soluble derivatives can also be used to enhance the delivery of the compounds described herein. A dosage form or composition containing a chemical entity as described herein in the range of 0.005% to 100% and the remainder being supplemented by a non-toxic excipient can be prepared. The composition under consideration can contain 0.001%-100% of the chemical entity provided herein, in one embodiment 0.1%-95%, in another embodiment 75%-85%, and in another embodiment 20%-80%. The actual method of preparing such dosage forms is known or will be apparent to those skilled in the art; for example, see Remington: The Science and Practice of Pharmacy, 22nd edition (Pharmaceutical Press, London, UK. 2012).

[0304] In some embodiments, the compounds and pharmaceutical compositions described herein or their pharmaceutical compositions can be applied to patients in need by any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, skin, intracervical, intranasal, intratracheal, intestinal, epidural, interstitial, intraperitoneal, intraarterial, intrabronchial, intracapsular, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinus, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal (e.g., intranasal), nasogastric, oral, parenteral, transdermal, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, external, transdermal, transmucosal, permeable trachea, ureter, urethra and vagina. In some embodiments, the route of administration is parenteral (eg, intratumoral).

[0305] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions thereof, as described herein, may be formulated for parenteral administration, for example, for injection via intra-arterial, intrasternal, intracranial, intravenous, intramuscular, subcutaneous, or intraperitoneal routes. For example, such compositions may be prepared as injectables, as liquid solutions or suspensions; solid forms suitable for preparing solutions or suspensions after adding liquids prior to injection may also be prepared; and the formulations may also be emulsified. In view of the present disclosure, the preparation of such formulations will be known to those skilled in the art. In some embodiments, a device is used for parenteral administration. For example, such devices may include needle syringes, microneedle syringes, needle-free syringes, and infusion techniques.

[0306] In some embodiments, pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations containing sesame oil, peanut oil, or propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In some embodiments, the form must be sterile and must be fluid to the extent that it can be easily injected. In some embodiments, the form should be stable under the conditions of manufacture and storage, and must be preserved against the contaminating effects of microorganisms such as bacteria and fungi.

[0307] In some embodiments, carrier can also be solvent or dispersion medium, and described solvent or dispersion medium contain water, ethanol, polyol (for example, glycerine, propylene glycol and liquid polyethylene glycol etc.), its suitable mixture and vegetable oil.In some embodiments, for example, by using coating (such as lecithin), by maintaining required particle size in the case of dispersion, and by using surfactant, suitable fluidity can be maintained.In some embodiments, the effect of preventing microorganism can be reached by various antibacterial and antifungal agents (for example, paraben, chlorobutanol, phenol, sorbic acid, thimerosal etc.).In some embodiments, include isotonic agent, for example sugar or sodium chloride.In some embodiments, by using the medicament (for example, aluminum monostearate and gelatin) of delayed absorption in composition, the absorption of injectable composition can be prolonged.

[0308] In some embodiments, sterile injectable solutions are prepared in the following manner: the desired amount of the compound disclosed herein or its pharmaceutically acceptable salt or solvate is incorporated into an appropriate solvent with various other ingredients listed above as required, followed by filtration sterilization. In some embodiments, dispersions are prepared in the following manner: various sterile active ingredients are incorporated into a sterile vehicle containing a basic dispersion medium and other ingredients required from those ingredients listed above. In some embodiments, sterile powders are used to prepare sterile injectable solutions. In some embodiments, the preparation method is vacuum drying and freeze drying techniques, which produce powders of active ingredients plus any additional desired ingredients from their previously sterile filtered solutions.

[0309] In some embodiments, pharmacologically acceptable excipients that can be used in rectal compositions as gels, creams, enemas, or rectal suppositories include, but are not limited to, any one or more of the following: cocoa butter glycerides, synthetic polymers such as polyvinyl pyrrolidone, PEG such as PEG ointment, glycerol, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and polyethylene glycol fatty acid esters, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharin, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosols, parabens in phenoxyethanol, sodium methylparaoxybenzoate, sodium propylparaoxybenzoate, diethylamine, carbomer, carbopol, methyloxybenzoate, polyethylene glycol cetearyl ether, cocoyl capryloyl caprate, caprylocaprate), isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium EDTA, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins (such as vitamins A and E), and potassium acetate.

[0310] In some embodiments, suppositories can be prepared by mixing a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as described herein, with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol, a suppository wax, and which is solid at ambient temperature but liquid at body temperature and thus melts in the rectum and releases the active compound. In some embodiments, compositions for rectal administration are in the form of enemas.

[0311] In some embodiments, a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as described herein, is formulated for local delivery to the digestive or gastrointestinal (GI) tract via oral administration (eg, solid or liquid dosage form).

[0312] In some embodiments, solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts or solvates thereof, are mixed with one or more pharmaceutically acceptable excipients such as 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, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants such as glycerol; d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retardants such as paraffin; f) absorption promoters such as quaternary ammonium compounds; g) wetting agents such as, for example, cetyl alcohol and glyceryl monostearate; h) adsorbents such as kaolin and bentonite; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. For example, in the case of capsules, tablets, and pills, the dosage form may also include a buffer. In some embodiments, solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0313] In some embodiments, the pharmaceutical composition will be in the form of a unit dosage form such as a pill or tablet, and thus, the composition contains a diluent such as lactose, sucrose, dicalcium phosphate, etc. together with a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof as provided herein; a lubricant such as magnesium stearate, etc.; and a binder such as starch, gum arabic, polyvinyl pyrrolidone, gelatin, cellulose, cellulose derivatives, etc. In some embodiments, a powder, spherical granulation (marume), solution or suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124 or triglyceride) as another solid dosage form is encapsulated in a capsule (gelatin or cellulose matrix capsule). In some embodiments, physically separated unit dosage forms of one or more compounds and pharmaceutical compositions or additional active agents as provided herein are also contemplated; for example, capsules (or tablets in capsules) with granules of each drug; two-layer tablets; two-chamber capsules (gel caps), etc. In some embodiments, enteric coatings or delayed release oral dosage forms are also contemplated.

[0314] In some embodiments, other physiologically acceptable compounds may include wetting agents, emulsifiers, dispersants or preservatives that are particularly useful for preventing the growth or activity of microorganisms. For example, various preservatives are well known and include, for example, phenol and ascorbic acid.

[0315] In some embodiments, excipients are sterile and generally do not contain undesirable substances. For example, these compositions can be sterilized by conventional well-known sterilization techniques. In some embodiments, for various oral dosage form excipients, such as tablets and capsules, sterility is not required. For example, United States Pharmacopeia / National Formulary (United States Pharmacopeia / National Formulary, USP / NF) standards can be sufficient.

[0316] In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts or solvates thereof as described herein or pharmaceutical compositions thereof are formulated for ocular administration. In some embodiments, ocular compositions may include, but are not limited to, any one or more of the following: viscogen (e.g., carboxymethylcellulose, glycerol, polyvinyl pyrrolidone, polyethylene glycol); stabilizers (e.g., pluronic (triblock copolymers), cyclodextrins); preservatives (e.g., benzalkonium chloride, EDTA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychlorine complex; Allergan, Inc.)).

[0317] In some embodiments, the compounds disclosed herein as described herein or their pharmaceutically acceptable salts or solvates or their pharmaceutical compositions are formulated for topical application to the skin or mucosa (e.g., percutaneous or transdermal). In some embodiments, topical compositions may include ointments and creams. In some embodiments, ointments are semisolid preparations typically based on petrolatum or other petroleum derivatives. In some embodiments, creams containing selected active agents are typically viscous liquids or semisolid emulsions, often oil-in-water or water-in-oil. For example, cream bases are typically washable and contain an oil phase, an emulsifier, and an aqueous phase. For example, the oil phase, sometimes also referred to as the "internal" phase, generally includes paraffin fats and fatty alcohols such as cetyl alcohol or stearyl alcohol; although not required, the volume of the aqueous phase generally exceeds the oil phase, and generally contains a moisturizer. In some embodiments, the emulsifier in the cream formulation is typically a nonionic, anionic, cationic, or amphoteric surfactant. In some embodiments, like other carriers or vehicles, the ointment base should be inert, stable, non-irritating, and non-sensitizing.

[0318] In any of the foregoing embodiments, the pharmaceutical composition as described herein may comprise one or more of the following: lipids, interbilayer cross-linked multilamellar vesicles, biodegradable poly (D, L-lactic-co-glycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and nanoporous particle-loaded lipid bilayers.

[0319] The amount of the compound in the pharmaceutical composition or formulation can vary within the full range used by those skilled in the art. Typically, the formulation will contain (based on weight percentage (wt%)) about 0.01-99.99wt% 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 1-80wt%. Representative pharmaceutical formulations are described below. Formulation Example 1 - Tablet Formulation

[0320] The following ingredients are intimately mixed and compressed into single scored tablets. Element Quantity / tablet, mg Compounds of the Disclosure 400 Corn starch 50 Croscarmellose Sodium 25 lactose 120 Magnesium Stearate 5 Formulation Example 2 - Capsule Formulation

[0321] The following ingredients are mixed intimately and loaded into hard shell gelatin capsules. Element Quantity / capsule, mg Compounds of the Disclosure 200 Lactose, spray-dried 148 Magnesium Stearate 2 Formulation Example 3 - Suspension Formulation

[0322] The following ingredients are mixed to form a suspension for oral administration. Element quantity Compounds of the Disclosure 1.0g Fumaric Acid 0.5g Sodium chloride 2.0g Methylparaben 0.15g Propylparaben 0.05g granulated sugar 25.0g Sorbitol (70% solution) 13.00g Veegum K (Vanderbilt Co.) 1.0g Flavoring 0.035mL Colorants 0.5mg Distilled water Make up to 100mL Formulation Example 4 - Injectable Formulation

[0323] The following ingredients are mixed to form an injectable formulation. Element quantity Compounds of the Disclosure 0.2mg-20mg Sodium acetate buffer solution, 0.4 M 2.0mL HCl (1N) or NaOH (1N) Make up to the appropriate pH Water (distilled, sterile) Make up to 20mL Formulation Example 5 - Suppository Formulation

[0324] By combining the compounds of the present disclosure with H-15 (triglycerides of saturated vegetable fatty acids; Riches-Nelson, Inc., New York) was mixed to prepare a suppository with a total weight of 2.5 g, and the suppository had the following composition:

[0325] In some embodiments, the dosage of the compounds disclosed herein or their pharmaceutically acceptable salts or solvates is determined based on a variety of factors, including but not limited to the type, age, weight, sex, medical condition of the patient; the severity of the patient's medical condition; the route of administration and the activity of the compound or its pharmaceutically acceptable salt or solvate. In some embodiments, the appropriate dosage for a particular situation can be determined by a medical technician. In some embodiments, the total daily dose can be divided into multiple portions and administered in multiple portions throughout the day or by providing continuous delivery.

[0326] In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts or solvates are 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.

[0327] In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, as described herein, is administered at about 0.0002 mg / Kg to about 100 mg / Kg (e.g., about 0.0002 mg / Kg to about 50 mg / Kg; about 0.0002 mg / Kg to about 25 mg / Kg; about 0.0002 mg / Kg to about 10 mg / Kg; about 0.0002 mg / Kg to about 5 mg / Kg; about 0.0 0.002mg / Kg to about 1mg / Kg; about 0.0002mg / Kg to about 0.5mg / Kg; about 0.0002mg / Kg to about 0.1mg / Kg; about 0.001mg / Kg to about 50mg / Kg; about 0.001mg / Kg to about 25mg / Kg; about 0.001mg / Kg to about 10mg / Kg; about 0.001mg / Kg to about 5mg / Kg; about 0.001mg / Kg to about g to about 1 mg / Kg; about 0.001 mg / Kg to about 0.5 mg / Kg; about 0.001 mg / Kg to about 0.1 mg / Kg; about 0.01 mg / Kg to about 50 mg / Kg; about 0.01 mg / Kg to about 25 mg / Kg; about 0.01 mg / Kg to about 10 mg / Kg; about 0.01 mg / Kg to about 5 mg / Kg; about 0.01 mg / Kg to about 1 mg / Kg; about 0.0 In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts or solvates thereof as described herein are administered at a dose of about 100 mg / Kg.

[0328] In some embodiments, the foregoing doses of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, can be administered daily (e.g., in a single dose or two or more divided doses) or non-daily (e.g., every other day, every two days, every three days, once a week, twice a week, once every two weeks, once a month).

[0329] In some embodiments, the period of administration of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, as described herein, is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In some embodiments, the time period of stopping administration is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer. In some embodiments, the compound disclosed herein or its pharmaceutically acceptable salt or solvate is administered to the patient for a certain period of time, followed by a separate period of stopping administration of the compound disclosed herein or its pharmaceutically acceptable salt or solvate. In some embodiments, the compound disclosed herein or its pharmaceutically acceptable salt or solvate is administered for a first period of time and a second period of time after the first period of time, wherein administration is stopped during the second period of time, followed by a third period of time in which administration of the compound disclosed herein or its pharmaceutically acceptable salt or solvate is started, and then a fourth period of time in which administration is stopped after the third period of time. For example, a period of administration of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, followed by a period of cessation of administration, is repeated over a defined or undefined period of time. In some embodiments, the administration period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer. In some embodiments, the period of time over 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 longer.

[0330] In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, is orally administered to a patient one or more times per day (eg, once per day, twice per day, three times per day, four times per day, or in a single daily dose).

[0331] In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, is administered to a patient via parenteral administration once or more per day (e.g., 1 to 4 times per day, once per day, twice per day, three times per day, four times per day, or in a single daily dose).

[0332] In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, is administered to a patient weekly via parenteral administration. Treatment

[0333] In some embodiments, the disclosure features methods for treating a patient (e.g., a human) having a disease, disorder, or condition, wherein modulation of GLP-1R (e.g., inhibition or attenuation and / or elevation or unwanted GLP-1R) is beneficial in treating the underlying pathology and / or symptoms and / or progression of the disease, disorder, or condition. In some embodiments, the methods described herein can include or further include treating one or more conditions, comorbidities, or sequelae associated with any one or more of the conditions described herein.

[0334] Provided herein are methods for treating a GLP-1 related disease, disorder or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as disclosed herein.

[0335] In some embodiments, the diseases, disorders, or conditions include, but are not limited to, type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of adults (LADA), obesity (including hypothalamic obesity and monogenic obesity), weight gain with other medications, idiopathic intracranial hypertension, Wolfram's syndrome, gout, sugar cravings, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance , restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial lipidemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataract, Glomerulosclerosis, arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depression, skin and connective tissue disorders, foot ulcers, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, and polycystic ovary syndrome (PCOS).

[0336] In some embodiments, the diseases, disorders, or conditions include, but are not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, idiopathic intracranial hypertension, Wolfram's syndrome, weight gain caused by the use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, kidney disease (e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes in the proximal tubules), adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic Cardiovascular disease, hyperglycemia, postprandial lipidosis, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, bipolar disorder / major 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.

[0337] In some embodiments, the diseases, disorders, or conditions include but are not limited to type 2 diabetes, early onset type 2 diabetes, obesity, idiopathic intracranial hypertension, Wolfram's syndrome, weight gain due to use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat deposition, myocardial infarction, peripheral arterial disease, stroke, transient ischemic attack, hyperglycemia, postprandial lipidosis, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, chronic renal failure, syndrome X, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, skin and connective tissue disorders, foot ulcers, or any combination thereof.

[0338] In some embodiments, the compounds and pharmaceutical compositions and methods for treating patients described herein induce one or more of the following: reduced blood glucose levels (e.g., reduced blood glucose levels), reduced blood hemoglobin A1c (HbA1c) levels, promotion of insulin synthesis, stimulation of insulin secretion, increase in beta cell mass, regulation of gastric acid secretion, regulation of gastric emptying, reduction in body mass index (BMI), and / or reduction in glucagon production (e.g., levels). In some embodiments, the compounds and pharmaceutical compositions and methods for treating patients described herein may reduce blood glucose levels, reduce blood hemoglobin A1c (HbA1c) levels, promote insulin synthesis, stimulate insulin secretion, increase in beta cell mass, regulate gastric acid secretion, regulate gastric emptying, reduce body mass index (BMI), reduce glucagon production (e.g., levels), or any combination thereof. In certain embodiments, the compounds and pharmaceutical compositions and methods for treating patients described herein stabilize serum glucose and serum insulin levels (e.g., serum glucose and serum insulin concentrations). Also provided herein are methods for regulating glucose or insulin levels in a patient in need of such regulation, 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.

[0339] In some embodiments, provided herein is a method for reducing the risk of major adverse cardiovascular events (MACE) in patients in need thereof (e.g., reducing by about at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70% or at least 80%), the method comprising administering an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as disclosed herein to the patient. In some of these embodiments, the patient is an adult diagnosed with type 2 diabetes (T2D). In certain embodiments, the patient is an adult diagnosed with heart disease. In certain embodiments, the patient is an adult diagnosed with type 2 diabetes (T2D) and heart disease. In certain embodiments, the patient is an adult suffering from type 2 diabetes (T2D). In certain embodiments, the patient is an adult suffering from heart disease. In certain embodiments, the patient suffers from type 2 diabetes (T2D) and heart disease. Indications Obesity

[0340] In some embodiments, the condition, disease or disorder is obesity and the condition, disease or disorder related to obesity or relevant. 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 excessive abdominal fat). Non-limiting examples of symptomatic obesity include endocrine obesity (e.g., Cushing syndrome, hypothyroidism, insulinoma, obesity type II diabetes, pseudoparathyroidism, hypogonadism), hypothalamic obesity, hereditary obesity (e.g., Prader-Willi syndrome, Laurence-Moon-Biedl syndrome) and drug-induced obesity (e.g., steroids, phenothiazines, insulin, sulfonylureas or beta-blocker-induced obesity).

[0341] In some embodiments, the disease, disease or disorder is related to obesity. Examples of such diseases, diseases or disorders include, but are not limited to, glucose tolerance disorders, diabetes (e.g., type 2 diabetes, obese diabetes), lipid metabolism disorders, hyperlipidemia, hypertension, heart failure, hyperuricemia, gout, fatty liver (including non-alcoholic fatty liver disease (NASH)), coronary heart disease (e.g., myocardial infarction, angina pectoris), cerebral infarction (e.g., cerebral thrombosis, transient cerebral ischemic attack), bone or joint disease (e.g., knee osteoarthritis, hip arthritis, deformed spondylitis, low back pain), sleep apnea syndrome, obesity hypoventilation syndrome (Pickwick syndrome (Pickwickian syndrome)), menstrual disorders (e.g., abnormal menstrual cycle, abnormal menstrual volume and cycle, amenorrhea, abnormal menstrual symptoms), visceral obesity syndrome, urinary incontinence and metabolic syndrome. In some embodiments, chemical compounds and pharmaceutical compositions described herein can be used to treat patients showing two symptoms of obesity and insulin deficiency. diabetes

[0342] In some embodiments, the condition, disease or disorder is diabetes. The non-limiting example of diabetes includes type 1 diabetes, type 2 diabetes (e.g., type 2 diabetes treated with diet, type 2 diabetes treated with sulfonylurea, very late type 2 diabetes, type 2 diabetes treated with long-term insulin), diabetes (e.g., non-insulin-dependent diabetes, insulin-dependent diabetes), gestational diabetes, obesity diabetes, autoimmune diabetes and borderline diabetes. In some embodiments, the condition, disease or disorder is type 2 diabetes (e.g., type 2 diabetes treated with diet, type 2 diabetes treated with sulfonylurea, very late type 2 diabetes, type 2 diabetes treated with long-term insulin).

[0343] Provided herein are methods for treating diabetes in a patient, the methods comprising (a) determining that the patient has type 2 diabetes, and (b) administering to the patient a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as disclosed herein.

[0344] Provided herein are methods for treating type 2 diabetes in a patient, comprising administering to a patient identified or diagnosed as having type 2 diabetes a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as disclosed herein.

[0345] Also provided herein is a method of treating type 2 diabetes in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as disclosed herein.

[0346] In some embodiments, the compounds and pharmaceutical compositions and methods for treating patients with conditions, diseases or disorders described herein (e.g., type 2 diabetes) reduce fasting plasma glucose levels. In some embodiments, the compounds and pharmaceutical compositions and methods for treating patients with conditions, diseases or disorders described herein (e.g., type 2 diabetes) reduce non-fasting plasma glucose levels. In some embodiments, the compounds and pharmaceutical compositions and methods for treating patients with conditions, diseases or disorders described herein (e.g., type 2 diabetes) reduce HbA1c levels. In some embodiments, the compounds and pharmaceutical compositions and methods for treating patients with conditions, diseases or disorders described herein (e.g., type 2 diabetes) reduce glucagon levels. In some embodiments, the compounds and pharmaceutical compositions and methods for treating patients with conditions, diseases or disorders described herein (e.g., type 2 diabetes) increase insulin levels. In some embodiments, the compounds and pharmaceutical compositions and methods for treating patients with conditions, diseases or disorders described herein (e.g., type 2 diabetes) reduce BMI.

[0347] In some embodiments, a decrease in fasting plasma glucose levels of about 5% to about 95% indicates treatment of type 2 diabetes. In some embodiments, a decrease in fasting plasma glucose levels of about 15% to about 80% indicates treatment of type 2 diabetes. In some embodiments, a decrease in fasting plasma glucose levels of about 25% to about 60% indicates treatment of type 2 diabetes. In some embodiments, a decrease in fasting plasma glucose levels to about or below 126 mg / dL, about or below 110 mg / dL, or about or below 90 mg / dL indicates treatment of type 2 diabetes.

[0348] In some embodiments, a reduction in non-fasting plasma glucose levels of about 5% to about 95% indicates treatment of type 2 diabetes. In some embodiments, a reduction in non-fasting plasma glucose levels of about 15% to about 80% indicates treatment of type 2 diabetes. In some embodiments, a reduction in non-fasting plasma glucose levels of about 25% to about 60% indicates treatment of type 2 diabetes. In some embodiments, a reduction in non-fasting plasma glucose levels to about or below 200 mg / dL, about or below 150 mg / dL, or about or below 130 mg / dL indicates treatment of type 2 diabetes.

[0349] In some embodiments, a decrease in HbA1c levels of about 5% to about 95% indicates treatment of type 2 diabetes. In some embodiments, a decrease in HbA1c levels of about 15% to about 80% indicates treatment of type 2 diabetes. In some embodiments, a decrease in HbA1c levels of about 25% to about 60% indicates treatment of type 2 diabetes. In some embodiments, a decrease in HbA1c levels to about or below 6.5%, about or below 6.0%, or about or below 5.0% indicates treatment of type 2 diabetes.

[0350] In some embodiments, a decrease in glucagon levels of about 5% to about 95% indicates treatment of type 2 diabetes. In some embodiments, a decrease in glucagon levels of about 15% to about 80% indicates treatment of type 2 diabetes. In some embodiments, a decrease in glucagon levels of about 25% to about 60% indicates treatment of type 2 diabetes. In some embodiments, an increase in insulin levels of about 5% to about 95% indicates treatment of type 2 diabetes. In some embodiments, an increase in insulin levels of about 15% to about 80% indicates treatment of type 2 diabetes. In some embodiments, an increase in insulin levels of about 25% to about 60% indicates treatment of type 2 diabetes.

[0351] In some embodiments, a decrease in BMI of about 5% to about 95% indicates treatment of type 2 diabetes. In some embodiments, a decrease in BMI of about 15% to about 80% indicates treatment of type 2 diabetes. In some embodiments, a decrease in BMI of about 25% to about 60% indicates treatment of type 2 diabetes. In some embodiments, a decrease in BMI of about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% indicates treatment of type 2 diabetes. In some embodiments, a decrease in BMI to about or below 40, about or below 30, or about or below 20 indicates treatment of type 2 diabetes.

[0352] In some embodiments, the condition, disease or disorder is associated with diabetes (e.g., complications of diabetes). Non-limiting examples of disorders associated with diabetes include obesity, obesity-related disorders, metabolic syndrome, neuropathy, nephropathy (e.g., diabetic nephropathy), retinopathy, diabetic cardiomyopathy, cataracts, macroangiopathy, osteopenia, hyperosmotic diabetic coma, infectious diseases (e.g., respiratory tract infection, urinary tract infection, gastrointestinal infection, skin and soft tissue infection, lower extremity infection), diabetic gangrene, xerostomia, hearing loss, cerebrovascular disorders, diabetic cachexia, slow wound healing, diabetic dyslipidemia, peripheral blood circulation disorders, cardiovascular risk factors. (e.g., coronary artery disease, peripheral artery disease, cerebrovascular disease, hypertension and risk factors related to unmanaged cholesterol and / or lipid levels, and / or inflammation), NASH, fractures and cognitive dysfunction.

[0353] Other non-limiting examples of disorders associated with diabetes include prediabetes, hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, high LDL-cholesterolemia, low HDL-cholesterolemia, postprandial hyperlipidemia), metabolic syndrome (e.g., a metabolic disorder in which activation of GLP-1R is beneficial, metabolic syndrome X), hypertension, impaired glucose tolerance (IGT), insulin resistance, and sarcopenia.

[0354] In some embodiments, the condition, disease or disorder is diabetes and obesity (diabetobias). In some embodiments, the compounds described herein may also be used to improve the therapeutic effectiveness of metformin. Disorders of metabolically important tissues

[0355] In some embodiments, the condition, disease or disorder is a disorder of a metabolically important tissue. Non-limiting examples of metabolically important tissues include liver, fat, pancreas, kidney, and intestine.

[0356] In some embodiments, the condition, disease or disorder is fatty liver disease. Fatty liver disease includes, but is not limited to, non-alcoholic fatty acid liver disease (NAFLD), steatohepatitis, non-alcoholic steatohepatitis (NASH), fatty liver disease caused by hepatitis, fatty liver disease caused by obesity, fatty liver disease caused by diabetes, fatty liver disease caused by insulin resistance, fatty liver disease caused by hypertriglyceridemia, abetalipoproteinemia, hyperlipoproteinemia, glycogen storage disease, Weber-Christian disease, Wolman's disease, acute fatty liver of pregnancy, and lipid dystrophy.

[0357] Non-alcoholic fatty liver disease (NAFLD) refers to a series of diseases that occur in the absence of alcohol abuse and is typically characterized by the presence of steatosis (fat in the liver). It is believed that NAFLD is associated with a variety of conditions, such as metabolic syndrome (including obesity, diabetes and hypertriglyceridemia) and insulin resistance. It may cause liver disease in adults and children and may eventually lead to cirrhosis (Skelly et al., J Hepatol 2001; 35: 195-9; Chitturi et al., Hepatology 2002; 35 (2): 373-9). The severity of NAFLD ranges from relatively benign isolated, mainly macrovesicular steatosis (i.e., non-alcoholic fatty liver or NAFL) to non-alcoholic steatohepatitis (NASH) (Angulo et al., J Gastroenterol Hepatol 2002; 17 Suppl: S186-90).

[0358] Other non-limiting examples of disorders of metabolically important tissues include joint disorders (e.g., osteoarthritis, secondary osteoarthritis), steatosis (e.g., in the liver); fibrosis (e.g., in the liver); cirrhosis (e.g., in the liver); cholelithiasis; gallbladder disorders; gastroesophageal reflux; sleep apnea; hepatitis; fatty liver; skeletal disorders characterized by altered bone metabolism, such as osteoporosis, including postmenopausal osteoporosis, poor bone strength, osteopenia, Paget's disease ( disease), osteolytic metastasis in cancer patients, osteodystrophy in liver disease, and bone metabolism changes caused by renal failure or hemodialysis, fractures, bone surgery, aging, pregnancy, protection of fractures, and malnutrition polycystic ovary syndrome; renal disease (e.g., chronic renal failure, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease); muscular dystrophy, angina, acute or chronic diarrhea, testicular dysfunction, respiratory dysfunction, weakness, sexual dysfunction (e.g., erectile dysfunction) and geriatric syndrome. In some embodiments, the compounds and pharmaceutical compositions described herein can be used to treat surgical trauma by improving postoperative recovery and / or by preventing the decomposition reaction caused by surgical trauma. Cardiovascular and vascular disease

[0359] In some embodiments, the condition, disease or disorder is a cardiovascular disease. Non-limiting examples of cardiovascular diseases include congestive heart failure, atherosclerosis, arteriosclerosis, coronary heart disease, coronary artery disease, congestive heart failure, coronary heart disease, hypertension, heart failure, cerebrovascular disorders (e.g., cerebral infarction), vascular dysfunction, myocardial infarction, elevated blood pressure (e.g., 130 / 85 mm Hg or higher), and prothrombotic states (exemplified by high fibrinogen or plasminogen activator inhibitors in the blood).

[0360] In some embodiments, the condition, disease or disorder is associated with a vascular disease. Non-limiting examples of vascular diseases include peripheral vascular disease, macrovascular complications (e.g., stroke), vascular dysfunction, peripheral arterial disease, abdominal aortic aneurysm, carotid artery disease, cerebrovascular disorders (e.g., cerebral infarction), pulmonary embolism, chronic venous insufficiency, critical limb ischemia, retinopathy, nephropathy, and neuropathy. Neurological disorders

[0361] In some embodiments, the condition, disease, or disorder is a neurological disorder (eg, a neurodegenerative disorder) or a psychiatric disorder. Non-limiting examples of nervous system disorders include idiopathic intracranial hypertension (IIH), brain insulin resistance, mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), anxiety disorders, dementia (e.g., Alzheimer's disease), traumatic brain injury, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, Morbus Parkinson, Steele-Richard syndrome, Down's syndrome, myasthenia gravis, neurotrauma, brain trauma, vascular amyloidosis, intracerebral hemorrhage I with amyloidosis, brain inflammation, Friedrich's ataxia, acute disorganization disorder, amyotrophic lateral sclerosis (ALS), glaucoma, and apoptosis-mediated degenerative diseases of the central nervous system (e.g., Creutzfeld-Jakob Disease, bovine spongiform encephalopathy (mad cow disease), and chronic wasting syndrome). See, e.g., U.S. Publication No. 20060275288A1.

[0362] In some embodiments, the condition, disease or disorder is idiopathic intracranial hypertension. Idiopathic intracranial hypertension is characterized by increased intracranial pressure and papilledema. See, for example, Virdee et al. Ophthalmol Ther. 2020; 9(4): 767-781. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce cerebrospinal fluid secretion in patients with idiopathic intracranial hypertension. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce intracranial pressure in patients with idiopathic intracranial hypertension. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce one or more symptoms of patients with idiopathic intracranial hypertension. Symptoms of idiopathic intracranial hypertension can include severe headaches and visual impairment. In some embodiments, the patient with idiopathic intracranial hypertension is a female. In some embodiments, the patient with idiopathic intracranial hypertension is about 20 to about 30 years old. In some embodiments, the patient with idiopathic intracranial hypertension is obese.

[0363] In some embodiments, the condition, disease or disorder is Wolfram syndrome. Wolfram syndrome is caused by biallelic mutations in the Wolframin ER transmembrane glycoprotein (Wfs1) gene. See, for example, Seppa et al. Sci Rep 9, 15742 (2019). Wolfram syndrome may first appear as diabetes, followed by symptoms of optic atrophy, deafness, and neurodegeneration. Patients with Wolfram syndrome may have symptoms of ataxia, sleep apnea, dysphagia, hearing loss, and taste loss due to brainstem atrophy. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce neuroinflammation in patients with Wolfram syndrome. In some embodiments, neuroinflammation in the inferior olive nucleus of the patient is reduced. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce retinal ganglion cell death in patients with Wolfram syndrome. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce axonal degeneration in patients with Wolfram syndrome. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce one or more symptoms (eg, any of the symptoms described herein) in a patient suffering from Wolfram's syndrome.

[0364] Non-limiting examples of mental disorders include drug dependence / addiction (narcotics and amphetamines) and attention deficit / hyperactivity disorder (ADHD). The compounds and pharmaceutical compositions described herein can be used to improve behavioral responses to addictive drugs, reduce drug dependence, prevent drug abuse relapse, and alleviate anxiety caused by lack of a given addictive substance. See, for example, U.S. Publication No. 20120021979A1.

[0365] In some embodiments, the compounds and pharmaceutical compositions described herein can be used to improve learning and memory by enhancing neuronal plasticity and promoting cell differentiation, and also protect dopamine neurons and motor function in Parkinson's disease. Insulin-related conditions and disorders

[0366] In some embodiments, the condition, disease, or disorder is impaired fasting glucose (IFG), impaired fasting glucose parameters (IFG), hyperglycemia, insulin resistance (impaired glucose homeostasis), hyperinsulinemia, elevated blood fatty acid or glycerol levels, hypoglycemic conditions, insulin resistance syndrome, paresthesias caused by hyperinsulinemia, hyperlipidemia, hypercholesterolemia, impaired wound healing, leptin resistance, glucose intolerance, increased fasting glucose, dyslipidemia (e.g., hyperlipidemia, atherogenic dyslipidemia characterized by high triglycerides and low HDL cholesterol), glucagonoma, hyperprolactinemia, hypoglycemia (e.g., nocturnal hypoglycemia), and concomitant insulin-related coma endpoints.

[0367] In some embodiments, the compounds and pharmaceutical compositions described herein can reduce or slow the progression of borderline, impaired fasting glucose, or impaired fasting glucose to diabetes. Autoimmune disorders

[0368] In some embodiments, the condition, disease or disorder is an autoimmune disorder. Non-limiting examples of autoimmune disorders include multiple sclerosis, experimental autoimmune encephalomyelitis, autoimmune disorders associated with immune rejection, graft-versus-host disease, uveitis, optic neuropathy, optic neuritis, transverse myelitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, myasthenia gravis and Graves' disease. See, for example, U.S. Publication No. 20120148586A1. Stomach and intestinal disorders

[0369] In some embodiments, the condition, disease, or disorder is a gastric or intestinal related disorder. Non-limiting examples of such disorders include ulcers of any etiology (e.g., gastric ulcers, Zollinger-Ellison syndrome, drug-induced ulcers, ulcers associated with infections or other pathogens), digestive disorders, malabsorption, short bowel syndrome, cul-de-sac syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), celiac sprue, hypogammaglobulinemic sprue, chemotherapy- and / or radiation therapy-induced mucositis and diarrhea, gastrointestinal inflammation, short bowel syndrome, ulcerative colitis, gastric mucosal damage (e.g., gastric mucosal damage caused by aspirin), small intestinal mucosal damage, and cachexia (e.g., cancer cachexia, tuberculous cachexia, cachexia associated with blood disorders, cachexia associated with endocrine disorders, cachexia associated with infectious diseases, and cachexia caused by acquired immunodeficiency syndrome). weight

[0370] In some embodiments, the compounds and pharmaceutical compositions described herein can be used to make patients (e.g., patients in need) lose weight (e.g., excess weight), prevent weight gain, induce weight loss, reduce body fat or reduce food intake. In some embodiments, the weight gain of the patient can be attributed to excessive food intake or an unbalanced diet, or can be weight gain from concomitant drugs (e.g., insulin sensitizers with PPARγ agonist-like effects, such as troglitazone, rosiglitazone, englitazone, ciglitazone, pioglitazone, etc.). In some embodiments, weight gain can be weight gain before reaching obesity, or it can be weight gain in obese patients. In some embodiments, weight gain can also be drug-induced weight gain or weight gain following cessation of smoking. In some embodiments, weight gain is induced by using steroids or antipsychotics.

[0371] In some embodiments, the condition, disease, or disorder is an eating disorder, such as overeating, binge eating, bulimia, compulsive eating, or syndromic obesity, such as Prader-Willi syndrome and Bardet-Biedl syndrome. Inflammatory diseases

[0372] In some embodiments, the condition, disease or disorder is an inflammatory disorder. Non-limiting examples of inflammatory disorders include chronic rheumatoid arthritis, deforming spondylitis, deforming arthritis, low back pain, gout, postoperative or post-traumatic inflammation, abdominal distension, neuralgia, pharyngitis, cystitis, pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory colorectal disease), inflammation in metabolically important tissues (including liver, fat, pancreas, kidney and intestine), and pro-inflammatory states (e.g., elevated levels of pro-inflammatory cytokines or markers of inflammatory-like C-reactive protein in the blood). cancer

[0373] In some embodiments, the condition, disease or disorder is cancer. Suitable examples of cancer include breast cancer (e.g., invasive ductal breast cancer, non-invasive ductal breast cancer, inflammatory breast cancer), prostate cancer (e.g., hormone-dependent prostate cancer, non-hormone-dependent prostate cancer), pancreatic cancer (e.g., ductal pancreatic cancer), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, malignant mesothelioma), colon cancer (e.g., gastrointestinal stromal tumor), rectal cancer (e.g., gastrointestinal stromal tumor), ), colorectal cancer (e.g., familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumor), small intestine cancer (e.g., non-Hodgkin 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 gallbladder cancer), duct cancer), kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter), bile duct cancer, endometrial cancer, cervical cancer, ovarian cancer (e.g., epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, low malignant potential ovarian tumor), bladder cancer, urethral cancer, skin cancer (e.g., intraocular (eye) melanoma, Merkel cell carcinoma), hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer (e.g., medullary thyroid carcinoma), parathyroid cancer, nasal cancer, Sinus cancer, bone tumors (e.g., osteosarcoma, Ewing's sarcoma, uterine sarcoma, soft tissue sarcoma), angiofibroma, retinosarcoma, penile cancer, testicular tumors, pediatric solid tumors (e.g., Wilms' tumor, childhood renal tumors), Kaposi's sarcoma, Kaposi's sarcoma caused by AIDS, maxillary sinus tumors, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemias (e.g., acute myeloid leukemia, acute lymphoblastic leukemia). Hypothalamic-pituitary disorders

[0374] In some embodiments, the condition, disease or disorder is associated with the hypothalamus-pituitary-gonadal axis. For example, the condition, disease or disorder is associated with the hypothalamus-pituitary-ovarian axis. In another example, the condition, disease or disorder is associated with the hypothalamus-pituitary-testicular axis. Hypothalamic-pituitary-gonadal axis diseases include, but are not limited to, hypogonadism, polycystic ovary syndrome, hypothyroidism, hypopituitarism, sexual dysfunction, and Cushing's disease.

[0375] In some embodiments, the condition, disease, or disorder associated with diabetes is related to the hypothalamic-pituitary-gonadal axis. pulmonary disease

[0376] In some embodiments, the condition, disease or disorder is associated with a pulmonary disease. Pulmonary diseases include, but are not limited to, asthma, idiopathic pulmonary fibrosis, pulmonary hypertension, obstructive sleep apnea-hypopnea syndrome, and chronic obstructive pulmonary disease (COPD) (e.g., emphysema, chronic bronchitis, and refractory (irreversible) asthma).

[0377] In some embodiments, the condition, disease, or disorder associated with diabetes is a pulmonary disease. Combination therapy

[0378] In some embodiments, the present disclosure contemplates both monotherapy regimens as well as combination therapy regimens.

[0379] In some embodiments, the methods described herein can further comprise administering one or more additional therapies (eg, one or more additional therapeutic agents and / or one or more treatment regimens) in combination with the compounds described herein.

[0380] In some embodiments, the methods described herein include administering a compound described herein in combination with one or more of the following: dietary therapy (e.g., dietary monitoring, dietary therapy for diabetes), exercise therapy (e.g., physical activity), blood glucose monitoring, gastric electrical stimulation (e.g., ) and dietary changes.

[0381] In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, as described herein, may be administered in combination with one or more additional therapeutic agents.

[0382] Representative additional therapeutic agents include, but are not limited to, anti-obesity agents, diabetes therapeutics, diabetic complications therapeutics, hyperlipidemia therapeutics, antihypertensive agents, diuretics, chemotherapeutics, immunotherapeutics, anti-inflammatory drugs, antithrombotic agents, antioxidants, osteoporosis therapeutics, vitamins, anti-dementia drugs, erectile dysfunction drugs, urinary frequency or incontinence therapeutics, NAFLD therapeutics, NASH therapeutics, dysuria therapeutics, and antiemetics.

[0383] In some embodiments, the one or more additional therapeutic agents include those suitable for use as anti-obesity agents. Non-limiting examples include monoamine uptake inhibitors (e.g., tramadol, phentermine, sibutramine, clomiphene, fluoxetine, tesofensine), serotonin 2C receptor agonists (e.g., lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptor modulators, GABA modulators (e.g., topiramate) (including GABA receptor agonists (e.g., gabapentin, pregabalin)), neuropeptide Y antagonists (e.g., velibactam), peptide YY or its analogs, cannabinoid receptor antagonists (e.g., rimonabant, tarenabant), orexin antagonists, orexin receptor ... Stimulant acylase 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, cetirizola), β3 agonists (e.g., N-5984), diacylglycerol acyltransferase 1 (DGAT1) inhibitors, acetyl-CoA carboxylase (ACC) inhibitors (e.g., described in International Publication No. WO 2020 / 234726, WO 2020 / 044266 and U.S. Pat. No. 8,859,577), stearoyl-CoA desaturase inhibitors, microsomal triglyceride transporter inhibitors (e.g., R-256918), sodium-glucose cotransporter 2 (SGLT-2) inhibitors (e.g., JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, repagliflozin, empagliflozin, canagliflozin, ipragliflozin, tolagliflozin, sergliflozin etabonate, remogliflozin etabonate etabonate or ertugliflozin), SGLT-1 inhibitors, MCR-4 agonists, monoamine reuptake inhibitors, melanocyte stimulating hormone analogs, 5HT2c agonists, galanin antagonists, anorectics (such as bombesin agonists), thyromimetic agents, dehydroepiandrosterone or its analogs, 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-1 929, GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB-219994), phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate, trodusquemin), GPR119 agonists (e.g., PSN-821, MBX-2982, APD597, described in International Publication Nos. WO 2010 / 140092, WO 2010 / 128425, WO 2010 / 128414, WO 2010 / 106457), glucokinase activators (e.g., pioglitazone, 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 WO 2008 / 156757), leptin, leptin derivatives (e.g., metreleptin), drugs that improve leptin resistance, CNTF (ciliary neurotrophic factor), BDNF (brain-derived neurotrophic factor), cholecystokinin agonists, amylin preparations (e.g., pramlintide, AC-2307), neuropeptide Y agonists (e.g., PYY3-36, derivatives of PYY3-36, obineptide, TM-30339, TM-30335), oxytocin (OXM) preparations, appetite suppressants (e.g., ephedrine ), FGF21 preparations (e.g., animal FGF21 preparations extracted from the pancreas of cows or pigs; human FGF21 preparations genetically synthesized using Escherichia coli or yeast; fragments or derivatives of FGF21), anorectics (e.g., P-57), human proinsulin peptide (HIP), melanocortin receptor 4 agonists (e.g., setmelanotide), melanin concentrating hormone receptor 1 antagonists, serotonergic agents (e.g., sibutramine, lorcaserin), farnesoid X receptor (FXR) agonists (e.g.,Obeticholic acid, tropifexor, cilofexor, LY2562175, Met409, TERN-101, EDP305, compounds described in International Publication Nos. WO 2020 / 234726 and WO 2020 / 044266), phentermine, zonisamide, norepinephrine / dopamine reuptake inhibitors (e.g., bupropion), GDF-15 analogs, methionine aminopeptidase 2 (MetAP2) inhibitors (e.g., beloranib or ZGN-1061), diethylpropion, phendimetrazine, benzphetamine, fibroblast growth factor receptor (FGFR) modulators, biotin, MAS receptor modulators, glucagon receptor agonists, CCKa agonists (e.g., described in International Publication No. WO 2005 / 116034 and U.S. Publication No. 2005 / 0287100) and AMP-activated protein kinase (AMPK) activators.

[0384] In some embodiments, the one or more additional therapeutic agents include those therapeutic agents that can be used, for example, as antidiabetic agents. Non-limiting examples include insulin and insulin preparations (e.g., animal insulin preparations extracted from the pancreas of cattle or pigs; human insulin preparations synthesized using E. coli or yeast genes; zinc insulin; protamine zinc insulin; insulin fragments or derivatives (e.g., INS-1), oral insulin preparations, synthetic human insulin), insulin sensitizers (e.g., pioglitazone or a salt thereof), biguanides (e.g., metformin, buformin or a salt thereof (e.g., hydrochloride, fumarate, succinate)), glucagon analogs (e.g., described in, for example, WO any glucagon analogue described in 2010 / 011439), agents that antagonize the action of glucagon or reduce glucagon secretion, sulfonylurea agents (e.g., chlorpropamide, tolazamide, glimepiride, tolbutamide, glyburide, gliclazide, acetohexamide, glyburide, glybuzole, glyburide, glipizide), thiazolidinedione agents (e.g., rosiglitazone, lobeglitazone, troglitazone, basiglitazone, rivoglitazone, lobeglitazone, or pioglitazone), glitazar (e.g., aleglitazar, chiglitazar, saroglitazar, muraglitazar, tesaglitazar), SGLT2 inhibitors (e.g., JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, THR1474, TS-071, ISIS388626, LX4211, repagliflozin, empagliflozin, canagliflozin, ipragliflozin, topagliflozin, sergliflozin etabonate, repagliflozin etabonate, erpagliflozin, described in WO 2010 / 023594), GPR40 agonists (e.g., FFAR1 / FFA1 agonists, such as fasiglifam), alpha glucosidase inhibitors (e.g., adiposin, camiglibose, pradimicin-Q, salbostatin, voglibose, acarbose, miglitol, emiglitate), insulin secretagogues such as prandial glucose regulators (sometimes referred to as "short-acting secretagogues") (e.g., meglitinides (e.g.,nateglinide), cholinesterase inhibitors (e.g., donepezil, galantamine, rivastigmine, tacrine), NMDA receptor antagonists, dual GLP-1 / GIP receptor agonists (e.g., LBT-2000, ZPD1-70), GLP-1R agonists (e.g., exenatide, liraglutide, albiglutide, dulaglutide, abiglutide, tasiglutide, 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).

[0385] In some embodiments, the one or more additional therapeutic agents include those useful, for example, 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., aramchol), anti-lysyl oxidase homolog 2 (LOXL2) monoclonal antibodies (e.g., sintuzumab), caspase inhibitors (e.g., enlicasin), 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., tipelukast), acetyl-CoA carboxylase (ACC) inhibitors (e.g., NDI 010976 and described in International Publication Nos. 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), diacylglycerol acyltransferase 2 (DGAT2) inhibitors (e.g., compounds described in WO 2003 / 072197, WO 2009 / 144555 and WO 2008 / 065508), 2020 / 234726 and compounds in U.S. Publication No. 20180051012), CB1 receptor antagonists, anti-CB1R antibodies, glycyrrhizin, Schisandra extract, ascorbic acid, glutathione, silymarin, lipoic acid and d-α-tocopherol, ascorbic acid, glutathione, vitamin B complex, glitazone / thiazolidinedione (e.g., troglitazone, rosiglitazone, pioglitazone, basiglitazone, rivoglitazone, lobeglitazone), metformin, cysteamine, sulfonylurea, α-glucosidase inhibitors, meglitinide, vitamin E, tetrahydrolipstatin, milk thistle protein, antiviral drugs and antioxidants.

[0386] In some embodiments, the one or more additional therapeutic agents include those therapeutic agents that can be used, for example, to treat diabetic complications. Non-limiting examples include aldose reductase inhibitors (e.g., tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat, lidorestat), neurotrophic factors and their increasers (e.g., NGF, NT-3, BDNF, neurotrophic production / secretion promoters described in WO01 / 14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole), compounds described in WO 2004 / 039365), PKC inhibitors (e.g., ruboxistaurin mesylate), levofloxacin, ... mesylate), AGE inhibitors (e.g., ALT946, N-benzoylthiazolium bromide (ALT766), EXO-226, pyridorin, pyridoxamine), serotonin and norepinephrine reuptake inhibitors (e.g., duloxetine), sodium channel inhibitors (e.g., lacosamide), reactive oxygen species scavengers (e.g., lipoic acid), cerebral vasodilators (e.g., tiapuride, mexiletine), somatostatin receptor agonists (e.g., BIM23190), and apoptosis signal-regulating kinase-1 (ASK-1) inhibitors.

[0387] In some embodiments, the one or more additional therapeutic agents include those useful, for example, for treating hyperlipidemia. Non-limiting examples include HMG-COA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or a salt thereof (e.g., sodium salt, calcium salt)), squalene synthase inhibitors (e.g., WO Compounds described in 97 / 10224, for example, N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-acetic acid), fibrate compounds (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate), anion exchange resins (e.g., colestyramine), nicotinic acid drugs (e.g., nicomol, niceritrol, niaspan), phytosterols (e.g., soysterol, gamma oryzanol),

[00136] The invention relates to the treatment of omega-3 fatty acid preparations (e.g., omega-3 fatty acid ethyl ester 90), cholesterol absorption inhibitors (e.g., zechia), CETP inhibitors (e.g., dalcetrapib, anacetrapib), and omega-3 fatty acid preparations (e.g., omega-3 fatty acid ethyl ester 90).

[0388] In some embodiments, the one or more additional therapeutic agents include those therapeutic agents that can be used, for example, as antihypertensive agents. Non-limiting examples include angiotensin converting enzyme inhibitors (e.g., captopril, zofenopril, fbsinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), angiotensin II antagonists (e.g., candesartan cilexetil, candesartan, losartan, losartan potassium), (e.g., potassium), eprosartan, valsartan, telmisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil, azilsartan, azilsartan medoxomil), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine, cilnidipine), and beta blockers (e.g., metoprolol, atenolol, propranolol, carvedilol, pindolol).Other non-limiting examples of antihypertensive agents include diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, m-ethylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid, acid, tricrynafen, chlorthalidone, torsemide, furosemide, musolimine, bumetanide, triamterene, amiloride, spironolactone), alpha-adrenergic blockers, beta-adrenergic blockers, calcium channel blockers (e.g., diltiazem ), verapamil, nifedipine and amlodipine), vasodilators (e.g., hydralazine), renin inhibitors, AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan), ET receptor antagonists (e.g., sitaxsentan, atrsentan, compounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265), dual ET / AII antagonists (e.g., compounds disclosed in WO 2000 / 01389), neutral endopeptidase (NEP) inhibitors, If channel blocker ivabradin, and vasopeptidase inhibitors (dual NEP-ACE inhibitors) (e.g., gemopatrilat and nitrates).

[0389] In some embodiments, the one or more additional therapeutic agents include those that can be used as, for example, diuretics. Non-limiting examples include xanthine derivatives (e.g., theobromine sodium salicylate, theobromine calcium salicylate), thiazide preparations (e.g., ethiazide, cyclopenthiazide, trichlorothiazide, hydrochlorothiazide, hydrofluthiazide, benzyl hydrochlorothiazide, penfluthiazide, polythiazide, methyclothiazide), anti-aldosterone preparations (e.g., spironolactone, triamterene), carbonic anhydrase inhibitors (e.g., acetazolamide), and chlorobenzenesulfonamide agents (e.g., chlortalidone, mefruside, indapamide).

[0390] In some embodiments, the one or more additional therapeutic agents include those that can be used as, for example, immunotherapeutic agents. Non-limiting examples include microbial or bacterial compounds (e.g., muramyl dipeptide derivatives, picibanil), polysaccharides with immunoenhancing activity (e.g., lentinan, sizofiran, krestin), cytokines obtained by genetic engineering methods (e.g., interferons, interleukins (IL), such as IL-1, IL-2, IL-12), and colony stimulating factors (e.g., granulocyte colony stimulating factor, erythropoietin).

[0391] In some embodiments, the one or more additional therapeutic agents include those that can be used as, for example, anti-embolic agents. Non-limiting examples include heparin (e.g., heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarin (e.g., warfarin potassium); antithrombin drugs (e.g., argatroban, dabigatran, boroarginine derivatives, boropeptides, heparin, hirudin, and melagatran), FXa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, betrixaban, YM150, described in WO 02 / 06234, WO 2004 / 048363, WO 2005 / 030740, WO 2005 / 058823, and WO 2005 / 113504), thrombolytics (e.g., anistreplase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), urokinase, tisokinase, alteplase, nateplase, monteplase, pamiteplase, factor 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, eicosapentaenoic acid ethyl, beraprost sodium, and sarpogrelate hydrochloride).

[0392] In some embodiments, the one or more additional therapeutic agents include those that can be used, for example, to treat osteoporosis. Non-limiting examples include alfacalcidol, calcitriol, elcatonin, calcitonin salmon, 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 drugs include apomorphine and sildenafil citrate. Suitable examples of agents for treating frequent urination or urinary incontinence include flavorxate hydrochloride, oxybutynin hydrochloride, and propiverine hydrochloride. Suitable examples of agents for treating dysuria include acetylcholinesterase inhibitors (e.g., distigmine). Suitable examples of anti-inflammatory agents include nonsteroidal anti-inflammatory drugs, such as aspirin, acetaminophen, indomethacin.

[0393] Other exemplary additional therapeutic agents include agents that regulate hepatic glucose homeostasis (e.g., fructose 1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glycogen synthase kinase inhibitors, glucokinase activators), agents designed to treat complications of chronic 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, ivastatin, statins, ZD-4522)), HMG-CoA synthase inhibitors, cholesterol-lowering agents, bile acid sequestrants (e.g., cholestyramine, questran, colestipol and colesevelam), cholesterol absorption inhibitors (e.g., plant sterols, such as phytosterol), cholesterol ester transfer protein (CETP) inhibitors, ileal bile acid transport system inhibitors (IBAT inhibitors), diacylglycerol acyltransferase 1 (DGAT1) inhibitors (e.g., AZD7687, LCQ908, described in WO 2009 / 016462, WO 2010 / 086820), monoglycerol O-acyltransferase inhibitors, α-amylase inhibitors (e.g., amylase inhibitors, trestatin, AL-3688), α-glucosidase inhibitors, SIRT-1 activators, c-Jun N-terminal kinase (JNK) inhibitors, VPAC2 receptor agonists, TGR5 receptor modulators (e.g., compounds described in), GPBAR1 receptor modulators, GPR120 modulators, high affinity nicotinic acid receptor (HM74A) activators, carnitine palmitoyltransferase inhibitors, mineralocorticoid receptor inhibitors, TORC2 inhibitors, fatty acid synthase inhibitors agents, 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., diriotapide, mitratapide and implitapide), lipoxygenase inhibitors, PCSK9 modulators (e.g.,alirocumab and evolocumab), RXRα modulators, cysteamine, cystamine, RNA antisense constructs that inhibit protein tyrosine phosphatase PTPRU, vitamin B complex, penetratin protein, protein tyrosine phosphatase-1B (PTP-1B) inhibitors (e.g., trodusquemine, hyrtiosal extract, and compounds described by Zhang et al. Drug Discovery Today. 2007, 12(9-10):373-381), ezetimibe, betaine, pentoxifylline, αδ-9 desaturase, BCKDK inhibitors, branched-chain α-ketoacid dehydrogenase kinase (BCBK) inhibitors, PNPLA3 inhibitors, FGF19 analogs, SCD1 inhibitors, bile acid binding resins, nicotinic acid acid / niacin) and its analogs, antioxidants (e.g., probucol), omega-3 fatty acids, antihypertensive agents (including adrenergic receptor antagonists (such as beta blockers (e.g., atenolol), alpha blockers (e.g., doxazosin) and mixed alpha / beta blockers (e.g., labetalol))), adrenergic receptor agonists (including alpha-2 agonists (e.g., clonidine)), angiotensin converting enzyme (ACE) inhibitors (e.g., lisinopril), calcium channel blockers (such as dihydropyridines (e.g., nifedipine), phenylalkylamines (e.g., verapamil) and benzthiazepines (e.g., diltiazem)), angiotensin II receptor antagonists (e.g., candesartan ), aldosterone receptor antagonists (e.g., eplerenone, spironolactone), centrally acting adrenergic drugs (such as central alpha agonists (e.g., clonidine), diuretics (e.g., furosemide), torsemide, bumetanide, ethacrynic acid), thiazide-type diuretics (e.g., chlorothiazide, hydrochlorothiazide, benzthiazide, hydroflumethiazide, benzflumethiazide, methychlorthiazide, polythiazide, trichlorothiazide, indapamide), benzopyrrolone-type diuretics (e.g., chlorthalidone, metolazone), quinazoline-type diuretics (e.g., quinethazolone), potassium-sparing diuretics (e.g., triamterene and amiloride), thyroid receptor agonists (e.g., described in WO 2020 / 117987), hemostatic modulators (including antithrombotic agents (e.g., fibrinolytic activators), thrombin antagonists, factor VIIa inhibitors, anticoagulants (e.g., vitamin K antagonists such as warfarin), heparin and its low molecular weight analogs, factor Xa inhibitors and direct thrombin inhibitors (e.g.,argatroban), antiplatelet agents (e.g., cyclooxygenase inhibitors (e.g., aspirin), nonsteroidal anti-inflammatory drugs (NSAIDS), thromboxane-A2-receptor antagonists (e.g., ifetroban), thromboxane-A2-synthetase inhibitors, PDE inhibitors (e.g., Pletal, dipyridamole), purinergic receptor antagonists (e.g., P2Y1 and P2Y12), adenosine diphosphate (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 agents (e.g., phentermine), serotonergic agents (e.g., sibutramine, lorcaserin), diacylglycerol acyltransferase (DGAT) inhibitors, feeding behavior modulators, pyruvate dehydrogenase kinase (PDK) modulators, serotonin receptor modulators, monoamine transmission modulators such as selective serotonin reuptake inhibitors (SSRI) (e.g., fluoxetine), norepinephrine reuptake inhibitors (NARI), norepinephrine-serotonin reuptake inhibitors (SNRI) and monoamine oxidase inhibitors (MAOI) (e.g., toloxatone and amifampicin), described in WO 2007 / 013694, WO 2007 / 018314, WO 2008 / 093639 and WO 2008 / 099794, GPR40 agonists (e.g., fasiglifam or a hydrate thereof, compounds described in WO 2004 / 041266, WO 2004 / 106276, WO 2005 / 063729, WO 2005 / 063725, WO 2005 / 087710, WO 2005 / 095338, WO 2007 / 013689 and WO 2008 / 001931), SGLT1 inhibitors, adiponectin or its agonist, IKK inhibitors (e.g., AS-2868), somatostatin receptor agonists, ACC2 inhibitors, cachexia improving agents (such as cyclooxygenase inhibitors (e.g., indomethacin)), progesterone derivatives (e.g., megestrol acetate), glucocorticoids (e.g., dexamethasone), metoclopramide agents, tetrahydrocannabinol agents, agents for improving fat metabolism (e.g., eicosapentaenoic acid), growth hormone, IGF-1, antibodies against cachexia-inducing factor TNF-α, LIF, IL-6 and oncostatin M, proteins or peptides that alter metabolism such as glucokinase (GK), glucokinase regulatory protein (GKRP), uncoupling proteins 2 and 3 (UCP2 and UCP3), peroxisome proliferator-activated receptor α (PPARα), MC4r agonists, insulin receptor agonists, PDE 5 inhibitors, glycosylation inhibitors (e.g., ALT-711), drugs that promote nerve regeneration (e.g.,Y-128, VX853, neurotrophic peptides), antidepressants (e.g., desipramine, amitriptyline, imipramine), antiepileptic drugs (e.g., lamotrigine, trileptal, levetiracetam (keppra), zonisamide (zonegran), pregabalin, harkoseride, carbamazepine), antiarrhythmic drugs (e.g., K, + channel openers, mexiletine, propranolol, metoprolol, atenolol, carvedilol, propranolol, sotalol, dofetilide, amiodarone, azimilide, ibutilide, diltiazem, and verapamil), acetylcholine receptor ligands (e.g., ABT-594), endothelin receptor antagonists (e.g., ABT-627), narcotic analgesics (e.g., morphine), alpha 2 receptor agonists (e.g., clonidine), topical analgesics (e.g., capsaicin), anxiolytics (e.g., benzothiazepines), phosphodiesterase inhibitors (e.g., sildenafil), dopamine receptor agonists (e.g., apomorphine), cytotoxic antibodies (e.g., T cell receptor and IL-2 receptor specific antibodies), B cell depleting therapies (e.g., anti-CD20 antibodies (e.g., rituxan), i-BLyS antibodies), drugs that affect T cell migration (e.g., anti-integrin α4 / β1 antibodies (e.g., tysabri), immunophilins Drugs that work with sirolimus (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 mofetil), meglitasen, AMG-131, balaglitazone, MBX-2044, rivoglitazone, aleglitazar, siglitazar, saxiglitazar, moleglitazar, tezomib Glitazar, lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, exenatide, exendin-4, memantine, midazolam, ketoconazole, icosapentaenoic acid ethyl, clonidine, azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, etoposide, piroxicam, NO donors (e.g., organic nitrates), NO promoters (e.g., phosphodiesterase inhibitors).

[0394] In some embodiments, the one or more additional therapeutic agents include therapeutic agents that can be used, for example, as antiemetics. As used herein, an "antiemetic" agent refers to any agent that resists (e.g., reduces or eliminates) nausea or vomiting (spitting). Without wishing to be bound by theory, it is believed that administering one or more antiemetics in combination with the compounds described herein can allow for administration of higher doses of the compounds, for example because the patient may be able to take in food normally and therefore respond faster to treatment.

[0395] Non-limiting examples of antiemetics include 5HT3 receptor antagonists (serotonin receptor antagonists), neuroleptics / antipsychotics, antihistamines, anticholinergics, steroids (e.g., corticosteroids), NK1 receptor antagonists (neurokinin substance 1P receptor antagonists), antidopaminergics / dopamine receptor antagonists, benzodiazepines, and cannabinoids.

[0396] For example, the antiemetic may be selected from neuroleptics, antihistamines, anticholinergics, steroids, 5HT-3 receptor antagonists, NK1 receptor antagonists, antidopaminergics / dopamine receptor antagonists, benzodiazepines, and non-psychoactive cannabinoids.

[0397] In some embodiments, the antiemetic 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, bemisetron, zatisetron, batapirde, MDL-73147EF; metoclopramide, N-3389 (endo-3,9-dimethyl-3,9-diazabicyclo[3,3,1]one-7-yl-1H-indazole-3-carboxamide dihydrochloride), Y-25130 hydrochloride, MDL72222, tropane-3,5-dimethylbenzoic acid, 3-(4-allylpiperazin-1-yl)-2-quinoxalinecarbonitrile maleic acid, zacopride hydrochloride, and mirtazapine. Other non-limiting examples of 5HT3 receptor antagonists (serotonin receptor antagonists) include: cilansetron, clozapine, cyproheptadine, dazopride, hydroxyzine, lerisetron, metoclopramide, mianserin, olanzapine, palonosetron (+ netupitant), quetiapine, qamosetron, ramosteron, licarsetron, risperidone, ziprasidone and zatosetron.

[0398] In certain embodiments, the 5HT-3 receptor antagonist is granisetron, dolasetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemisetron, zatisetron, batanopride, MDL-73147EF, metoclopramide, N-3389, Y-25130 hydrochloride, MDL 72222, tropane-3,5-dimethylbenzoic acid, 3-(4-allyl-piperazin-1-yl)-2-quinoxalinecarbonitrile maleic acid, zacopride hydrochloride, and mirtazapine.

[0399] In certain embodiments, the 5HT-3 receptor antagonist is granisetron, dolasetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemisetron, zalosetron.

[0400] In certain embodiments, the 5HT-3 receptor antagonists are granisetron, dolasetron, and ondansetron.

[0401] In certain embodiments, the 5HT-3 receptor antagonist is granisetron.

[0402] In certain embodiments, the 5HT-3 receptor antagonist is ondansetron.

[0403] In some embodiments, the antiemetic is an antihistamine. Non-limiting examples of antihistamines include: piperazine derivatives (e.g., cyclizine, meclizine, and cinnarizine); promethazine; dimenhydrinate (Dramamine, Gravol); diphenhydramine; hydroxyzine; buclizine; and meclizine hydrochloride (Bonine, Antivert), doxylamine, and mirtazapine.

[0404] In some embodiments, the antiemetic is an anticholinergic (acetylcholine receptor inhibitor). Non-limiting examples of anticholinergics include: atropine, scopolamine, glycopyrron, hyoscine, Trihexy-5 (benzhexol hydrochloride), benztropine (benztropine mesylate), Ankejing (biperiden hydrochloride), Disipal (orphenadrine citrate), diphenhydramine, hydroxyzine, hyoscyamine, and carmatelin (procyclidine hydrochloride).

[0405] In some embodiments, the antiemetic is a steroid (e.g., a corticosteroid). Non-limiting examples of steroids include: betamethasone, dexamethasone, methylprednisolone, and trimethobenzamide (Tigan).

[0406] In some embodiments, the antiemetic is a NK1 receptor antagonist (eg, a neurokinin substance 1P receptor antagonist). Non-limiting examples of NK1 receptor antagonists include: aprepitant, casopitant, elopitant, fosaprepitant, maropitant, netupitant, lolapitant, and viltepitant.

[0407] 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 (bensulfonopitant ammonium / chloride), LY 303870 (lanapitant), 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-11974j. Benserazide and carbidopa k. TAK-637 [(aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazacyclooctatetraeno[2,1-g][1,7]naphthyridine-6,13-dione], PD 154075, ([(2-Benzofuran)-CH2OCO]-(R)-α-MeTrp-(S)-NHCH(CH3)Ph), FK888 and (D-Pro4,D-Trp7,9,10,Phe11)SP4-11.

[0408] In some embodiments, the antiemetic is an antidopaminergic agent / dopamine receptor antagonist (e.g., a dopamine receptor antagonist, such as a D2 or D3 antagonist). Non-limiting examples include phenothiazines (e.g., promethazine, chlorpromazine, prochlorperazine, perphenazine, hydroxyzine, thiethylperazine, metoprazine); benzamides (e.g., metoclopramide, domperidone), butyrophenones (e.g., haloperidol, droperidol); alizapride, bromopride, clebopride, domperidone, itopride, metoclopramide, trimeramide, and amisulpride.

[0409] In some embodiments, the antiemetic is a non-psychoactive cannabinoid (e.g., cannabidiol (CBD), cannabidiol dimethylheptyl (CBD-DMH), tetrahydrocannabidiol (THC), a cannabinoid agonist such as WIN 55-212 (CB1 and CB2 receptor agonist), dronabinol and Nabilone (Cesamet).

[0410] Other exemplary antiemetics include: c-9280 (Merck); benzodiazepines (diazepam, midazolam, lorazepam); neuroleptics / antipsychotics (e.g., dextromethorphan, haloperidol, and prochlorperazine); ); cerium oxalate; propofol; sodium citrate; dextrose; fructose (Nauzene); orthophosphoric acid; fructose; glucose (Emetrol); bismuth subsalicylate (Pepto Bismol); ephedrine; vitamin B6; peppermint, lavender, and lemon essential oils; and ginger.

[0411] Still other exemplary antiemetics include those disclosed in US20120101089A1; US10,071,088B2; US 6,673,792B1; US ​​6,197,329 B1; US10,828,297B2; US10,322,106B2; US 10,525,033B2; WO 2009080351A1; WO 2019203753 A2; WO 2002020001 A2; US 8,119,697B2; US 5,039,528; US20090305964A1; and WO 2006 / 111169, each of which is incorporated by reference in its entirety.

[0412] In some embodiments, the additional therapeutic agent or regimen is administered to the patient prior to contact with or administration of the compounds and pharmaceutical compositions (e.g., about an hour before, or about 6 hours before, or about 12 hours before, or about 24 hours before, or about 48 hours before, or about 1 week before, or about 1 month before).

[0413] In some embodiments, the additional therapeutic agent or regimen is administered to the patient at about the same time as the contact or administration of the compound and pharmaceutical composition. For example, the additional therapeutic agent or regimen and the compound and pharmaceutical composition are provided to the patient simultaneously in the same dosage form. For another example, the additional therapeutic agent or regimen and the compound and pharmaceutical composition are provided to the patient in separate dosage forms in parallel. Patient selection

[0414] In some embodiments, the methods described herein further comprise the step of identifying a patient (eg, subject) in need of such treatment (eg, by blood assays, body mass index, or other routine methods known in the art).

[0415] In some embodiments, the methods described herein further comprise the step of identifying a patient (eg, a patient) suffering from a disease, disorder, or condition (eg, a GLP-1 related disease, disorder, or condition) as provided herein.

[0416] In some embodiments, the methods described herein further include the following steps: identifying a patient (e.g., a patient) with type 2 diabetes. In some embodiments, determining whether a patient has type 2 diabetes includes performing an assay to determine the level of hemoglobin A1c (HbA1c), fasting plasma glucose, non-fasting plasma glucose, or any combination thereof. In some embodiments, the level of HbA1c is about 6.5% to about 24.0%. In some embodiments, the level of HbA1c is greater than or about 6.5%. In some embodiments, the level of HbA1c is greater than or about 8.0%. In some embodiments, the level of HbA1c is greater than or about 10.0%. In some embodiments, the level of HbA1c is greater than or about 12.0%. In some embodiments, the level of HbA1c is greater than or about 14.0%. In some embodiments, the level of HbA1c is greater than or about 16.0%. In some embodiments, the level of HbA1c is greater than or about 18.0%. In some embodiments, the level of HbA1c is greater than or about 20.0%. In some embodiments, the level of HbA1c is greater than or about 22.0%. In some embodiments, the level of HbA1c is greater than or about 24.0%.

[0417] In some embodiments, the level of fasting plasma glucose is greater than or about 120 mg / dL to greater than or about 750 mg / dL. In some embodiments, the level of fasting plasma glucose is greater than or about 200 mg / dL to greater than or about 500 mg / dL. In some embodiments, the level of fasting plasma glucose is greater than or about 300 mg / dL to greater than or about 700 mg / dL.

[0418] In some embodiments, the level of non-fasting plasma glucose is greater than or about 190 mg / dL to greater than or about 750 mg / dL. In some embodiments, the level of non-fasting plasma glucose is greater than or about 250 mg / dL to greater than or about 450 mg / dL. In some embodiments, the level of non-fasting plasma glucose is greater than or about 400 mg / dL to greater than or about 700 mg / dL.

[0419] In some embodiments, determining whether the patient suffers from type 2 diabetes further comprises determining the patient's BMI. In some embodiments, the patient's BMI is greater than or about 22kg / m2 to greater than or about 100kg / m2. In some embodiments, the patient's BMI is greater than or about 30kg / m2 to greater than or about 90kg / m2. In some embodiments, the patient's BMI is greater than or about 40kg / m2 to greater than or about 80kg / m2. In some embodiments, the patient's BMI is greater than or about 50kg / m2 to greater than or about 70kg / m2.

[0420] In some embodiments, the additional factors (e.g., risk factors) used to determine whether a patient suffers from type 2 diabetes further include the patient's age and race. In some embodiments, the patient's age is greater than or about 10 years old. In some embodiments, the patient's age is greater than or about 15 years old. In some embodiments, the patient's age is greater than or about 20 years old. In some embodiments, the patient's age is greater than or about 25 years old. In some embodiments, the patient's age is greater than or about 30 years old. In some embodiments, the patient's age is greater than or about 35 years old. In some embodiments, the patient's age is greater than or about 40 years old. In some embodiments, the patient's age is greater than or about 42 years old. In some embodiments, the patient's age is greater than or about 44 years old. In some embodiments, the patient's age is greater than or about 46 years old. In some embodiments, the patient's age is greater than or about 48 years old. In some embodiments, the patient's age is greater than or about 50 years old. In some embodiments, the patient's age is greater than or about 52 years old. In some embodiments, the patient's age is greater than or about 54 years old. In some embodiments, the patient's age is greater than or about 56 years old. In some embodiments, the age of the patient is greater than or about 58 years old. In some embodiments, the age of the patient is greater than or about 60 years old. In some embodiments, the age of the patient is greater than or about 62 years old. In some embodiments, the age of the patient is greater than or about 64 years old. In some embodiments, the age of the patient is greater than or about 66 years old. In some embodiments, the age of the patient is greater than or about 68 years old. In some embodiments, the age of the patient is greater than or about 70 years old. In some embodiments, the age of the patient is greater than or about 72 years old. In some embodiments, the age of the patient is greater than or about 74 years old. In some embodiments, the age of the patient is greater than or about 76 years old. In some embodiments, the age of the patient is greater than or about 78 years old. In some embodiments, the age of the patient is greater than or about 80 years old. In some embodiments, the age of the patient is greater than or about 85 years old. In some embodiments, the age of the patient is greater than or about 90 years old. In some embodiments, the age of the patient is greater than or about 95 years old. In some embodiments, the patient's race can be African American, American Indian or Alaska Native, Asian American, Hispanic or Latino, or Native Hawaiian or Pacific Islander.

[0421] In some embodiments, the patient is a pediatric patient. As used herein, the term "pediatric patient" refers to a patient under the age of 21 at the time of diagnosis or treatment. The term "pediatric" can be further divided into different subgroups, including: newborns (from birth to the first month of life); infants (1 month to two years old); children (two years old to 12 years old); and adolescents (12 to 21 years old (until but not including the 22nd birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Edition Philadelphia: WB Saunders Company, 1996; Rudolph AM et al. Rudolph's Pediatrics, 21st Edition New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Edition Baltimore: Williams & Wilkins; 1994. In some embodiments, a pediatric patient is from birth to the first 28 days of life, 29 days to less than two years of age, two years to less than 12 years of age, or 12 years to 21 years of age (up to but not including the 22nd birthday). In some embodiments, a pediatric patient is from birth to the first 28 days of life, 29 days to less than 1 year of age, one month to less than four months of age, three months to less than seven months of age, six months to less than 1 year of age, 1 year to less than 2 years of age, 2 years to less than 3 years of age, 2 years to less than seven years of age, 3 years to less than 5 years of age, 5 years to less than 10 years of age, 6 years to less than 13 years of age, 10 years to less than 15 years of age, or 15 years to less than 22 years of age. In some embodiments, the patient is an adult patient. General synthetic method

[0422] The compounds of the present disclosure can be prepared from readily available starting materials using, for example, the following general methods and procedures. It should be understood that, unless otherwise stated, other method conditions may also be used given certain method conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.). Optimum reaction conditions may vary with the reactants or solvents used, but such conditions may be determined by conventional optimization procedures by those skilled in the art.

[0423] In addition, as will be clear to those skilled in the art, conventional blocking groups may be necessary to prevent certain functional groups from experiencing undesirable reactions. Suitable blocking groups for various functional groups and suitable conditions for protecting and deprotecting certain functional groups are well known in the art. For example, many blocking groups are described in TW Greene and GM Wuts (1999) Protecting Groups in Organic Synthesis, the 3rd edition, Wiley, New York and the references cited therein.

[0424] In addition, the compounds of the present disclosure may contain one or more chiral centers. Therefore, if desired, such compounds may be prepared or separated into pure stereoisomers, i.e., as individual enantiomers or diastereomers or as a mixture enriched in stereoisomers. Unless otherwise indicated, all such stereoisomers (and enriched mixtures) are included within the scope of the present disclosure. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective agents well known in the art. Alternatively, the racemic mixture of such compounds may be separated using, for example, chiral column chromatography, chiral resolving agents, etc.

[0425] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or their obvious modifications. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), EMKA-Chemie Gmbh & Co. KG (Eching, Germany) or Millipore Sigma (Burlington, Massachusetts, USA). Other starting materials can be prepared by procedures described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or obvious modifications thereof.

[0426] Scheme 1 illustrates a general method that can be used to synthesize 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 X 6 Each is as defined herein, and LG is a leaving group such as a halo (eg, Cl, Br, or I) or a residue with -L 1 -L 2 An oxo group is formed. Scheme I

[0427] The compound 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, polar aprotic solvents (e.g., acetonitrile), optionally in the presence of a base (e.g., potassium carbonate) or reductive amination conditions.

[0428] For any compound shown in Scheme 1, it should be understood that various derivatives can be provided by functional group interconversion at any step. 0 -T 1 or T 1 , various compounds of Formula I can be provided by functional group interconversion using methods known to those skilled in the art. Similarly, various compounds of Formula I can be prepared by making R b is a leaving group (e.g., a halide (such as Cl, Br or I) or a pseudohalide (such as a triflate, sulfonate or phosphate)) and a compound of formula R b -B, wherein B is a suitable functional group, such as but not limited to boric acid or its derivatives (such as boric acid esters), zinc halides or magnesium halides, organotin compounds (such as tributyltin or trimethyltin), fluorosulfonyl esters, tin, sodium, hydrogen, etc. Such reactions are commonly used for aromatic functionalization and are typically carried out in the presence of a suitable catalyst using a suitable solvent / solvent mixture, the catalyst being such as but not limited to a palladium catalyst (including [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), Pd(OAc)2, Pd(PPh3)4, PdCl2(PPh3)2 or tris(dibenzylideneacetone)dipalladium(0), etc.) or a copper catalyst (such as CuCl or CuI), and if necessary, a suitable medium, a cocatalyst and / or a base known to those skilled in the art. After the reaction is complete, the compound of formula I can be recovered by conventional techniques (such as neutralization, extraction, precipitation, chromatography, filtration, etc.). In certain embodiments, when control of stereochemistry is desired, appropriate control of reaction conditions and selection of substituents of reagents can at least partially determine or maintain the formation of various stereoisomers.

[0429] In some embodiments, various substituents of Formula I-1, I-2, or I-3 (e.g., 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 X 6) as defined herein. However, derivatization of compound I, I-1 or I-2 and / or further derivatization of the resulting reaction product prior to reacting in any step provides various compounds of formula I. Appropriate starting materials and reagents may be purchased or prepared by methods known to those skilled in the art. After each reaction is completed, each intermediate or final compound may be recovered and optionally purified by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, etc. Other modifications to obtain compounds of the present disclosure are within the skill of the art. Example

[0430] General Information: All evaporations were performed in vacuo using a rotary evaporator. Analytical samples were dried in vacuo (1-5 mm Hg) at room temperature. Thin layer chromatography (TLC) was performed on silica gel plates with spots visualized using UV light (214 and 254 nm). Purification was performed by column and flash chromatography using silica gel (100-200 mesh). Solvent systems are reported as mixtures by volume. NMR spectra were recorded on a Bruker 400 or Varian (400 MHz) spectrometer. 1H chemical shifts are reported as δ values ​​in ppm with deuterated solvents as internal standards. Data are reported as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, br=broad, m=multiplet), coupling constant (Hz), integration. LCMS spectra were obtained by electrospray ionization on a SHIMADZULC20-MS2020 or Agilent 1260 series 6125B mass spectrometer or Agilent 1200 series 6110 or 6120 mass spectrometer unless otherwise indicated.

[0431] The present disclosure is further understood by reference to the following examples, which are intended to be purely illustrative of the present disclosure. The scope of the present disclosure is not limited to the exemplary embodiments, which are intended only to illustrate a single aspect of the present disclosure. Any method that is functionally equivalent is within the scope of the present disclosure. In addition to those described herein, various modifications of the present disclosure will become apparent to those skilled in the art due to the foregoing description and accompanying drawings. Such modifications fall within the scope of the appended claims. Procedure 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)

[0432] Step A: (Z)-5-Bromo-N'-hydroxy-6-methylpyridinecarboxamidine

[0433] A mixture of 5-bromo-6-methylnicotinonitrile (60 mg, 0.31 mmol) and 50% NH2OH aqueous solution (202 mg, 3.1 mmol) in EtOH (3 mL) was stirred at 90°C for 1 h. The mixture was concentrated to obtain (Z)-5-bromo-N'-hydroxy-6-methylpyridinecarboximidamide (60 mg, yield: 87%). MS calculated value: 229.0; MS found value: 230.0 [M+H] +

[0434] Step B: 3-(5-bromo-6-methylpyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole

[0435] To a solution of (Z)-5-bromo-N'-hydroxy-6-methylpyridinecarboxamidine (60 mg, 0.26 mmol) in THF (3 mL) was added TFAA (550 mg, 2.6 mmol) dropwise at 0°C. The mixture was warmed to room temperature to stir for 16 h. Aqueous NaHCO3 and EtOAc were added to the mixture to adjust the pH above 7, the organic phase was washed with brine, dried over Na2SO4, the solvent was concentrated to dryness to give a residue, which was purified by preparative TLC to obtain 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] +

[0436] Step C: 3-(5-(3,6-dihydro-2H-pyran-4-yl)-6-methylpyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole

[0437] To a mixture of 3-(5-bromo-6-methylpyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (80 mg, 0.26 mmol) in dioxane / H2O (4 mL / 1 mL) was added 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)Cl2 (21 mg, 0.03 mmol) under N2. The mixture was stirred at 90°C for 8 hours. Water and EtOAc were added to the mixture, the organic phase was washed with brine, dried over Na2SO4, and the residue was purified by preparative TLC to obtain 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 value: 311.1; MS found value: 312.1 [M+H] + .

[0438] Step D: 3-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridine

[0439] 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% NH2NH2.H2O aqueous solution (0.2 mL) in EtOH (0.5 mL) was stirred at 70°C for 1 h. The crude product was obtained by freeze drying with a solvent. The crude product was purified by preparative 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 value: 310.1; MS found value: 311.1 [M+H] +

[0440] Step E: 2-methyl-3-(tetrahydro-2H-pyran-4-yl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridine

[0441] To 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 Pd / C wet 10% content (10 mg) under a H2 balloon at room temperature and stirred for 16 hours. The mixture was purified by preparative TLC to obtain 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 value: 312.1; MS found value: 313.0 [M+H] + .

[0442] Step F: 5-(Tetrahydro-2H-pyran-4-yl)-3-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)picolinaldehyde

[0443] 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 SeO2 (50 mg, 0.448 mmol) at 80°C and stirred for 16 hours. The mixture was filtered and the filtrate was concentrated to obtain 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] + .

[0444] 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)

[0445] 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 minutes. 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)3 (34 mg, 0.16 mol) was slowly added at 0°C and stirred for 15 min. The mixture was then warmed to room temperature to stir for 3 h. Water and DCM were added to the mixture and the organic phase was washed with brine and dried over Na2SO4. The solvent was concentrated to dryness. The residue was purified by preparative HPLC (0.1% NH3.H2O) to afford (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] + .

[0446] 1H NMR (400MHz, MeOD-d4): δ9.09 (s, 1H), 8.45 (s, 1H), 7.63-7.58 (t, J = 16.4Hz, 1H), 7.29 (dd, J =2.0Hz / J=10.8Hz,2H),7.22(dd,J=2.0Hz / J=8.4Hz,1H),6.82-6.75(m,3H),4.58(s,2H),4. 12-4.09(dd,J=3.2Hz / J=11.2Hz,2H),3.67(s,1H),3.64-3.61(dd,J=1.6Hz / J=12Hz,1H),3. 48(m,1H),3.30(m,1H),3.13(m,1H),2.05-1.93(m,2H),1.83-1.79(m,2H),1.33-1.29(m,6). 19 F NMR (377MHz, MeOD-d4): δ65.01, -112.37. Procedure 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)

[0447] Step A: 5-(3,4-dihydro-2H-pyran-5-yl)-6-methylnicotinonitrile

[0448] 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 / H2O (4 mL / 1 mL) was added 5-bromo-6-methylnicotinonitrile (186 mg, 0.95 mmol), Pd(dppf)Cl2 (70 mg, 0.01 mmol) and K2CO3 (393 mg, 2.8 mmol) under N2. The mixture was stirred at 90°C for 8 hours. Water and EtOAc were added to the mixture, the organic phase was washed with brine, dried over Na2SO4, and the residue was purified by preparative TLC to obtain 5-(3,4-dihydro-2H-pyran-5-yl)-6-methylnicotinonitrile (60 mg, yield: 31.6%). MS calculated value: 200.0; MS found value: 201.0 [M+H] + .

[0449] Step B: (Z)-5-(3,4-dihydro-2H-pyran-5-yl)-N'-hydroxy-6-methylpyridinecarboximidamide

[0450] A mixture of 5-(3,4-dihydro-2H-pyran-5-yl)-6-methylnicotinonitrile (60 mg, 0.3 mmol) and 50% NH2OH aqueous solution (198 mg, 3 mmol) in EtOH (3 mL) was stirred at 90°C for 1 h. The mixture was concentrated to obtain (Z)-5-(3,4-dihydro-2H-pyran-5-yl)-N'-hydroxy-6-methylpyridinecarboximidamide (70 mg). MS calculated value: 233.0; MS found value: 234.1 [M+H] +

[0451] Step C: 3-(5-(3,4-dihydro-2H-pyran-5-yl)-6-methylpyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole

[0452] To a solution of (Z)-5-(3,4-dihydro-2H-pyran-5-yl)-N'-hydroxy-6-methylpyridinecarboximidamide (70 mg, 0.3 mmol) in THF (3 mL) was added TFAA (500 mg, 2.4 mmol) dropwise at 0°C. The mixture was warmed to room temperature to stir for 16 h. Aqueous NaHCO3 solution and EtOAc were added to the mixture to adjust the pH above 7, the organic phase was washed with brine, dried over Na2SO4, the solvent was concentrated to dryness to give a residue, which was purified by preparative TLC to obtain 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] +

[0453] Step D: 3-(3-(3,4-dihydro-2H-pyran-5-yl)-4-methylphenyl)-5-(trifluoromethyl)-4H-1,2,4-triazole

[0454] 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% NH2NH2.H2O aqueous solution (0.2 mL) in EtOH (0.5 mL) was stirred at 70°C for 1 h. The crude product was obtained by freeze drying with a solvent. The crude product was purified by preparative 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 value: 310.10; MS found value: 311.1 [M+H] +

[0455] 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

[0456] 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 by a similar method to Example 1. MS calculated value: 657.2; MS found value: 658.2 [M+H] + .

[0457] 1 H NMR (400MHz, MeOD-d4): δ8.95(d,J=1.6Hz,1H),8.29(d,J=2.0Hz,1H),7.58-7.52(m,2H),7.35-7.31(m,1H),6.80-6.78(m,2H),6.70(dd,J1=4.0Hz, J2=8.8Hz,1H),3.99-3.82(m,4H),3.49-3.40(m,3H),2.93-2.91(m,2H),2 .68-2.64(m,1H),2.33-2.26(m,2H),2.04-1.97(m,5H),1.75-1.67(m,6H). 19 F NMR (377MHz, MeOD-d4): δ65.01, -112.37. Procedure 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)

[0458] Step A: 2-methyl-3-(oxetan-3-yl)-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridine

[0459] 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(oxetane-3-yl)borate (118 mg, 0.72 mmol), Pd(dppf)Cl2 (18 mg, 0.02 mmol), K2CO3 (133 mg, 0.96 mmol), water (0.5 ml) and tert-butanol (1 ml) in toluene (10 mL) was stirred at 100°C in a microwave oven 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 purified by preparative TLC (PE:EA=4:1) to afford 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] +

[0460] Step B: 3-(Oxetane-3-yl)-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)picolinaldehyde

[0461] A mixture of 2-methyl-3-(oxetane-3-yl)-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridine (22 mg, 0.05 mmol) and SeO2 (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-(oxetane-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] +

[0462] 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

[0463] 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-(oxetane-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)3 (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 afford (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 calcd: 759.3; MS found: 760.3 [M+H] +

[0464] Step D: (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(oxetane-3-yl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridine

[0465] 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 preparative HPLC to obtain (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(oxetane-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] +

[0466] 1 H NMR (400MHz, CD3OD): δ8.97(s,1H),8.24(s,1H),7.61(t,J=7.4Hz,1H),7.25(dd,J=6.8Hz / J =23.6Hz,2H),6.84-6.74(m,3H),3.67-3.52(m,11H),3.07-2.91(m,1H),2.26-2.20(m,7H). 19 F NMR (377MHz, CD3OD): δ-73.9), -75.85, -112.05. Procedure 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)

[0467] Step A: 5-Bromo-3-(cyclopentyloxy)picolinonitrile

[0468] A mixture of 5-bromo-3-fluoropicolinonitrile (2.0 g, 9.9 mmol), cyclopentanol (943 mg, 10.9 mmol) and Cs2CO3 (9.7 g, 29.8 mmol) in ACN (20 mL) was stirred at 70 ° C for 13 hours. The reaction mixture was cooled to room temperature. The mixture was diluted with H2O (100 mL) and extracted with EA (3x200 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 (eluted with PE / EA (5 / 1)) to obtain 5-bromo-3-(cyclopentyloxy)picolinonitrile (2.0 g, yield: 76.2%). MS calculated value: 266.0; MS found value: 267.0 [M+H] + .

[0469] Step B: 5-Bromo-3-(cyclopentyloxy)picolinaldehyde

[0470] Under nitrogen, at -78 ° C, DIBAH (1.0M 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). The reaction mixture was stirred at -60 ° C for 1 hour. The mixture was diluted with saturated sodium potassium tartrate solution (100 mL) and extracted with EA (3 x 200 mL). The combined organic layer was 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 (eluted with PE / EA (3 / 1)) to obtain 5-bromo-3-(cyclopentyloxy) picolinaldehyde (390 mg, yield: 38.5%). MS calculated value: 269.01; MS found value: 269.9 [M + H] +.

[0471] 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

[0472] 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 room temperature for 2 hours. The mixture was diluted with H2O (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 Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted 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] + .

[0473] Step D: 6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-(cyclopentyloxy)nicotinonitrile

[0474] 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)2(117 mg, 1.00 mmol), Pd(PPh3)4(34 mg, 0.03 mmol) in DMF (2 mL) was stirred at 160 ° C for 2 hours under N2 and microwave. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (3x 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 (eluted 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] + .

[0475] 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'-hydroxypyridinecarboximidamide

[0476] 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), NH2OH·HCl (87 mg, 1.25 mmol) in EtOH (2 mL). The reaction mixture was stirred at 90 °C for 2 hours. The mixture was diluted with H2O (50 mL) and extracted with EA (3 x 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 (eluted 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'-hydroxypyridinecarboximidamide (115 mg, yield: 95.2%). MS calculated: 580.23; MS found: 581.0 [M+H] + .

[0477] 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

[0478] 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'-hydroxypyridinecarboxamidine (115mg, 0.20mmol), TFAA (166mg, 0.79mmol) in THF (2mL). The reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted with H2O (50mL) and extracted with EA (3x 100mL). The combined organic layers were washed with brine (150mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted 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] + .

[0479] 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)

[0480] 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 the reaction was completed. The reaction mixture was purified by preparative 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] + .

[0481] 1H NMR (400MHz, DMSO-d6): 8.76 (d, J=1.6Hz, 1H), 7.94 (s, J=1.2Hz, 1H), 7.53-7.59 (m, 2H), 7.34 (dd, J=8.4Hz, 1.6Hz, 1H), 6.79-6.80 (m, 2H), 6.71 -6.75(m,1H),5.04-5.05(m,1H),3.91(s,2H),3.16-3.18(m,2H),2.67- 2.71(m,1H),2.55-2.61(m,2H),1.89-2.02(m,5H),1.65-1.83(m,10H). Procedure 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]pyridine-3-yl Amine (F-4)

[0482] Step A: 5-Amino-6-methylnicotinonitrile

[0483] A mixture of 5-bromo-2-methylpyridin-3-amine (8.0 g, 42.8 mmol), Zn(CN)2 (15.0 g, 128.2 mmol) and Pd(PPh3)4 (2.48 g, 2.15 mmol) in DMF (20 mL) was stirred at 100° C. under Ar under microwave irradiation for 2 h. The reaction mixture was filtered, the filter cake was washed with a small amount of DMF, and the filtrate was then purified by flash reverse phase chromatography and concentrated under vacuum to give 5-amino-6-methylnicotinonitrile (3.0 g, yield: 52.8%).

[0484] Step B: 5-Bromo-6-methylnicotinonitrile

[0485] To a solution of 5-amino-6-methylnicotinonitrile (3.0 g, 21.9 mmol) and isoamyl nitrite (15.5 g, 87.6 mmol) in ACN (50 ml). The mixture was stirred at room temperature for 2 h, then heated to 60 ° C and stirred for 2 h. HBr (48% in water, 140 mL) and CuBr (4.7 g, 32.8 mmol) in water were added, and the mixture was stirred at 60 ° C under Ar for 2 h. The mixture was poured into a NaHCO3 aqueous 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. The residue was purified by silica gel column chromatography (PE: EA = 20: 1) to obtain 5-bromo-6-methylnicotinonitrile (2.8 g, yield: 65.1%).

[0486] MS calculated value: 196.0; MS found value: 197.2 [M+H] +

[0487] Step C: 5-Bromo-N'-hydroxy-6-methylpyridinecarboxamidine

[0488] A mixture of 5-bromo-6-methylnicotinonitrile (2.8 g, 14.3 mmol) and aqueous NH2OH (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-methylpicolinamidine (3.0 g, crude).

[0489] MS calculated value: 229.0; MS found value: 230.0 [M+H] + .

[0490] Step D: 3-(5-bromo-6-methylpyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole

[0491] At 0 ° C, TFAA (25.7 g, 131.0 mmol) in THF (20 mL) was added to a solution of 5-bromo-N'-hydroxy-6-methylpyridine carboxamidine (3.0 g, crude product) in THF (10 mL) in a dropwise manner. The mixture was stirred at room temperature for 16 h. The mixture was poured into a sodium bicarbonate aqueous solution (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated to obtain 3- (5-bromo-6-methylpyridin-3-yl) -5- (trifluoromethyl) -1,2,4- oxadiazole (4.0 g).

[0492] MS calculated value: 307.0; MS found value: 308.1 [M+H] +

[0493] Step E: 3-Bromo-2-methyl-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridine

[0494] A mixture of 3-(5-bromo-6-methylpyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (4.0 g, 13.0 mmol) and NH2NH2.H2O (6 ml) in EtOH (30 mL) was stirred at 70° C. for 1 h. The mixture was purified by preparative HPLC to give 3-bromo-2-methyl-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridine (4.5 g, crude).

[0495] MS calculated value: 306.0; MS found value: 307.1 [M+H] +

[0496] Step F: 3-Bromo-2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridine

[0497] 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). Then NaH (60%, w / w 2.4 g, 58.8 mmol) was added and the mixture was stirred at 50 °C for 0.5 h. Then SEMCl (7.4 g, 44.10 mmol) was added and 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 silica gel column chromatography (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%).

[0498] MS calculated value: 436.0; MS found value: 437.1 [M+H] +

[0499] Several regioisomers may exist. We chose A-1 as a representative structure.

[0500] 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

[0501] 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-methoxyeth-1-amine (20 mg, 0.28 mmol), Pd(OAc)2 (3 mg, 0.01 mmol), Xphos (13 mg, 0.03 mmol) and Cs2CO3 (134 mg, 0.41 mmol) in toluene (5 mL) was stirred at 90° C. under argon for 16 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative 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%).

[0502] MS calculated value: 431.2; MS found value: 432.2 [M+H] +

[0503] Step H: 3-((2-methoxyethyl)amino)-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)picolinaldehyde

[0504] 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 SeO2 (82 mg, 0.74 mmol) in 1,4-dioxane (2 mL) was stirred at 80° C. for 16 hours. 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] +

[0505] 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

[0506] 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 hours. 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%).

[0507] MS calculated value: 776.3; MS found value: 777.4 [M+H] +

[0508] 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)

[0509] 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 (1 M, 2 mL) in THF (1 mL) was stirred at 60 °C for 6 h. The mixture was purified by preparative 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%).

[0510] MS calculated value: 646.2; MS found value: 647.3 [M+H] +

[0511] 1 H NMR (400MHz, CD3OD): δ8.37(s,1H),7.63-7.55(m,2H),7.34-7.17(m,2H),6.83-6.67(m,3H),3.86(s,2H),3.7 7-3.68(m,2H),3.50-3.37(m,6H),3.08-2.97(m,2H),2.83-2.70(m,1H),2.40-2.25(m,2H),2.03(s,3H),1.99 -1.80(m,4H). 19 F-NMR (377MHz, CD3OD): δ-66.36,-112.28. Procedure 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)

[0512] Step A: N-cyclopentyl-2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-amine

[0513] 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), cyclopentaneamine (23 mg, 0.28 mmol), Pd(OAc)2 (3 mg, 0.014 mmol), XPhos (13 mg, 0.027 mmol) and Cs2CO3 (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 freed of volatiles under vacuum and purified by preparative TLC to afford N-cyclopentyl-2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-amine (32 mg, yield: 52.5%). MS calculated: 441.2; MS found: 442.2 [M+H] +

[0514] 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)

[0515] (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 by a method similar to Procedure 5. MS Calculated: 656.2; MS Found: 659.5 [M+H] +

[0516] 1H NMR (400MHz, CD3OD): δ8.33(s,1H),7.63-7.55(m,2H),7.31-7.18(m,2H),6.80-6.74(m,1H),6.71-6.66(m,2H),3.96-3.91(m,1H) ,3.84-3.79(m,2H),3.06-2.95(m,2H),2.76-2.65(m,1H),2.33-2.24(m,2H),2.16-2.04(m,2H),2.04(s,3H),1.92-1.57(m,10H). 19 F NMR (377MHz, CD3OD): δ-66.22,-112.06. Procedure 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)

[0517] Step A: 4-(2-methyl-5-(5-(trifluoromethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)morpholine

[0518] 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)2 (3 mg, 0.01 mmol), Xphos (11 mg, 0.02 mmol) and Cs2CO3 (112 mg, 0.34 mmol) in toluene (8 mL) was stirred at 90° C. under argon for 16 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative 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%).

[0519] MS calculated value: 443.2; MS found value: 444.6 [M+H] +

[0520] 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)

[0521] 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 by a method similar to Procedure 5.

[0522] MS calculated value: 658.2; MS found value: 659.3 [M+H] +

[0523] 1 H NMR (400MHz, CD3OD): δ9.05(d,J=1.6Hz,1H),8.29(d,J=1.6Hz,1H),7.62(t,J=8.4Hz,1H),7.33-7.20(m,2H),6.89-6.73(m,3H ), 4.61 (s, 2H), 3.91 (t, J = 4.4Hz, 4H), 3.70-3.60 (m, 2H), 3.30-3.21 (m, 2H), 3.09-3.00 (m, 5H), 2.35-2.05 (m, 4H), 2.08 (s, 3H). 19 F-NMR (377MHz, CD3OD): δ-65.47,-112.21. Procedure 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)

[0524] 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

[0525] 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)2 (3 mg, 0.01 mmol), Xphos (11 mg, 0.02 mmol) and Cs2CO3 (150 mg, 0.46 mmol) in toluene (8 mL) was stirred at 90° C. under argon for 16 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative 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%).

[0526] MS calculated value: 455.2; MS found value: 456.3 [M+H] +

[0527] 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)

[0528] 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 by a method similar to Procedure 5.

[0529] MS calculated value: 670.2; MS found value: 671.4 [M+H] +

[0530] 1H NMR (400MHz, CD3OD): δ8.82(s,1H),8.00(s,1H),7.62(t,J=8.4Hz,1H),7.34- 7.18(m,2H),6.88-6.72(m,3H),4.67(s,1H),4.60-4.49(m,1H),4.44(s,1H), 4.39-4.30(m,1H),4.11(d,J=8Hz,1H),3.90(d,J=8Hz,1H),3.73-3.50(m,4H) ,3.30-3.15(m,2H),3.08-2.98(m,1H),2.35-2.13(m,2H),2.13-1.98(m,7H). 19 F-NMR (377MHz, CD3OD): δ-64.99,-112.25. Procedure 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)

[0531] 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

[0532] 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 Pd2(dba)3 (11 mg, 0.011 mmol) in toluene (5 mL) was stirred with Xantphos (13 mg, 0.023 mmol) and Cs2CO3 (112 mg, 0.344 mmol) at 110° C. under argon for 16 h. 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 obtain 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 value: 456.2; MS found value: 457.3 [M+H] +

[0533] 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

[0534] (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 by a method similar to Procedure 5. MS Calculated: 671.2; MS Found: 672.3 [M+H] +

[0535] 1 H NMR (400MHz, CD3OD): δ9.06(s,1H),8.34(s,1H),7.65-7.59(m,1H),7.30-7.21(m,2H),6.84-6.73(m,3H),4.54(s,2H),3 .73(s,2H),3.58-3.48(m,2H),3.43-3.41(m,2H),3.07-3.03(m,4H),3.01(s,1H),2.28-2.13(m,2H),2.02-2.00(m,5H).19 F NMR (377MHz, CD3OD-d4): δ-64.96,-112.31. Procedure 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)

[0536] 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

[0537] 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 (2 mg, 0.01 mmol), Xphos (9 mg, 0.02 mmol) and Cs2CO3 (120 mg, 0.37 mmol) in toluene (5 mL) was stirred at 90° C. under argon for 16 h. The mixture was filtered and the residue was concentrated. The residue was purified by preparative TLC to obtain 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 value: 452.2; MS found value: 453.3 [M+H] +

[0538] 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)

[0539] (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 by a method similar to Procedure 5. MS Calculated: 667.2; MS Found: 668.4 [M+H] +

[0540] 1 H NMR (400MHz, CD3OD): δ8.80(d,J=1.6Hz,1H),7.67-7.59(m,2H),7.33-7.20(m,2H),6.89-6.74(m,3H),4.53(s,2H),4.46(d,J=7.2Hz,2H),4.10 (d,J=7.2Hz,2H),3.79(d,J=10.0Hz,2H),3.40-3.32(m,2H),3.16-3.14 (m,1H),2.39-2.27(m,2H),2.21-2.01(m,2H),2.06(s,3H),1.79(s,3H). 19 F NMR (377MHz, CD3OD): δ-66.74, -77.13, -112.22. Procedure 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-yl Formonitrile (F-13)

[0541] Step A: 3-Methylpyrrolidine-3-carbonitrile hydrochloride

[0542] 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 obtain 3-methylpyrrolidine-3-carbonitrile hydrochloride (79 mg, yield: 96.8%). MS calculated value: 110.1; MS found value: 111.3 [M+H] +

[0543] 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

[0544] 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 Pd2(dba)3 (8 mg, 0.009 mmol) in toluene (5 mL) was stirred with BINAP (11 mg, 0.018 mmol) and t-BuOK (31 mg, 0.27 mmol) at 120° C. under argon for 16 h. 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 preparative TLC gel to obtain 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 value: 466.2; MS found value: 467.4 [M+H] +

[0545] 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

[0546] 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 by a method similar to Procedure 5. MS Calculated: 681.2; MS Found: 682.4 [M+H] +

[0547] 1H NMR (400MHz, CD3OD-d4): δ8.88(s,1H),8.09(s,1H),7.61(t,J=8.4Hz,1H),7.29(d,J=11.2Hz,1H),7.22(d,J=9.6Hz,1H),6.83-6.76(m,3H),4. 52-4.48(m,2H),3.78-3.61(m,4H),3.39-3.37(m,1H),3.24-3.15(m,2H ),3.04-2.98(m,1H),2.58-2.50(m,1H),2.21-2.05(m,9H),1.62(s,3H). 19 F NMR (377MHz, CD3OD-d4): δ: (-65.22), (-112.23). Procedure 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

[0548] 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

[0549] 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 Pd2(dba)3 (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. under argon for 16 hours. 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%).

[0550] MS calculated value: 443.2; MS found value: 444.0 [M+H]+

[0551] 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)

[0552] 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 by a method similar to Procedure 5.

[0553] MS calculated value: 658.2; MS found value: 659.0 [M+H] +

[0554] 1 H NMR (400MHz, CD3OD): δ8.80(s,1H),8.48(s,1H),7.99(s,1H),7.65-7.60(m,1H),7.30(dd,J=1.2Hz / J=10.0Hz,1H) ,7.22(dd,J=2.4Hz / J=4.8Hz,1H),6.86-6.75(m,3H),5.37-5.32(m,1H),4.57-4.53(m,4H),3.70-3.55(m,4H),3.23 -3.20(m,2H),3.08-2.99(m,1H),2.38-2.17(m,2H),2.17-1.99(m,7H). 19 F-NMR (377MHz, CD3OD): δ-65.28,-112.25. Procedure 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-oxazolidine -2-Keto(F-2)

[0555] 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

[0556] 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 (2 mg, 0.01 mmol), Xphos (9 mg, 0.01 mmol) and Cs2CO3 (89 mg, 0.27 mmol) in toluene (5 mL) was stirred at 90° C. under argon for 16 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative 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%).

[0557] MS calculated value: 443.2; MS found value: 444.3 [M+H] +

[0558] 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)

[0559] 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 by a method similar to Procedure 5.

[0560] MS calculated value: 658.2; MS found value: 659.4 [M+H] +

[0561] 1H NMR (400MHz, CD3OD): δ9.26 (s, 1H), 8.51 (s, 1H), 7.62 (t, J = 8.2Hz, 1H), 7.29 (d, J = 10.8Hz, 1H), 7.23 (d, J = 8.0Hz, 1H), 6.89-6. 74(m,3H),4.67(t,J=8.0Hz,2H),4.58(s,2H),4.24(t,J=7.8Hz,2H),3.78-3.68(m,2H),3.15-3.01(m,2H),2.40-2.05(m,8H). 19 F-NMR (377MHz, CD3OD): δ-66.18,-112.43. Procedure 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)

[0562] Step A: 5-Chloro-6-methylpyridazine-3-carbonitrile

[0563] A mixture of 4,6-dichloro-3-methylpyridazine (1.89 g, 11.6 mmol), zinc cyanide (0.68 g, 5.8 mmol), Pd2(dba)3 (0.53 g, 0.58 mmol) and dppf (0.51 g, 0.9 mmol) in DMF (20 mL) was stirred at 90 ° C under a nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature. The mixture was diluted with water (40 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine (2 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with (PE / EA=10 / 1)) to obtain 5-chloro-6-methylpyridazine-3-carbonitrile (1.59 g, yield: 89.3%).

[0564] Step B: 6-Methyl-5-(2-methylmorpholino)pyridazine-3-carbonitrile

[0565] A mixture of 5-chloro-6-methylpyridazine-3-carbonitrile (300mg, 1.96mmol), 2-methylmorpholine (238mg, 2.35mmol) and DIEA (379mg, 2.94mmol) in DMF (5mL) was stirred at 80°C under N2 atmosphere for one hour. The reaction mixture was cooled to room temperature. The mixture was quenched with H2O (10mL) and extracted with EA (3x 20mL). The combined organic layers were washed with brine (10mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (1 / 1)) to obtain 6-methyl-5-(2-methylmorpholino)pyridazine-3-carbonitrile (440mg, yield: 92.7%, purity 90%). MS calculated value: 218.1; MS found value: 219.1 [M+H] + .

[0566] Step C: 6-Formyl-5-(2-methylmorpholino)pyridazine-3-carbonitrile

[0567] A mixture of 6-methyl-5-(2-methylmorpholino)pyridazine-3-carbonitrile (400mg, 1.83mmol) and SeO2(407mg, 3.67mmol) in dioxane (6mL) was stirred at 80°C under a nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature, quenched with H2O(10mL), and extracted with EA(3x 20mL). The combined organic layer was washed with brine (10mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA(1 / 1)) to obtain 6-formyl-5-(2-methylmorpholino)pyridazine-3-carbonitrile (330mg, yield: 66%, purity 85%). MS calculated value: 232.1; MS found value: 233.1[M+H] + .

[0568] 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

[0569] To 6-formyl-5-(2-methylmorpholino)pyridazine-3-carbonitrile (330mg, 1.4mmol) and (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo [d] [1,3] dioxol-4-yl) piperidine (740mg, 1.4mmol, TsOH salt) in MeOH (8mL) solution, sodium cyanoborohydride (268mg, 4.3mmol) is added. The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is quenched with H o (20mL), extracted with EA (3x 40mL). The organic layers are merged and washed with brine (20mL). The organic layer is dried over Na sO , filtered, and concentrated under reduced pressure. The residue was purified by preparative 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] + .

[0570] 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

[0571] 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 ethanol (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 one hour. The reaction mixture was diluted with EA (20 mL) and washed with H2O (10 mL). The organic layer was dried over Na2SO4 and filtered. 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] + .

[0572] 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

[0573] At room temperature, 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 (110mg, 0.18mmol) in THF (4mL), TFAA (155mg, 0.74mmol) was added. The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10mL) and then extracted with EA (3x 20mL). The organic layers were merged and washed with brine (20mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative 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] + .

[0574] 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)

[0575] 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 one hour. The solvent was removed in vacuo. The residue was purified by preparative 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] + .

[0576] 1 H NMR (400MHz, DMSO-d6): δ10.27(brs,1H),7.77(s,1H),7.57-7.65(m,2H),7.35(dd, J=8.4Hz,2.0Hz,1H),6.84-6.92(m,2H),6.73-6.80(m,1H),4.71-4.89(m,2H),3.93- 3.96(m,1H),3.73-3.85(m,2H),3.53-3.68(m,2H),3.28-3.45(m,4H),2.93-3.13(m, 2H), 2.74-2.84 (m, 1H), 2.10-2.26 (m, 2H), 1.92-2.05 (m, 5H), 1.19 (d, J = 6.4Hz, 3H). 19 F NMR (377MHz, DMSO-d6): δ-63.72,-110.51. Procedure 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)

[0577] Step A: 6-methyl-5-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyridazine-3-carbonitrile

[0578] 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), DIEA (1.1 g, 8.8 mmol) in DMF (7.0 mL) was stirred at 90 ° C for 1 hour. After the reaction was completed, the mixture was diluted with H2O (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 obtain 6-methyl-5-(4-oxa-7-azaspiro [2.5] octane-7-yl) pyridazine-3-carbonitrile (535 mg, yield: 79%). MS calculated value: 230.1MS found value: 231.2 [M+H] + .

[0579] 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

[0580] (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 Procedure 14. MS Calculated: 685.2; MS Found: 686.0 [M+H] + .

[0581] 1 H NMR (400MHz, DMSO-d6): δ7.51-7.61(m,3H),7.33(d,J=10.0Hz,1H),6.75-6 .81(m,2H),6.68-6.75(m,1H),3.85-3.92(m,2H),3.81(s,2H),3.61-3.70(m ,2H),3.51-3.57(m,2H),2.93-3.04(m,2H),2.60-2.71(m,1H),2.20-2.35(m ,2H),2.01(s,3H),1.64-1.78(m,4H),0.71-0.78(m,2H),0.58-0.66(m,2H). 19F NMR (377MHz, DMSO-d6): δ-62.95,-110.74. Procedure 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)

[0582] Step A: 6-Methyl-5-(3-methylmorpholino)pyridazine-3-carbonitrile

[0583] A mixture of 5-chloro-6-methylpyridazine-3-carbonitrile (300 mg, 1.96 mmol), 3-methylmorpholine (397 mg, 3.92 mmol), 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 H2O (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 obtain 6-methyl-5-(3-methylmorpholino)pyridazine-3-carbonitrile (128 mg, yield: 30%).

[0584] MS calculated value: 218.1MS found value: 219.1[M+H] + .

[0585] 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)

[0586] 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 as disclosed herein.

[0587] MS calculated value: 673.22; MS found value: 674.4 [M+H] + .

[0588] 1H NMR (400MHz, DMSO-d6): δ7.51-7.63(m,3H),7.30-7.37(m,1H),6.69-6.82 (m,3H),4.24-4.38(m,1H),3.79-4.02(m,4H),3.53-3.72(m,3H),3.13-3.2 1(m,1H),3.00-3.08(m,1H),2.89-2.98(m,1H),2.60-2.71(m,1H),2.20-2. 35(m,2H),2.01(d,J=1.6Hz,3H),1.66-1.85(m,4H),1.07(d,J=6.0Hz,3H). 19 F NMR (377MHz, DMSO-d6): δ-63.41, -110.77, -110.78. Procedure 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)

[0589] Step A: 5-(3-Hydroxypyrrolidin-1-yl)-6-methylpyridazine-3-carbonitrile

[0590] A mixture of 5-chloro-6-methylpyridazine-3-carbonitrile (400mg, 2.6mmol), pyrrolidin-3-ol (454mL, 5.2mmol), DIEA (1.7g, 13.0mmol) in DMF (5mL) was stirred at 90°C under a nitrogen atmosphere for 2 hours. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (50mL) and extracted with EtOAc (3x 50mL). The combined organic layers were washed with brine (2x 50mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE) to obtain 5-(3-hydroxypyrrolidin-1-yl)-6-methylpyridazine-3-carbonitrile (300mg, yield: 56.4%). MS calculated value: 204.10; MS found value: 205.2[M+H]+.

[0591] 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)

[0592] 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 by a method similar to Procedure 14. MS Calculated: 659.20; MS Found: 660.1 [M+H] + .

[0593] 1 H NMR (400MHz, DMSO-d6): δ7.51-7.61(m,2H),7.33(d,J=8.4Hz,1H),7.13(s,1H),6.69-6.80(m,3H),4.39-4.51(m,1H ),3.69-4.06(m,7H),2.89-3.00(m,2H),2.65-2.72(m,1H),2.14-2.25(m,2H),1.92-2.05(m,5H),1.65-1.79(m,4H). 19 F NMR (377MHz, DMSO-d6): δ-63.18,-110.82. Procedure 18: 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine -1-yl)methyl)-3-methoxy-5-(1H-tetrazolyl-5-yl)pyridine (F-20)

[0594] Step A: 5-Bromo-3-methoxypicolinonitrile

[0595] At 0 ° C, MeONa (3.2 g, 59.7 mmol) was added to a solution of 5-bromo-3-fluoropicolinonitrile (10.0 g, 49.7 mmol) in THF (100 mL), and the reaction was stirred at room temperature for 1 h. The resulting mixture was quenched with water (200 mL) and extracted with EA (200 mL * 3). The combined organic layer was dried over Na2SO4, filtered, concentrated, and the residue was purified by silica gel column chromatography (PE: EA = 4: 1) to give 5-bromo-3-methoxypicolinonitrile (9.7 g, yield: 91.5%). MS calculated value: 212.0; MS found value: 212.9 [M + H] + .

[0596] Step B: 5-Bromo-3-methoxypicolinic acid

[0597] To a solution of 5-bromo-3-methoxypicolinonitrile (200 mg, 0.94 mmol) in MeOH (5 mL) and H2O (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 1N HCl. The aqueous phase was extracted with EA (50 mL*2). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give 5-bromo-3-methoxypicolinic acid (170 mg, yield: 74%). MS calculated: 230.9; MS found: 231.9 [M+H] + .

[0598] Step C: (5-bromo-3-methoxypyridin-2-yl)methanol

[0599] At room temperature, to a solution of 5-bromo-3-methoxypicolinic acid (800mg, 3.5mmol) in THF (8mL), BH3 (7mL, 7.0mmol, 1M in THF) was added, and the mixture was stirred for 12 hours. After the reaction was complete, the mixture was quenched with MeOH (4mL) and diluted with EA (50mL), washed with brine (50mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA=1 / 1) to obtain (5-bromo-3-methoxypyridin-2-yl)methanol (400mg, yield: 52.6%). MS calculated value: 216.97; MS found value: 218.0[M+H] + .

[0600] Step D: 5-Bromo-3-methoxypyridinecarboxaldehyde

[0601] A mixture of (5-bromo-3-methoxypyridin-2-yl)methanol (400 mg, 1.8 mmol), MnO2 (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).

[0602] 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

[0603] To a solution of 5-bromo-3-methoxypicolinaldehyde (300 mg, 1.4 mmol), 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine HCl salt (483 mg, 1.4 mmol) in DCM (10 mL) was added NaBH(OAc)3 (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, yield: 52.7%). MS calculated: 546.1; MS found: 547.1 [M+H] + .

[0604] Step F: 6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methoxynicotinonitrile

[0605] 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)2(250 mg, 2.19 mmol), Pd(PPh3)4(80 mg, 0.07 mmol) in DMF (5 mL) was stirred at 160 ° C. under microwave for 2 hours. After the reaction was complete, the mixture was diluted with EA (70 mL) and washed with H2O (40 mL*3). The organic layer was dried over anhydrous sodium sulfate, filtered, 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, yield: 33.1%). MS calculated: 493.2; MS found: 494.2 [M+H] + .

[0606] 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

[0607] 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), Bu2SnO (89 mg, 0.36 mmol), TMSN3 (70 mg, 0.60 mmol) in dioxane (1 mL) was stirred at 100° C. for 6 hours. After completion of the reaction, the mixture was filtered, and the filtrate was purified by preparative 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 value: 536.2; MS found value: 537.2 [M+H] + .

[0608] 1H NMR (400MHz, DMSO-d6): δ8.91(d,J=1.2Hz,1H),8.07(d,J=1.6Hz,1H),7.68(t,J=8.4Hz,1H),7.57(dd ,J=11.2Hz,2.0Hz,1H),7.40(dd,J=8.4Hz,1.2Hz,1H),6.87-6.95(m,2H),6.80-6.83(m,1H),4.40(br s,2H),4.05(s,3H),3.52-3.59(m,2H),3.11-3.15(m,2H),2.96-3.03(m,1H),1.97-2.18(m,7H). 19 F NMR (377MHz, DMSO-d6): δ-110.45. Procedure 19: 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine -1-yl)methyl)-3-cyclopropyl-5-(1H-tetrazol-5-yl)pyridine (F-14)

[0609] Step A: 6-Chloro-5-cyclopropylnicotinonitrile

[0610] A mixture of 5-bromo-6-chloronicotinonitrile (200 mg, 0.92 mmol), cyclopropylboronic acid (119 mg, 1.38 mmol), Pd(dppf)Cl2 (50 mg, 0.07 mmol) and K2CO3 (381 mg, 2.76 mmol) in 1,4-dioxane (2 mL) was stirred at 90°C under argon for 12 hours. 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 silica gel column chromatography to obtain 6-chloro-5-cyclopropylnicotinonitrile (90 mg, yield: 55%). MS calculated: 178.0; MS found: 179.1 [M+H] + .

[0611] Step B: 5-Cyclopropyl-6-methylnicotinonitrile

[0612] A mixture of 6-chloro-5-cyclopropylnicotinonitrile (90 mg, 0.51 mmol), Me2Zn in toluene (1.01 mL, 1 M, 1.01 mmol) and Pd(PPh3)4 (58 mg, 0.05 mmol) in THF (6 mL) was stirred at 80 °C under Ar 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 silica gel column chromatography to obtain 5-cyclopropyl-6-methylnicotinonitrile (60 mg, yield: 75.1%). MS calculated: 158.1; MS found: 159.2 [M+H] + .

[0613] Step C: 6-(Bromomethyl)-5-cyclopropylnicotinonitrile

[0614] 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 silica gel column chromatography to obtain 6-(bromomethyl)-5-cyclopropylnicotinonitrile (25 mg, yield: 27.9%). MS calculated value: 236.0; MS found value: 239.0 [M+H] + .

[0615] Step D: 6-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-cyclopropylnicotinonitrile

[0616] 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 KCO (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 (2×30 mL), the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the residue was concentrated. The residue was purified by silica gel column chromatography to obtain 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 value: 503.2; MS found value: 504.1 [M+H] + .

[0617] 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)

[0618] 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), NaN3 (5 mg, 0.077 mmol) and NH4Cl (4 mg, 0.077 mmol) in DMF (1 mL) was stirred at 110° C. in a sealed tube for 16 h. The mixture was filtered and the residue was purified by preparative HPLC to obtain 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 value: 546.2; MS found value: 547.1 [M+H] +

[0619] 1H NMR (400MHz, CD3OD): δ9.08 (s, 1H), 8.12 (s, 1H), 7.62 (t, J = 8.4Hz, 1H), 7.31-7.22 (m, 2H), 6.83-6.75 (m, 3H), 4.61-4. 50(m,2H),3.66-3.58(m,2H),3.11-2.97(m,2H),2.23-2.13(m,3H),2.05(s,5H),1.14-1.12(m,2H),0.87-0.86(m,2H). 19 F-NMR (377MHz, CD3OD): δ-112.25.

[0620] The compounds of Table 1 can be or have been synthesized according to the general syntheses or procedures described herein using appropriate starting materials. Biological Examples Biological Example 1: cAMP Assay

[0621] Activation of the GLP-1 receptor is known to stimulate cyclic AMP (cAMP) production in cells, demonstrating primary coupling to the Gas subunit of the G protein heterotrimeric complex. Evidence suggests that cAMP-stimulated signaling induced by Gas elicits the desired pharmacological response regarding insulin release from pancreatic β cells.

[0622] To optimize functional activity against Gαs coupling, HEK293 / CRE-Luc cell line generated by HDB stably expressing GLP-1 receptor was used. Compound working solutions (Agilent Technologies Bravo) at 200× concentration were prepared in 1 / 2 log serial dilutions in 384-well Echo LDV plates (Labcyte, catalog number LP-0200). 50 nL / well of the 200× concentration compound working solution was transferred to 384-well white low-volume plates (Greiner, catalog number 784075) using Labcyte ECHO550. Prepare 1×105 cells / mL HEK293 / GLP1R / CRE-LUC (HD Biosciences) cell suspension in assay buffer [DPBS containing 0.5 mM IBMX (Sigma, catalog number I5879) and 0.1% BSA (GENVIEW, catalog number FA016-100g)], and add 10 μL of cell suspension to each well of a previously generated assay plate (1000 cells / well) containing 50 nL of compound at a concentration of 200× using a ThermoFisher Multidrop Combi. Seal the plate and incubate for 30 min at 37°C and 5% CO2.

[0623] After incubation, the cAMP assay signal was generated using the cAMP dynamic 2 kit (Cisbio). Using a ThermoFisher Multidrop Combi, 5 μL of cAMP-d2 working solution was added to each well, and then 5 μL of anti-cAMP antibody-cryptate working solution was added to each well. Incubate for 1 hour at room temperature in the dark. Read the fluorescence at 665 and 615 nm with a ReaderPerkinElmer EnVision. Activity % = 100% x (average RLU of test sample - average RLU of vehicle control) / (average RLU of maximum control - average RLU of vehicle control))

[0624] Table 3 shows the biological activity of the compounds in the GLP-1R agonist cAMP stimulation assay (EC 50 The activities of the test compounds are provided in Table 3 below: +++ = EC 50 <1 nM; ++ = EC 50 1-100nM; + = EC 50 >100nM. Table 3

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt or solvate thereof, wherein: X 1 , X 2 and X 5 independently C or N; X 3 and X 4 Independently selected from: N, NR x , CR y , C(O), O and S; X 6 Selected from: bond, N, NR x , CR y and C(O); Each is a single bond or a double bond, provided that X 1 -X 6 At least one of X is an independently selected heteroatom or heteroatom group; 1 -X 6 At least one of them is C or CR y ; and contains X 1 -X 6 The ring is aromatic; Each R x independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, C(O)(C1-C6)alkyl, S(O)2(C1-C6)alkyl and C(O)O(C1-C6)alkyl; Each R y independently selected from the group consisting of hydrogen, -OH, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, CN and halogen; L 0 Yes key or #-P 0 -P 1 , where # indicates that the 5 Attachment point; -P 0 is a bond, -NH-, -N(C1-C6 alkyl)-, -O- or S(O) 0-2 ; -P 1 is selected from: (C1-C6)alkylene, (C2-C6)alkenylene, (C2-C6)alkynylene, (C3-C8)cycloalkylene and 4- to 8-membered heterocycloalkylene, each of which is optionally substituted by 1-3 R 0 replace; Each R 0 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 a C(O)OH or carboxylic acid bioisostere; or Part-L 0 -T 1 yes: ● -C(O)NH-(C1-C6)alkyl or -C(O)NH-(C3-C6)cycloalkyl; each of which is optionally substituted by 1 to 4 R T replace; or · 5- to 6-membered heteroaryl optionally substituted by -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 -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 are each optionally substituted with 1-4 R T replace; T 2 yes: =Hydrogen, CN, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, or (C1-C6)alkyl 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)cycloalkyloxy, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein each of said (C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted with 1-4 R T replace; 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 3-10 membered heterocycloalkyl; Among them -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 heterocycloalkyl are each optionally substituted by 1-4 R T replace; Each R T independently selected from OH, SH, CN, NO2, halogen, =O, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C1-C6)cyanoalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C3-C6)cycloalkyl, amino, (C1-C6)alkylamino, (C1-C6)alkylamino(C1-C6alkyl)-C(O)-C1-C6alkyl, S(O)2(C1-C6alkyl) and di(C1-C6)alkylamino; L 1 is a bond or optionally 1-3 R L Substituted (C1-C3) alkylene; L 2 is a bond, -O-, -S(O) 0-2 - or -NH-; Each R L independently selected from: halogen, (C1-C3) alkyl and (C1-C3) haloalkyl; or a pair of R located on the same carbon atom or adjacent carbon atoms L Together with the atom or atoms to which they are attached, they form a (C3-C6)cycloalkyl ring; Ring A is selected from: Where n1 is 0, 1 or 2, W 1 Yes CR Y1 or N, and W 2 Yes CR Y2 or N; Where W 3 Yes C, CR Y3 or N, L w is (C1-C3)alkylene, and as valence permits, each are independently a single bond or a double bond; Optionally 1-4 R Y Substituted phenylene; Optionally 1-3 R Y substituted 5- to 6-membered heteroarylene; Optionally 1-4 R Y Substituted (C5-C8)cycloalkylene; Optionally 1-4 R Y Substituted partially unsaturated monocyclic (C5-C8) cycloalkylene; and Optionally 1-4 R Y substituted partially unsaturated monocyclic 5- to 8-membered heterocycloalkylene; Where mm represents L 2 , and nn represents the attachment point to ring B; Each occurrence of R Y independently selected from halogen, CN, -OH, oxo, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy and (C1-C3)haloalkoxy; R Y1 , R Y2 and R Y3 are each independently selected from hydrogen, halogen, CN, -OH, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy and (C1-C3)haloalkoxy; or When W 1 Yes CR Y1 And W 2 Yes CR Y2 When R Y1 and R Y2 The groups can together form a (C1-C4)alkylene group, wherein one of the CH2 units of the (C1-C4)alkylene group is optionally selected from O, S, NH and N(C 1-3 ) heteroatom substitution of an alkyl group; Ring B is selected from: (BI), (B-II), (B-III), (B-IV), (BV), (B-VI) and (B-VII): Where aa represents the point of attachment to ring A; B 1 , B 2 , B 3 and B 4 Each of which is independently selected from CR 1 and N; B 5 and B 6 Each of which is independently selected from N, NR 1 , C, CR 1 , O and S, provided that B is contained 5 and B 6 The ring of is heteroaryl; Where aa represents the point of attachment to ring A; B 7 and B 8 Independently selected from: -O-, -NR N -and-C(R 1 )2-; B 9 Is N or CR aa ; nb is 0 or 1; B 10 , B 11 and B 12 Independently selected from CR 1 and N; B 13 , B 14 and B 15 Each is independently CR 1 ; Each R 1 independently selected from hydrogen, halogen, CN, (C1-C6)alkyl, (C1-C6)haloalkyl; (C1-C3)alkyl (C3-C6)cycloalkyl, (C1-C3)alkyl (3 to 5 membered heterocycloalkyl) and -C(O)NR 2 R 3 ; R 2 and R 3 Each independently selected from H and (C1-C6) alkyl; Each R N independently selected from hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, C(O)(C1-C6)alkyl, S(O)2(C1-C6)alkyl and C(O)O(C1-C6)alkyl; R aa , R ab and R ac Each independently selected from H, (C1-C6)alkyl and (C1-C6)haloalkyl; L 3 Yes key or -Z 1 -Z 2 -*, where * indicates the point of attachment to ring C; -Z 1 is a bond, NH, N(C1-C6 alkyl), O or S(O) 0-2 ; -Z 2 is optionally replaced by 1-2 R c Substituted C 1-3 Alkylene; Each R c independently selected from halogen, (C1-C6)alkyl and (C1-C3)haloalkyl; Ring C is selected from phenyl, 5- to 6-membered heteroaryl, (C3-C6)cycloalkyl, (C5-C 10 ) bicycloalkyl, 5- to 10-membered bicycloheteroaryl, and 3- to 6-membered heterocycloalkyl; Each R b is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C3-C6)cycloalkyl, CN, -C(O)NH2 or -C(O)OH; and b is an integer selected from 0-3; The condition is that at least one of the following occurs: 1) At least one R b is -C(O)NH2 or -C(O)OH; 2) Ring A is optionally substituted with 1-4 R Y Substituted (C5-C8)cycloalkylene; 3) Ring B is 4) Part-L 0 -T 1 yes: -C(O)NH-(C1-C6)alkyl or -C(O)NH-(C3-C6)cycloalkyl; each of which is optionally substituted by 1 to 4 R T replace; or · 5- to 6-membered heteroaryl optionally substituted by -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 -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 are each optionally substituted with 1-4 R T replace; or 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 3-10 membered heterocycloalkyl; wherein -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 heterocycloalkyl are each optionally substituted by 1-4 R T substitution; provided that the compound is not:

2. A compound of formula II: in: or a pharmaceutically acceptable salt or solvate thereof, wherein: L 0 Yes key or -P 0 -P 1 ; -P 0 is a bond, -NH-, -N(C1-C6 alkyl)-, -O- or S(O) 0-2 ; -P 1 is selected from: (C1-C6)alkylene, (C2-C6)alkenylene, (C2-C6)alkynylene, (C3-C8)cycloalkylene and 4- to 8-membered heterocycloalkylene, each of which is optionally substituted by 1-3 R 0 replace; Each R 0 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 a C(O)OH or carboxylic acid bioisostere; or Part-L 0 -T 1 yes: ● -C(O)NH-(C1-C6)alkyl or -C(O)NH-(C3-C6)cycloalkyl; each of which is optionally substituted by 1 to 4 R T replace; or · 5- to 6-membered heteroaryl optionally substituted by -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 -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 are each optionally substituted with 1-4 R T replace; T 2 yes: hydrogen, CN, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, or (C1-C6)alkyl optionally substituted by (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)cycloalkyloxy, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein each of said (C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted by 1-4 R T replace; 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 3-10 membered heterocycloalkyl; Among them -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 heterocycloalkyl are each optionally substituted by 1-4 R T replace; Each R T independently selected from OH, SH, CN, NO2, halogen, =O, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C1-C6)cyanoalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C3-C6)cycloalkyl, amino, (C1-C6)alkylamino, (C1-C6)alkylamino(C1-C6alkyl)-C(O)-C1-C6alkyl, S(O)2(C1-C6alkyl) and di(C1-C6)alkylamino; W 1 is CH or N; Ring B is selected from: (BI), (B-II), (B-III), (B-IV), (BV), (B-VI) and (B-VII): where aaa represents the point of attachment to ring A; B 1 , B 2 , B 3 and B 4 Each of which is independently selected from CR 1 and N; B 5 and B 6 Each of which is independently selected from N, NR 1 , C, CR 1 , O and S, provided that B is contained 5 and B 6 The ring of is heteroaryl; Where aa represents the point of attachment to ring A; B 7 and B 8 Independently selected from: -O-, -NR N -and-C(R 1 )2-; B 9 Is N or CR aa ; nb is 0 or 1; B 10 , B 11 and B 12 Independently selected from CR 1 and N; B 13 , B 14 and B 15 Each is independently CR 1 ; Each R 1 independently selected from hydrogen, halogen, CN, (C1-C6)alkyl, (C1-C6)haloalkyl; (C1-C3)alkyl (C3-C6)cycloalkyl, (C1-C3)alkyl (3 to 5 membered heterocycloalkyl) and -C(O)NR 2 R 3 ; R 2 and R 3 Each independently selected from H and (C1-C6) alkyl; Each R N independently selected from hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, C(O)(C1-C6)alkyl, S(O)2(C1-C6)alkyl and C(O)O(C1-C6)alkyl; R aa , R ab and R ac Each independently selected from H, (C1-C6)alkyl and (C1-C6)haloalkyl; L 3 Yes key or -Z 1 -Z 2 -*, where * indicates the point of attachment to ring C; -Z 1 is a bond, NH, N(C1-C6 alkyl), O or S(O) 0-2 ; -Z 2 is optionally replaced by 1-2 R c Substituted C 1-3 Alkylene; Each R c independently selected from halogen, (C1-C6)alkyl and (C1-C3)haloalkyl; Ring C is selected from phenyl, 5- to 6-membered heteroaryl, (C3-C6)cycloalkyl, (C5-C 10 ) bicycloalkyl, 5- to 10-membered bicycloheteroaryl, and 3- to 6-membered heterocycloalkyl; Each R b is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C3-C6)cycloalkyl, CN, -C(O)NH2 or -C(O)OH; and b is an integer selected from 0-3; The condition is that at least one of the following occurs: 1) At least one R b is -C(O)NH2 or -C(O)OH; 2)W 1 It is CH; 3) Ring B is 4) Part-L 0 -T 1 yes: ● -C(O)NH-(C1-C6)alkyl or -C(O)NH-(C3-C6)cycloalkyl; each of which is optionally substituted by 1 to 4 R T replace; or · 5- to 6-membered heteroaryl optionally substituted by -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 -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 are each optionally substituted with 1-4 R T replace; or 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 3-10 membered heterocycloalkyl; wherein -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 heterocycloalkyl are each optionally substituted by 1-4 R T replace; Provided that the compound is not:

3. The compound according to claim 1 or 2, wherein at least one R b It is -C(O)NH2 or -C(O)OH.

4. The compound according to claim 2, which is represented by Formula IIA: or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 It is -OH or -NH2.

5. The compound according to claim 4, which has the following structure: or a pharmaceutically acceptable salt or solvate thereof.

6. The compound according to claim 1 or 2, wherein ring A is optionally substituted with 1 to 4 R Y Substituted (C5-C8)cycloalkylene.

7. The compound according to claim 2, which is represented by Formula IIB: or a pharmaceutically acceptable salt or solvate thereof.

8. The compound according to claim 7, which has the following structure: or a pharmaceutically acceptable salt or solvate thereof.

9. The compound according to claim 1 or 2, wherein ring B is 10. The compound according to claim 2, which is represented by Formula IIC: or a pharmaceutically acceptable salt or solvate thereof.

11. The compound according to claim 10, which has the following structure: or a pharmaceutically acceptable salt or solvate thereof.

12. The compound according to claim 1 or 2, wherein the moiety -L 0 -T 1 is -C(O)NH-(C1-C6)alkyl or -C(O)NH-(C3-C6)cycloalkyl; wherein each is optionally substituted by 1-4 R T replace.

13. The compound according to claim 2, which is represented by Formula IID: or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is -(C1-C6)alkyl or -(C3-C6)cycloalkyl; and wherein said -(C1-C6)alkyl or -(C3-C6)cycloalkyl is optionally replaced by 1-4 R T replace.

14. The compound according to claim 13, which has the following structure: or a pharmaceutically acceptable salt or solvate thereof.

15. The compound according to claim 1 or 2, wherein the moiety -L 0 -T 1 is a 5- to 6-membered heteroaryl, -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 optionally substituted with -C(O)OH; wherein -C(O)NH(C1-C6)alkyl, -C(O)O(C1-C6)alkyl, -C(O)NH-(C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, and 6-membered heteroaryl are each optionally substituted with 1-4 R T replace.

16. The compound according to claim 2, which is represented by Formula IIE: or a pharmaceutically acceptable salt or solvate thereof, wherein: Ring D is a 5- to 6-membered heteroaryl group; 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 optionally substituted by 1-4 R T replace.

17. The compound according to claim 16, which has the following structure: or a pharmaceutically acceptable salt or solvate thereof.

18. The compound according to claim 1 or 2, wherein 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 3-10 membered heterocycloalkyl; wherein -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 heterocycloalkyl are each optionally substituted by 1-4 R T replace.

19. The compound according to claim 2, which is represented by Formula IIF: or a pharmaceutically acceptable salt or solvate thereof, wherein: L 4 is a bond, -NH-, -CH2-S(O)2, or -O-; and R 7 is (C1-C6)alkyl, (C3-C6)cycloalkyl or 3-10 membered heterocycloalkyl, wherein each of the (C1-C6)alkyl, (C3-C6)cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted by 1 to 4 R T Replacement; the condition is that when L 4 When it is a key, then R 7 It is a substituted or unsubstituted (C3-C6)cycloalkyl group, or a substituted or unsubstituted 3-10 membered heterocycloalkyl group.

20. The compound according to claim 19, which has the following structure: or a pharmaceutically acceptable salt or solvate thereof.

21. A compound of Table 1 or Table 2 or a pharmaceutically acceptable salt or solvate thereof.

22. A pharmaceutical composition comprising a compound according to any preceding claim, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

23. A method for treating a GLP-1 related disease, disorder or condition, the method comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 22.

24. The method of claim 23, wherein the disease, disorder or condition is selected from type 1 diabetes, type 2 diabetes, early onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of adults (LADA), obesity, weight gain due to the use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient 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 lipidosis, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, addiction treatment, 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. A method for treating type 2 diabetes in a patient in need thereof, the method comprising administering to the patient in need thereof an effective amount of a compound according to any one of claims 1-21 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 22.

26. A method for regulating insulin levels in a patient in need of such regulation, the method comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 22.

27. A method for regulating glucose levels in a patient in need of such regulation, the method comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1-21 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 22.

28. The method of any one of claims 23-27, further comprising administering an additional therapy or therapeutic agent to the patient.

29. The method of claim 28, wherein the additional therapy or therapeutic agent is selected from an anti-diabetic agent, an anti-obesity agent, a GLP-1 receptor agonist, an antiemetic, an agent for treating non-alcoholic steatohepatitis (NASH), gastric electrical stimulation, dietary monitoring, physical activity, or a combination thereof.

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