Heteroaryl-heterocycloalkyl-based 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

[0001] This application claims priority to International Patent Application No. PCT / CN2023 / 116141, filed on August 31, 2023, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0002] This open document relates to GLP-1 agonists, pharmaceutical compositions and methods of use thereof. Background Technology

[0003] Incretin metabolism hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (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 mellitus refers to a group of metabolic disorders characterized by persistent hyperglycemia. The most common form, type 2 diabetes mellitus (T2DM), is an acquired condition that accounts for more than 90% of diabetes cases. Typical onset occurs in obese or otherwise sedentary adults and begins with insulin resistance. While lifestyle modifications can be used to effectively manage this disorder, patients with T2DM may require antidiabetic medications, particularly dipeptidyl peptidase-4 inhibitors, SGLT2 inhibitors, and sulfonylureas.

[0005] In healthy individuals, the incretin hormones glucose-dependent insulinotropic peptide (GIP) and glucagon-like 1 (GLP-1) provide tandem regulation of the insulin secretory response to glucose intake. Although this incretin effect is significantly diminished (if fully present) in cases of type 2 diabetes mellitus (T2DM), GLP-1 retains its insulinotropic properties, even when the endocrine pancreatic response to GIP is effectively terminated. Therefore, incretin mimics and other GLP-1-based therapies can help stimulate insulin production in patients with T2DM. Summary of the Invention

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

[0007] On one hand, compounds of formula I are provided: I Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein ring A, ring B, X, Z, Q 1 Q 2 Q 3 Q4 Q 5 L 1 L 2 , q, m, s, R 1 and R C Each is defined independently as described in this article.

[0008] This disclosure also provides pharmaceutical compositions comprising one or more compounds of Formula I or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a mixture of stereoisomers, or a prodrug, and a pharmaceutically acceptable excipient.

[0009] This document also provides pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a mixture of stereoisomers, or a prodrug, and a pharmaceutically acceptable excipient.

[0010] This article also provides a method for treating type 2 diabetes in patients in need, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer thereof, a mixture of stereoisomers thereof, or a prodrug thereof, or a pharmaceutical composition thereof.

[0011] This article also provides a method for treating a patient with type 2 diabetes, the method comprising administering to a patient identified or diagnosed with type 2 diabetes a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a mixture of stereoisomers, or a prodrug thereof, or a pharmaceutical composition thereof.

[0012] This document also provides a method for treating a patient with diabetes, the method comprising determining that the patient has type 2 diabetes; and administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, or a pharmaceutical composition thereof. In some embodiments, the step of determining that the patient has type 2 diabetes includes performing a 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 HbA1c level is greater than or about 6.5%. In some embodiments, the fasting plasma glucose level is greater than or about 126 mg / dL. In some embodiments, the non-fasting plasma glucose level is greater than or about 200 mg / dL.

[0013] In some embodiments, the method further includes obtaining a sample from the patient. In some embodiments, the sample is a body fluid sample. In some embodiments, the patient is approximately 40 to approximately 70 years old and is overweight or obese. In some embodiments, the patient's body mass index (BMI) is greater than or approximately 22 kg / m². 2 In some implementations, the patient's BMI is greater than or approximately 30 kg / m². 2 .

[0014] In some embodiments, the method for treating type 2 diabetes includes lowering fasting plasma glucose levels. In some embodiments, the fasting plasma glucose level is lowered to about or below 100 mg / dL.

[0015] In some embodiments, the method for treating type 2 diabetes includes lowering HbA1c levels. In some embodiments, the HbA1c level is lowered to about or below 5.7%.

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

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

[0018] In some embodiments, the method for treating type 2 diabetes includes reducing BMI. In some embodiments, the BMI is reduced to about or below 25 kg / m². 2 .

[0019] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer thereof, a mixture of stereoisomers thereof, or a prodrug thereof, or a pharmaceutical composition thereof, is administered orally.

[0020] In some embodiments, the method of treating type 2 diabetes further includes administering additional therapies or therapeutic agents to the patient. In some embodiments, the additional therapies or therapeutic agents are 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 biguanide, sulfonylureas, glipizide, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, megglitinide, sodium-glucose cotransporter 2 (SGLT2) inhibitors, thiazolidinediones, GRP40 agonists, glucose-dependent insulinotropic peptide (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 neuropeptide Y receptor type 2 (NPYR2) agonists, NPYR1 or NPYR5 antagonists, human pro-insulin peptide (HIP), cannabinoid receptor type 1 (CB1R) antagonists, lipase inhibitors, melanocortin receptor 4 agonists, farnesyl X receptor (FXR) agonists, phenbutamine, zonisamide, norepinephrine / dopamine reuptake inhibitors, GDF-15 analogs, opioid receptor antagonists, cholecystokinin agonists, serotonergic agents, methionine aminopeptidase 2 (MetAP2) inhibitors, diethylamine acetone, benzotriazine, benzylphenamine, fibroblast growth factor receptor (FGFR) modulators, AMP-activated protein kinase (AMPK) activators, or any combination thereof. In some embodiments, the GLP-1 receptor agonist is selected from liraglutide, exenatide, duraglutide, abiglutide, tasglutide, lixilatide, smegglutide, 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, galactagogue 3 inhibitors, fibroblast growth factor 21 (FGF21) agonists, niacin analogs, leukotriene D4 (LTD4) receptor antagonists, acetyl-CoA carboxylase (ACC) inhibitors, hexokinase (KHK) inhibitors, ileal bile acid transporter (IBAT) inhibitors, apoptosis signal-regulated kinase 1 (ASK1) inhibitors, or any combination thereof. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug, or a pharmaceutical composition thereof, and the additional therapeutic agent are administered sequentially as individual doses in any order.

[0021] This document also provides a method for regulating insulin levels in a patient requiring such regulation, the method comprising administering to the patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a mixture of stereoisomers, or a prodrug thereof, or a pharmaceutical composition thereof. In some embodiments, the regulation results in an increase in insulin levels.

[0022] This document also provides a method for regulating glucose levels in patients requiring such regulation, the method comprising administering to the patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a mixture of stereoisomers, or a prodrug thereof, or a pharmaceutical composition thereof. In some embodiments, the regulation results in a decrease in glucose levels.

[0023] This article also provides methods for treating GLP-1-related diseases, disorders, or conditions, the methods comprising administering to a patient in need an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer thereof, a mixture of stereoisomers thereof, or a prodrug thereof, or a pharmaceutical composition thereof. In some implementations, 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), juvenile-onset atypical diabetes (YOAD), adolescent-onset adult-onset diabetes (MODY), latent autoimmune diabetes in adults (LADA), obesity, weight gain due to the use of other medications, gout, excessive sugar consumption, 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 artery 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, and pulmonary hypertension. Restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, essential polydipsia, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof.In some implementations, the disease, disorder, or condition is selected from type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar consumption, 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 artery disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis. Diseases, 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, essential 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 implementations, the diseases, disorders, or conditions include, but are not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar consumption, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat deposition, myocardial infarction, peripheral artery disease, stroke, transient ischemic attack, hyperglycemia, postprandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, chronic renal failure, syndrome X, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, skin and connective tissue disorders, foot ulcers, or any combination thereof.

[0024] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference as if each individual publication, patent, or patent application were explicitly and individually indicated to be incorporated by reference. Where a publication, patent, or patent application incorporated by reference contradicts the disclosure included in this specification, this specification is intended to supersede and / or give precedence to any such contradictory material. Detailed Implementation

[0025] Before describing the compounds and methods of this disclosure, it should be understood that this 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 terminology used herein is intended to describe embodiments of this disclosure and is in no way intended to limit the scope of this disclosure as set forth in the appended claims.

[0026] This article provides heterocyclic GLP-1 agonists for the management of type 2 diabetes mellitus (T2DM) and other conditions, in which activation of GLP-1 activity is useful.

[0027] Before describing the compounds and methods of this disclosure, it should be understood that this 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 terminology used herein is intended to describe embodiments of this disclosure and is in no way intended to limit the scope of this disclosure as set forth in the appended claims. definition

[0028] The following description illustrates exemplary embodiments of the present invention. However, it should be understood that this description is not intended to limit the scope of this disclosure, but is provided as a description of exemplary embodiments.

[0029] As used in this specification, the following words, phrases and symbols are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0030] A dash ("-") not located between two letters or symbols is used to indicate the attachment point of a substituent. For example, -C(O)NH2 is attached via a carbon atom. A dash at the beginning or end of a chemical group is for convenience; a chemical group may be depicted with or without one or more dashes without losing its ordinary meaning. A wavy or dashed line drawn in the structure indicates a designated attachment point of the group. Unless chemically or structurally required, the order in which chemical groups are written or named does not indicate or imply directionality or stereochemistry.

[0031] prefix "C" u-v This indicates that the subsequent group has u to v carbon atoms. For example, "C 1-6 "alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0032] The reference to "about" in this document includes (and describes) embodiments relating to that value or parameter itself. In some embodiments, the term "about" includes the indicated amount ± 10%. In other embodiments, the term "about" includes the indicated amount ± 5%. In some still embodiments, the term "about" includes the indicated amount ± 1%. Furthermore, the term "about X" includes a description of "X". Additionally, unless the context clearly specifies otherwise, the singular forms "an" and "the" include plural indicators. Thus, for example, reference to "the compound" includes multiple such compounds, and reference to "the assay" includes reference to one or more assays known to those skilled in the art and their equivalents.

[0033] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl groups have 1 to 20 carbon atoms (i.e., C64-C ... 1-20 Alkyl groups, 1 to 12 carbon atoms (i.e., C464) 1-12 Alkyl groups, 1 to 8 carbon atoms (i.e., C464-C ... 1-8 Alkyl groups, 1 to 6 carbon atoms (i.e., C646) 1-6 Alkyl groups or 1 to 4 carbon atoms (i.e., C46) 1-4 Alkyl groups. Examples of alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue with a specific number of carbons is named by its chemical name or identified by its molecular formula, it can encompass all positional isomers having that number of carbons; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -(CH2)3CH3), and tert-butyl (i.e., -(CH2)3CH3). -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2) and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0034] "Alkenyl" refers to an alkyl group that contains at least one (e.g., 1-3 or 1) carbon-carbon double bond and has from 2 to 20 carbon atoms (i.e., C36, C46, ​​C56, C6 ... 2-20 alkenyl), 2 to 12 carbon atoms (i.e., C 2-12 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 Alkenyl) or 2 to 4 carbon atoms (i.e., C) 2-4 Alkenyl). Examples of alkenyl groups include, for example, vinyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0035] "Alkynyl" refers to an alkyl group that contains at least one (e.g., 1-3 or 1) carbon-carbon triple bond and has 2 to 20 carbon atoms (i.e., C360, C46, ​​C56, C6 ... 2-20 alkynyl group), 2 to 12 carbon atoms (i.e., C 2-12 acetylsyl), 2 to 8 carbon atoms (i.e., C 2-8 acetylsyl), 2 to 6 carbon atoms (i.e., C 2-6 (alkynyl group) or 2 to 4 carbon atoms (i.e., C46) 2-4 (Alkynyl group). The term "alkynyl group" also includes those groups that have one triple bond and one double bond.

[0036] Some commonly used alternative chemical names can be used. For example, divalent groups (such as divalent "alkyl", divalent "aryl", etc.) can also be called "alkylene" groups (or "alkylenyl" groups) and "arylene" groups (or "arylenyl" groups), respectively.

[0037] "Alkoxy" refers to the "alkyl-O-" group. Examples of alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0038] "Thioalkoxy" refers to the "alkyl-S-" group.

[0039] "Haloalkyl" refers to an unbranched or branched alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen. For example, when a residue is substituted by more than one halogen, it can be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted by two ("di") or three ("tri") halogen groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl groups include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0040] "Haloalkoxy" refers to an alkoxy group as defined above, in which one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by halogens.

[0041] "Hydroxyalkyl" refers to an alkyl group as defined above, in which one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by hydroxyl groups.

[0042] "Cyanoalkyl" means an alkyl group as defined above, in which one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by hydroxyl groups.

[0043] "Alkylthio" refers to the "alkyl-S-" group.

[0044] "Acyl" refers to the group -C(O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted, as defined herein. Examples of acyl groups include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0045] "Amide group" refers to the "C-amide group" (which refers to the group -C(O)NR). y R z) and "N-amide" group (which refers to the -NR group) y C(O)R z ), where R y and R z Independently, it is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted, or R y and R z Together they form cycloalkyl or heterocyclic groups; each of which may optionally be substituted, as defined herein.

[0046] "Amino" refers to the -NR group. y R z , where R y and R z Independently, it is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein.

[0047] "Amino group" refers to -C(NR) y (NR) z 2), where R y and R z Independently, it is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein.

[0048] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl groups have 6 to 20 ring carbon atoms (i.e., C646-C ... 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C 6-10 Aryl groups. Examples of aryl groups include, for example, phenyl, naphthyl, fluorenyl, and anthracene. However, aryl groups do not in any way encompass or overlap with heteroaryl groups as defined below. If one or more aryl groups are fused with a heteroaryl group, the resulting ring system is a heteroaryl, regardless of the attachment point. If one or more aryl groups are fused with a heterocyclic group, the resulting ring system is a heterocyclic, regardless of the attachment point. If one or more aryl groups are fused with a cycloalkyl group, the resulting ring system is a cycloalkyl, regardless of the attachment point.

[0049] "Carbamoyl" refers to the "O-carbamoyl" group, which is -OC(O)NR y R z Group; and "N-carbamoyl" group, which refers to -NR y C(O)OR z Group, wherein Ry and R z Independently, it is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein.

[0050] "Carboxylic ester" or "ester" refers to -OC(O)R x and -C(O)OR x Of the two, R x It is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein.

[0051] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single or multiple rings, including fused, bridged, and spirocyclic systems. The term "cycloalkyl" includes cycloalkenyl (i.e., a cyclic group having at least one double bond) and cycloalkenyl (a cyclic group having at least one sp). 3 A carbon-cyclic fused-ring system (i.e., at least one non-aromatic ring). As used herein, cycloalkyl groups have 3 to 20 ring carbon atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 3-20 cycloalkyl groups), 3 to 14 cyclic carbon atoms (i.e., C 3-12 cycloalkyl groups), 3 to 12 cyclic carbon atoms (i.e., C12+ ... 3-12 cycloalkyl groups), 3 to 10 cyclic carbon atoms (i.e., C146 ... 3-10 cycloalkyl groups), 3 to 8 cyclic carbon atoms (i.e., C1646-C ... 3-8 cycloalkyl groups), 3 to 6 cyclic carbon atoms (i.e., C164 ...646464 3-6 Cycloalkyl. Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Furthermore, the term cycloalkyl is intended to include any non-aromatic ring that can fused with an aryl ring, regardless of its attachment to the rest of the molecule. In addition, when having two substitution positions on the same carbon atom, cycloalkyl also includes "spirocycloalkyl", such as spiro[2.5]octyl, spiro[4.5]decyl, or spiro[5.5]undecyl.

[0052] "Imine" refers to the group -C(NR) y )R z , where R y and R z Each is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein.

[0053] "Halogen" or "halogen group" refers to an atom that occupies Group VIIA of the periodic table, such as fluorine, chlorine, bromine, or iodine.

[0054] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are each independently replaced by the same or different heteroatom groups. The term "heteroalkyl" includes unbranched saturated chains or branched saturated chains having carbon atoms and heteroatoms. For example, one, two, or three carbon atoms may be independently replaced by the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O)2-, etc., where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclic, each of which may be optionally substituted. Examples of heteroalkyl groups include -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NRCH3, and -CH2NRCH3, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. As used herein, heteroalkyl groups include 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0055] "Hybrid alkylene" refers to a divalent heteroalkyl group. The "heteroalkylene" group must have at least one carbon atom and at least one heteroatom group within the chain. The term "heteroalkylene" includes unbranched saturated chains or branched saturated chains having carbon atoms and heteroatoms. For example, one, two, or three carbon atoms can be independently replaced by the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR. y -, -O-, -S-, -S(O)-, -S(O)2-, etc., among which R y It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein. Examples of heteroalkylene groups include, for example, -CH2OCH2-, -CH(CH3)OCH2-, -CH2CH2OCH2-, -OCH2-, -CH(CH3)O-, -CH2CH2O-, -CH2CH2OCH2CH2OCH2-, -CH2CH2OCH2CH2O-, -CH2SCH2-, -CH(CH3)SCH2-, -CH2CH2SCH2-, -CH2CH2SCH2CH2SCH2-, -SCH2-, -CH(CH3)S-, -CH2CH2S-, -CH2CH2SCH2CH2S-, -CH2S(O)2CH2-, -CH(CH3)S(O)2CH2-, -CH2CH2S(O)2CH2-, -CH2CH2S(O)2CH2CH2OCH2-, -CH2NR y CH2-、-CH(CH3)NRy CH2-、-CH2CH2NR y CH2-、-CH2CH2NR y CH2CH2NR y CH2- etc., where R y It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein. As used herein, a heteroalkylene comprises 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. As used herein, the term "heteroalkylene" does not include groups such as amides or other functional groups having an oxo group on one or more carbon atoms.

[0056] "Heteroaryl" refers to an aromatic group having a single ring or multiple fused rings, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl groups comprise 1 to 20 ring carbon atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 1-20 (heteroaryl), 3 to 12 cyclic carbon atoms (i.e., C 3-12 (heteroaryl) or 3 to 8 carbon ring atoms (i.e., C 3-8The heteroaryl group comprises 1 to 5 cyclic heteroatoms, 1 to 4 cyclic heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatomium, wherein the cyclic heteroatoms are independently selected from nitrogen, oxygen, and sulfur. In some cases, the heteroaryl group comprises a 5-10 membered ring system, a 5-7 membered ring system, or a 5-6 membered ring system, each independently having 1 to 4 cyclic heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatomium, wherein the cyclic heteroatoms are independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinel, benzimidazolyl, benzothiazolyl, benzoindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzooxazolyl, benzothiophenel, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolel, cenolinyl, dibenzofuranyl, dibenzothiaphenel, furanyl, isothiazolyl, imidazolyl, indazolel, indolyl, indazolel, isothiazolyl, imidazolyl, indazolel, and isothiazolyl. Indolyl, isoquinolinyl, isoxazolyl, naphridinyl, oxadiazolyl, oxazolyl, 1-pyridinyl oxide, 1-pyrimidinyl oxide, 1-pyrazinyl oxide, 1-pyridazinyl oxide, phenazinyl, phthalazinyl, pteridinyl, purine, pyrroleyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxolinyl, quinolinyl, quininecycloyl, isoquinolinyl, thiazolyl, thiadiazolyl, thiophene, triazolyl, tetrazolyl, and triazinyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophene, inzolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, wherein the heteroaryl group can be linked via any ring of the fused system. Any aromatic ring having a single or multiple fused rings containing at least one heteroatom is considered a heteroaryl, regardless of its attachment to the rest of the molecule (i.e., through any one of the fused rings). A heteroaryl does not encompass or overlap with aryl groups as defined above.

[0057] "Heterocyclic group" refers to a saturated or partially unsaturated cyclic alkyl group, wherein one or more cyclic heteroatoms are independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclic group" includes heterocyclic alkenyl groups (i.e., heterocyclic groups having at least one double bond), bridged heterocyclic groups, fused heterocyclic groups, and spirocyclic groups. Heterocyclic groups can be a single ring or multiple rings, wherein the multiple rings can be fused, bridged, or spirocyclic, and can contain one or more (e.g., 1 to 3) oxo groups (=O) or N-oxides (-O). -The term "heterocyclic group" refers to any non-aromatic ring or fused ring system containing at least one heteroatom and one non-aromatic ring, regardless of its attachment to the rest of the molecule. For example, fused ring systems such as decahydroquinazoline, 1,2,3,4-tetrahydroquinazoline, and 5,6,7,8-tetrahydroquinazoline are heterocyclic groups regardless of their attachment (i.e., they can be bonded by carbon atoms or heteroatoms). Furthermore, the term "heterocyclic group" is intended to cover any non-aromatic ring containing at least one heteroatom, which may be fused to a cycloalkyl, aryl, or heteroaryl ring, regardless of its attachment to the rest of the molecule. As used herein, heterocyclic groups have 2 to 20 ring carbon atoms (i.e., C64 ... 2-20 Heterocyclic group), 2 to 12 ring carbon atoms (i.e., C 2-12 Heterocyclic group), 2 to 10 ring carbon atoms (i.e., C 2-10 Heterocyclic group), 2 to 8 ring carbon atoms (i.e., C 2-8 Heterocyclic group), 3 to 12 ring carbon atoms (i.e., C 3-12 Heterocyclic group), 3 to 8 ring carbon atoms (i.e., C 3-8 Heterocyclic group), or 3 to 6 ring carbon atoms (i.e., C 3-6Heterocyclic groups); having 1 to 5 cyclic heteroatoms, 1 to 4 cyclic heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatomide, wherein the cyclic heteroatoms are independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclic groups include, for example, azirrocyclobutyl, azirrocycloheptatrienyl, benzodioxane-pentenyl, benzo[b][1,4]dioxane-heptatrienyl, 1,4-benzodioxyl, benzopyranyl, benzodioxinyl, benzopyranoneyl, benzofuranoneyl, dioxopentyl, dihydropyranyl, hydropyranyl, thiophene[1,3]dithiaalkyl, decahydroisoquinolinyl, furanoneyl, imidazolinyl, imidazolinyl, indololinyl, indolazinyl, isoindololinyl, isothiazolyl, isoxazolinyl Azoalkyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidylyl, oxazolyl, ethylene oxide, oxacyclobutyl, phenothiazinyl, phenothiazinyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolylyl, pyrazolyl, quininecycloyl, thiazoalkyl, tetrahydrofuranyl, tetrahydropyranyl, trithiaalkyl, tetrahydroquinolinyl, thiomorpholinyl, thio-morpholinyl, 1-oxo-thiomorpholinyl combined with 1,1-dioxo-thiomorpholinyl. In cases where there are two substitution positions on the same carbon atom, the term "heterocyclic group" also includes "spiroheterocyclic group". Examples of spiroheterocyclic rings include, for example, bicyclic and tricyclic ring systems, such as oxabicyclo[2.2.2]octyl, 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl, and 6-oxa-1-azaspiro[3.3]heptyl. Examples of fused heterocyclic rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridyl, indololinyl, and isoindolinyl, wherein the heterocyclic group can be linked via any ring of the fused system. The term "heterocyclic group" also includes rings containing a sulfonylimide moiety, such as, but not limited to, 3,4-dihydro-1λ 6 2-Thiazine 1-oxide, 1λ 6 2-Thiazine 1-oxide, 4,5-dihydro-3H-1λ 6 -isothiazol 1-oxide, 1-(imino)tetrahydro-1H-1λ 6 -Thiophene 1-oxide, 4,5-dihydro-3H-1λ 6 , 2-thiazozin 1-oxide, etc. See, for example, Cram et al., J. Org. Chem., 1973, 38(1), 20-26.

[0058] "Sulfonyl" refers to the group -S(O)2R y , where R yIt is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein. Examples of sulfonyl groups are methanesulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0059] "alkylsulfonyl" refers to the group -S(O)2R, where R is an alkyl group.

[0060] "alkyl sulfinyl" refers to the group -S(O)R, where R is an alkyl group.

[0061] The terms “optional” or “optionally” mean that the event or condition described below may or may not occur, and the description includes both scenarios in which the event or condition occurs and scenarios in which the event or condition does not occur. Furthermore, the term “optionally substituted” means that any one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms on a specified atom or group may or may not be substituted with any of the components other than hydrogen.

[0062] As used herein, the term "compound" means any or all stereoisomers, geometric isomers, tautomers, and isotopically enriched analogs (e.g., deuterated analogs) that include the structure described. Unless otherwise stated, compounds identified herein as a particular tautomer form by name or structure are intended to include other tautomer forms.

[0063] Some compounds exist as tautomers. These tautomers exist in equilibrium with each other. For example, compounds containing amides can exist in equilibrium with imine tautomers. Regardless of which tautomer is exhibited, and regardless of the equilibrium nature between the tautomers, those skilled in the art will understand that the compound comprises both amide and imine tautomers. Therefore, compounds containing amides should be understood to include their imine tautomers. Similarly, compounds containing imines should be understood to include their amide tautomers.

[0064] Any compound or structure described herein is also intended to represent both the unlabeled and isotopically labeled forms of the compound. These forms of the compound may also be referred to as “isotopically enriched analogs.” Isotopically labeled compounds have the structures described herein, except that one or more atoms are replaced by atoms having selected atomic masses or mass numbers. Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as… 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 36 Cl、 123 I and 125 I. Various isotopically labeled compounds, such as those doped with radioactive isotopes, are disclosed herein. 3 H and 14 Compounds containing C. These isotope-labeled compounds can be used in metabolic studies, reaction kinetic studies, detection or imaging techniques (such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or basal tissue distribution assays), or in the treatment of patients with radiotherapy.

[0065] The term “isotope-enriched analogues” includes “deuterated analogues” of the compounds described herein, wherein one or more hydrogen atoms are replaced by deuterium (such as hydrogen on a carbon atom). These compounds exhibit increased metabolic resistance and are therefore used to increase the half-life of any compound when administered to mammals, particularly humans. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0066] The deuterium-labeled or substituted therapeutic compounds disclosed herein may have improved DMPK (drug metabolism and pharmacokinetics) properties, involving distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope such as deuterium may provide certain therapeutic advantages due to its greater metabolic stability, such as prolonged in vivo half-life, reduced dose requirement, and / or improved therapeutic index. 18 F, 3 H, 11 C-labeled compounds can be used for PET, SPECT, or other imaging studies. The isotopically labeled compounds and their prodrugs of this disclosure can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents, by implementing the procedures disclosed in the schemes described below or in the examples and preparations. It should be understood that, in this context, deuterium is considered a substituent in the compounds described herein.

[0067] The concentration of such heavier isotopes (particularly deuterium) can be defined by the isotope enrichment factor. In the compounds of this disclosure, any atom not explicitly designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as “H” or “hydrogen,” the position should be understood as hydrogen having its naturally occurring isotopic composition. Therefore, in the compounds of this disclosure, any atom specifically designated as deuterium (D) is intended to represent deuterium.

[0068] In many cases, the compounds of this disclosure are capable of forming acidic and / or basic salts due to the presence of amino and / or carboxyl groups or similar groups.

[0069] Pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms, and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human use.

[0070] The term "pharmaceutically acceptable salt" for a given compound refers to a salt that retains the biological efficacy and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salt" or "physiologically acceptable salt" includes, for example, salts formed with inorganic acids and salts formed with organic acids. Furthermore, if the compound described herein is obtained as an acid addition salt, the free base can be obtained by alkalizing a solution of the acidic salt. Conversely, if the product is a free base, the addition salt (particularly pharmaceutically acceptable addition salts) can be produced by dissolving the free base in a suitable organic solvent and treating said solution with an acid, following conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize the various synthetic methods that can be used to prepare non-toxic, pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. 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, and salicylic acid. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. For example, salts derived from inorganic bases include sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of NH3 or primary, secondary, and tertiary amines, such as those derived from N-containing heterocycles, N-containing heteroaryl groups, or those derived from the formula N(R) N )3 amine salts (e.g., HN) + (R N )3 or (alkyl)N + (RN )3), where each R N Independently, it is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, each of which is optionally substituted, such as by one or more (e.g., 1-5 or 1-3) substituents (e.g., halo, cyano, hydroxyl, amino, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, or haloalkoxy). Specific examples of suitable amines, by way of example only, include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, etc.

[0071] The term "substitution" means that any one or more hydrogen atoms on a specified atom or group are replaced by one or more substituents that are not hydrogen, provided that the substitution does not exceed the normal valence of the specified atom. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amide, amidyl, aryl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, guanidinyl, halogen, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclic, hydroxyl, hydrazine, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thion, or combinations thereof. In some embodiments, the one or more substituents include, but are not limited to, alkyl, alkenyl, alkoxy, alkoxyalkyl, acyl, amino, amide, amidyl, aryl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanidinyl, halogen, haloalkyl, hydroxyalkyl, haloalkoxy, haloalkoxyalkyl, heteroalkyl, heteroaryl, heterocyclic, hydroxy, hydrazine, imino, imino, oxo, nitro, sulfinyl, sulfonic acid, sulfonyl, thiocyanate, thiol, thion, or combinations thereof.

[0072] Polymers or similar indeterminate structures obtained by defining substituents with an unlimited number of additional substituents (e.g., substituted aryl groups with substituted alkyl groups, where the substituted alkyl group itself is substituted by a substituted aryl group, the substituted aryl group is further substituted by a substituted heteroalkyl group, etc.) are not intended to be included herein. Unless otherwise stated, the maximum number of successive substitutions in the compounds described herein is three. For example, the successive substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl) substituted aryl) substituted aryl. Similarly, the above definitions are not intended to include disallowed substitution patterns (e.g., methyl groups substituted with five fluorine atoms or heteroaryl groups having two adjacent oxygen ring atoms). Such disallowed substitution patterns are well known to those skilled in the art. When used to modify chemical groups, the term "substituted" may describe other chemical groups as defined herein. Unless otherwise stated, in cases where a group is described as optionally substituted, any substituents in that group are themselves unsubstituted. For example, in some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents, including hydroxyl, halogen, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups. In other embodiments, the one or more substituents may be further substituted with a halogen, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl group, each of which is substituted. In other embodiments, the substituents may be further substituted with a halogen, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group, each of which is unsubstituted.

[0073] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutical acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delay agents. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or reagent is incompatible with the active ingredient, its use in a therapeutic composition should be considered. Complementary active ingredients may also be incorporated into the composition.

[0074] "Solvates" are formed through the interaction between a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0075] 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, pyridinone, pyrrole, pyrazole, oxazole, thiazole, isoxazole, isothiazole, etc. When a ring system containing at least two rings is described as “aromatic,” it means that the ring system contains one or more aromatic rings. Therefore, when a ring system containing at least two rings is described as “non-aromatic,” the constituent rings of the ring system are not aromatic.

[0076] As used herein, when a ring is described as “partially unsaturated,” it means that the ring has one or more additional degrees of unsaturation (in addition to the unsaturation attributable to the ring itself; for example, one or more double bonds between the constituent atoms of the ring), 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 containing at least two rings is described as “partially unsaturated,” it means that the ring system contains one or more partially unsaturated rings, provided that none of the constituent rings of the ring system are aromatic.

[0077] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the described structure. Unless otherwise stated, compounds identified herein as a particular tautomer form by name or structure are intended to include other tautomer forms.

[0078] As used herein, the term "tautomer" refers to a compound whose structure is significantly different in terms of atomic arrangement but exists in an easy and rapid equilibrium manner, and it should be understood that the compounds provided herein can be described as different tautomers, and when a compound has a tautomer form, all tautomer forms are intended to fall within the scope of this disclosure, and the naming of compounds does not exclude any tautomer.

[0079] 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, allotropes, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and their active fragments.

[0080] As used herein, the term “GLP-1-related disease” is intended to include, but is not limited to, all such diseases, disorders or conditions in which glucagon-like peptide-1 (GLP-1) receptor signaling modulates the pathology and / or symptoms and / or progression of the disease, disorder or condition.

[0081] As used herein, the term “GLP-1 agonist” or “GLP-1 RA” refers to an agonist of the glucagon-like peptide-1 (GLP-1) receptor. GLP-1 RAs enhance glucose-dependent insulin secretion; suppress inappropriately elevated glucagon levels in both fasting and postprandial states; and slow 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-April; 20(2): 254-267. GLP-1 RAs have been shown to be effective in treating type 2 diabetes. Examples of GLP-1 RAs include, but are not limited to, abiglutide (Tanzeum®), duraglutide (LY2189265, Trulicity®), efpeglenatide, exenatide (Byetta®, Bydureon®, Exendin-4), liraglutide (Victoza®, NN2211), lixumia®, smegglutide (Ozempic®), tirzepatide, ZP2929, NNC0113-0987, BPI-3016, and TT401.

[0082] As used herein, the term “pharmaceutical acceptable” indicates that a compound or its salt or composition is chemically and / or toxicologically compatible with other components constituting the formulation and / or with the subject being treated therein.

[0083] The term "administration" or "administering" refers to the method of administering a given dose of a compound or pharmaceutical composition to a vertebrate or invertebrate (including mammals, birds, fish, or amphibians). The method of administration can vary depending on various factors, such as the components of the pharmaceutical composition, the site of the disease, and the severity of the disease.

[0084] As used herein, the terms “effective amount” or “effective dose” or “pharmaceutically effective amount” or “therapeutic effective amount” refer to a sufficient amount of a chemical entity (e.g., a compound of formula I or a pharmaceutically acceptable salt or solvate thereof) applied, said amount of the chemical entity to provide relief to one or more symptoms of the disease or condition being treated, and may include curing the disease. “Cure” means the elimination of symptoms of an active disease. Results include a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired alteration of 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. An appropriate “effective” amount in any single case is determined using any suitable technique, such as dose escalation studies. In some embodiments, a “therapeutic effective amount” of a compound as provided herein refers to the amount of a compound that is effective as a monotherapy or combination therapy.

[0085] The term "excipient" or "pharmaceuticalally acceptable excipient" means a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulation material. In some embodiments, a component is "pharmaceuticalally acceptable" in the sense that it is compatible with other components of the pharmaceutical formulation and suitable for use in contact with human or animal tissues or organs without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, in proportion to a reasonable benefit / risk ratio. See, for example, Remington: The Science and Practice of Pharmacy, 21st edition; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th edition; edited by Rowe et al.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd edition; edited by Ash and Ash; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd edition; edited by Gibson; CRC Press LLC: Boca Raton, FL, 2009.

[0086] The term "pharmaceutical composition" refers to a compound of Formula I as provided herein, or a pharmaceutically acceptable salt or solvation thereof, mixed with other chemical components (collectively referred to herein as "excipients," such as carriers, stabilizers, diluents, dispersants, suspending agents, and / or thickeners). Pharmaceutical compositions facilitate the administration of compounds to a living organism. Various techniques for administering compounds exist in the art, including but not limited to rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0087] In the context of treating a disease, disorder, or symptom, the terms “treat,” “treating,” and “treatment” are intended to include relieving or eradicating a disorder, disease, or symptom, or one or more symptoms associated with said disorder, disease, or symptom; or slowing the progression, spread, or worsening of a disease, disorder, or symptom, or one or more symptoms thereof.

[0088] As used herein, the term “prevention” means the complete or partial prevention of the onset, recurrence, or spread of a disease or condition or its symptoms as described herein.

[0089] 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 term refers to a subject who desires or requires a diagnosis, prognosis, or therapy, particularly a mammalian subject. In some embodiments, the subject 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.

[0090] The terms “treatment regimen” and “dosing regimen” are used interchangeably to refer to the dosage and timing of administration of each therapeutic agent in a combination.

[0091] As used herein, the term "drug combination" refers to a pharmaceutical treatment resulting from a mixture or combination of more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients.

[0092] As used herein, the term “combination therapy” refers to a dosing regimen of two different therapeutic agents (i.e., combined components or combination couples) wherein the therapeutic agents are administered together or separately in a manner prescribed by a healthcare professional or in accordance with a regulatory body as defined herein.

[0093] As used herein, the term “modulate, modulating, or modulation” refers to regulation or adjustment (e.g., increasing or decreasing) and may include, for example, agonistic, partial agonistic, or antagonistic effects. compound

[0094] This article provides compounds of formula I: I Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein ring A, ring B, X, Z, Q 1 Q 2 Q 3 Q 4 Q 5 L 1 L 2 , q, m, s, R 1 and R C Each is independent as defined in this article.

[0095] This article provides compounds of formula I: I Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein: X is CR 2 And Z is N, or X is NR. 3 And Z is C; m and s are each independently 1, 2 or 3; q is 0, 1, 2, 3, or 4; Each R 1 It is independently hydrogen, halogen, cyano, or optionally surrounded by 1-6 groups independently selected from halogen, hydroxyl, and C. 1-6 alkoxy substituents of C 1-6 alkyl; Or any two R 1 Each of these is connected to a 4-8 membered ring to provide a fused, bridged, or spiroheterocyclic group comprising 4-11 carbon atoms and 1-3 heteroatoms, wherein the fused, bridged, or spiroheterocyclic group is optionally connected to 1-3 independently selected C atoms. 1-6 Alkyl substitution; R 2 and R 3 Each is independently hydrogen, a halogen group, a cyano group, or optionally surrounded by 1-6 independently selected halogen groups, hydroxyl groups, and C. 1-6 alkoxy substituents of C 1-6 alkyl; Q 1 and Q 5 Each is independently N or CR QA And Q 2 Q 3 and Q 4 Each is independent of N and CR QA or CRQB ;or Q 1 It is a key; and Q 2 Q 3 Q 4 and Q 5 Each is independently O, S, N, NR c CR QA or CR QB ; The condition is that it contains Q. 1 -Q 5 The ring is from the Aromatic tribe; Each R QA Independently, it is hydrogen, halogen, cyano, hydroxyl, -NR c R d C 3-6 cycloalkyl, optionally with 1-6 independently selected R f Replacement C 1-6 Alkyl groups or optionally surrounded by 1-6 groups, each independently selected from hydroxyl, halogen, and C. 1-6 alkoxy substituents of C 1-6 Alkoxy; Or two R atoms on adjacent carbon atoms QA Together with their respective attached atoms, they form a 5-8 membered heterocyclic group or a 5-6 membered heteroaryl group; wherein the 5-8 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally formed by 1-2 independently selected R groups. h replace; Each R QB Independently is -C(O)NR c R d -P(O)R 1a R 1b -C(R) i R j ) n -P(O)R 1a R 1b -S(O)2R 1a -C(R) i R j ) n -S(O)2R 1a -S(O)(=NR) 2a )R 2b -C(R) i R j ) n -S(O)(=NR 2a )R 2b -N=S(O)(R 3a )R 2b -O-(CR) i R j )n -S(O)(=NR 2a )R 2b Optionally selected by one or more independently chosen from C 1-6 Alkyl groups and -C(O)(C 1-6 3-12 membered heterocyclic groups substituted with alkyl groups, optionally with 1-3 independently selected -C(O)(C 1-6 alkyl) substituted C 6-10 aryl and optionally 1-6 independently selected R g Substituted 5-10 heteroaryl groups; n is 1, 2, 3, 4, 5, or 6; R 1a and R 1b Selected independently from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally surrounded by 1 to 6 hydroxyl groups, each independently selected from C10, C20, C30, C40, C50, C6 ... 1-6 Alkoxy, C 3-6 Substitution of cycloalkyl and halogen groups; C 3-6 cycloalkyl, the C 3-6 The cycloalkyl group is optionally composed of 1 to 3 independently selected from C10. 1-3 Substitution of alkyl and halogen groups; and C 6-10 Aryl, the C 6-10 The aryl group is optionally selected by 1-3 independently chosen C 1-3 Alkyl substitution; or R 1a and R 1b Together with the phosphorus atoms to which they are attached, they form a ring containing 5-8 ring atoms, except for those attached to R. 1a and R 1b Apart from phosphorus, 0-2 ring atoms are heteroatoms independently selected from O, S, and N, wherein the ring is optionally separated by 1-3 independently selected C atoms. 1-6 Alkyl substitution; R 2a It is hydrogen, cyano, optionally surrounded by 1-6 groups, each independently selected from halogen, oxo, C 1-6 Alkoxy, C 3-6 C substituents of cycloalkyl and heteroaryl groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected from C 1-3 Substituents of alkyl and halogen groups on C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C 1-3 Alkyl-substituted C 6-10 Aryl; R 2b It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C3-6 C substituents of cycloalkyl and halogen groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected from C 1-3 Substituents of alkyl and halogen groups on C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C 1-3 Alkyl-substituted C 6-10 Aryl; or R 2a and R 2b Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally separated by 1-3 independently selected carbon atoms. 1-6 Alkyl substitution; or R 2a or R 2b and adjacent R QA Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally separated by 1-2 independently selected R atoms. h replace; R 3a It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C substituents of cycloalkyl and halogen groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected from C 1-3 Substituents of alkyl and halogen groups on C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C 1-3 Alkyl-substituted C 6-10 Aryl; Each R i It can be hydrogen, halogen, or C independently. 1-6 alkyl; or R 2a and R i 、or R 2b and R i Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally separated by 1-3 independently selected carbon atoms. 1-6 Alkyl substitution; Each R j It can be hydrogen, halogen, or C independently. 1-6 alkyl; Or an R i And an R j Together with one or more atoms attached to each of them, they form C 3-6 cycloalkyl groups, wherein the cycloalkyl group is optionally composed of 1-3 independently selected C atoms. 1-6 Alkyl substitution; L 2 R is arbitrarily selected by 1-2 independent choicesh Replacement C 6-10 aryl, optionally selected by 1-2 independent R h Replaced 5-10 aryl groups, , , , or , where aa represents the combination with Q 1 -Q 5 The attachment point of the ring; n1 is 1, 2, or 3; L 2A Is it a key or C? 1-10 Alkylene; R La It is hydrogen, C 1-6 Alkyl or -C(O)C 1-6 alkyl; R Lb and R Lc Each of them is independently hydrogen or C. 1-6 alkyl; Ring A is C 6-10 Aryl, C 5-7 Cycloalkyl, 5-7-membered heterocyclic or 5-10-membered heteroaryl, each optionally consisting of 1-5 independently selected R groups. A replace; Each R A Independently, it is a halogen group, C 1-6 Alkyl, C 1-6 Haloalkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl; L 1 It is -C(O)-, -CH2-, -CH(C 1-6 Alkyl)- or -S(O)2-; Ring B is a phenyl group or a 5-6 fused heteroaryl group having 5 to 8 carbon atoms and 1 to 3 heteroatoms independently selected from O, S, and N; wherein ring B is optionally surrounded by 1 to 5 heteroatoms independently selected from R. 8 halogenated, oxo-substituted and C 1-6 Alkyl substituents; R 8 It is phenyl, 5-6 heteroaryl or The phenyl group or the 5-6 heteroaryl group is optionally R 8c Replace, and optionally further by 1-3 independently selected R h replace; L 3 Is it a key or C? 1-3 Alkylene; L 4 Is it a key or C? 1-5 Alkylene; R 8a and R 8b Each is independently hydrogen or optionally composed of one or more halogen groups and C. 3-15 Cycloalkyl substituents substituted C 1-6 Alkyl; or R 8a and R 8b Together with the carbon atoms to which they are attached, they form C atoms that are optionally selected by 1-3 independent groups. 1-6 Alkyl-substituted C 3-15 cycloalkyl rings; wherein C 1-6 Alkyl groups are optionally surrounded by 1-6 independently selected R groups. f replace; Each R 8c Independently, they are -C(O)OH, -S(O)2OH, -S(O)2NH2, -L 5 -C 1-6 Alkyl, -L 5 -C 3-6 cycloalkyl, -L 5 -C 6-10 Aryl, -L 5 -5-6 membered heterocyclic group, -L 5 -(5-6 heteroaryl groups), wherein each is optionally surrounded by 1-6 independently selected from hydroxyl, halogen, and C groups. 1-6 Substitution of alkoxy groups; Each L 5 Independently, they are -C(O)-, -C(O)O-, -OC(O)-, and -S(O). 1-2 -、-S(O)2O-、-S(O)2NH- or -NHS(O)2-; R 9 It is -C(O)OR 9a -C(O)NR 9a R 9b R can be arbitrarily selected by 1-3 independent choices. 9c Substituted 5-6 aryl groups, or ; X 1 Is it O or S? R 9a Is it hydrogen or C? 1-6 alkyl; R 9b It is hydrogen, C 1-6 Alkyl, -C(O)(C 1-6 Alkyl groups, -S(O) 0-2 (C1-6 Alkyl or cyano groups; Each R 9c Independently hydrogen, oxo group, optionally 1-6 independently selected halogen groups and C 1-6 alkoxy-substituted C 1-6 Alkyl, or -C(O)(C 1-6 alkyl); R C It is C 1-6 Alkyl or cyclic C, wherein C 1-6 The alkyl group is optionally surrounded by 1-3 independently selected from halogen, cyano, C... 1-6 Haloalkyl, C 1-6 Alkoxy and -NR c R d Substituents of the substituents; Cyclic C is a 3-12 membered heterocyclic group, C 3-15 Cycloalkyl or 5-10-membered heteroaryl groups, each optionally surrounded by 1-3 R groups. Ca replace; Each R Ca Independently, it is a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c R d ; Or a pair of R atoms on the same or different ring atoms Ca Together with one or more ring atoms to which each ring is attached, they form a carbon ring containing 3 to 8 ring atoms; Each R c and R d Each is independently hydrogen, C 1-6 Alkyl, -C(O)(C 1-6 Alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)O(C 1-6 Alkyl groups, -S(O) 1-2 (C 1-6 Alkyl group or -S(O) 1-2 (C 3-6 cycloalkyl), wherein C 1-6 Alkyl, -C(O)(C 1-6 Alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)O(C 1-6 Alkyl groups, -S(O) 1-2 (C 1-6 Alkyl groups and -S(O) 1-2 (C 3-6 Each of the cycloalkyl groups is optionally surrounded by 1-6 independently selected from hydroxyl, halogen, and C groups. 1-6Substitution of alkoxy groups; Each R f Independently, it is a halogen group, hydroxyl group, or -NR group. c R d C 1-6 Alkoxy, C 1-6 Haloalkoxy, or optionally surrounded by 1-4 groups, each independently selected from hydroxyl, C 1-6 3-12-membered heterocyclic groups substituted with alkyl groups and 3-12-membered heterocyclic groups; Each R g C is independent 1-6 Alkyl, C 1-6 Alkoxy, -NR c R d Or optionally selected by one or more independently chosen from C 1-6 Alkyl and C(O)C 1-6 Alkyl substituents of 3 to 12-membered heterocyclic groups; and Each R h Independently, it is a halogen group, cyano group, hydroxyl group, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups.

[0096] On the one hand, this article provides compounds of formula I: I Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein: X is CR 2 And Z is N, or X is NR. 3 And Z is C; m and s are each independently 1, 2 or 3; q is 0, 1, 2, 3, or 4; Each R 1 It is independently hydrogen, halogen, cyano, or optionally surrounded by 1-6 groups independently selected from halogen, hydroxyl, and C. 1-6 alkoxy substituents of C 1-6 alkyl; Or any two R 1 Each of these is connected to a 4-8 membered ring to provide a fused, bridged, or spiroheterocyclic group comprising 4-11 carbon atoms and 1-3 heteroatoms, wherein the fused, bridged, or spiroheterocyclic group is optionally connected to 1-3 independently selected C atoms. 1-6 Alkyl substitution; R2 and R 3 Each is independently hydrogen, a halogen group, a cyano group, or optionally surrounded by 1-6 independently selected halogen groups, hydroxyl groups, and C. 1-6 alkoxy substituents of C 1-6 alkyl; Q 1 and Q 5 Each is independently N or CR QA And Q 2 Q 3 and Q 4 Each is independent of N and CR QA or CR QB ;or Q 1 It is a key; and Q 2 Q 3 Q 4 and Q 5 Each is independently O, S, N, NR c CR QA or CR QB ; The condition is that it contains Q. 1 -Q 5 The ring is from the Aromatic tribe; Each R QA Independently, it is hydrogen, halogen, cyano, hydroxyl, -NR c R d C 3-6 cycloalkyl, optionally with 1-6 independently selected R f Replacement C 1-6 Alkyl groups or optionally surrounded by 1-6 groups, each independently selected from hydroxyl, halogen, and C. 1-6 alkoxy substituents of C 1-6 Alkoxy; Or two R atoms on adjacent carbon atoms QA Together with their respective attached atoms, they form a 5-8 membered heterocyclic group or a 5-6 membered heteroaryl group; wherein the 5-8 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally formed by 1-2 independently selected R groups. h replace; Each R QB Independently is -C(O)NR c R d -P(O)R 1a R 1b -C(R) i R j ) n -P(O)R 1a R 1b -S(O)2R 1a -C(R) i Rj ) n -S(O)2R 1a -S(O)(=NR) 2a )R 2b -C(R) i R j ) n -S(O)(=NR 2a )R 2b Optionally selected by one or more independently chosen from C 1-6 Alkyl groups and -C(O)(C 1-6 3-12 membered heterocyclic groups substituted with alkyl groups, optionally with 1-3 independently selected -C(O)(C 1-6 alkyl) substituted C 6-10 aryl, and optionally R, selected independently by 1-6 g Substituted 5-10 heteroaryl groups; n is 1, 2, 3, 4, 5, or 6; R 1a and R 1b Selected independently from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally surrounded by 1 to 6 hydroxyl groups, each independently selected from C10, C20, C30, C40, C50, C6 ... 1-6 Alkoxy, C 3-6 Substitution of cycloalkyl and halogen groups; C 3-6 cycloalkyl, the C 3-6 The cycloalkyl group is optionally composed of 1 to 3 independently selected from C10. 1-3 Substitution of alkyl and halogen groups; and C 6-10 Aryl, the C 6-10 The aryl group is optionally selected by 1-3 independently chosen C 1-3 Alkyl substitution; or R 1a and R 1b Together with the phosphorus atoms to which they are attached, they form a ring containing 5-8 ring atoms, except for those attached to R. 1a and R 1b Apart from phosphorus, 0-2 ring atoms are heteroatoms independently selected from O, S, and N, wherein the ring is optionally separated by 1-3 independently selected C atoms. 1-6 Alkyl substitution; R 2a It is hydrogen, cyano, optionally surrounded by 1-6 groups, each independently selected from halogen, oxo, C 1-6 Alkoxy, C 3-6 C substituents of cycloalkyl and heteroaryl groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected from C 1-3 Substituents of alkyl and halogen groups on C 3-6cycloalkyl, or optionally composed of 1-3 independently selected C 1-3 Alkyl-substituted C 6-10 Aryl; R 2b It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C substituents of cycloalkyl and halogen groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected from C 1-3 Substituents of alkyl and halogen groups on C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C 1-3 Alkyl-substituted C 6-10 Aryl; or R 2a and R 2b Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally separated by 1-3 independently selected carbon atoms. 1-6 Alkyl substitution; or R 2a or R 2b and adjacent R QA Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally separated by 1-2 independently selected R atoms. h replace; Each R i It can be hydrogen, halogen, or C independently. 1-6 alkyl; or R 2a and R i 、or R 2b and R i Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally separated by 1-3 independently selected carbon atoms. 1-6 Alkyl substitution; Each R j It can be hydrogen, halogen, or C independently. 1-6 alkyl; Or an R i And an R j Together with one or more atoms attached to each of them, they form C 3-6 cycloalkyl groups, wherein the cycloalkyl group is optionally composed of 1-3 independently selected C atoms. 1-6 Alkyl substitution; L 2 R is arbitrarily selected by 1-2 independent choices h Replacement C 6-10 aryl, optionally selected by 1-2 independent R h Replaced 5-10 aryl groups, , , , or , where aa represents the combination with Q 1 -Q 5 The attachment point of the ring; n1 is 1, 2, or 3; L 2A Is it a key or C? 1-10 Alkylene; R La It is hydrogen, C 1-6 Alkyl or -C(O)C 1-6 alkyl; R Lb and R Lc Each of them is independently hydrogen or C. 1-6 alkyl; Ring A is C 6-10 Aryl, C 5-7 Cycloalkyl, 5-7-membered heterocyclic or 5-10-membered heteroaryl, each optionally consisting of 1-5 independently selected R groups. A replace; Each R A Independently, it is a halogen group, C 1-6 Alkyl, C 1-6 Haloalkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl; L 1 It is -C(O)-, -CH2-, -CH(C 1-6 Alkyl)- or -S(O)2-; Ring B is a phenyl group or a 5-6 fused heteroaryl group having 5 to 8 carbon atoms and 1 to 3 heteroatoms independently selected from O, S, and N; wherein ring B is optionally surrounded by 1 to 5 heteroatoms independently selected from R. 8 halogenated, oxo-substituted and C 1-6 Alkyl substituents; R 8 It is phenyl, 5-6 heteroaryl or The phenyl group or the 5-6 heteroaryl group is optionally R 8c Replace, and optionally further by 1-3 independently selected R h replace; L 3 Is it a key or C? 1-3 Alkylene; L 4 Is it a key or C? 1-5 Alkylene; R 8a and R 8bEach is independently hydrogen or optionally composed of one or more halogen groups and C. 3-15 Cycloalkyl substituents substituted C 1-6 Alkyl; or R 8a and R 8b Together with the carbon atoms to which they are attached, they form C atoms that are optionally selected by 1-3 independent groups. 1-6 Alkyl-substituted C 3-15 cycloalkyl ring; wherein C 1-6 Alkyl groups are optionally surrounded by 1-6 independently selected R groups. f replace; Each R 8c Independently, they are -C(O)OH, -S(O)2OH, -S(O)2NH2, -L 5 -C 1-6 Alkyl, -L 5 -C 3-6 cycloalkyl, -L 5 -C 6-10 Aryl, -L 5 -5-6 membered heterocyclic group, -L 5 -(5-6 heteroaryl groups), wherein each is optionally surrounded by 1-6 independently selected from hydroxyl, halogen, and C groups. 1-6 Substitution of alkoxy groups; Each L 5 Independently, they are -C(O)-, -C(O)O-, -OC(O)-, and -S(O). 1-2 -、-S(O)2O-、-S(O)2NH- or -NHS(O)2-; R 9 It is -C(O)OR 9a -C(O)NR 9a R 9b R can be arbitrarily selected by 1-3 independent choices. 9c Substituted 5-6 aryl groups, or ; X 1 Is it O or S? R 9a Is it hydrogen or C? 1-6 alkyl; R 9b It is hydrogen, C 1-6 Alkyl, -C(O)(C 1-6 Alkyl groups, -S(O) 0-2 (C 1-6 Alkyl or cyano groups; Each R 9c Independently hydrogen, oxo group, optionally 1-6 independently selected halogen groups and C 1-6 alkoxy-substituted C 1-6Alkyl, or -C(O)(C 1-6 alkyl); R C It is C 1-6 Alkyl or cyclic C, wherein C 1-6 The alkyl group is optionally surrounded by 1-3 independently selected from halogen, cyano, C... 1-6 Haloalkyl, C 1-6 Alkoxy and -NR c R d Substituents of the substituents; Cyclic C is a 3-12 membered heterocyclic group, C 3-15 Cycloalkyl or 5-10-membered heteroaryl groups, each optionally surrounded by 1-3 R groups. Ca replace; Each R Ca Independently, it is a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c R d ; Or a pair of R atoms on the same or different ring atoms Ca Together with one or more ring atoms to which each ring is attached, they form a carbon ring containing 3 to 8 ring atoms; Each R c and R d Each is independently hydrogen, C 1-6 Alkyl, -C(O)(C 1-6 Alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)O(C 1-6 Alkyl groups, -S(O) 1-2 (C 1-6 Alkyl group or -S(O) 1-2 (C 3-6 cycloalkyl), wherein C 1-6 Alkyl, -C(O)(C 1-6 Alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)O(C 1-6 Alkyl groups, -S(O) 1-2 (C 1-6 Alkyl groups and -S(O) 1-2 (C 3-6 Each of the cycloalkyl groups is optionally surrounded by 1-6 independently selected from hydroxyl, halogen, and C groups. 1-6 Substitution of alkoxy groups; Each R f Independently, it is a halogen group, hydroxyl group, or -NR group. c R d C 1-6 Alkoxy, C 1-6Haloalkoxy, or optionally surrounded by 1-4 groups, each independently selected from hydroxyl, C 1-6 3-12-membered heterocyclic groups substituted with alkyl groups and 3-12-membered heterocyclic groups; Each R g C is independent 1-6 Alkyl, C 1-6 Alkoxy, -NR c R d Or optionally selected by one or more independently chosen from C 1-6 Alkyl and C(O)C 1-6 Alkyl substituents of 3 to 12-membered heterocyclic groups; and Each R h Independently, it is a halogen group, cyano group, hydroxyl group, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups.

[0097] In some implementation schemes, R C It is optionally composed of 1-3 independently selected groups: halogen, cyano, C 1-6 Haloalkyl, C 1-6 Alkoxy and -NR c R d The substituents of C 1-6 alkyl.

[0098] In some implementation schemes, R C It is C 1-6 Alkyl group. In some embodiments, R C It is a methyl group.

[0099] In some embodiments, compounds of formula II are provided herein: II Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein ring A, ring B, ring C, X, Z, Q 1 Q 2 Q 3 Q 4 Q 5 L 1 L 2 q, m, s and R 1 Each is independent as defined in this article.

[0100] On the one hand, this article provides compounds of formula II: II Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein: X is CR 2 And Z is N, or X is NR. 3 And Z is C; m and s are each independently 1, 2 or 3; q is 0, 1, 2, 3, or 4; Each R 1 It is independently hydrogen, halogen, cyano, or optionally surrounded by 1-6 groups independently selected from halogen, hydroxyl, and C. 1-6 alkoxy substituents of C 1-6 alkyl; Or any two R 1 Each of these is connected to a 4-8 membered ring to provide a fused, bridged, or spiroheterocyclic group comprising 4-11 carbon atoms and 1-3 heteroatoms, wherein the fused, bridged, or spiroheterocyclic group is optionally connected to 1-3 independently selected C atoms. 1-6 Alkyl substitution; R 2 and R 3 Each is independently hydrogen, a halogen group, a cyano group, or optionally surrounded by 1-6 independently selected halogen groups, hydroxyl groups, and C. 1-6 alkoxy substituents of C 1-6 alkyl; Q 1 and Q 5 Each is independently N or CR QA And Q 2 Q 3 and Q 4 Each is independent of N and CR QA or CR QB ;or Q 1 It is a key; and Q 2 Q 3 Q 4 and Q 5 Each is independently O, S, N, NR c CR QA or CR QB ; The condition is that it contains Q. 1 -Q 5 The ring is from the Aromatic tribe; Each R QA Independently, it is hydrogen, halogen, cyano, hydroxyl, -NR c R d C 3-6 cycloalkyl, optionally with 1-6 independently selected R fReplacement C 1-6 Alkyl groups or optionally surrounded by 1-6 groups, each independently selected from hydroxyl, halogen, and C. 1-6 alkoxy substituents of C 1-6 Alkoxy; Or two R atoms on adjacent carbon atoms QA Together with their respective attached atoms, they form a 5-8 membered heterocyclic group or a 5-6 membered heteroaryl group; wherein the 5-8 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally formed by 1-2 independently selected R groups. h replace; Each R QB Independently is -C(O)NR c R d -P(O)R 1a R 1b -C(R) i R j ) n -P(O)R 1a R 1b -S(O)2R 1a -C(R) i R j ) n -S(O)2R 1a -S(O)(=NR) 2a )R 2b -C(R) i R j ) n -S(O)(=NR 2a )R 2b Optionally selected by one or more independently chosen from C 1-6 Alkyl groups and -C(O)(C 1-6 3-12 membered heterocyclic groups substituted with alkyl groups, optionally with 1-3 independently selected -C(O)(C 1-6 alkyl) substituted C 6-10 aryl, and optionally R, selected independently by 1-6 g Substituted 5-10 heteroaryl groups; n is 1, 2, 3, 4, 5, or 6; R 1a and R 1b Selected independently from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally surrounded by 1 to 6 hydroxyl groups, each independently selected from C10, C20, C30, C40, C50, C6 ... 1-6 Alkoxy, C 3-6 Substitution of cycloalkyl and halogen groups; C 3-6 cycloalkyl, the C 3-6 The cycloalkyl group is optionally composed of 1 to 3 independently selected from C10. 1-3Substitution of alkyl and halogen groups; and C 6-10 Aryl, the C 6-10 The aryl group is optionally selected by 1-3 independently chosen C 1-3 Alkyl substitution; or R 1a and R 1b Together with the phosphorus atoms to which they are attached, they form a ring containing 5-8 ring atoms, except for those attached to R. 1a and R 1b Apart from phosphorus, 0-2 ring atoms are heteroatoms independently selected from O, S, and N, wherein the ring is optionally separated by 1-3 independently selected C atoms. 1-6 Alkyl substitution; R 2a It is hydrogen, cyano, optionally surrounded by 1-6 groups, each independently selected from halogen, oxo, C 1-6 Alkoxy, C 3-6 C substituents of cycloalkyl and heteroaryl groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected from C 1-3 Substituents of alkyl and halogen groups on C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C 1-3 Alkyl-substituted C 6-10 Aryl; R 2b It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C substituents of cycloalkyl and halogen groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected from C 1-3 Substituents of alkyl and halogen groups on C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C 1-3 Alkyl-substituted C 6-10 Aryl; or R 2a and R 2b Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally separated by 1-3 independently selected carbon atoms. 1-6 Alkyl substitution; or R 2a or R 2b and adjacent R QA Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally separated by 1-2 independently selected R atoms. h replace; Each R i It can be hydrogen, halogen, or C independently. 1-6 alkyl; or R 2aand R i 、or R 2b and R i Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally separated by 1-3 independently selected carbon atoms. 1-6 Alkyl substitution; Each R j It can be hydrogen, halogen, or C independently. 1-6 alkyl; Or an R i And an R j Together with one or more atoms attached to each of them, they form C 3-6 cycloalkyl groups, wherein the cycloalkyl group is optionally composed of 1-3 independently selected C atoms. 1-6 Alkyl substitution; L 2 R is arbitrarily selected by 1-2 independent choices h Replacement C 6-10 aryl, optionally selected by 1-2 independent R h Replaced 5-10 aryl groups, , , , or , where aa represents the combination with Q 1 -Q 5 The attachment point of the ring; n1 is 1, 2, or 3; L 2A Is it a key or C? 1-10 Alkylene; R La It is hydrogen, C 1-6 Alkyl or -C(O)C 1-6 alkyl; R Lb and R Lc Each of them is independently hydrogen or C. 1-6 alkyl; Ring A is C 6-10 Aryl, C 5-7 Cycloalkyl, 5-7-membered heterocyclic or 5-10-membered heteroaryl, each optionally consisting of 1-5 independently selected R groups. A replace; Each R A Independently, it is a halogen group, C 1-6 Alkyl, C 1-6 Haloalkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl; L 1It is -C(O)-, -CH2-, -CH(C 1-6 Alkyl)- or -S(O)2-; Ring B is a phenyl group or a 5-6 fused heteroaryl group having 5 to 8 carbon atoms and 1 to 3 heteroatoms independently selected from O, S, and N; wherein ring B is optionally surrounded by 1 to 5 heteroatoms independently selected from R. 8 halogenated, oxo-substituted and C 1-6 Alkyl substituents; R 8 It is phenyl, 5-6 heteroaryl or The phenyl group or the 5-6 heteroaryl group is optionally R 8c Replace, and optionally further by 1-3 independently selected R h replace; L 3 Is it a key or C? 1-3 Alkylene; L 4 Is it a key or C? 1-5 Alkylene; R 8a and R 8b Each is independently hydrogen or optionally composed of one or more halogen groups and C. 3-15 Cycloalkyl substituents substituted C 1-6 Alkyl; or R 8a and R 8b Together with the carbon atoms to which they are attached, they form C atoms that are optionally selected by 1-3 independent groups. 1-6 Alkyl-substituted C 3-15 cycloalkyl rings; wherein C 1-6 Alkyl groups are optionally surrounded by 1-6 independently selected R groups. f replace; Each R 8c Independently, they are -C(O)OH, -S(O)2OH, -S(O)2NH2, -L 5 -C 1-6 Alkyl, -L 5 -C 3-6 cycloalkyl, -L 5 -C 6-10 Aryl, -L 5 -5-6 membered heterocyclic group, -L 5 -(5-6 heteroaryl groups), wherein each is optionally surrounded by 1-6 independently selected from hydroxyl, halogen, and C groups. 1-6 Substitution of alkoxy groups; Each L 5 Independently, they are -C(O)-, -C(O)O-, -OC(O)-, and -S(O). 1-2-、-S(O)2O-、-S(O)2NH- or -NHS(O)2-; R 9 It is -C(O)OR 9a -C(O)NR 9a R 9b R can be arbitrarily selected by 1-3 independent choices. 9c Substituted 5-6 aryl groups, or ; X 1 Is it O or S? R 9a Is it hydrogen or C? 1-6 alkyl; R 9b It is hydrogen, C 1-6 Alkyl, -C(O)(C 1-6 Alkyl groups, -S(O) 0-2 (C 1-6 Alkyl or cyano groups; Each R 9c Independently hydrogen, oxo group, optionally 1-6 independently selected halogen groups and C 1-6 alkoxy-substituted C 1-6 Alkyl, or -C(O)(C 1-6 alkyl); Cyclic C is a 3-12 membered heterocyclic group, C 3-15 Cycloalkyl or 5-10-membered heteroaryl groups, each optionally surrounded by 1-3 R groups. Ca replace; Each R Ca Independently, it is a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c R d ; Or a pair of R atoms on the same or different ring atoms Ca Together with one or more ring atoms to which each ring is attached, they form a carbon ring containing 3 to 8 ring atoms; Each R c and R d Each is independently hydrogen, C 1-6 Alkyl, -C(O)(C 1-6 Alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)O(C 1-6 Alkyl groups, -S(O) 1-2 (C 1-6 Alkyl group or -S(O) 1-2 (C 3-6 cycloalkyl), wherein C 1-6 Alkyl, -C(O)(C1-6 Alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)O(C 1-6 Alkyl groups, -S(O) 1-2 (C 1-6 Alkyl groups and -S(O) 1-2 (C 3-6 Each of the cycloalkyl groups is optionally surrounded by 1-6 independently selected from hydroxyl, halogen, and C groups. 1-6 Substitution of alkoxy groups; Each R f Independently, it is a halogen group, hydroxyl group, or -NR group. c R d C 1-6 Alkoxy, C 1-6 Haloalkoxy, or optionally surrounded by 1-4 groups, each independently selected from hydroxyl, C 1-6 3-12-membered heterocyclic groups substituted with alkyl groups and 3-12-membered heterocyclic groups; Each R g C is independent 1-6 Alkyl, C 1-6 Alkoxy, -NR c R d Or optionally selected by one or more independently chosen from C 1-6 Alkyl and C(O)C 1-6 Alkyl substituents of 3 to 12-membered heterocyclic groups; and Each R h Independently, it is a halogen group, cyano group, hydroxyl group, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups.

[0101] In some implementations, m is 1. In some implementations, m is 2. In some implementations, m is 3.

[0102] In some implementations, s is 1. In some implementations, s is 2. In some implementations, s is 3.

[0103] In some implementations, m is 1; and s is 1. In some implementations, m is 1; and s is 2. In some implementations, m is 1; and s is 3.

[0104] In some implementations, m is 2; and s is 1. In some implementations, m is 2; and s is 2. In some implementations, m is 2; and s is 3.

[0105] In some implementations, m is 3; and s is 1. In some implementations, m is 3; and s is 2. In some implementations, m is 3; and s is 3.

[0106] In some implementations, m+s is 2. In some implementations, m+s is 3. In some implementations, m+s is 4. In some implementations, m+s is 5. In some implementations, m+s is 6. In some implementations, m+s is 2, 3, or 4.

[0107] In some embodiments, compounds of formula IIA are provided herein: IIA Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein ring A, ring B, ring C, or ring Q 1 Q 2 Q 3 Q 4 Q 5 L 1 L 2 , q, R 1 and R 2 Each is independent as defined in this article.

[0108] In some embodiments, compounds of formula IIB are provided herein: IIB Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein ring A, ring B, ring C, or ring Q 1 Q 2 Q 3 Q 4 Q 5 L 2 q, R1 and R 2 Each is independent as defined in this article.

[0109] In some implementation schemes, Q 1 It is N. In some implementations, Q 1 It is N; and Q 2 Q 3 Q 4 and Q 5 Each is independent of N and CR QA or CR QB .

[0110] In some implementation schemes, Q 1 It is CR QA or CR QBIn some implementations, Q 1 It is CR QA And Q 2 Q 3 Q 4 and Q 5 Each is independent of N and CR QA or CR QB .

[0111] In some implementation schemes, Q 1 It is CR QA In some implementations, Q 1 It is CR QA And Q 2 Q 3 Q 4 and Q 5 Each is independent of N and CR QA or CR QB .

[0112] In some implementation schemes, Q 1 It is CR QB In some implementations, Q 1 It is CR QB And Q 2 Q 3 Q 4 and Q 5 Each is independently N or CR QA .

[0113] In some implementation schemes, Q 2 It is N. In some implementations, Q 2 It is N; and Q 1 Q 3 Q 4 and Q 5 Each is independent of N and CR QA or CR QB .

[0114] In some implementation schemes, Q 2 It is CR QA or CR QB In some implementations, Q 2 It is CR QA And Q 1 Q 3 Q 4 and Q 5 Each is independent of N and CR QA or CR QB .

[0115] In some implementation schemes, Q 2 It is CRQA In some implementations, Q 2 It is CR QA And Q 1 Q 3 Q 4 and Q 5 Each is independent of N and CR QA or CR QB .

[0116] In some implementation schemes, Q 2 It is CR QB In some implementations, Q 2 It is CR QB And Q 1 Q 3 Q 4 and Q 5 Each is independently N or CR QA .

[0117] In some implementation schemes, Q 3 It is N. In some implementations, Q 3 It is N; and Q 1 Q 2 Q 4 and Q 5 Each is independent of N and CR QA or CR QB .

[0118] In some implementation schemes, Q 3 It is CR QA or CR QB In some implementations, Q 3 It is CR QA And Q 1 Q 2 Q 4 and Q 5 Each is independent of N and CR QA or CR QB .

[0119] In some implementation schemes, Q 3 It is CR QA In some implementations, Q 3 It is CR QA And Q 1 Q 2 Q 4 and Q 5 Each is independent of N and CR QA or CR QB .

[0120] In some implementation schemes, Q 3It is CR QB In some implementations, Q 3 It is CR QB And Q 1 Q 2 Q 4 and Q 5 Each is independently N or CR QA .

[0121] In some implementation schemes, Q 4 It is N. In some implementations, Q 4 It is N; and Q 1 Q 2 Q 3 and Q 5 Each is independent of N and CR QA or CR QB .

[0122] In some implementation schemes, Q 4 It is CR QA or CR QB In some implementations, Q 4 It is CR QA And Q 1 Q 2 Q 3 and Q 5 Each is independent of N and CR QA or CR QB .

[0123] In some implementation schemes, Q 4 It is CR QA In some implementations, Q 4 It is CR QA And Q 1 Q 2 Q 3 and Q 5 Each is independent of N and CR QA or CR QB .

[0124] In some implementation schemes, Q 4 It is CR QB In some implementations, Q 4 It is CR QB And Q 1 Q 2 Q 3 and Q 5 Each is independently N or CR QA .

[0125] In some implementation schemes, Q 5It is N. In some implementations, Q 5 It is N; and Q 1 Q 2 Q 3 and Q 4 Each is independent of N and CR QA or CR QB .

[0126] In some implementation schemes, Q 5 It is CR QA or CR QB In some implementations, Q 5 It is CR QA And Q 1 Q 2 Q 3 and Q 4 Each is independent of N and CR QA or CR QB .

[0127] In some implementation schemes, Q 5 It is CR QA In some implementations, Q 5 It is CR QA And Q 1 Q 2 Q 3 and Q 4 Each is independent of N and CR QA or CR QB .

[0128] In some implementation schemes, Q 5 It is CR QB In some implementations, Q 5 It is CR QB And Q 1 Q 2 Q 3 and Q 4 Each is independently N or CR QA .

[0129] In some implementation schemes, Q 1 and Q 5 Each is independently N or CR QA And Q 2 Q 3 and Q 4 Each is independent of N and CR QA or CR QB .

[0130] In some implementation schemes, Q 1 and Q 5 Each is CR independentlyQA .

[0131] In some implementation schemes, Q 1 and Q 5 Each is CR independently QA And Q 2 Q 3 and Q 4 Each is independent of N and CR QA or CR QB .

[0132] In some implementation schemes, Q 2 Q 3 and Q 4 One of them is CR QB .

[0133] In some implementation schemes, Q 1 and Q 5 Each is independently N or CR QA And Q 2 and Q 4 Each is independently N or CR QA And Q 3 It is CR QA or CR QB .

[0134] In some implementation schemes, Q 1 and Q 5 Each is CR independently QA And Q 2 and Q 4 Each is independently N or CR QA And Q 3 It is CR QA or CR QB .

[0135] In some implementation schemes, Q 1 and Q 5 Each is CR independently QA And Q 2 Q 3 and Q 4 Each is independent of N and CR QA or CR QB Q 2 Q 3 and Q 4 One of them is CR QB .

[0136] In some implementation schemes, Q 1 and Q 5 Each is independently N or CR QA And Q2 and Q 4 Each is independently N or CR QA And Q 3 It is CR QB .

[0137] In some implementations, each R QA Independently, it is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or -NR c R d .

[0138] In some implementations, each R QA Independently, it is hydrogen, halogen, C 1-6 Alkoxy, -NR c R d Or optionally selected by 1-6 independently chosen R f Replacement C 1-6 Alkyl group. In some embodiments, each R QA Independently, it is hydrogen, halogen, C 1-6 Alkoxy, -NR c R d Or C 1-6 Alkyl group. In some embodiments, each R QA It is independently hydrogen, halogroup, methyl group, or ethyl group. In some embodiments, each R... QA It is hydrogen.

[0139] In some implementation schemes, R c and R d Each is independently either hydrogen or C. 1-6 Alkyl group. In some embodiments, R c and R d Each is either hydrogen or methyl.

[0140] In some implementation schemes, Q 1 and Q 5 Each is CR independently QA ; where each R QA It can be hydrogen or a halogen group independently. In some embodiments, Q 1 and Q 5 Each is independently CH or CF.

[0141] In some implementation schemes, Q 2 Q 3 and Q 4 One of them is N.

[0142] In some implementation schemes, part yes , , or .

[0143] In some implementation schemes, part yes .

[0144] In some implementation schemes, part yes .

[0145] In some implementation schemes, part yes .

[0146] In some implementation schemes, part yes .

[0147] In some implementation schemes, part yes .

[0148] In some implementation schemes, part yes .

[0149] In some implementation schemes, part yes .

[0150] In some implementation schemes, part yes , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0151] In some implementation schemes, part yes .

[0152] In some implementation schemes, part yes , , , , , , or .

[0153] In some implementation schemes, Q 2 Q 3 and Q 4 One of them is CR QB .

[0154] In some implementation schemes, part yes .

[0155] In some implementation schemes, R QB It is -P(=O)R 1a R 1b .

[0156] In some implementation schemes, R 1a and R 1b Each is C independently 1-6 alkyl.

[0157] In some implementation schemes, R QB It is -S(O)(=NR) 2a )R 2b .

[0158] In some implementation schemes, R QB It is -C(R) i R j ) n -S(O)(=NR 2a )R 2b .

[0159] In some implementation schemes, R QB It is -S(O)(=NR) 2a )R 2b or -C 1-6 Alkyl-S(O)(=NR) 2a )R 2b .

[0160] In some implementation schemes, R QB It is -C 1-6 Alkyl-S(O)(=NR) 2a )R 2b .

[0161] In some implementation schemes, R QB It is -S(O)(=NR) 2a )R 2b or -CH2-S(O)(=NR 2a )R 2b .

[0162] In some implementation schemes, R QB It is -CH2-S(O)(=NR) 2a )R 2b .

[0163] In some implementation schemes, R 2a It is hydrogen, cyano, or optionally surrounded by 1-6 groups, each independently selected from a halogen group, an oxo group, a C group, or a cyano group. 1-6 Alkoxy, C 3-6 C substituents of cycloalkyl and heteroaryl groups 1-6 alkyl.

[0164] In some implementation schemes, R 2b It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C substituents of cycloalkyl and halogen groups 1-6 Alkyl, or C 3-6 Cycloalkyl.

[0165] In some implementation schemes, R 2a and R 2b Together with their respective attached atoms, they form 5-8 membered heterocyclic groups. In some embodiments, R 2a and R 2b Together with the atoms to which they are attached, they form a 5-membered heterocyclic group.

[0166] In some implementations, L 2 R is arbitrarily selected by 1-2 independent choices h Replacement C 6-10 aryl, optionally selected by 1-2 independent R hReplaced 5-10 aryl groups, or ; where aa represents the combination with Q 1 -Q 5 The attachment point of the ring.

[0167] In some implementations, L 2 R is arbitrarily selected by 1-2 independent choices h Replacement C 6-10 Aryl, or Where aa represents the combination with Q. 1 -Q 5 The attachment point of the ring.

[0168] In some implementations, L 2 R is arbitrarily selected by 1-2 independent choices h Replacement C 6-10 Aryl.

[0169] In some implementations, L 2 R is arbitrarily selected by 1-2 independent choices h Substituted 5-10 heteroaryl groups.

[0170] In some implementations, L 2 yes or ; where aa represents the combination with Q 1 -Q 5 The attachment point of the ring.

[0171] In some implementations, L 2 yes ; where aa represents the combination with Q 1 -Q 5 The attachment point of the ring.

[0172] In some implementations, L 2 yes ; where aa represents the combination with Q 1 -Q 5 The attachment point of the ring.

[0173] In some implementations, L 2A It is a key.

[0174] In some implementation schemes, R 1 It is hydrogen. In some implementations, R 1 It is C 1-6 Alkyl group. In some embodiments, q is 1; and R 1 It is either hydrogen or methyl.

[0175] In some implementations, X is CR2 And Z is N.

[0176] In some implementation schemes, R 2 It is hydrogen.

[0177] In some implementation schemes, R 1 and R 2 Each is hydrogen.

[0178] In some implementations, X is NR 3 And Z is C.

[0179] In some implementation schemes, R 3 Is it hydrogen or C? 1-6 Alkyl group. In some embodiments, R 3 It is hydrogen. In some implementations, R 3 It is C 1-6 Alkyl group. In some embodiments, R 3 It is hydrogen or methyl. In some embodiments, R 3 It is a methyl group.

[0180] In some implementations, L 1 It is -C(O)-. In some implementations, L 1 It is -CH2-. In some implementations, L 1 It is -CH(C) 1-6 Alkyl)-. In some embodiments, L 1 It is -CH(CH3)-. In some implementations, L 1 It is -S(O)2-.

[0181] In some implementations, ring A is optionally composed of 1-5 independently selected R... A Replacement C 6-10 Aryl.

[0182] In some implementations, ring A is optionally composed of 1-5 independently selected R... A Replacement C 5-7 Cycloalkyl.

[0183] In some implementations, ring A is optionally composed of 1-5 independently selected R... A Substituted 5-7 membered heterocyclic groups.

[0184] In some implementations, ring A is optionally composed of 1-5 independently selected R... A Substituted 5-10 heteroaryl groups.

[0185] In some implementations, each R A Independently, it is a halogen group, C 1-6 Alkyl or C 3-6Cycloalkyl.

[0186] In some implementations, ring A is optionally composed of 1-5 independently selected halogen groups, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-6 Cycloalkyl substituents substituted C 6-10 Aryl.

[0187] In some implementations, ring A is optionally composed of 1-3 independently selected halogen groups, C 1-6 Alkyl group, -S(O)2C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 A phenyl group substituted with a cycloalkyl substituent.

[0188] In some embodiments, ring B is a 5,6-fused heteroaryl group having 5 to 8 carbon atoms and 1 to 3 heteroatoms independently selected from O, S, and N, wherein ring B is optionally surrounded by 1 to 5 heteroatoms independently selected from R 8 halogenated, oxo-substituted and C 1-6 Alkyl substituents; and the 5-membered ring of the 5,6-fused heteroaryl group is associated with L... 1 Bonding. In some embodiments, ring B is a 5,6-fused heteroaryl group having 5 to 8 carbon atoms and 1 to 3 heteroatoms independently selected from O, S, and N, wherein ring B is optionally bonded by 1 to 5 heteroatoms independently selected from R. 8 halogenated, oxo-substituted and C 1-6 Alkyl substituents; 5,6-fused heteroaryl 5-membered ring with L 1 Bonding; and the ring C is bonded to the 6-membered ring of the 5,6-fused heteroaryl group.

[0189] In some embodiments, cyclic B is a 5,6-fused heteroaryl group having 5 to 8 carbon atoms and 1 to 3 heteroatoms independently selected from O, S, and N, wherein cyclic B is bounded by R 8 The group is substituted and optionally replaced by one to four independently selected from halogen groups, oxo groups, and C groups. 1-6 Alkyl substituents; and the 5-membered ring of the 5,6-fused heteroaryl group is associated with L... 1 Bonding. In some embodiments, ring B is a 5,6-fused heteroaryl group having 5 to 8 carbon atoms and 1 to 3 heteroatoms independently selected from O, S, and N, wherein ring B is bonded by R 8 The group is substituted and optionally replaced by one to four independently selected from halogen groups, oxo groups, and C groups. 1-6 Alkyl substituents; 5,6-fused heteroaryl 5-membered ring with L 1 Bonding; and the ring C is bonded to the 6-membered ring of the 5,6-fused heteroaryl group.

[0190] In some implementation schemes, ring B is: , , , , , , , , , , , , , , , , , , , or ; Where bb represents L 1 Attachment point; R 4 R 5 R 6 and R 7 Each is independently hydrogen, halogen, or C. 1-6 alkyl; R 8 It is phenyl, 5-6 heteroaryl or In which the phenyl or 5-6 heteroaryl group is R 8c Replace, and optionally further by 1-3 independently selected R h replace; L 3 Is it a key or C? 1-3 Alkylene; L 4 Is it a key or C? 1-5 Alkylene; R 8a and R 8b Each is independently hydrogen or optionally composed of one or more halogen groups and C. 3-15 Cycloalkyl substituents substituted C 1-6 Alkyl; or R 8a and R 8b Together with the carbon atoms to which they are attached, they form C atoms that are optionally selected by 1-3 independent groups. 1-6 Alkyl-substituted C 3-15 cycloalkyl ring; wherein C 1-6 Alkyl groups are optionally surrounded by 1-6 independently selected R groups. f replace; Each R 8c Independently, they are -C(O)OH, -S(O)2OH, -S(O)2NH2, -L5 -C 1-6 Alkyl, -L 5 -C 3-6 cycloalkyl, -L 5 -C 6-10 Aryl, -L 5 -5-6 membered heterocyclic group, -L 5 -(5-6 heteroaryl groups), wherein each is optionally surrounded by 1-6 independently selected from hydroxyl, halogen, and C groups. 1-6 Substitution of alkoxy groups; Each L 5 Independently, they are -C(O)-, -C(O)O-, -OC(O)-, and -S(O). 1-2 -、-S(O)2O-、-S(O)2NH- or -NHS(O)2-; R 9 It is -C(O)OR 9a -C(O)NR 9a R 9b R can be arbitrarily selected by 1-3 independent choices. 9c Substituted 5-6 aryl groups, or ; X 1 Is it O or S? R 9a Is it hydrogen or C? 1-6 alkyl; R 9b It is hydrogen, C 1-6 Alkyl, -C(O)(C 1-6 Alkyl groups, -S(O) 0-2 (C 1-6 Alkyl or cyano groups; Each R 9c Independently hydrogen, oxo group, optionally 1-6 independently selected halogen groups and C 1-6 alkoxy-substituted C 1-6 Alkyl, or -C(O)(C 1-6 alkyl).

[0191] In some implementation schemes, ring B is: , , , , , , , , , , , , , , , , , , or ; Where bb represents L 1 Attachment point; R 4 R 5 R 6 and R 7 Each is independently hydrogen, halogen, or C. 1-6 alkyl; R 8 It is phenyl, 5-6 heteroaryl or In which the phenyl or 5-6 heteroaryl group is R 8c Replace, and optionally further by 1-3 independently selected R h replace; L 3 Is it a key or C? 1-3 Alkylene; L 4 Is it a key or C? 1-5 Alkylene; R 8a and R 8b Each is independently hydrogen or optionally composed of one or more halogen groups and C. 3-15 Cycloalkyl substituents substituted C 1-6 Alkyl; or R 8a and R 8b Together with the carbon atoms to which they are attached, they form C atoms that are optionally selected by 1-3 independent groups. 1-6 Alkyl-substituted C 3-15 cycloalkyl ring; wherein C 1-6 Alkyl groups are optionally surrounded by 1-6 independently selected R groups. f replace; Each R 8c Independently, they are -C(O)OH, -S(O)2OH, -S(O)2NH2, -L 5 -C 1-6 Alkyl, -L 5 -C 3-6 cycloalkyl, -L 5 -C 6-10 Aryl, -L 5 -5-6 membered heterocyclic group, -L 5 -(5-6 heteroaryl groups), wherein each is optionally surrounded by 1-6 independently selected from hydroxyl, halogen, and C groups. 1-6 Substitution of alkoxy groups; Each L 5Independently, they are -C(O)-, -C(O)O-, -OC(O)-, and -S(O). 1-2 -、-S(O)2O-、-S(O)2NH- or -NHS(O)2-; R 9 It is -C(O)OR 9a -C(O)NR 9a R 9b R can be arbitrarily selected by 1-3 independent choices. 9c Substituted 5-6 aryl groups, or ; X 1 Is it O or S? R 9a Is it hydrogen or C? 1-6 alkyl; R 9b It is hydrogen, C 1-6 Alkyl, -C(O)(C 1-6 Alkyl groups, -S(O) 0-2 (C 1-6 Alkyl or cyano groups; Each R 9c Independently hydrogen, oxo group, optionally 1-6 independently selected halogen groups and C 1-6 alkoxy-substituted C 1-6 Alkyl, or -C(O)(C 1-6 alkyl).

[0192] In some implementation schemes, ring B is ; where bb represents the relationship with L 1 Attachment point.

[0193] In some implementation schemes, ring B is ; where bb represents the relationship with L 1 Attachment point.

[0194] In some implementation schemes, ring B is ; where bb represents the relationship with L 1 Attachment point.

[0195] In some implementation schemes, ring B is ; where bb represents the relationship with L 1 Attachment point.

[0196] In some implementation schemes, ring B is , where bb represents L 1 Attachment point.

[0197] In some implementation schemes, ring B is ; where bb represents the relationship with L 1 Attachment point.

[0198] In some implementation schemes, ring B is ; where bb represents the relationship with L 1 Attachment point.

[0199] In some implementation schemes, ring B is ; where bb represents the relationship with L 1 Attachment point.

[0200] In some implementation schemes, ring B is: or ; where bb represents the relationship with L 1 Attachment point.

[0201] In some implementation schemes, R 8 It was R 8c Substituted phenyl, R 8c Substituted 5-6 aryl groups, or .

[0202] In some implementation schemes, R 8 It was R 8c Substituted phenyl groups.

[0203] In some implementation schemes, R 8 It was R 8c Substituted 5-6 membered heteroaryl groups. In some embodiments, R 8 It was R 8c Substituted pyridinyl group. In some embodiments, R 8 It was R 8c Substituted phenyl or R 8c Substituted pyridinyl group.

[0204] In some implementation schemes, R 8 yes .

[0205] In some implementation schemes, ring B is: , , , , , , or ; where bb represents the relationship with L 1 Attachment point.

[0206] In some implementation schemes, ring B is: or ; where bb represents the relationship with L 1 Attachment point.

[0207] In some implementation schemes, ring B is , where bb represents L 1 Attachment point.

[0208] In some implementation schemes, ring B is , where bb represents L 1 Attachment point.

[0209] In some implementation schemes, R 4 It is hydrogen. In some implementations, R 4 It is hydrogen or a halogen group.

[0210] In some implementation schemes, R 4 R 5 R 6 and R 7 Each is hydrogen.

[0211] In some implementation schemes, R 5 R 6 and R 7 Each is hydrogen.

[0212] In some implementations, q is 0.

[0213] In some implementations, L 3 It is a key.

[0214] In some implementations, L 4 It is a key.

[0215] In some implementations, L 3 It is a key and L 4 It is a key.

[0216] In some implementations, compounds of formula IIC are provided herein: IIC Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein p is 0, 1, 2, 3, 4, or 5; and the ring C, Q 2 Q 3 L 4 R A R 8a R 8b R 9 and R QA Each is independent as defined in this article.

[0217] In some implementation schemes, R 8a and R 8b Each is hydrogen on its own.

[0218] In some implementation schemes, R 8a and R 8b Together with the carbon atoms to which they are attached, they form a group that is optionally C 1-6 Alkyl-substituted C 3-15 Cycloalkyl ring. In some embodiments, R 8a and R 8b Together with the carbon atoms to which they are attached, they form C atoms that are optionally substituted with methyl groups. 3-15 Cycloalkyl rings.

[0219] In some implementation schemes, R 9 R is arbitrarily selected by 1-3 independent choices 9c Substituted 5-6 aryl groups, or In some implementations, R 9 R is arbitrarily selected by 1-3 independent choices 9c Substituted 5-6 membered heteroaryl groups. In some embodiments, R 9 yes .

[0220] In some implementation schemes, R 9 It is a 6-membered heteroaryl group.

[0221] In some implementation schemes, R 9 yes or In some implementations, R 9 yes .

[0222] In some implementations, ring C is optionally surrounded by 1-3 R Ca The 3-12 membered heterocyclic group is replaced. In some embodiments, the ring C is optionally replaced by 1-3 R groups. Ca Substituted 6-membered heterocyclic group.

[0223] In some implementations, each R Ca It is C 1-6 Alkyl group. In some embodiments, each R Ca It is a methyl group.

[0224] In some implementations, ring C is , , , , or .

[0225] In some implementations, ring C is or In some implementations, ring C is... In some implementations, ring C is... .

[0226] In some implementations, ring C is or .

[0227] In some implementations, ring C is or .

[0228] In some implementations, compounds of formula IID are provided herein: IID Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein p is 0, 1, 2, 3, 4, or 5; v is 0, 1, 2, or 3; and each R Ca R 8a R 8b R 9 R A Q 1 Q 2 and R QA Independently as defined in this article.

[0229] In some implementations, v is 0 or 2.

[0230] In some implementation schemes, Q 2 It is N. In some implementations, Q 2 It is CR QA or CR QB In some implementations, Q 2 It is CR QA .

[0231] In some implementation schemes, Q 3 It is N. In some implementations, Q 3 It is CR QA or CR QB In some implementations, Q 3 It is CR QA In some implementations, Q 3 It is CR QB .

[0232] In some implementations, each R QA Independently, it is hydrogen, halogen, or -NH(C) 1-6 Alkyl), C 1-6 Alkyl or C 1-6 Alkyl groups. In some embodiments, each R QA It can be hydrogen, fluorine, chlorine, -NHCH3, methyl, isopropyl, or -OCH3 independently.

[0233] In some implementation schemes, R 8a and R 8b Each is hydrogen on its own.

[0234] In some implementation schemes, R 8a and R 8b Together with the carbon atoms to which they are attached, they form a group that is optionally C 1-6 Alkyl-substituted C 3-15 Cycloalkyl ring. In some embodiments, R 8a and R 8b Together with the carbon atoms to which they are attached, they form C atoms that are optionally substituted with methyl groups. 3-15 Cycloalkyl rings.

[0235] In some embodiments, a compound selected from Table 1 or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug is provided: Table 1

[0236] In some embodiments, a compound selected from Table 2, or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug is provided: Table 2

[0237] Compounds of Formula I include their pharmaceutically acceptable salts. Additionally, compounds of Formula I include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts and can be used as intermediates for the preparation and / or purification of compounds of Formula I and / or the isolation of enantiomers of compounds of Formula I. Non-limiting examples of pharmaceutically acceptable salts of compounds of Formula I include trifluoroacetate salts.

[0238] It should be further understood that compounds of Formula I or their salts can be isolated as solvates, and accordingly, any such solvates are included within the scope of this disclosure. For example, compounds of Formula I and their salts can exist in non-solventized forms as well as in solvated forms formed with pharmaceutically acceptable solvents such as water, ethanol, etc. Pharmaceutical composition and administration

[0239] When used as a medicine, compounds as described herein (e.g., compounds of Formula I or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs) can be administered in the form of pharmaceutical compositions. These compositions can be prepared in ways well known in the pharmaceutical field and can be administered via a variety of routes, depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (including transdermal, epidermal, ocular, and mucous membrane delivery, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or blowing of powders or aerosols, including via nebulizers; intratracheal or intranasal), oral, or parenteral. Oral administration can include formulations for once-daily or twice-daily (BID) administration. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, injection, or infusion; or intracranial, such as intrathecal or intraventricular administration. Parenteral administration can be in the form of a single bolus dose or can be, for example, via a continuous infusion pump. Pharmaceutical compositions and formulations for external application may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional drug carriers, aqueous bases, powder or oily bases, thickeners, etc., may be required or desired.

[0240] This document also provides pharmaceutical compositions comprising a compound of Formula I or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug as an active ingredient, combined with one or more pharmaceutically acceptable excipients (carriers). For example, pharmaceutical compositions prepared using a compound of Formula I or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug. In some embodiments, the composition is suitable for topical application. In manufacturing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted with the excipient, or encapsulated in a carrier, such as a capsule, sachet, paper, or other container. When the excipient is used as a diluent, it can be a solid, semi-solid, or liquid material that acts as a medium, carrier, or carrier of the active ingredient. Therefore, the composition can be in the form of tablets, pills, powders, lozenges, sachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid 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 tablets or capsules.

[0241] This document further provides pharmaceutical compositions comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer thereof, a mixture of stereoisomers thereof, or a prodrug thereof, and a pharmaceutically acceptable excipient. Pharmaceutical compositions comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer thereof, a mixture of stereoisomers thereof, or a prodrug thereof as an active ingredient can be prepared by thoroughly mixing a compound of Formula I or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer thereof, a mixture of stereoisomers thereof, or a prodrug thereof with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take many forms, depending on the desired route of administration (e.g., oral, parenteral). In some embodiments, the composition is a solid oral composition.

[0242] 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.

[0243] Methods for preparing pharmaceutical compositions have been described in numerous publications, such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1–3, edited by Lieberman et al.; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1–2, edited by Avis et al.; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1–2, edited by Lieberman et al.; published by Marcel Dekker, Inc.

[0244] In some embodiments, the compound or pharmaceutical composition may 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-tocopherol 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; buffering substances, such as phosphates, tris, glycine, sorbic acid, potassium sorbate; mixtures of saturated vegetable fatty acids in the form of glycerides; water, salts, or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride; zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; 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 hydroxyalkylcyclodextrins (including 2- and 3-hydroxypropyl-β-cyclodextrin) or other soluble derivatives can also be used to enhance the delivery of compounds as provided herein. Dosage forms or compositions containing 0.005% to 100% of the chemical entities described herein, with the remainder supplemented by non-toxic excipients, can be prepared. The compositions considered may contain 0.001% to 100%, 0.1% to 95% in one embodiment, 75% to 85% in another embodiment, and 20% to 80% in yet another embodiment of the chemical entities provided herein. Practical methods for preparing such dosage forms are known to or will be apparent to those skilled in the art; see, for example, Remington: The Science and Practice of Pharmacy, 22nd edition (Pharmaceutical Press, London, UK. 2012).

[0245] In some embodiments, the compounds and pharmaceutical compositions described herein, or pharmaceutical compositions thereof, may be administered to patients in need via any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, skin, intracervical, intranasal sinus, intratracheal, intraintestinal, epidural, interstitial, intraperitoneal, intraarterial, intrabronchial, intracystic, intracerebral, intracisary, intracoronary, intradermal, intracatheter, intraduodenal, intradural, intraepithelial, intraepithelial, intraesophageal, intragastric, intragingival, intraileum, intraileum, intraesophageal, intragastric, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinus, intraspinal, intrasynovial, intratestinal, intrasheath, intraduct, intratumoral, intrauterine, intravascular, intravenous, nasal (e.g., intranasal), nasogastric, oral, parenteral, percutaneous, transdural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, tracheal, ureteral, urethral, ​​and vaginal. In some implementations, the route of administration is parenteral (e.g., intratumoral).

[0246] In some embodiments, compounds of Formula I as described herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs, or pharmaceutical compositions thereof, can be formulated for parenteral administration, for example, for injection via intra-arterial, intrasternal, intracranial, intravenous, intramuscular, subcutaneous, or intraperitoneal routes. For example, such compositions can be prepared as injectable preparations, as liquid solutions or suspensions; they can also be prepared in solid forms suitable for preparing solutions or suspensions by adding liquid prior to injection; and the formulations can also be emulsified. The preparation of such formulations will be known to those skilled in the art in light of this disclosure. In some embodiments, parenteral administration is performed using a device. For example, such devices can include needle injectors, microneedle injectors, needle-free injectors, and infusion techniques.

[0247] In some embodiments, suitable pharmaceutical forms for injection include sterile aqueous solutions or dispersions; formulations containing sesame oil, peanut oil, or propylene glycol; and sterile powders for the ad hoc preparation of sterile injectable solutions or dispersions. In some embodiments, the form must be sterile and must be fluid in a manner that facilitates injection. In some embodiments, the form should be stable under manufacturing and storage conditions and must be preserved against contamination by microorganisms such as bacteria and fungi.

[0248] In some embodiments, the carrier may also be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. In some embodiments, suitable flowability can be maintained, for example, by using a coating (e.g., lecithin), in the case of a dispersion, by maintaining a desired particle size, and by using a surfactant. In some embodiments, the antimicrobial effect can be achieved by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.). In some embodiments, isotonic agents, such as sugars or sodium chloride, are included. In some embodiments, the absorption of the injectable composition can be prolonged by using agents that delay absorption (e.g., aluminum monostearate and gelatin) in the composition.

[0249] In some embodiments, a sterile injectable solution is prepared by incorporating a desired amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug into a suitable solvent having, as desired, a plurality of other components listed above, followed by filtration sterilization. In some embodiments, a dispersion is prepared by incorporating a plurality of sterile active ingredients into a sterile medium containing a base dispersion medium and desired other components from those listed above. In some embodiments, sterile powder is used to prepare the sterile injectable solution. In some embodiments, the preparation method is a vacuum drying and freeze-drying technique, which produces a powder of the active ingredient plus any other desired components from its previously sterile filtered solution.

[0250] In some embodiments, pharmacologically acceptable excipients that may 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: glyceryl cocoa butter, synthetic polymers (such as polyvinylpyrrolidone), PEG (such as PEG ointment), glycerin, glycerin-treated gelatin, hydrogenated vegetable oils, poloxamer, mixtures of polyethylene glycol and polyethylene glycol fatty acid esters of various molecular weights, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharin, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxidase, etc. SBN, vanilla essential oil, aerosols, parabens in phenoxyethanol, sodium methylparaben, sodium propylparaben, diethylamine, carbomer, carbopol, methylparaben, polyethylene glycol cetearyl ether, cocoylcaprylocaprate, isopropanol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metasulfite, sodium edetate, sodium benzoate, potassium metasulfite, grapefruit seed extract, methanesulfonylmethane (MSM), lactic acid, glycine, vitamins (such as vitamins A and E), and potassium acetate.

[0251] In some embodiments, suppositories can be prepared by mixing a compound of Formula I or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug, or a pharmaceutical composition as described herein, with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, 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, the composition for rectal administration is in the form of an enema.

[0252] In some embodiments, a compound of Formula I as described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, or a pharmaceutical composition thereof, is formulated for local delivery to the digestive or gastrointestinal (GI) tract by means of oral administration (e.g., solid or liquid dosage form).

[0253] In some implementations, solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug is 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 silica; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; e) solution blockers, such as paraffin; f) absorption enhancers, such as quaternary ammonium compounds; g) wetting agents, such as 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 contain a buffer. In some embodiments, similar type of solid compositions may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or toffee and high molecular weight polyethylene glycol.

[0254] In some embodiments, the pharmaceutical composition will be in the form of a unit dosage form such as a pill or tablet, and therefore, the composition may contain a diluent, such as lactose, sucrose, dicalcium phosphate, etc., together with a compound of Formula I as provided herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug; a lubricant, such as magnesium stearate; and a binder, such as starch, gum arabic, polyvinylpyrrolidone, gelatin, cellulose, cellulose derivatives, etc. In some embodiments, a powder, granule, solution, or suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) as another solid dosage form will be encapsulated in capsules (gelatin or cellulose matrix capsules). In some embodiments, unit dosage forms in which one or more compounds and pharmaceutical compositions or additional active agents as provided herein are physically separated are also contemplated; for example, capsules (or tablets in capsules) having particles of each drug; two-layer tablets; two-compartment gel caps, etc. In some implementations, enteric-coated or delayed-release oral dosage forms have also been considered.

[0255] In some embodiments, other physiologically acceptable compounds may include wetting agents, emulsifiers, dispersants, or preservatives specifically designed to prevent microbial growth or activity. Various preservatives are well known and include, for example, phenol and ascorbic acid.

[0256] In some embodiments, the excipients are sterile and generally free of undesirable substances. For example, these compositions can be sterilized using conventional, well-known sterilization techniques. In some embodiments, sterilization is not required for various oral dosage form excipients, such as tablets and capsules. For example, United States Pharmacopeia / National Formulary (USP / NF) standards may be sufficient.

[0257] In some embodiments, a compound of Formula I as described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, or a pharmaceutical composition thereof, is formulated for ocular application. In some embodiments, the ocular composition may contain, but is not limited to, any one or more of the following: viscogen (e.g., carboxymethyl cellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizer (e.g., Pluronic (triblock copolymer), cyclodextrin); preservative (e.g., benzalkonium chloride, EDTA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloride complex; Allergan, Inc.)).

[0258] In some embodiments, a compound of formula I as described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, or a pharmaceutical composition thereof, is formulated for topical application to the skin or mucous membranes (e.g., transdermal or percutaneous). In some embodiments, the topical composition may include ointments and creams. In some embodiments, ointments are typically semi-solid formulations based on petrolatum or other petroleum derivatives. In some embodiments, creams containing selected active agents are typically viscous liquids or semi-solid emulsions, often oil-in-water or water-in-oil. For example, the cream matrix is ​​typically washable and contains an oil phase, an emulsifier, and an aqueous phase. For example, the oil phase, sometimes referred to as the “internal” phase, typically consists of petrolatum and fatty alcohols such as cetyl alcohol or stearyl alcohol; although not essential, the aqueous phase typically exceeds the volume of the oil phase and typically contains a humectant. In some embodiments, the emulsifier in the cream formulation is typically a nonionic, anionic, cationic, or amphoteric surfactant. In some implementations, like other carriers or media, the ointment base should be inert, stable, non-irritating, and non-sensitizing.

[0259] In any of the foregoing embodiments, the pharmaceutical composition described herein may comprise one or more of the following: lipids, interlayer cross-linked multilayer vesicles, biodegradable poly(D,L-lactic acid-co-glycolic acid) (PLGA) or polyanhydride nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[0260] The amount of compounds in a pharmaceutical composition or formulation can vary within the full range applicable to those skilled in the art. Typically, based on weight percentage (wt%), the formulation will contain about 0.01-99.99 wt% of the compounds of this disclosure in the total formulation, with the balance being one or more suitable pharmaceutical excipients. In one embodiment, the compounds are present at a level of about 1-80 wt%. Representative pharmaceutical formulations are described below. Example 1 of formulation - Tablet formulation

[0261] Mix the following ingredients tightly and compress them into single-score tablets. Example 2 of formulation - Capsule formulation

[0262] Mix the following ingredients tightly and load them into hard-shell gelatin capsules. Formulation Example 3 - Suspension Formulation

[0263] Mix the following ingredients to form a suspension for oral administration. Example 4 of formulations - Injectable formulations

[0264] Mix the following ingredients to form an injectable formulation. Example 5 of formulation - Suppository formulation

[0265] A suppository with a total weight of 2.5 g was prepared by mixing the compounds of this disclosure with Wiptsol® H-15 (a triglyceride of saturated vegetable fatty acids; Riches-Nelson, Inc., New York), and the suppository had the following composition:

[0266] In some embodiments, the dosage of a compound of Formula I or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug is determined based on a variety of factors, including but not limited to patient type, age, weight, sex, medical condition, severity of the patient's medical condition, route of administration, and the activity of the compound or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug. In some embodiments, the appropriate dosage for a particular situation can be determined by a person skilled in the medical field. In some embodiments, the total daily dose can be divided into multiple doses and administered in multiple doses throughout the day or by means of a continuous delivery method.

[0267] In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug is administered in doses of about 0.01 mg to about 1000 mg. For example, about 0.1 mg to about 30 mg, about 10 mg to about 80 mg, about 0.5 mg to about 15 mg, about 50 mg to about 200 mg, about 100 mg to about 300 mg, about 200 mg to about 400 mg, about 300 mg to about 500 mg, about 400 mg to about 600 mg, about 500 mg to about 800 mg, about 600 mg to about 900 mg, or about 700 mg to about 1000 mg. In some embodiments, the dose is a therapeutically effective amount.

[0268] In some embodiments, a compound of formula I as described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, is administered in doses of about 0.0002 mg / kg to about 100 mg / kg (e.g., about 0.0002 mg / kg to about 50 mg / kg; about 0.0002 mg / kg to about 25 mg / kg; about 0.0002 mg / kg to about 10 mg / kg; about 0.0002 mg / kg to about 5 mg / kg; about 0.0002 mg / kg to about 1 mg / kg; about 0.0002 mg / kg to about 0.5 mg / kg; about 0.0002 mg / kg to about 0.1 mg / kg; about 0.001 mg / kg to about 50 mg / kg; about 0.001 mg / kg to about 25 mg / kg; about 0.001 mg / kg to about 25 mg / kg; about 0.001 mg / kg to about 100 mg / kg). mg / Kg to about 10 mg / Kg; about 0.001 mg / Kg to about 5 mg / Kg; about 0.001 mg / Kg 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 0.01 mg / Kg to about 0.5 mg / Kg; about 0.01 mg / Kg to about 0.1 mg / Kg; about 0.1 mg / Kg to about 50 mg / Kg; about 0.1 mg / Kg to about 25 mg / Kg; about 0.1 mg / Kg to about 10 mg / Kg. mg / Kg; about 0.1 mg / Kg to about 5 mg / Kg; about 0.1 mg / Kg to about 1 mg / Kg; about 0.1 mg / Kg to about 0.5 mg / Kg). In some embodiments, a compound of formula I as described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, is administered at a dose of about 100 mg / Kg.

[0269] In some embodiments, the aforementioned dose of the compound of Formula I or its pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug may be administered daily (e.g., in a single dose or in two or more fractional 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).

[0270] In some embodiments, the compound of formula I described herein, or its pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, is administered for a period of 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 implementations, the discontinuation 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 implementations, a compound of Formula I or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug is administered to the patient for a continuous period of time, followed by a separate period of discontinuation of the compound of Formula I or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug. In some embodiments, a first time period is administered of a compound of Formula I or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer thereof, a mixture of stereoisomers thereof, or a prodrug, followed by a second time period after the first time period, during which administration is discontinued; then a third time period is initiated for administration of the compound of Formula I or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer thereof, a mixture of stereoisomers thereof, or a prodrug; followed by a fourth time period after the third time period for discontinuation of administration. For example, the time periods for administration of a compound of Formula I or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer thereof, a mixture of stereoisomers thereof, or a prodrug, and the subsequent time period for discontinuation of administration, may be repeatedly defined or undefined time periods. In some implementations, the application 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 implementations, the discontinuation 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.

[0271] In some implementations, a compound of Formula I orally, or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug, is administered to a patient once or more daily (e.g., once daily, twice daily, three times daily, four times daily, or a single daily dose).

[0272] In some implementations, a compound of Formula I or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof is administered to a patient once or more daily (e.g., once to four times, once daily, twice daily, three times daily, four times daily, or a single daily dose) via parenteral administration.

[0273] In some implementations, a compound of formula I or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug is administered to a patient weekly via parenteral administration. Treatment

[0274] In some embodiments, this disclosure is characterized by methods for treating patients (e.g., persons) suffering from diseases, disorders, or conditions, wherein modulating GLP-1R (e.g., inhibiting or weakening and / or increasing or detrimental GLP-1R) is beneficial in treating the underlying pathology and / or symptoms and / or progression of the disease, disorder, or condition. In some embodiments, the methods described herein may include or further include treating one or more conditions, comorbidities, or sequelae associated with any one or more of the conditions described herein.

[0275] This article provides methods for treating GLP-1-related diseases, disorders, or conditions, the methods comprising administering to a patient in need an effective amount of a compound of formula I disclosed herein, or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a mixture of stereoisomers, or a prodrug or pharmaceutical composition thereof.

[0276] In some implementation schemes, 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), juvenile-onset atypical diabetes (YOAD), adolescent-onset adult-onset diabetes (MODY), latent autoimmune diabetes in adults (LADA), obesity, weight gain due to the use of other medications, gout, excessive sugar consumption, 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 artery 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, and lung disease. Arterial hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, essential polydipsia, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, and polycystic ovary syndrome (PCOS).

[0277] In some implementation schemes, diseases, disorders, or conditions include, but are not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar consumption, 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 artery disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, hyperglycemia, postprandial hyperlipidemia, and metabolic acidosis. Ketoacidosis, 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, essential polydipsia, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS), or any combination thereof.

[0278] In some implementations, the disease, disorder, or condition includes, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar consumption, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat deposition, myocardial infarction, peripheral artery disease, stroke, transient ischemic attack, hyperglycemia, postprandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, chronic renal failure, syndrome X, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, skin and connective tissue disorders, foot ulcers, or any combination thereof.

[0279] In some embodiments, the compounds and pharmaceutical compositions and methods described herein for treating a patient induce one or more of the following: lowering blood glucose (e.g., lowering blood glucose levels), lowering blood hemoglobin A1c (HbA1c) levels, promoting insulin synthesis, stimulating insulin secretion, increasing β-cell mass, regulating gastric acid secretion, regulating gastric emptying, lowering body mass index (BMI), and / or lowering glucagon production (e.g., levels). In some embodiments, the compounds and pharmaceutical compositions and methods described herein for treating a patient stabilize serum glucose and serum insulin levels (e.g., serum glucose and serum insulin concentrations). Methods for regulating glucose or insulin levels in patients requiring such regulation are also provided herein, the methods comprising administering to the patient an effective amount of a compound of formula I disclosed herein, or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug or pharmaceutical composition.

[0280] In some embodiments, this document provides a method for reducing the risk of major adverse cardiovascular events (MACE) in patients in need (e.g., a reduction of about 20%, 30%, 40%, 50%, 60%, 70%, or 80%), said method comprising administering to said patient an effective amount of a compound of formula I disclosed herein, or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug or pharmaceutical composition. In some of these embodiments, the patient is an adult diagnosed with type 2 diabetes (T2D). In some embodiments, the patient is an adult diagnosed with heart disease. In some embodiments, the patient is an adult diagnosed with both type 2 diabetes (T2D) and heart disease. In some embodiments, the patient is an adult with type 2 diabetes (T2D). In some embodiments, the patient is an adult with heart disease. In some embodiments, the patient has both type 2 diabetes (T2D) and heart disease. Indications obesity

[0281] In some implementations, the condition, disease, or disorder is obesity and conditions, diseases, or disorders related to or associated with obesity. Non-limiting examples of obesity and obesity-related conditions include symptomatic obesity, simple obesity, childhood obesity, morbid obesity, and abdominal obesity (central obesity characterized by excessive abdominal fat). Non-limiting examples of symptomatic obesity include endocrine obesity (e.g., Cushing syndrome, hypothyroidism, insulinoma, type II diabetes mellitus, pseudohypoparathyroidism, hypogonadism), hypothalamic obesity, hereditary obesity (e.g., Prader-Willi syndrome, Laurence-Moon-Biedl syndrome), and drug-induced obesity (e.g., obesity induced by steroids, phenothiazines, insulin, sulfonylureas, or beta-blockers).

[0282] In some implementations, the condition, disease, or disorder is associated with obesity. Examples of such conditions, diseases, or disorders include, but are not limited to, glucose intolerance, diabetes (e.g., type 2 diabetes, obese diabetes), lipid metabolism disorders, hyperlipidemia, hypertension, heart failure, hyperuricemia, gout, fatty liver (including non-alcoholic steatohepatitis (NASH)), coronary artery disease (e.g., myocardial infarction, angina pectoris), cerebral infarction (e.g., cerebral thrombosis, transient ischemic attack), skeletal or joint disorders (e.g., knee osteoarthritis, hip osteoarthritis, degenerative spondylitis, low back pain), sleep apnea syndrome, obesity-hypopnea syndrome (Pickwick syndrome), menstrual disorders (e.g., abnormal menstrual cycles, abnormal menstrual flow and cycle, amenorrhea, abnormal menstrual symptoms), visceral obesity syndrome, and metabolic syndrome. In some implementations, the chemical compounds and pharmaceutical compositions described herein can be used to treat patients exhibiting symptoms of both obesity and insulin deficiency. diabetes

[0283] In some implementations, the condition, disease, or disorder is diabetes. Non-limiting examples of diabetes include type 1 diabetes, type 2 diabetes (e.g., type 2 diabetes treated with diet, type 2 diabetes treated with sulfonylureas, very advanced type 2 diabetes, type 2 diabetes treated with long-term insulin therapy), diabetes (e.g., non-insulin-dependent diabetes, insulin-dependent diabetes), gestational diabetes, obese diabetes, autoimmune diabetes, and borderline diabetes. In some implementations, the condition, disease, or disorder is type 2 diabetes (e.g., type 2 diabetes treated with diet, type 2 diabetes treated with sulfonylureas, very advanced type 2 diabetes, type 2 diabetes treated with long-term insulin therapy).

[0284] This article also provides a method for treating a patient with diabetes, the method comprising (a) determining that the patient has type 2 diabetes, and (b) administering to the patient a therapeutically effective amount of a compound of formula I as disclosed herein, or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a mixture of stereoisomers, or a prodrug, or a pharmaceutical composition thereof.

[0285] This article provides a method for treating a patient with type 2 diabetes, the method comprising administering to a patient identified or diagnosed with type 2 diabetes a therapeutically effective amount of a compound of formula I disclosed herein, or a pharmaceutically acceptable salt thereof, isotopically enriched analog thereof, stereoisomer, mixture of stereoisomers, or prodrug, or pharmaceutical composition thereof.

[0286] This article also provides a method for treating type 2 diabetes in patients in need, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I as disclosed herein, or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a mixture of stereoisomers, or a prodrug, or a pharmaceutical composition thereof.

[0287] In some embodiments, compounds and pharmaceutical compositions and methods for treating patients with the conditions, diseases, or disorders described herein (e.g., type 2 diabetes) reduce fasting plasma glucose levels. In some embodiments, compounds and pharmaceutical compositions and methods for treating patients with the conditions, diseases, or disorders described herein (e.g., type 2 diabetes) reduce non-fasting plasma glucose levels. In some embodiments, compounds and pharmaceutical compositions and methods for treating patients with the conditions, diseases, or disorders described herein (e.g., type 2 diabetes) reduce HbA1c levels. In some embodiments, compounds and pharmaceutical compositions and methods for treating patients with the conditions, diseases, or disorders described herein (e.g., type 2 diabetes) reduce glucagon levels. In some embodiments, compounds and pharmaceutical compositions and methods for treating patients with the conditions, diseases, or disorders described herein (e.g., type 2 diabetes) increase insulin levels. In some embodiments, compounds and pharmaceutical compositions and methods for treating patients with the conditions, diseases, or disorders described herein (e.g., type 2 diabetes) reduce BMI.

[0288] In some embodiments, a reduction in fasting plasma glucose levels of about 5% to about 95% indicates treatment for type 2 diabetes. In some embodiments, a reduction in fasting plasma glucose levels of about 15% to about 80% indicates treatment for type 2 diabetes. In some embodiments, a reduction in fasting plasma glucose levels of about 25% to about 60% indicates treatment for type 2 diabetes. In some embodiments, a reduction in fasting plasma glucose levels of about or below 126 mg / dL, about or below 110 mg / dL, or about or below 90 mg / dL indicates treatment for type 2 diabetes.

[0289] In some embodiments, a reduction in non-fasting plasma glucose levels of about 5% to about 95% indicates treatment for type 2 diabetes. In some embodiments, a reduction in non-fasting plasma glucose levels of about 15% to about 80% indicates treatment for type 2 diabetes. In some embodiments, a reduction in non-fasting plasma glucose levels of about 25% to about 60% indicates treatment for type 2 diabetes. In some embodiments, a reduction in non-fasting plasma glucose levels of about or below 200 mg / dL, about or below 150 mg / dL, or about or below 130 mg / dL indicates treatment for type 2 diabetes.

[0290] In some embodiments, a reduction in HbA1c levels of about 5% to about 95% indicates treatment for type 2 diabetes. In some embodiments, a reduction in HbA1c levels of about 15% to about 80% indicates treatment for type 2 diabetes. In some embodiments, a reduction in HbA1c levels of about 25% to about 60% indicates treatment for type 2 diabetes. In some embodiments, a reduction in HbA1c levels of about or less than 6.5%, about or less than 6.0%, or about or less than 5.0% indicates treatment for type 2 diabetes.

[0291] In some embodiments, a decrease in glucagon levels of about 5% to about 95% indicates treatment for type 2 diabetes. In some embodiments, a decrease in glucagon levels of about 15% to about 80% indicates treatment for type 2 diabetes. In some embodiments, a decrease in glucagon levels of about 25% to about 60% indicates treatment for type 2 diabetes. In some embodiments, an increase in insulin levels of about 5% to about 95% indicates treatment for type 2 diabetes. In some embodiments, an increase in insulin levels of about 15% to about 80% indicates treatment for type 2 diabetes. In some embodiments, an increase in insulin levels of about 25% to about 60% indicates treatment for type 2 diabetes.

[0292] In some embodiments, a BMI reduction of about 5% to about 95% indicates treatment for type 2 diabetes. In some embodiments, a BMI reduction of about 15% to about 80% indicates treatment for type 2 diabetes. In some embodiments, a BMI reduction of about 25% to about 60% indicates treatment for type 2 diabetes. In some embodiments, a BMI reduction 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 for type 2 diabetes. In some embodiments, a BMI reduction of about or below 40, about or below 30, or about or below 20 indicates treatment for type 2 diabetes.

[0293] In some implementations, the condition, disease, or disorder is associated with diabetes (e.g., complications of diabetes). Non-limiting examples of diabetes-related disorders include obesity, obesity-related disorders, metabolic syndrome, neuropathy, nephropathy (e.g., diabetic nephropathy), retinopathy, diabetic cardiomyopathy, cataracts, macrovascular disease, osteoporosis, hyperosmolar diabetic coma, infectious diseases (e.g., respiratory infections, urinary tract infections, gastrointestinal infections, skin and soft tissue infections, lower extremity infections), diabetic gangrene, xerostomia, hearing loss, cerebrovascular disorders, diabetic cachexia, delayed wound healing, diabetic dyslipidemia, peripheral circulatory disorders, cardiovascular risk factors (e.g., coronary artery disease, peripheral artery disease, cerebrovascular disease, hypertension and risk factors associated with unmanaged cholesterol and / or lipid levels, and / or inflammation), NASH, fractures, and cognitive impairment.

[0294] Other non-limiting examples of diabetes-related disorders include prediabetes, hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, hyperLDL-cholesterolemia, hypoHDL-cholesterolemia, postprandial hyperlipidemia), metabolic syndrome (e.g., metabolic X syndrome, where activation of GLP-1R is a beneficial metabolic disorder), hypertension, impaired glucose tolerance (IGT), insulin resistance, and sarcopenia.

[0295] In some implementations, the condition, disease, or disorder is diabetes and obesity (diabetic obesity). In some implementations, the compounds described herein may also be used to improve the therapeutic efficacy of metformin. Metabolic barriers

[0296] In some implementations, the condition, disease, or disorder is a disorder of a metabolically important tissue. Non-limiting examples of metabolically important tissues include the liver, fat, pancreas, kidneys, and intestines.

[0297] In some implementations, the condition, disease, or disorder is fatty liver disease. Fatty liver disease includes, but is not limited to, non-alcoholic fatty liver disease (NAFLD), steatohepatitis, non-alcoholic steatohepatitis (NASH), fatty liver disease 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, abeta-lipoproteinemia, glycogen storage disease, recurrent nodular non-suppurative panniculitis, acid lipase deficiency, acute fatty liver of pregnancy, and lipid dystrophy.

[0298] Nonalcoholic fatty liver disease (NAFLD) refers to a range of diseases that occur in the absence of alcohol abuse and are typically characterized by the presence of steatosis (fat in the liver). NAFLD is believed to be associated with a variety of conditions, such as metabolic syndrome (including obesity, diabetes, and hypertriglyceridemia) and insulin resistance. It can 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, predominantly macrovesicular steatosis (i.e., nonalcoholic fatty liver or NAFL) to nonalcoholic steatohepatitis (NASH) (Angulo et al., J Gastroenterol Hepatol 2002; 17 Suppl:S186-90). In some implementations, the patient is a pediatric patient. As used herein, the term “pediatric patient” refers to a patient under the age of 21 years at the time of diagnosis or treatment. The term “pediatric” can be further subdivided into different subgroups, including: neonates (from birth to the first month of life); infants (1 month to two years); children (two years to 12 years); and adolescents (12 to 21 years (until, but not including, their twenty-second birthday)). (References: Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th edition Philadelphia: WBSaunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st edition New York: McGraw-Hill, 2002; and Avery MD, FirstLR. Pediatric Medicine, 2nd edition Baltimore: Williams & Wilkins; 1994.) In some implementations, pediatric patients are defined as those born within the first 28 days of life, 29 days old to under two years of age, two years old to under 12 years of age, or 12 years old to 21 years of age (up to but not including the twenty-second birthday). In some implementations, pediatric patients are defined as those born within the first 28 days of life, 29 days old to under one year of age, one month old to under four months of age, three months old to under seven months of age, six months old to under one year of age, one year old to under two years of age, two years old to under three years of age, two years old to under seven years of age, three years old to under five years of age, five years old to under ten years of age, six years old to under 13 years of age, ten years old to under 15 years of age, or 15 years old to under 22 years of age. In some implementations, patients are adult patients.

[0299] Other non-limiting examples of disorders affecting metabolically important tissues include joint disorders (e.g., osteoarthritis, secondary osteoarthritis), fatty degeneration (e.g., in the liver); gallstones; gallbladder disorders; gastroesophageal reflux; sleep apnea; hepatitis; fatty liver; skeletal disorders characterized by changes in bone metabolism, such as osteoporosis, including postmenopausal osteoporosis, poor bone strength, osteopenia, Paget's disease, osteolytic metastases in cancer patients, osteodystrophy in liver disease, and changes in bone metabolism caused by renal failure or hemodialysis, fractures, bone surgery, aging, pregnancy, fracture protection, and malnutrition due to polycystic ovary syndrome; kidney diseases (e.g., chronic renal failure, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease); muscular dystrophy, angina pectoris, acute or chronic diarrhea, testicular dysfunction, respiratory dysfunction, frailty, sexual dysfunction (e.g., erectile dysfunction), and geriatric syndromes. In some embodiments, the compounds and pharmaceutical compositions described herein can be used to treat surgical trauma by improving postoperative recovery and / or by preventing catabolism caused by surgical trauma. Cardiovascular and vascular diseases

[0300] In some implementations, the symptom, disease, or disorder is a cardiovascular disease. Non-limiting examples of cardiovascular diseases include congestive heart failure, atherosclerosis, arteriosclerosis, coronary artery disease, coronary artery 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 prethrombotic states (exemplified by high levels of fibrinogen or plasminogen activator inhibitors in the blood).

[0301] In some implementations, the condition, disease, or disorder is associated with vascular disease. Non-limiting examples of vascular disease include peripheral vascular disease, large vessel complications (e.g., stroke), vascular dysfunction, peripheral artery disease, abdominal aortic aneurysm, carotid artery disease, cerebrovascular disorders (e.g., cerebral infarction), pulmonary embolism, chronic venous insufficiency, severe limb ischemia, retinopathy, nephropathy, and neuropathy. Nervous system diseases

[0302] In some implementations, the symptom, disease, or disorder is a neurological disorder (e.g., neurodegenerative disorder) or a mental disorder. Non-limiting examples of neurological disorders include cerebral 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 chores, tardive dyskinesia, hyperkinesia, mania, Morbus Parkinson's disease, Steele-Richard syndrome, Down's syndrome, myasthenia gravis, neurological trauma, brain trauma, angioamylindness, intracerebral hemorrhage with amyloidosis, encephalitis, Friedrich's ataxia, acute confusion disorder, amyotrophic lateral sclerosis (ALS), glaucoma, and apoptosis-mediated central nervous system degenerative diseases (e.g., Creutzfeld-Jakob disease, bovine spongiform encephalopathy (BSE), and chronic wasting syndrome). For example, see US 2006 / 0275288 A1.

[0303] Non-limiting examples of mental disorders include substance dependence (narcotics) and attention deficit / hyperactivity disorder (ADHD). The compounds and pharmaceutical compositions described herein can be used to reduce substance dependence, prevent relapse of substance abuse, and alleviate anxiety caused by the lack of a given substance. See, for example, US 2012 / 0021979 A1.

[0304] 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 to protect dopamine neurons and motor function in Parkinson's disease. Insulin-related conditions and disorders

[0305] In some implementations, the symptoms, diseases, or disorders are impaired fasting glucose (IFG), impaired fasting glucose (IFG), hyperglycemia, insulin resistance (impaired glucose homeostasis), hyperinsulinemia, elevated blood fatty acid or glycerol levels, hypoglycemia, insulin resistance syndrome, paresthesia 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 insulin-related coma endpoints.

[0306] 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

[0307] In some implementations, 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, US 20120148586 A1. Gastrointestinal disorders

[0308] In some implementations, the symptom, disease, or disorder is a gastrointestinal-related disorder. Non-limiting examples of these disorders include ulcers of any etiology (e.g., gastric ulcers, Zollinger-Ellison syndrome, drug-induced ulcers, ulcers associated with infection or other pathogens), digestive disorders, malabsorption disorders, short bowel syndrome, cul-de-sac syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), steatorrhea (celiac sprue), hypogammaglobulinemic sprue, mucositis and diarrhea induced by chemotherapy and / or radiation therapy, 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

[0309] In some embodiments, the compounds and pharmaceutical compositions described herein can be used to reduce weight (e.g., excess weight) in patients (e.g., patients in need), prevent weight gain, induce weight loss, reduce body fat, or reduce food intake. In some embodiments, a patient's weight gain may be attributed to excessive food intake or an unbalanced diet, or it may be due to weight gain from accompanying medications (e.g., insulin sensitizers with PPARγ agonist-like effects, such as troglitazone, rosiglitazone, empaglitazone, cycloglitazone, pioglitazone, etc.). In some embodiments, the weight gain may be pre-obesity weight gain or weight gain in obese patients. In some embodiments, the weight gain may also be drug-induced weight gain or weight gain following cessation of smoking.

[0310] In some implementations, the symptom, disease, or disorder is an eating disorder, such as overeating, binge eating, bulimia, or compulsive eating. Inflammatory diseases

[0311] In some implementations, the symptom, disease, or disorder is an inflammatory disorder. Non-limiting examples of inflammatory disorders include chronic rheumatoid arthritis, degenerative spondylitis, osteoarthritis, low back pain, gout, postoperative or post-traumatic inflammation, abdominal distension, neuralgia, pharyngitis, cystitis, pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory colitis), inflammation in metabolically important tissues (including the liver, fat, pancreas, kidneys, and intestines), and pro-inflammatory states (e.g., elevated levels of pro-inflammatory cytokines or markers such as inflammatory-like C-reactive protein in the blood). cancer

[0312] In some implementations, the symptom, disease, or obstacle 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), and rectal cancer (e.g., stomach cancer). Gastrointestinal stromal tumors (GISTs), colorectal cancers (e.g., familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumors), small bowel cancers (e.g., non-Hodgkin's lymphoma, gastrointestinal stromal tumors), esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer (e.g., nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer), salivary gland cancer, brain tumors (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma), schwannomas, liver cancers (e.g., Primary liver cancer, extrahepatic bile duct cancer, kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter), bile duct cancer, endometrial cancer, cervical cancer, ovarian cancer (e.g., epithelial ovarian cancer, extragonadal germ cell tumors, ovarian germ cell tumors, low-potency ovarian tumors), bladder cancer, urethral cancer, skin cancer (e.g., intraocular (ocular) melanoma, Merkel cell carcinoma), hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer (e.g., medullary thyroid carcinoma). Parathyroid carcinoma, nasal cavity carcinoma, sinus carcinoma, bone tumors (e.g., osteosarcoma, Ewing tumor, uterine sarcoma, soft tissue sarcoma), angiofibroma, retinal sarcoma, penile cancer, testicular tumors, childhood solid tumors (e.g., nephroblastoma, childhood kidney tumors), Kaposi's sarcoma, Kaposi's sarcoma caused by AIDS, maxillary sinus tumors, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia). Hypothalamic-pituitary disorders

[0313] In some implementations, the condition, disease, or disorder is associated with the hypothalamic-pituitary-gonadal axis. For example, the condition, disease, or disorder is associated with the hypothalamic-pituitary-ovarian axis. In another example, the condition, disease, or disorder is associated with the hypothalamic-pituitary-testicular axis. Hypothalamic-pituitary-gonadal axis disorders include, but are not limited to, hypogonadism, polycystic ovary syndrome, hypothyroidism, hypopituitarism, sexual dysfunction, and Cushing's disease.

[0314] In some implementations, conditions, diseases, or disorders associated with diabetes are linked to the hypothalamic-pituitary-gonadal axis. pulmonary disease

[0315] In some implementations, the condition, disease, or disorder is associated with a lung disease. Lung 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).

[0316] In some implementations, the condition, disease, or disorder associated with diabetes is lung disease. Combination therapy

[0317] In some implementations, this disclosure considers both monotherapy regimens and combination therapy regimens.

[0318] In some embodiments, the methods described herein may further include administering one or more additional therapies (e.g., one or more additional therapeutic agents and / or one or more treatment regimens) in combination with the compounds described herein.

[0319] In some embodiments, the methods described herein include administering the compounds described herein in combination with one or more of the following: diet therapy (e.g., diet monitoring, diet therapy for diabetes), exercise therapy (e.g., physical activity), blood glucose monitoring, gastric electrical stimulation (e.g., TANTALUS®), and dietary modification.

[0320] In some embodiments, a compound of Formula I as described herein, or a pharmaceutically acceptable salt isotope-enriched analog, stereoisomer, mixture of stereoisomers, or prodrug may be administered in combination with one or more other therapeutic agents.

[0321] Other representative therapeutic agents include, but are not limited to, anti-obesity agents, diabetes treatment agents, treatment agents for diabetic complications, treatment agents for hyperlipidemia, antihypertensive agents, diuretics, chemotherapy drugs, immunotherapy drugs, anti-inflammatory drugs, antithrombotic agents, antioxidants, treatment agents for osteoporosis, vitamins, antidementia drugs, erectile dysfunction drugs, treatment agents for urinary frequency or incontinence, NAFLD treatment agents, NASH treatment agents, treatment agents for dysuria, and antiemetics.

[0322] 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, phenbutylide, mazindol, fluoxetine, tesofensine), serotonin 2C receptor agonists (e.g., lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptor modulators, GABA modulators (e.g., topiramate) (including GABA receptor agonists (e.g., gabapentin, pregabalin)), neuropeptide Y antagonists (e.g., velneperitone), rimonabant, and taranabant. Orexin antagonists, orexin receptor antagonists, orexin acyltransferase inhibitors, opioid receptor antagonists (e.g., GSK-1521498), orexin receptor antagonists, melanocortin 4 receptor agonists, 11β-hydroxysteroid dehydrogenase inhibitors (e.g., AZD-4017, BVT-3498, INCB-13739), pancreatic lipase inhibitors (e.g., orlistat, cetilistat), β3 agonists (e.g., N-5984), diacylglycerol acyltransferase 1 (DGAT1) inhibitors, acetyl-CoA carboxylase (ACC) inhibitors, stearoyl-CoA... A desaturase inhibitors, microsomal triglyceride transfer protein inhibitors (e.g., R-256918), sodium-glucose cotransporter 2 (SGLT-2) inhibitors (e.g., JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, remogliflozin), NFK inhibitors (e.g., HE-3286), PPAR agonists (e.g., GFT-505, DRF-11605, gemfibrozil, and fenofibra) te), phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate, trodusquemin), GPR119 agonists (e.g., PSN-821, MBX-2982, APD597), glucosamine activators (e.g., piraglitin, AZD-1656, AZD6370, TTP-355, compounds described in W0006 / 112549, W0007 / 028135, W0008 / 047821, W0008 / 050821, W0008 / 136428 and W0008 / 156757), leptin, leptin derivatives (e.g.,Metriptine), leptin resistance modifiers, 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), oximin (OXM) preparations, appetite suppressants (e.g., ephedrine), FGF21 preparations (e.g., animal FGF21 preparations extracted from bovine or porcine pancreas; using Escherichia coli (Escherichia coli) preparations). Human FGF21 preparations synthesized from genes of *C. coli* or yeast; fragments or derivatives of FGF21; appetite suppressants (e.g., P-57); human pro-insulin peptide (HIP); farnesoid X receptor (FXR) agonists; phenbutylamine; zonisamide; norepinephrine / dopamine reuptake inhibitors; GDF-15 analogs; methionine aminopeptidase 2 (MetAP2) inhibitors; diethylamine phenylacetone; benzotriazine; benzylphenamine; fibroblast growth factor receptor (FGFR) modulators; and AMP-activated protein kinase (AMPK) activators.

[0323] In some embodiments, the one or more additional therapeutic agents include those that can be used as, for example, antidiabetic agents.Non-limiting examples include insulin and insulin preparations (e.g., animal insulin preparations extracted from bovine or porcine pancreas; 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 its salts), biguanides (e.g., metformin, buformin or their salts (e.g., hydrochloride, fumarate, succinate)), and glucagon analogs (e.g., WO4). Any glucagon analogues described in 2010 / 011439), agents that antagonize the action of glucagon or reduce glucagon secretion, sulfonylurea agents (e.g., chlorpropamide, tolazamide, gliclazide, glimepiride, tolbutamide, glibenclamide, acetohexamide, glipizide, glybuzole, glibenclamide), thiazolidinedione agents (e.g., roxarsone), and thiazolidinediones (e.g., roxarsone). Glitter or pioglitazone), alpha-glucosidase inhibitors (e.g., voglibose, acarbose, miglitol, emiglitate), insulin secretagogues such as dietary glucose regulators (sometimes called "short-acting secretagogues"), such as megglitinide (e.g., repaglinide and nateglinide), cholinesterase inhibitors (e.g., donepezil, galantamine, rivastigmine, tacrine), NMDA receptor antagonists, dual GLP-1 / GIP receptor agonists (e.g., LBT-2000, ZPD1-70), GLP-1R agonists (e.g., exenatide, liraglutide, abiglutide, duraglutide, abiglutide, tasglutide, lixinaglutide, smegglutide, AVE-0010, S4P, and Boc5), and dipeptidyl peptidase IV (DPP-4) inhibitors (e.g., vildagliptin, dutogliptin, gemigliptin, alogliptin). (ptin), saxagliptin, sitagliptin, linagliptin, berberine, adogliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, SK-0403, ALS2-0426, TA-6666, TS-021, KRP-104, trelagliptin.

[0324] In some embodiments, the one or more additional therapeutic agents include those that can be used, for example, to treat NAFL and NASH. Non-limiting examples include FXR agonists, PF-05221304, synthetic fatty acid-bile conjugates, anti-lysyl oxidase homolog 2 (LOXL2) monoclonal antibodies, caspase inhibitors, MAPK5 inhibitors, galactagogue 3 inhibitors, fibroblast growth factor 21 (FGF21) agonists, niacin analogs, leukotriene D4 (LTD4) receptor antagonists, acetyl-CoA carboxylase (ACC) inhibitors, hexokinase (KHK) inhibitors, apoptosis signal-regulated kinase 1 (ASK1) inhibitors, ileal bile acid transporter (IBAT) inhibitors, glycyrrhizin, and Schisandra chinensis extract. extract), ascorbic acid, glutathione, silymarin, lipoic acid and d-α-tocopherol, ascorbic acid, glutathione, vitamin B complex, glitazone / thiazolidinediones (e.g., troglitazone, rosiglitazone, pioglitazone), metformin, cysteine, sulfonylureas, alpha-glucosidase inhibitors, megglitinide, vitamin E, tetrahydrolipstatin, milk thistle protein, antiviral agents and antioxidants.

[0325] In some embodiments, the one or more additional therapeutic agents include those that can be used, for example, to treat complications of diabetes. Non-limiting examples include aldose reductase inhibitors (e.g., tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat, lidorestat), neurotrophic factors and their enhancers (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 WO2004 / 039365), and PKC inhibitors (e.g., rubostaurin). mesylate), AGE inhibitors (e.g., ALT946, N-benzoylthiazolium bromide (ALT766), EXO-226, pyridorin hydrochloride, 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-regulated kinase-1 (ASK-1) inhibitors.

[0326] In some embodiments, the one or more additional therapeutic agents include those that can be used, for example, to treat hyperlipidemia. Non-limiting examples include HMG-COA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin, or salts thereof (e.g., sodium, calcium salts)), squalene synthase inhibitors (e.g., compounds described in WO97 / 10224, such as N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazazepone-3-yl]acetyl]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., daidzepine, gamma oryzanol, γ-oryzanol), cholesterol absorption inhibitors (e.g., zechia), CETP inhibitors (e.g., dalcetrapib, anacetrapib), and ω-3 fatty acid preparations (e.g., ω-3 fatty acid ethyl ester 90).

[0327] In some embodiments, the one or more additional therapeutic agents include those that can be used as, for example, antihypertensive agents. Non-limiting examples include angiotensin-converting enzyme inhibitors (e.g., captopril, enalapril, delapril), angiotensin II antagonists (e.g., candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil, azilsartan, azilsartan medoxomil). medoxomil), calcium channel blockers (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine, cilnidipine) and beta-blockers (e.g., metoprolol, atenolol, propranolol, carvedilol, pindolol).

[0328] 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., sodium theobromine salicylate, calcium theobromine salicylate), thiazide preparations (e.g., ethiothiazide, cyclopenthiazine, trichlorothiazide, hydrochlorothiazide, hydrofluorothiazide, benzyl hydrochlorothiazide, penfluthiazide, polythiazide, methyclothiazide)), antialdosterone preparations (e.g., spironolactone, triamterene)), carbonic anhydrase inhibitors (e.g., acetazolamide) and chlorobenzenesulfonamides (e.g., chlortalidone, mefruside, indapamide)).

[0329] 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 immunomodulatory activity (e.g., lentinan, sizofiran, krestin), cytokines obtained through genetic engineering (e.g., interferons, interleukins (ILs), such as IL-1, IL-2, IL-12), and colony-stimulating factors (e.g., granulocyte colony-stimulating factor, erythropoietin).

[0330] In some embodiments, the one or more additional therapeutic agents include those that can be used as, for example, antithrombotic agents. Non-limiting examples include heparin (e.g., heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarin (e.g., warfarin potassium); antithrombin drugs (e.g., aragatroban, dabigatran), FXa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, betrixaban), YM150, described in WO 02 / 06234, WO 2004 / 048363, WO2005 / 030740, WO 2005 / 058823 and WO Compounds listed in 2005 / 113504), thrombolytic agents (e.g., urokinase, tisokinase, alteplase, nateplase, monteplase, pamiteplase), and platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cilostazol, ethyl eicosapentaenoate, beraprost sodium, and sarpogrelate hydrochloride).

[0331] In some embodiments, the one or more additional therapeutic agents include those 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 risedronated sodium. Suitable examples of vitamins include vitamin B1 and vitamin B12. Suitable examples of erectile dysfunction medications include apomorphine and sildenafil citrate. Suitable examples of medications for treating urinary frequency or incontinence include flavorxate hydrochloride, oxybutynin hydrochloride, and propiverine hydrochloride. Suitable examples of medications for treating dysuria include acetylcholinesterase inhibitors (e.g., distigmine). Suitable examples of anti-inflammatory agents include nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, acetaminophen, and indomethacin.

[0332] Other illustrative additional therapeutic agents include agents that regulate hepatic glucose balance (e.g., fructose-1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glycogen synthase kinase inhibitors, glucosamine activators), agents designed to treat complications of long-term hyperglycemia such as aldose reductase inhibitors (e.g., epalrestat and ranisitar), agents for treating complications associated with microvascular complications, anti-dyslipidemia agents such as HMG-CoA reductase inhibitors (statins, such as rosuvastatin), cholesterol lowering agents, bile acid sequestrants (e.g., cholestyramine), and cholesterol absorption inhibitors (e.g., plant sterols). sterols, such as phytosterols, cholesterol ester transfer protein (CETP) inhibitors, ileal bile acid transport system inhibitors (IBAT inhibitors), bile acid conjugating resins, nicotinic acid (nicotinic acid) and its analogues, 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 α-2 agonists (e.g., clonidine), angiotensin-converting enzyme (ACE) inhibitors (e.g., lisinopril), calcium channel blockers (such as dihydropyridine (e.g., nifedipine), phenylalkylamines (e.g., verapamil), and benzothiazazepines (e.g., diltiazem), angiotensin II receptor antagonists (e.g., candesartan), and aldosterone receptor antagonists (e.g., eplerenone). Centrally acting adrenergic drugs such as central alpha agonists (e.g., clonidine), diuretics (e.g., furosemide), hemostatic modifiers (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)), and adenosine diphosphate (ADP) receptor inhibitors (…). For example, clopidogrel), phosphodiesterase inhibitors (e.g., cilostazol), glycoprotein IIB / IIA inhibitors (e.g., tirofiban), adenosine reuptake inhibitors (e.g., dipyridamole), norepinephrine agents (e.g., phenbutazone), serotonergic agents, diacylglycerol acyltransferase (DGAT) inhibitors, feeding behavior modulators, pyruvate dehydrogenase kinase (PDK) modulators, serotonin receptor modulators, and monoamine transmission modulators such as selective serotonin reuptake inhibitors (SSRIs) (e.g., ...).Fluoxetine), norepinephrine reuptake inhibitors (NARIs), norepinephrine-serotonin reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs) (e.g., toloxatone and amiflamine), compounds described in WO 2007 / 013694, WO 2007 / 018314, WO 2008 / 093639, and WO 2008 / 099794, GPR40 agonists (e.g., fasiglimum or its hydrate, compounds described in WO 2004 / 041266, WO 2004 / 106276, WO 2005 / 063729, WO 2005 / 063725, WO 2005 / 087710, WO 2005 / 095338, WO 2007 / 013689, and WO Compounds listed in 2008 / 001931), SGLT1 inhibitors, adiponectin or its agonists, IKK inhibitors (e.g., AS-2868), somatostatin receptor agonists, ACC2 inhibitors, cachexia improvers (e.g., cyclooxygenase inhibitors (e.g., indomethacin)), progesterone derivatives (e.g., megestrol acetate), glucocorticoids (e.g., dexamethasone), metoclopramide agents, agents for improving lipid metabolism (e.g., eicosapentaenoic acid), growth hormone, IGF-1, antibodies against cachexia-inducing factor TNF-α, LIF, IL-6 and oncokinase M, metabolically modified proteins or peptides such as glucoskinase (GK), glucoskinase regulatory protein (GKRP), uncoupling proteins 2 and 3 (UCP2 and UCP3), peroxisome proliferator-activated receptor α (PPARα), MC4r agonists, insulin receptor agonists, PDEs 5. Inhibitors, glycosylation inhibitors (e.g., ALT-711), neurotrophic drugs (e.g., Y-128, VX853, prosaptide), antidepressants (e.g., desipramine, amitriptyline, imipramine), and antiepileptic drugs (e.g., lamotrigine, trileptal, levetiracetam, zonisamide). Ran), pregabalin, harkoseride, carbamazepine, antiarrhythmic drugs (e.g., mexiletine), acetylcholine receptor ligands (e.g., ABT-594), endothelin receptor antagonists (e.g., ABT-627), narcotic analgesics, α2 receptor agonists (e.g., clonidine), local analgesics (e.g., capsaicin), anxiolytics (e.g., benzothiazazepine), phosphodiesterase inhibitors (e.g., sildenafil), dopamine receptor agonists, cytotoxic antibodies (e.g., ...T-cell receptor and IL-2 receptor-specific antibodies, B-cell depletion therapies (e.g., anti-CD20 antibodies (e.g., rituxan), i-BLyS antibodies), drugs affecting T-cell migration (e.g., anti-integrin α4 / β1 antibodies (e.g., tysabri)), drugs acting on immunoaffinity (e.g., cyclosporine, tacrolimus, sirolimus, rapamicin), interferons (e.g., IFN-β), immunomodulators (e.g., glatiramer), TNF-binding proteins (e.g., circulating receptors), immunosuppressants (e.g., mycophenolate mofetil), and megglitazone (e.g., methacin). Dasen, AMG-131, balaglitazone, MBX-2044, rivoglitazone, aglitazone, siglitazone, lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, exenatide, kinin-4, memantine, midazolam, ketoconazole, ethyl eicosapentaenoate, clonidine, azosemide, isosorbide, ethacrylic acid, piretatanide, bumetanide, etoposide, piroxicam, NO donors (e.g., organic nitrates) and NO promoters (e.g., phosphodiesterase inhibitors).

[0333] In some embodiments, the one or more additional therapeutic agents include those that can be used, for example, as antiemetics. As used herein, an "antiemetic" means any agent that counteracts (e.g., reduces or eliminates) nausea or vomiting (vomiting). It should be understood that when referring to a therapeutically effective amount of an antiemetic, the amount administered is the amount required to counteract (e.g., reduce or eliminate) nausea or vomiting (vomiting). Without wishing to be bound by theory, it is believed that administering one or more antiemetics in combination with a compound of formula (I) described herein may allow for the administration of higher doses of the compound of formula (I), for example because the patient may be able to ingest food normally and therefore respond to treatment more quickly.

[0334] Non-limiting examples of antiemetics include 5HT3 receptor antagonists (serotonin receptor antagonists), tranquilizers / antipsychotics, antihistamines, anticholinergics, steroids (e.g., corticosteroids), NK1 receptor antagonists (neurokine 1 substance P receptor antagonists), antidopaminergics / dopamine receptor antagonists, and benzodiazepines.

[0335] For example, antiemetics can be selected from neuroleptics, antihistamines, anticholinergics, sterols, 5HT-3 receptor antagonists, NK1 receptor antagonists, antidopaminergics / dopamine receptor antagonists, benzodiazepines, and non-psychoactive cannabinoids.

[0336] 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, bemistron, zatisetron, batanopirde, MDL-73147EF; metoclopramide, N-3389 (ne-3,9-dimethyl-3,9-diazabicyclo[3,3,1]one-7-yl-1H-indazole-3-carboxamide dihydrochloride), Y-25130 hydrochloride, MDL72222, tropyl-3,5-dimethylbenzoic acid, 3-(4-allylpiperazin-1-yl)-2-quinoxaloline carboxylic acid, zacopride hydrochloride, and mirtazapine. Other non-limiting examples of 5HT3 receptor antagonists (serotonin receptor antagonists) include: celanisetron, clozapine, cyproheptadine, dazopride, hydroxyzine, lerisetron, metoclopramide, mianserin, olanzapine, palonosetron (+ netutoptan), quetiapine, qamosetron, ramosteron, licastron, risperidone, ziprasidone, and zatosetron.

[0337] In some implementations, the 5HT-3 receptor antagonist is granisetron, dolasetron, ondansetron, hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemyrosetron, zatisetron, batanopirde, MDL-73147EF, metoclopramide, N-3389, Y-25130 hydrochloride, MDL 72222, tropyl-3,5-dimethylbenzoic acid, 3-(4-allyl-piperazin-1-yl)-2-quinoxaloline carboxylate maleic acid, zacopride hydrochloride, and mirtazapine.

[0338] In some implementations, the 5HT-3 receptor antagonist is granisetron, dolasetron, ondansetron, hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemyrosetron, or zatisetron.

[0339] In some implementations, the 5HT-3 receptor antagonist is granisetron, dolasetron, or ondansetron.

[0340] In some implementations, the 5HT-3 receptor antagonist is granisetron.

[0341] In some implementations, the 5HT-3 receptor antagonist is ondansetron.

[0342] In some implementations, the antiemetic is an antihistamine. Non-limiting examples of antihistamines include: piperazine derivatives (e.g., cyclazine, meclozine, and cinnarizine); promirtine; dimenhydrinate (Dramamine, Gravol); diphenhydramine; hydroxyzine; bucrozine; and meclozine hydrochloride (chlorobenzamine (Bonine, Antivert)), doxylamine, and mirtazapine.

[0343] In some implementations, the antiemetic is an anticholinergic agent (acetylcholine receptor inhibitor). Non-limiting examples of anticholinergic agents include: atropine, scopolamine, glycopyrron, hyoscine, Trihexy-5 (benhexol hydrochloride), benzalkonium chloride, bisperidone hydrochloride, disipal (olfenadine citrate), diphenhydramine, hydroxyzine, hyoscyamine, and carmatrazine (propiconazole hydrochloride).

[0344] In some implementations, the antiemetic is a steroid (e.g., a corticosteroid). Non-limiting examples of steroids include betamethasone, dexamethasone, methylprednisolone, Prednisone®, and trimetrazine (Tigan).

[0345] In some implementations, the antiemetic is an NK1 receptor antagonist (e.g., a neurokinin 1 substance P receptor antagonist). Non-limiting examples of NK1 receptor antagonists include aprepitant, cassopindant, elopitant, fosaprepitant, maropitant, netupitant, lorapitant, and vertepitant.

[0346] 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 (nomipitan ammonium besylate / nomipitan ammonium chloride), LY 303870 (lanepitan), MDL-105172A, MDL-103896, MEN-11149, MEN-11467, DNK 333A, YM-49244, YM-44778, ZM-274773, MEN-10930, S-19752, Neuronorm, YM-35375, DA-5018, MK-869, L-754030, CJ-11974, L-758298, DNK-33A, 6b-l, CJ-11974 j, 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]diaza-aranoctano[2,1-g][1,7]naphthidine-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.

[0347] 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., propranolol, chlorpromazine, prochlorazine, perphenazine, hydroxyzine, thiotetracycline, metoprolol); benzamides (e.g., metoclopramide, domperidone); butyrophenones (e.g., haloperidol, droperidol); aripiprazole, bromapride, clopazole, domperidone, itopride, metoclopramide, trimebenzamide, and amisulpride.

[0348] In some implementations, the antiemetic is WIN 55-212 (a CB1 and CB2 receptor agonist).

[0349] Other exemplary antiemetics include: c-9280 (Merck); benzodiazepines (diazepam, midazolam, chlorhexidine); tranquilizers / antipsychotics (e.g., diazepam, haloperidol, and prochlorazine (Compazine®)); cerium oxalate; propofol; sodium citrate; dextran; fructose (Nauzene); orthophosphate; fructose; glucose (Emetrol); bismuth subsalicylate (Pepto Bismol); ephedrine; vitamin B6; peppermint, lavender, and lemon essential oils; and ginger.

[0350] Other exemplary antiemetics include those disclosed in US 20120101089 A1; US ​​10,071,088 B2; US 6,673,792 B1; US ​​6,197,329 B1; US ​​10,828,297 B2; US 10,322,106 B2; US 10,525,033 B2; WO2009080351 A1; WO 2019203753 A2; WO 2002020001 A2; US 8,119,697 B2; US 5,039,528; US20090305964A1; and WO 2006 / 111169, each of which is incorporated herein by reference in its entirety.

[0351] In some embodiments, an additional therapeutic agent or regimen is administered to the patient before contact with or application of the compound and pharmaceutical composition (e.g., about one hour, about six hours, about 12 hours, about 24 hours, about 48 hours, about one week, or about one month prior).

[0352] In some embodiments, an additional therapeutic agent or regimen is administered to the patient at approximately the same time as the compound and pharmaceutical composition is contacted or applied. For example, the additional therapeutic agent or regimen is administered to the patient simultaneously with the compound and pharmaceutical composition in the same dosage form. As another example, the additional therapeutic agent or regimen is administered to the patient in parallel with the compound and pharmaceutical composition in a separate dosage form. Patient selection

[0353] In some implementations, the method described herein further includes the step of identifying patients (e.g., subjects) who require such treatment (e.g., by means of blood tests, body mass index, or other conventional methods known in the art).

[0354] In some implementations, the methods described herein further include the step of identifying a patient (e.g., a patient) suffering from a disease, disorder, or condition as described herein (e.g., a GLP-1 related disease, disorder, or condition).

[0355] In some embodiments, the method described herein further includes the step of identifying a patient with type 2 diabetes (e.g., a patient). In some embodiments, determining whether a patient has type 2 diabetes includes performing measurements to determine the levels of hemoglobin A1c (HbA1c), fasting plasma glucose, non-fasting plasma glucose, or any combination thereof. In some embodiments, the HbA1c level is from about 6.5% to about 24.0%. In some embodiments, the HbA1c level is greater than or about 6.5%. In some embodiments, the HbA1c level is greater than or about 8.0%. In some embodiments, the HbA1c level is greater than or about 10.0%. In some embodiments, the HbA1c level is greater than or about 12.0%. In some embodiments, the HbA1c level is greater than or about 14.0%. In some embodiments, the HbA1c level is greater than or about 16.0%. In some embodiments, the HbA1c level is greater than or about 18.0%. In some embodiments, the HbA1c level is greater than or about 20.0%. In some implementations, the HbA1c level is greater than or about 22.0%. In some implementations, the HbA1c level is greater than or about 24.0%.

[0356] In some embodiments, the fasting plasma glucose level is greater than or about 120 mg / dL to greater than or about 750 mg / dL. In some embodiments, the fasting plasma glucose level is greater than or about 200 mg / dL to greater than or about 500 mg / dL. In some embodiments, the fasting plasma glucose level is greater than or about 300 mg / dL to greater than or about 700 mg / dL.

[0357] In some embodiments, the non-fasting plasma glucose level is greater than or about 190 mg / dL to greater than or about 750 mg / dL. In some embodiments, the non-fasting plasma glucose level is greater than or about 250 mg / dL to greater than or about 450 mg / dL. In some embodiments, the non-fasting plasma glucose level is greater than or about 400 mg / dL to greater than or about 700 mg / dL.

[0358] In some embodiments, determining whether a patient has type 2 diabetes further includes determining the patient's BMI. In some embodiments, the patient's BMI is greater than or about 22 kg / m² to greater than or about 100 kg / m². In some embodiments, the patient's BMI is greater than or about 30 kg / m² to greater than or about 90 kg / m². In some embodiments, the patient's BMI is greater than or about 40 kg / m² to greater than or about 80 kg / m². In some embodiments, the patient's BMI is greater than or about 50 kg / m² to greater than or about 70 kg / m².

[0359] In some embodiments, additional factors (e.g., risk factors) used to determine whether a patient has type 2 diabetes further include the patient's age and race. In some embodiments, the patient's age is greater than or approximately 10 years. In some embodiments, the patient's age is greater than or approximately 15 years. In some embodiments, the patient's age is greater than or approximately 20 years. In some embodiments, the patient's age is greater than or approximately 25 years. In some embodiments, the patient's age is greater than or approximately 30 years. In some embodiments, the patient's age is greater than or approximately 35 years. In some embodiments, the patient's age is greater than or approximately 40 years. In some embodiments, the patient's age is greater than or approximately 42 years. In some embodiments, the patient's age is greater than or approximately 44 years. In some embodiments, the patient's age is greater than or approximately 46 years. In some embodiments, the patient's age is greater than or approximately 48 years. In some embodiments, the patient's age is greater than or approximately 50 years. In some embodiments, the patient's age is greater than or approximately 52 years. In some embodiments, the patient's age is greater than or approximately 54 years. In some embodiments, the patient's age is greater than or approximately 56 years. In some embodiments, the patient's age is greater than or about 58 years. In some embodiments, the patient's age is greater than or about 60 years. In some embodiments, the patient's age is greater than or about 62 years. In some embodiments, the patient's age is greater than or about 64 years. In some embodiments, the patient's age is greater than or about 66 years. In some embodiments, the patient's age is greater than or about 68 years. In some embodiments, the patient's age is greater than or about 70 years. In some embodiments, the patient's age is greater than or about 72 years. In some embodiments, the patient's age is greater than or about 74 years. In some embodiments, the patient's age is greater than or about 76 years. In some embodiments, the patient's age is greater than or about 78 years. In some embodiments, the patient's age is greater than or about 80 years. In some embodiments, the patient's age is greater than or about 85 years. In some embodiments, the patient's age is greater than or about 90 years. In some embodiments, the patient's age is greater than or about 95 years. In some implementation schemes, the patient's race can be African American, American Indian or Alaskan Native, Asian American, Hispanic or Latino or Native Hawaiian or Pacific Islander. General Synthesis Method

[0360] The compounds disclosed herein can be prepared from readily available starting materials using, for example, the following general methods and procedures. It will be understood that, unless otherwise stated, other process conditions may also be used where certain process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given. Optimal reaction conditions may vary depending on the reactants or solvents used, but such conditions can be determined by those skilled in the art through conventional optimization procedures.

[0361] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting a particular functional group, are well known in the art. For example, many protecting groups are described in, for example, TW Greene and GM Wuts (1999), Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and the references cited therein.

[0362] Furthermore, the compounds of this disclosure may contain one or more chiral centers. Therefore, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as mixtures enriched with stereoisomers, if desired. Unless otherwise indicated, all such stereoisomers (and enriched mixtures) are included within the scope of this disclosure. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, etc.

[0363] The starting materials used in the following reactions are commonly known compounds or can be prepared by known procedures or obvious modifications thereof. 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 (Escherich, Germany), or Millipore Sigma (Burlington, Massachusetts, USA). Other starting materials may be prepared by procedures described in standard reference texts, such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1–15 (John Wiley, and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1–5 and 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).

[0364] Scheme I demonstrates a general method that can be used to synthesize the compounds described herein, wherein ring A, ring B, X, Z, and Q... 1 Q 2 Q 3 Q 4 Q 5 L 1 L 2 R 1 R C , q, m and s are each independently as defined herein, and LG is a leaving group such as a halogen (e.g., hydroxyl, alkoxy, halogen, etc.). Option I

[0365] Compounds of Formula I can be provided by coupling compound I-1 with compound I-2 under suitable coupling reaction conditions (such as amide bond formation reaction conditions or nucleophilic substitution reaction conditions). The resulting product can be further derivatized by methods and chemical transformations known to those skilled in the art to obtain alternative compounds of Formula I. For example, when the leaving group is an electrophilic agent (such as an aldehyde), the coupling reaction conditions may include reductive amination reaction conditions. Therefore, the transformation may include more than one reaction or more than one set of reactants.

[0366] After the reaction is complete, the compound of Formula I can be recovered using conventional techniques such as neutralization, extraction, precipitation, chromatography, and filtration. In some embodiments, when it is desirable to control stereochemistry, appropriate control of the reaction conditions and the selection of substituents for the reagents can at least partially determine or preserve the formation of various stereoisomers.

[0367] In some embodiments, the various substituents of Formula I-1 or I-2 are as defined herein. However, derivatization and / or further derivatization of the resulting reaction products prior to any step of the reaction provide compounds of various Formula I. Suitable starting materials and reagents can be purchased or prepared by methods known to those skilled in the art. After each reaction, each of the intermediate or final compounds can be recovered and optionally purified by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, etc. Other modified methods for obtaining the compounds of this disclosure are within the scope of the art.

[0368] In some embodiments, methods are provided for preparing compounds of formula I or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, said methods comprising: […]. I-1 Compounds of formula I-2: I-2 Contact under conditions sufficient to provide a compound of Formula I or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug, wherein ring A, ring B, X, Z, Q 1 Q 2 Q 3 Q 4 Q 5 L 1 L 2 R 1 R C , q, m and s are as defined herein, and LG is a leaving group.

[0369] In some embodiments, the method further includes a hydrolysis or transesterification step before or after contact. In some embodiments, the method includes an alkali. In some embodiments, the method includes an elevated temperature. Example

[0370] This disclosure can be further understood by referring to the following embodiments, which are intended to be purely illustrative. The scope of this disclosure is not limited to the exemplary embodiments, which are only intended to illustrate a single aspect of this disclosure. Any functionally equivalent methods are within the scope of this disclosure. Various modifications to this disclosure, in addition to those described herein, will become apparent to those skilled in the art from the foregoing description and drawings. Such modifications fall within the scope of the appended claims.

[0371] Abbreviations (as used in this article):

[0372] General Information: All evaporation or concentration was performed in a rotary evaporator under vacuum. Analytical samples were dried in a vacuum (1–5 mmHg) 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 using silica gel (100–200 mesh) via column chromatography and rapid chromatography. Solvent systems are reported as mixtures by volume. NMR spectra were recorded on a Bruker 400 or Varian (400 MHz) spectrometer. 1 H chemical shifts are reported as δ values ​​in ppm, with the deuterated solvent used as an internal standard. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad peak, m = multiply), coupling constant (Hz), and integral. Unless otherwise specified, LCMS spectra were obtained on a SHIMADZU LC20-MS2020 or Agilent 1260 series 6125B mass spectrometer or an Agilent 1200 series 6110 or 6120 mass spectrometer with electrospray ionization. Example A1 3-{1-[2-({3-[1-(4-fluoro-3,5-xylyl)-5-(2-oxo-3-phenyl-1,3-dihydro-1-imidazolyl)-4-pyrazolyl]-1-azacyclobutyl}carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1-indolyl]cyclopropyl}-1,2,4-oxadiazol-5(2H)-one (Compound 107)

[0373] Step A: tert-butyl 3-(cyanomethyl)azacyclobutane-1-carboxylate

[0374] Under a nitrogen atmosphere, 10% Pd / C (1.00 g) was added to a solution of tert-butyl 3-(cyanomethylene)azacyclobutane-1-carboxylate (10.00 g, 51.50 mmol) in EtOAc (100 mL). The mixture was degassed and purged three times with H2. The mixture was stirred at 25ºC under H2 (15 Psi) for 12 h. The reaction mixture was filtered and concentrated to give tert-butyl 3-(cyanomethylene)azacyclobutane-1-carboxylate (7.80 g, 77.1% yield). LC-MS: m / z 246.1 (M+H) + .

[0375] Step B: tert-butyl 3-(1-cyano-2-oxoethyl)azacyclobutane-1-carboxylate

[0376] At -70ºC under N2 atmosphere, tert-butyllithium (19.08 mL, 47.70 mmol, 2.5 mol / L in THF) was added to a solution of tert-butyl 3-(cyanomethyl)azacyclobutane-1-carboxylate (7.80 g, 39.70 mmol) in 78 mL of THF. After addition, the reaction mixture was stirred at -70ºC under N2 atmosphere for 0.5 h. Ethyl formate (3.88 mL, 47.70 mmol) was added to the mixture, followed by stirring at -70ºC under N2 atmosphere for 2 h. The mixture was poured into ice water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with 25%–100% EtOAc / PE) to give tert-butyl 3-(1-cyano-2-oxoethyl)azacyclobutane-1-carboxylate (4.10 g, 46.0% yield).

[0377] Step C: 3-(5-amino-1-(4-fluoro-3,5-dimethylphenyl)-1H-pyrazol-4-yl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0378] A mixture of tert-butyl 3-(1-cyano-2-oxoethyl)azacyclobutane-1-carboxylate (3.00 g, 13.38 mmol), (4-fluoro-3,5-dimethylphenyl)hydrazine (2.06 g, 13.38 mmol), and TEA (5.59 mL, 40.10 mmol) in EtOH (30 mL) was degassed and purged three times with N2. The mixture was then stirred at 80ºC under N2 atmosphere for 16 h. The resulting mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with 25%–40% EtOAc / PE) to give tert-butyl 3-(5-amino-1-(4-fluoro-3,5-dimethylphenyl)-1H-pyrazol-4-yl)azacyclobutane-1-carboxylate (3.08 g, 63.9% yield). LC-MS: m / z 361.3 (M+H) + .

[0379] Step D: tert-butyl 3-(5-(3-(2,2-dimethoxyethyl)ureo)-1-(4-fluoro-3,5-dimethylphenyl)-1H-pyrazol-4-yl)azacyclobutane-1-carboxylate

[0380] To a mixture of tert-butyl 3-(5-amino-1-(4-fluoro-3,5-dimethylphenyl)-1H-pyrazol-4-yl)azacyclobutane-1-carboxylate (1.70 g, 4.71 mmol) in DMA (17 mL), N-(2,2-dimethoxyethyl)-1H-imidazol-1-carboxamide (1.03 g, 5.18 mmol) and potassium tert-butoxide (1.59 g, 14.12 mmol) were added. After addition, the mixture was degassed and purged three times with N2, followed by stirring at 25ºC under N2 atmosphere for 4 h. The resulting mixture was diluted with water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (eluting with 25%–100% EtOAc / PE) to give tert-butyl 3-(5-(3-(2,2-dimethoxyethyl)ureido)-1-(4-fluoro-3,5-dimethylphenyl)-1H-pyrazol-4-yl)azacyclobutane-1-carboxylate (1.83 g, 79.1% yield). LC-MS: m / z 492.2 (M+H) + .

[0381] Step E 3-(1-(4-fluoro-3,5-dimethylphenyl)-5-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-1H-pyrazol-4-yl) tert-butyl azelazone-1-carboxylate

[0382] A mixture of tert-butyl 3-(5-(3-(2,2-dimethoxyethyl)ureido)-1-(m-tolyl)-1H-pyrazol-4-yl)azacyclobutane-1-carboxylic acid (1.83 g, 3.98 mmol) and 4-methylbenzenesulfonic acid (0.69 g, 3.98 mmol) in THF (100 mL) was degassed and purged three times with N2, followed by stirring at 60ºC under N2 atmosphere for 2 h. The reaction mixture was quenched by adding 25 mL of saturated NaHCO3 aqueous solution at 25ºC. The resulting mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with 5%–20% EtOAc / PE) to give tert-butyl 3-(1-(4-fluoro-3,5-dimethylphenyl)-5-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-1H-pyrazol-4-yl)azacyclobutane-1-carboxylate (1.11 g, 65.4% yield). LC-MS: m / z 428.1 (M+H) + .

[0383] Step F 3-(1-(4-fluoro-3,5-dimethylphenyl)-5-(2-oxo-3-phenyl-2,3-dihydro-1H-imidazol-1-yl)-1H-pyrazol-4-yl) tert-butyl azelazone-1-carboxylate

[0384] To a solution of tert-butyl 3-(1-(4-fluoro-3,5-dimethylphenyl)-5-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-1H-pyrazol-4-yl)azacyclobutane-1-carboxylate (300.0 mg, 0.70 mmol) in NMP (3 mL), iodobenzene (0.30 mL, 1.05 mmol), copper(I) iodide (268.0 mg, 1.40 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (49.9 mg, 0.35 mmol) and potassium carbonate (194.0 mg, 1.40 mmol) were added. The reaction mixture was then stirred at 130ºC for 1 h. The mixture was then cooled to 25ºC, diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by preparative TLC (SiO₂, DCM: MeOH = 20:1) to give tert-butyl 3-(1-(4-fluoro-3,5-dimethylphenyl)-5-(2-oxo-3-phenyl-2,3-dihydro-1H-imidazol-1-yl)-1H-pyrazol-4-yl)azacyclobutane-1-carboxylate (150.0 mg, 42.4% yield). LC-MS: m / z 504.4 (M+H) + .

[0385] Step F 1-(4-(azacyclobutane-3-yl)-1-(4-fluoro-3,5-dimethylphenyl)-1H-pyrazol-5-yl)-3-phenyl-1,3-dihydro-2H-imidazol-2-one TFA salt

[0386] At 25ºC, a solution of TFA (1 mL, 12.89 mmol) was added to a solution of tert-butyl 3-(1-(4-fluoro-3,5-dimethylphenyl)-5-(2-oxo-3-phenyl-2,3-dihydro-1H-imidazol-1-yl)-1H-pyrazol-4-yl)azacyclobutane-1-carboxylate (0.08 g, 0.159 mmol) in DCM (1 mL). After addition, the reaction was stirred at 25ºC for 2 h. The reaction mixture was then concentrated to give the TFA salt of 1-(4-(azacyclobutane-3-yl)-1-(4-fluoro-3,5-dimethylphenyl)-1H-pyrazol-5-yl)-3-phenyl-1,3-dihydro-2H-imidazol-2-one (0.064 g, crude), which was used directly for the next step without further purification. LC-MS: m / z 404.3 (M+H) + .

[0387] Step F 3-{1-[2-({3-[1-(4-fluoro-3,5-xylyl)-5-(2-oxo-3-phenyl-1,3-dihydro-1-imidazolyl)-4-pyrazolyl]-1-azacyclobutyl}carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1-indolyl]cyclopropyl}-1,2,4-oxadiazol-5(2H)-one (Compound 107)

[0388] To a solution of 1-(4-(azacyclobutan-3-yl)-1-(4-fluoro-3,5-dimethylphenyl)-1H-pyrazol-5-yl)-3-phenyl-1,3-dihydro-2H-imidazol-2-one TFA salt (0.065 g, 0.161 mmol) in DMF (1 mL), 1-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (0.060 g, 0.16 mmol), DIEA (0.11 mL, 0.64 mmol), and HATU (0.074 g, 0.19 mmol) were added. The reaction mixture was stirred at 25ºC for 2 h. The reaction mixture was diluted with H2O (2 mL) and extracted with ethyl acetate (2 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (SiO2, DCM: MeOH = 20:1) and further purified by HPLC (SHIMADZU LC-20AP, column: Welch XB-C18, 20*250 mm, 10 μm; mobile phase A: 0.1% FA / H2O, B: CH3CN; gradient: 67% - 90% B; flow rate: 20 mL / min; retention time: 18 min, for a total of 20 runs). (min) purification to give 3-{1-[2-({3-[1-(4-fluoro-3,5-xylyl)-5-(2-oxo-3-phenyl-1,3-dihydro-1-imidazolyl)-4-pyrazolyl]-1-azacyclobutyl}carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1-indolyl]cyclopropyl}-1,2,4-oxadiazol-5(2H)-one (41.6 mg, 34.2% yield). LC-MS: m / z 755.3 (M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.58 - 7.55(m, 2H), 7.46 - 7.38 (m, 4H), 7.28 - 7.19 (m, 3H), 7.13 (d, J = 8.0 Hz, 2H), 6.89 (d, J = 4.0 Hz, 1H), 6.82 (s, 1H), 4.55 - 4.25 (m, 3H), 3.99 - 3.95 (m,2H), 3.87 - 3.81 (m, 1H), 3.50 - 3.44 (m, 2H), 2.88 - 2.82 (m, 1H), 2.20 (d,J = 2.1 Hz, 6H), 2.05 - 1.99 (m, 1H), 1.75 - 1.66 (m, 6H), 1.54 - 1.50 (m, 2H). Example A2 3-(1-(2-(3-(1-(4-fluoro-3,5-dimethylphenyl)-5-(3-(1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-1H-pyrazol-4-yl)azacyclobutane-1-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(2H)-one (Compound 104)

[0389] Step A: 3-(1-(4-fluoro-3,5-dimethylphenyl)-5-(3-(1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-1H-pyrazol-4-yl) tert-butyl azacyclobutane-1-carboxylate

[0390] A mixture of tert-butyl 3-(1-(4-fluoro-3,5-dimethylphenyl)-5-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-1H-pyrazol-4-yl)azacyclobutane-1-carboxylate (120.0 mg, 0.28 mmol), copper iodide (I) (107.0 mg, 0.56 mmol), 5-bromo-1-methyl-1H-indazole (89.0 mg, 0.42 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (0.022 mL, 0.14 mmol), and potassium carbonate (78.0 mg, 0.56 mmol) in NMP (3 mL) was degassed and purged three times with N2. The mixture was stirred at 130ºC under N2 atmosphere for 2 h. After cooling to room temperature, the resulting mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by preparative TLC (SiO₂, PE : EtOAc = 1 : 1) to give tert-butyl 3-(1-(4-fluoro-3,5-dimethylphenyl)-5-(3-(1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-1H-pyrazol-4-yl)azacyclobutane-1-carboxylate (146.0 mg, 93.2% yield). LC-MS: m / z 558.4 (M+H) + .

[0391] Step B: 1-(4-(azacyclobutane-3-yl)-1-(4-fluoro-3,5-dimethylphenyl)-1H-pyrazol-5-yl)-3-(1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one TFA salt

[0392] Trifluoroacetic acid (1 mL, 12.98 mmol) was added to a solution of tert-butyl 3-(1-(1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-1H-pyrazol-4-yl)azacyclobutane-1-carboxylate (146.0 mg, 0.26 mmol) in DCM (2 mL). The mixture was stirred at 25ºC for 2 h. The resulting mixture was concentrated to give 1-(4-(azacyclobutan-3-yl)-1-(4-fluoro-3,5-dimethylphenyl)-1H-pyrazol-5-yl)-3-(1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one TFA salt (120.0 mg, crude), which was used directly in the next step without further purification. LC-MS: m / z 458.3 (M+H) + .

[0393] Step C 3-(1-(2-(3-(1-(4-fluoro-3,5-dimethylphenyl)-5-(3-(1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-1H-pyrazol-4-yl)azacyclobutane-1-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(2H)-one (Compound 104)

[0394] To a solution of 1-(4-(azacyclobutan-3-yl)-1-(4-fluoro-3,5-dimethylphenyl)-1H-pyrazol-5-yl)-3-(1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one TFA salt (120.0 mg, 0.26 mmol) in DMF (2 mL), 1-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (97.0 mg, 0.26 mmol), HATU (130.0 mg, 0.34 mmol), and DIEA (0.18 mL, 1.05 mmol) were added. After addition, the mixture was stirred at 25ºC for 2 h. The resulting mixture was diluted with H2O (2 mL) and extracted with ethyl acetate (2 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (SiO2, DCM: MeOH = 20:1) and further purified by preparative HPLC (SHIMADZU LC-20AP, column: YMC Triart C18, 20*250 mm, 5 μm; mobile phase A: 0.1% FA / H2O, B: CH3CN; gradient: 40%-60% B; flow rate: 15 mL / min; retention time: 24-28 min, for a total of 30 runs). (min) Purification yielded 3-(1-(2-(3-(1-(4-fluoro-3,5-dimethylphenyl)-5-(3-(1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-1H-pyrazol-4-yl)azacyclobutane-1-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(2H)-one (8.6 mg, 4.1% yield) as a white solid. LC-MS: m / z 809.3 (M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 7.97 - 7.94 (m, 2H), 7.85 (s, 1H), 7.63 - 7.61 (m, 1H), 7.53 -7.51 (m, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.33 (s,1H), 7.18 - 7.14 (m, 4H), 6.88 (d, J = 4.0 Hz, 1H), 6.73 (s, 1H), 4.65 - 4.45(m, 2H), 4.25 - 4.15 (m, 1H), 4.04 (s, 3H), 3.99 - 3.94 (m, 2H), 3.86 - 3.78(m, 1H), 3.49 - 3.43 (m, 4H), 2.84 - 2.76 (m, 1H), 2.21 - 2.20 (m, 6H), 1.72- 1.63 (m, 6H), 1.45 - 1.40 (m, 2H). Example A3 3-[(1S,2S)-1-[2-({3-[5-(3-{4-[diethyl(oxo)-λ5-phosphino]-3-(methylamino)phenyl}-2-oxoimidazol-1-yl)-1-(4-fluoro-3,5-dimethylphenyl)pyrazol-4-yl]azacyclobutane-1-yl}carbonyl)-5-(3,4,5,6-tetrahydro-2H-pyran-4-yl)indol-1-yl]-2-methylcyclopropyl]-2H,5H-1,2,4-oxadiazol-5-one (Compound 101)

[0395] Step A: 3-[5-(3-{4-[diethyl(oxo)-λ5-phosphino]-3-(methylamino)phenyl}-2-oxoimidazol-1-yl)-1-(4-fluoro-3,5-dimethylphenyl)pyrazol-4-yl]azacyclobutane-1-carboxylic acid tert-butyl ester

[0396] To a solution of 3-[1-(4-fluoro-3,5-dimethylphenyl)-5-(2-oxo-3H-imidazol-1-yl)pyrazol-4-yl]azacyclobutane-1-carboxylic acid tert-butyl ester (100 mg, 0.234 mmol) in NMP (5 mL), {5-bromo-2-[diethyl(oxo)-λ5-phosphino]phenyl}(methyl)amine (101.84 mg, 0.351 mmol), methyl[(1R,2R)-2-(methylamino)cyclohexyl]amine (49.93 mg, 0.351 mmol), CuI (53.48 mg, 0.281 mmol), and K₂CO₃ (64.68 mg, 0.468 mmol) were added. The reaction mixture was stirred at 130ºC for 3 h. The reaction mixture was poured into H₂O (10.0 mL) and extracted with EtOAc (10 mL x 3). The combined organic compounds were washed with brine and dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluting with 5% MeOH / DCM) to give tert-butyl 3-[5-(3-{4-[diethyl(oxo)-λ5-phosphino]-3-(methylamino)phenyl}-2-oxoimidazol-1-yl)-1-(4-fluoro-3,5-dimethylphenyl)pyrazol-4-yl]azacyclobutane-1-carboxylate (90 mg, 60.4% yield). LC-MS: m / z 637.5 (M+H) + .

[0397] Step B: 1-[4-(azacyclobutane-3-yl)-2-(4-fluoro-3,5-dimethylphenyl)pyrazol-3-yl]-3-{4-[diethyl(oxo)-λ5-phosphino]-3-(methylamino)phenyl}-2,3-dihydro-1H-imidazol-2-one TFA salt

[0398] TFA (0.3 mL) was added to a solution of tert-butyl 3-[5-(3-{4-[diethyl(oxo)-λ5-phosphino]-3-(methylamino)phenyl}-2-oxoimidazol-1-yl)-1-(4-fluoro-3,5-dimethylphenyl)pyrazol-4-yl]azacyclobutane-1-carboxylate (90 mg, 0.141 mmol) in DCM (1 mL). The reaction was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum to give 1-[4-(azacyclobutane-3-yl)-2-(4-fluoro-3,5-dimethylphenyl)pyrazol-3-yl]-3-{4-[diethyl(oxo)-λ5-phosphino]-3-(methylamino)phenyl}-2,3-dihydro-1H-imidazol-2-one TFA salt (75 mg, crude). LC-MS: m / z 537.4 (M+H) + .

[0399] Step C: 3-[(1S,2S)-1-[2-({3-[5-(3-{4-[diethyl(oxo)-λ5-phosphino]-3-(methylamino)phenyl}-2-oxoimidazol-1-yl)-1-(4-fluoro-3,5-dimethylphenyl)pyrazol-4-yl]azacyclobutane-1-yl}carbonyl)-5-(3,4,5,6-tetrahydro-2H-pyran-4-yl)indol-1-yl]-2-methylcyclopropyl]-2H,5H-1,2,4-oxadiazol-5-one (Compound 101)

[0400] Add DIEA (54.28 mg, 0.420 mmol), 1-[(1S,2S)-2-methyl-1-(5-oxo-2H-1,2,4-oxadiazol-3-yl)cyclopropyl]-5-(3,4,5,6-tetrahydro-2H-pyran-4-yl)indole-2-carboxylic acid (53.59 mg, 0.140 mmol), and HATU (106.47 mg, 0.280 mmol) to a solution of 1-[4-(azacyclobutan-3-yl)-2-(4-fluoro-3,5-dimethylphenyl)pyrazol-3-yl]-3-{4-[diethyl(oxo)-λ5-phosphono]-3-(methylamino)phenyl}-2,3-dihydro-1H-imidazol-2-one TFA salt (75 mg, 0.140 mmol) in DMF (5 mL). The reaction was stirred at room temperature for 3 h. The mixture was then passed directly through a preparative HPLC system (Waters 2767 / Qda, column: SunFire Sunfire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / H2O, B: CH3CN; gradient: 60%-65% B; flow rate: 20 mL / min; retention time: 8.1-8.6 min, for a total run of 17). (min) Purification yielded 3-[(1S,2S)-1-[2-({3-[5-(3-{4-[diethyl(oxo)-λ5-phosphino]-3-(methylamino)phenyl}-2-oxoimidazol-1-yl)-1-(4-fluoro-3,5-dimethylphenyl)pyrazol-4-yl]azacyclobutane-1-yl}carbonyl)-5-(3,4,5,6-tetrahydro-2H-pyran-4-yl)indol-1-yl]-2-methylcyclopropyl]-2H,5H-1,2,4-oxadiazol-5-one (2.1 mg, 1.65% yield). LC-MS: m / z 902.4 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ 7.97 (s, 1 H), 7.67 (d, J= 5.2 Hz, 1 H), 7.43 (s, 1 H), 7.38 (d, J= 8.0 Hz, 1 H), 7.25 - 7.23 (m, 2 H), 7.17 - 7.13 (m, 3 H), 6.90 - 6.89 (m, 1 H), 6.86 - 6.82 (m, 3 H), 4.56 - 4.50 (m, 2 H), 4.34 - 4.21 (m, 2 H), 3.99-3.96 (m, 2 H), 3.89 - 3.83 (m, 1 H), 3.52 - 3.44 (m, 2 H), 2.89 - 2.82(m, 1 H), 2.72 - 2.65 (m, 4 H), 2.35 - 2.31 (m, 1 H), 2.22 (s, 6 H), 1.95 -1.86 (m, 4 H), 1.77 - 1.70 (m, 4 H), 1.68 - 1.64 (m, 1H), 1.51 - 1.44 (m, 1H), 1.29 - 1.21 (m, 3H), 1.07 - 0.96 (m, 6H).

[0401] Compounds 102, 103, 105, 109, 110, 111, 117 and 119 of the examples were synthesized using appropriate materials using a similar procedure to that described in Example A3 above. Example A4 3-((1S,2S)-2-methyl-1-(2-(3-(5-(2-oxo-3-phenyl-2,3-dihydro-1H-imidazol-1-yl)-1-phenyl-1H-pyrazol-4-yl)azacyclobutane-1-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 106)

[0402] Step A: tert-butyl 3-(5-amino-1-phenyl-1H-pyrazole-4-yl)azacyclobutane-1-carboxylate

[0403] Phenylated hydrazine (116.0 mg, 1.07 mmol) and pyridine hydrochloride (10.31 mg, 0.089 mmol) were added to a mixture of 3-(1-cyano-2-oxoethyl)azacyclobutane-1-carboxylic acid tert-butyl ester (200.0 mg, 0.89 mmol) in EtOH (2 mL). After addition, the resulting mixture was stirred at 80ºC for 16 h. After cooling to room temperature, the reaction mixture was concentrated. The residue was analyzed by preparative TLC (SiO2, PE: EtOAc).

[0404] = 1 : 1) Purification to give tert-butyl 3-(5-amino-1-phenyl-1H-pyrazol-4-yl)azacyclobutane-1-carboxylate (120.0 mg, 42.8% yield). LC-MS: m / z 315.1 (M+H) + .

[0405] Step B: 3-(5-(3-(2,2-dimethoxyethyl)ureo)-1-phenyl-1H-pyrazole-4-yl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0406] To a mixture of tert-butyl 3-(5-amino-1-phenyl-1H-pyrazol-4-yl)azacyclobutane-1-carboxylate (120.0 mg, 0.38 mmol) in DMF (1 mL), N-(2,2-dimethoxyethyl)-1H-imidazol-1-carboxamide (84 mg, 0.420 mmol) and potassium tert-butoxide (128 mg, 1.145 mmol) were added. The resulting mixture was stirred at 25ºC for 3 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL) and concentrated on ice by drying with Na2SO4. The residue was purified by preparative TLC (SiO2, PE: EtOAc = 1:1) to give tert-butyl 3-(5-(3-(2,2-dimethoxyethyl)ureido)-1-phenyl-1H-pyrazol-4-yl)azacyclobutane-1-carboxylate (107.0 mg, 62.9% yield). LC-MS: m / z 446.3 (M+H) + .

[0407] Step C: 3-(5-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-1-phenyl-1H-pyrazol-4-yl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0408] 4-Methylbenzenesulfonic acid (124.0 mg, 0.72 mmol) was added to a solution of tert-butyl 3-(5-(3-(2,2-dimethoxyethyl)ureido)-1-phenyl-1H-pyrazol-4-yl)azacyclobutane-1-carboxylic acid (107.0 mg, 0.24 mmol) in THF (5 mL). The resulting mixture was stirred at 60ºC for 2 h. After cooling to room temperature, the reaction was quenched with a saturated aqueous solution of NaHCO3. The reaction mixture was then poured into water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by preparative TLC (SiO2, PE: EtOAc = 1:1) to give tert-butyl 3-(5-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-1-phenyl-1H-pyrazol-4-yl)azacyclobutane-1-carboxylate (78.0 mg, 85.0% yield). LC-MS: m / z 382.1 (M+H) + .

[0409] Step D: 3-(5-(2-oxo-3-phenyl-2,3-dihydro-1H-imidazol-1-yl)-1-phenyl-1H-pyrazol-4-yl) tert-butyl azepine-1-carboxylate

[0410] To a solution of tert-butyl 3-(5-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-1-phenyl-1H-pyrazol-4-yl)azacyclobutane-1-carboxylate (78.0 mg, 0.20 mmol) in NMP (1 mL), K₂CO₃ (56.5 mg, 0.41 mmol), iodobenzene (45.78 mg, 0.22 mmol), copper(I) iodide (78.0 mg, 0.41 mmol), and (1S,2S)-N₁,N₂-dimethylcyclohexane-1,2-diamine (14.54 mg, 0.10 mmol) were added. After addition, the resulting mixture was stirred at 130ºC for 2 h under a N₂ atmosphere. After cooling to room temperature, the reaction mixture was poured into water (30 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by preparative TLC (PE:EtOAc = 1:1) to give tert-butyl 3-(5-(2-oxo-3-phenyl-2,3-dihydro-1H-imidazol-1-yl)-1-phenyl-1H-pyrazol-4-yl)azacyclobutane-1-carboxylate (67.0 mg, 71.6% yield). LC-MS: m / z 457.2 (M+H) + .

[0411] Step E: 1-(4-(azacyclobutane-3-yl)-1-phenyl-1H-pyrazol-5-yl)-3-phenyl-1,3-dihydro-2H-imidazol-2-one TFA salt

[0412] TFA (1 mL, 12.98 mmol) was added to a mixture of tert-butyl 3-(5-(2-oxo-3-phenyl-2,3-dihydro-1H-imidazol-1-yl)-1-phenyl-1H-pyrazol-4-yl)azacyclobutane-1-carboxylate (67.0 mg, 0.15 mmol) in DCM (1 mL). The resulting mixture was stirred at 25ºC for 1 h. The reaction mixture was concentrated to give the TFA salt of 1-(4-(azacyclobutane-3-yl)-1-phenyl-1H-pyrazol-5-yl)-3-phenyl-1,3-dihydro-2H-imidazol-2-one (53.0 mg, crude), which was used directly for the next step without further purification. LC-MS: m / z 358.2 (M+H) + .

[0413] Step F 3-((1S,2S)-2-methyl-1-(2-(3-(5-(2-oxo-3-phenyl-2,3-dihydro-1H-imidazol-1-yl)-1-phenyl-1H-pyrazol-4-yl)azacyclobutane-1-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 106)

[0414] To a solution of 1-(4-(azacyclobutan-3-yl)-1-phenyl-1H-pyrazol-5-yl)-3-phenyl-1,3-dihydro-2H-imidazol-2-one TFA salt (53.0 mg, 0.15 mmol) in DMF (600 µL), 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (144.0 mg, 0.38 mmol), DIEA (131 µL, 0.75 mmol), and HATU (93.0 mg, 0.24 mmol) were added. After addition, the mixture was stirred at 25ºC for 2 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Welch, XB-C18 (250*20 mm, 10 μm); mobile phase: [water (0.1% FA) - CH3CN]; gradient: 67%-87% B, retention time: 10.0-10.5 min, run for 20 min) to give 3-((1S,2S)-2-methyl-1-(2-(3-(5-(2-oxo-3-phenyl-2,3-dihydro-1H-imidazol-1-yl)-1-phenyl-1H-pyrazol-4-yl)azacyclobutane-1-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (41.0 mg, 38.3% yield). LC-MS: m / z 723.0 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.04(s, 1H), 7.65 - 7.55 (m, 2H), 7.51 - 7.37 (m, 9H),7.28 - 7.22 (m, 3H), 6.92(d, J = 4.0 Hz, 1H), 6.88 - 6.80 (m, 1H), 4.60 - 4.20 (m, 4H), 3.99 - 3.96(m, 1H), 3.90 - 3.85 (m, 1H), 3.51 - 3.45 (m, 2H), 2.91 - 2.81 (m, 1H), 2.55(s, 1H), 1.90 - 1.65 (m, 6H), 1.47 - 1.39 (m, 1H), 1.30 - 1.15 (m, 3H).

[0415] Compounds 108, 112-116, and 120-125 of the examples were synthesized using appropriate materials using a similar procedure to that described in Example A4 above. Example A5 3-[(1S,2S)-1-[2-({3-[5-(1-{4-[cyclopropyl(methylazinyl)(oxo)-λ6-thioalkyl]-2-fluoro-3-methylphenyl}-2-oxoimidazol-3-yl)-1-(4-fluoro-3,5-dimethylphenyl)pyrazol-4-yl]azacyclobutane-1-yl}carbonyl)-5-(3,4,5,6-tetrahydro-2H-pyran-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H,5H-1,2,4-oxadiazol-5-one (compound 126)

[0416] Step A: 4-Bromo-3-fluoro-2-methylbenzene-1-thiol

[0417] Concentrated HCl (2.205 mL, 26.465 mmol) was added to a mixture of 4-bromo-3-fluoro-2-methylaniline (2.7 g, 13.233 mmol) in H₂O (10 mL). The reaction mixture was cooled in an ice / NaCl bath (approximately -5ºC to -10ºC), and a solution of sodium nitrite (958.6 mg, 13.894 mmol) in H₂O (10 mL) was slowly added over 10 minutes. The mixture was then stirred for another 30 minutes while still cooled. Separately, a solution of potassium [(ethoxythioformyl)thioalkyl] (2545.3 mg, 15.879 mmol) in H₂O (30 mL) was prepared and heated to 65ºC. The cold solution of the diazonium salt was then slowly added to the warm solution of potassium ethyl xanthate over 20 minutes. The reaction mixture was stirred for another 30 minutes at 65ºC and then cooled to ambient temperature. A solution of NaOH (2646.6 mg, 66.165 mmol) in H₂O (10 mL) was added, and the reaction was stirred at 70ºC for 18 h. After the reaction was complete (monitored by TLC), the mixture was cooled to room temperature, poured into ice (200 g), acidified to pH = 1 with concentrated HCl, and extracted with EtOAc (50 mL x 3). The combined organic extracts were dried over anhydrous Na₂SO₄, filtered, and concentrated to give 4-bromo-3-fluoro-2-methylbenzene-1-thiol (3.7 g, crude), which was used in the next step without purification.

[0418] Step B (4-bromo-3-fluoro-2-methylphenyl)(cyclopropyl)thion

[0419] Potassium tert-butoxide (3.76 g, 33.471 mmol) and bromocyclopropane (10.12 g, 83.676 mmol) were added to a solution of 4-bromo-3-fluoro-2-methylphenyl-1-thiol (3.7 g, 16.735 mmol) in DMSO (60 mL). The reaction was stirred at 100ºC under N2 for 18 h. TLC showed that the reaction was complete. The mixture was poured into water (100 mL) and extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (eluting with PE 100%) to give (4-bromo-3-fluoro-2-methylphenyl)(cyclopropyl)thione (2.23 g, 50.3% yield).

[0420] Step C (4-bromo-3-fluoro-2-methylphenyl)(cyclopropyl)(oxo)-λ6-thionimine

[0421] Add (diacetoxyiodine)benzene (8.29 g, 25.572 mmol) and ammonium carbamate (2.66 g, 34.095 mmol) to a solution of (4-bromo-2-fluorophenyl)(cyclopropyl)thione (2.2 g, 8.524 mmol) in MeOH (30 mL). Stir the reaction at room temperature for 1 h. After the reaction is complete, add water (50 mL). Extract the mixture with EtOAc (30 mL x 3). Wash the combined organic layers with brine, dry over sodium sulfate, filter, and concentrate. Purify the residue by silica gel chromatography (eluting with 0–50% EtOAc / PE) to give (4-bromo-3-fluoro-2-methylphenyl)(cyclopropyl)(oxo)-λ6-thionimine (1.17 g, 47.5% yield). LC-MS: m / z 294.0 (M+H) + .

[0422] Step D (4-bromo-3-fluoro-2-methylphenyl)(cyclopropyl)(oxo)-λ6-thionimine (enantiomer 1) 12-5a

[0423] A mixture of compounds (4-bromo-3-fluoro-2-methylphenyl)(cyclopropyl)(oxo)-λ6-thionimine (1.17 g, 4.00 mmol) was separated by SFC (column: DAICELCHIRALCEL® AS 250 mm*25 mm, 10 μm, mobile phase A (supercritical CO2), mobile phase B (MeOH (0.1% 7.0 M ammonia in MeOH)), gradient: B = 20%, flow rate: 100 mL / min, column temperature: 25ºC) to give (4-bromo-3-fluoro-2-methylphenyl)(cyclopropyl)(oxo)-λ6-thionimine (enantiomer 1) (517 mg, 44.2% yield) as the rapid eluent. LC-MS: m / z 294.0 (M+H)+, and (4-bromo-3-fluoro-2-methylphenyl)(cyclopropyl)(oxo)-λ6-thionimine (enantiomer 2) as a slow eluent (460 mg, 39.3% yield), LC-MS: m / z 294.0 (M+H) + .

[0424] Step E 1-(4-bromo-3-fluoro-2-methylphenyl)-1-cyclopropyl-N-methyl-1-oxo-λ6-thionimine

[0425] A solution of (4-bromo-3-fluoro-2-methylphenyl)(cyclopropyl)(oxo)-λ6-thioalkylimine (enantiomer 1) (3.2 g, 10.953 mmol) in dioxane (50 mL) was reacted with copper(II) acetate (5.97 mg, 32.858 mmol), Py (3.54 mL, 43.810 mmol), and methylboranediol (2.62 g, 43.810 mmol). The reaction was stirred at 100ºC under O2 for 1.5 h. After cooling, the mixture was concentrated. The resulting residue was purified by silica gel chromatography (eluting with 10% EtOAc / PE) to give 1-(4-bromo-3-fluoro-2-methylphenyl)-1-cyclopropyl-N-methyl-1-oxo-λ6-thioalkylimine (2.62 g, 78.0% yield). LC-MS: m / z 306.0 (M+H) + .

[0426] Step F 3-[5-(1-{4-[cyclopropyl(methylazinyl)(oxo)-λ6-thioalkyl]-2-fluoro-3-methylphenyl}-2-oxoimidazol-3-yl)-1-(4-fluoro-3,5-dimethylphenyl)pyrazol-4-yl]azacyclobutane-1-carboxylic acid tert-butyl ester

[0427] To a solution of tert-butyl 3-[1-(4-fluoro-3,5-dimethylphenyl)-5-(2-oxo-1H-imidazol-3-yl)pyrazol-4-yl]azacyclobutane-1-carboxylate (50 mg, 0.117 mmol) in NMP (5 mL), 1-(4-bromo-3-fluoro-2-methylphenyl)-1-cyclopropyl-N-methyl-1-oxo-λ6-thionimine (40 mg, 0.14 mmol), methyl[(1R,2R)-2-(methylamino)cyclohexyl]amine (24.96 mg, 0.175 mmol), CuI (26.73 mg, 0.140 mmol), and K₂CO₃ (32.33 mg, 0.234 mmol) were added. The reaction was stirred at 130ºC under N₂ for 3 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL x 3), dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (eluting with DCM / MeOH = 30 / 1) to give tert-butyl 3-[5-(1-{4-[cyclopropyl(methylazinyl)(oxo)-λ6-thioalkyl]-2-fluoro-3-methylphenyl}-2-oxoimidazol-3-yl)-1-(4-fluoro-3,5-dimethylphenyl)pyrazol-4-yl]azacyclobutane-1-carboxylate (76 mg, 99.5% yield). LC-MS: m / z 653.6 (M+H) + .

[0428] Step G 3-[4-(azacyclobutane-3-yl)-2-(4-fluoro-3,5-dimethylphenyl)pyrazol-3-yl]-1-{4-[cyclopropyl(methylazine)(oxo)-λ6-thioalkyl]-2-fluoro-3-methylphenyl}-2,3-dihydro-1H-imidazol-2-one TFA salt

[0429] Add TFA (1 mL, 13.059 mmol) to a solution of tert-butyl 3-[5-(1-{4-[cyclopropyl(methylazinyl)(oxo)-λ6-thioalkyl]-2-fluoro-3-methylphenyl}-2-oxoimidazol-3-yl)-1-(4-fluoro-3,5-dimethylphenyl)pyrazol-4-yl]azacyclobutane-1-carboxylate (76 mg, 0.116 mmol) in DCM (5 mL). Heat the mixture at 25 °C. oThe mixture was stirred at C and N2 for 1 h. The reaction mixture was concentrated to give 3-[4-(azacyclobutan-3-yl)-2-(4-fluoro-3,5-dimethylphenyl)pyrazol-3-yl]-1-{4-[cyclopropyl(methylazine)(oxo)-λ6-thioalkyl]-2-fluoro-3-methylphenyl}-2,3-dihydro-1H-imidazol-2-one TFA salt (64 mg, crude). LC-MS: m / z 553.0 (M+H) + .

[0430] Step H 3-[(1S,2S)-1-[2-({3-[5-(1-{4-[cyclopropyl(methylazinyl)(oxo)-λ6-thioalkyl]-2-fluoro-3-methylphenyl}-2-oxoimidazol-3-yl)-1-(4-fluoro-3,5-dimethylphenyl)pyrazol-4-yl]azacyclobutane-1-yl}carbonyl)-5-(3,4,5,6-tetrahydro-2H-pyran-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H,5H-1,2,4-oxadiazol-5-one

[0431] Add 3-[4-(azacyclobutane-3-yl)-2-(4-fluoro-3,5-dimethylphenyl)pyrazol-3-yl]-1-{4-[cyclopropyl(methylazine)(oxo)-λ6-thioalkyl]-2-fluoro-3-methylphenyl}-2,3-dihydro-1H-imidazol-2-one TFA salt (64 mg, 0.116 mmol), HATU (48.44 mg, 0.127 mmol), and DIEA (74.84 mg, 0.579 mmol) to a solution of 1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]-5-(3,4,5,6-tetrahydro-2H-pyran-4-yl)indole-2-carboxylic acid (44.40 mg, 0.116 mmol) in DMF (5 mL). The reaction was stirred at 35ºC under N2 for 18 h. The mixture was poured into water (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by preparative TLC (DCM / CH3OH = 15 / 1) and further purified by preparative HPLC (Waters 3767 / Qda column: SunFire SunfireC18, 19*250 mm*10 μm; mobile phase A: 0.1% FA / H2O, B: CH3CN; flow rate: 20 mL / min; gradient: 72%-77% B; retention time: 5.7-6.9 min, for a total of 16 runs). (min) Purification yielded 3-[(1S,2S)-1-[2-({3-[5-(1-{4-[cyclopropyl(methylazinyl)(oxo)-λ6-thioalkyl]-2-fluoro-3-methylphenyl}-2-oxoimidazol-3-yl)-1-(4-fluoro-3,5-dimethylphenyl)pyrazol-4-yl]azacyclobutane-1-yl}carbonyl)-5-(3,4,5,6-tetrahydro-2H-pyran-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H,5H-1,2,4-oxadiazol-5-one (14.3 mg, 13.5% yield) as a white solid. LC-MS: m / z 918.2 (M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 11.76 (brs, 1 H), 7.98 (s, 1 H), 7.70 (d, J= 8.4 Hz, 1 H), 7.46 (m, 2 H), 7.41 (d, J= 8.4 Hz, 1 H), 7.27 (dd, J1= 8.8 Hz, J2= 1.6 Hz, 1 H), 7.15 (d, J= 6.4 Hz, 2 H), 7.01 (m, 1H), 6.89-6.88 (d, J= 3.2 Hz, 1 H), 6.85 (s, 1 H), 4.57 (m, 2 H), 4.29 (m, 2H), 3.97 (m, 2 H), 3.87 (m, 1 H), 3.47 (m, 2 H), 2.85 - 2.81 (m, 2 H), 2.59 (d, J= 3.2 Hz, 3 H), 2.55 (s, 3 H), 2.25 (d, J= 2.0 Hz, 6 H), 1.86 (m,1 H),1.76 - 1.67 (m, 5 H), 1.50 (m, 1 H), 1.27 (m, 4 H), 1.11 (m, 1 H), 0.95 -0.82 (m, 2 H).

[0432] Compound 127 of Example 1 was synthesized using suitable materials following a similar procedure to that described in Example A5 above. For (4-bromo-3-fluorophenyl)(cyclopropyl)(oxo)-λ 6 SFC separation conditions for thioalkylimine (column: DAICELCHIRALCEL®AS 250 mm*25 mm, 10 μm, mobile phase A (supercritical CO2), mobile phase B (MeOH (0.1% 7.0 M ammonia in MeOH)), gradient: B = 20%, flow rate: 100 mL / min, column temperature: 25ºC). Preparative HPLC separation conditions for the final compound 127 (Waters 3767 / Qda column: SunFire Sunfire C18, 19*250 mm*10 μm; mobile phase A: 0.1% FA / H2O, B: CH3CN; flow rate: 20 mL / min; gradient: 60%-70%; retention time: 9-9.6 min, total run time 17 min). Example A6 3-[(1S,2S)-1-[2-({3-[5-(3-{4-[diethyl(oxo)-λ5-phosphino]-3-(methylamino)phenyl}-2-oxoimidazol-1-yl)-1-(4-fluoro-3,5-dimethylphenyl)pyrazol-4-yl]azacyclobutane-1-yl}carbonyl)-5-[(4S)-2,2-dimethyl-3,4,5,6-tetrahydro-2H-pyran-4-yl]indol-1-yl]-2-methylcyclopropyl]-5H,4H-1,2,4-oxadiazol-5-one (Compound 128)

[0433] Step A 3-[5-(3-{4-[diethyl(oxo)-λ 5 [-phosphino]-3-(methylamino)phenyl}-2-oxoimidazol-1-yl)-1-(4-fluoro-3,5-dimethylphenyl)pyrazole-4-yl]azacyclobutane-1-tert-butyl ester

[0434] To a solution of tert-butyl 3-[1-(4-fluoro-3,5-dimethylphenyl)-5-(2-oxo-3H-imidazol-1-yl)pyrazol-4-yl]azacyclobutane-1-carboxylate (58 mg, 0.136 mmol) in NMP (5 mL), {5-bromo-2-[diethyl(oxo)-λ5-phosphino]phenyl}(methyl)amine (43.30 mg, 0.149 mmol), CuI (31.01 mg, 0.163 mmol), K2CO3 (37.50 mg, 0.271 mmol) and methyl[(1R,2R)-2-(methylamino)cyclohexyl]amine (28.95 mg, 0.204 mmol) were added, and the reaction was carried out at 130 °C. o The mixture was stirred at C under N2 for 3 h. After cooling, the mixture was poured into water (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by rapid column chromatography (eluting with PE / EtOAc = 1 / 2), followed by reverse-phase ISCO (eluting with 50% CH3CN in water (0.1% FA)) to give tert-butyl 3-[5-(3-{4-[diethyl(oxo)-λ5-phosphino]-3-(methylamino)phenyl}-2-oxoimidazol-1-yl)-1-(4-fluoro-3,5-dimethylphenyl)pyrazol-4-yl]azacyclobutane-1-carboxylate (115 mg, crude). LC-MS: m / z 637.1 (M+H) + .

[0435] Step B: 3-[4-(azacyclobutane-3-yl)-2-(4-fluoro-3,5-dimethylphenyl)pyrazol-3-yl]-1-{4-[diethyl(oxo)-λ5-phosphino]-3-(methylamino)phenyl}-2,3-dihydro-1H-imidazol-2-one TFA salt

[0436] TFA (0.052 mL, 0.675 mmol) was added to a solution of 3-[5-(3-{4-[diethyl(oxo)-λ5-phosphino]-3-(methylamino)phenyl}-2-oxoimidazol-1-yl)-1-(4-fluoro-3,5-dimethylphenyl)pyrazol-4-yl]azacyclobutane-1-carboxylic acid tert-butyl ester (86 mg, 0.135 mmol) in DCM (10 mL). The mixture was stirred at room temperature under N2 for 1 h. The mixture was concentrated to give 3-[4-(azacyclobutan-3-yl)-2-(4-fluoro-3,5-dimethylphenyl)pyrazol-3-yl]-1-{4-[diethyl(oxo)-λ5-phosphino]-3-(methylamino)phenyl}-2,3-dihydro-1H-imidazol-2-one TFA salt (73 mg, 99.9% yield), which was used in the next step without purification. LC-MS: m / z 537.2 (M+H) + .

[0437] Step C 3-[(1S,2S)-1-[2-({3-[5-(3-{4-[diethyl(oxo)-λ5-phosphino]-3-(methylamino)phenyl}-2-oxoimidazol-1-yl)-1-(4-fluoro-3,5-dimethylphenyl)pyrazol-4-yl]azacyclobutane-1-yl}carbonyl)-5-[(4S)-2,2-dimethyl-3,4,5,6-tetrahydro-2H-pyran-4-yl]indol-1-yl]-2-methylcyclopropyl]-5H,4H-1,2,4-oxadiazol-5-one

[0438] HATU (77.57 mg, 0.204 mmol) was added to a solution of 5-[(4S)-2,2-dimethyl-3,4,5,6-tetrahydro-2H-pyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (55.96 mg, 0.136 mmol) in DMF (10 mL), and the mixture was stirred at 35ºC for 30 min. A solution of 3-[4-(azacyclobutan-3-yl)-2-(4-fluoro-3,5-dimethylphenyl)pyrazol-3-yl]-1-{4-[diethyl(oxo)-λ5-phosphino]-3-(methylamino)phenyl}-2,3-dihydro-1H-imidazol-2-one TFA salt (73 mg, 0.136 mmol) and DIEA (87.89 mg, 0.680 mmol) in DMF (10 mL) was added to the above solution. The reaction was stirred at 35ºC under N2 for 3 h. After cooling, the reaction mixture was poured into water (30 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by preparative TLC (DCM / MeOH = 20 / 1) to obtain a crude product (50 mg), which was then further purified by preparative HPLC (Waters 3767 / Qda column: SunFire Sunfire C18, 19*250 mm*10 μm; mobile phase A: 0.1% FA / H2O, B: CH3CN; flow rate: 20 ml / min; gradient: 65%-75% B; retention time: 8.9-10.3 min, for a total of 17 runs). (min) Purification yielded 3-[(1S,2S)-1-[2-({3-[5-(3-{4-[diethyl(oxo)-λ5-phosphino]-3-(methylamino)phenyl}-2-oxoimidazol-1-yl)-1-(4-fluoro-3,5-dimethylphenyl)pyrazol-4-yl]azacyclobutane-1-yl}carbonyl)-5-[(4S)-2,2-dimethyl-3,4,5,6-tetrahydro-2H-pyran-4-yl]indol-1-yl]-2-methylcyclopropyl]-5H,4H-1,2,4-oxadiazol-5-one (12.9 mg, 10.1% yield). LC-MS: m / z 930.9 (M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 11.71 (brs, 1 H), 7.97 (s, 1 H), 7.68 - 7.66 (m, 1 H), 7.43 (s, 1H), 7.37 (d, J= 8.8 Hz, 1 H), 7.24 - 7.22 (m, 2 H), 7.17 - 7.13 (m, 3 H), 6.89 (d, J= 2.8 Hz, 1 H), 6.84 - 6.81 (m, 3 H), 4.55 (m, 2 H), 4.28 (m, 2 H), 3.88 - 3.84 (m, 1 H), 3.74 - 3.72 (m, 2 H), 2.70 (d, J= 4.8 Hz, 3 H), 2.22(d, J= 1.6 Hz, 6 H), 1.94 - 1.85 (m, 5 H), 1.73 - 1.48 (m, 6 H), 1.29 - 1.27(m, 6 H), 1.23 - 1.20 (m, 4 H), 1.05 - 0.97 (m, 6H).

[0439] The following molecules were synthesized using a similar procedure to that described in the above embodiments with appropriate starting materials. Biological Examples Biological Example 1: cAMP Assay

[0440] Activation of the GLP-1 receptor is known to stimulate the production of cyclic AMP (cAMP) in cells, indicating a major coupling with the Gαs subunit of the G protein heterotrimeric complex. Evidence suggests that Gαs-induced cAMP-stimulated signaling triggers the desired pharmacological response regarding the release of insulin from pancreatic β-cells.

[0441] To optimize the functional activity against Gαs coupling, the HEK293 / CRE-Luc cell line, stably expressing the GLP-1 receptor and developed by HDB, was used. Working solutions of the compound at 200× concentration were prepared by serial dilution at 1 / 2 log in 384-well Echo LDV plates (Labcyte, catalog LP-0200) (Agilent Technologies Bravo). 50 nL / well of the 200× working solution was transferred to 384-well white low-volume plates (Greiner, catalog 784075) using a Labcyte ECHO550. Prepare a 1×10⁵ cell / mL HEK293 / GLP1R / CRE-LUC (HD Biosciences) cell suspension using assay buffer [DPBS containing 0.5 mM IBMX (Sigma, catalog number I5879) and 0.1% BSA (GENVIEW, catalog number FA016-100g)]. Add 10 µL of the cell suspension to each well of a previously prepared assay plate (1000 cells / well) using a ThermoFisher Multidrop Combi. The assay plate already contains 50 nL of the compound at a concentration of 200×. Seal the plate and incubate at 37ºC and 5% CO₂ for 30 min.

[0442] After incubation, cAMP assay signals were generated using a cAMP dynamic 2 kit (Cisbio). Using a ThermoFisher Multidrop Combi, 5 μL of cAMP-d2 working solution was added to each well, followed by 5 μL of anti-cAMP antibody-camber compound working solution. Incubation was performed at room temperature in the dark for 1 hour. Fluorescence at 665 and 615 nm was read using a ReaderPerkinElmer EnVision. Activity % = 100% x (mean RLU of test sample - mean RLU of medium control) / (mean RLU of maximum control - mean RLU of medium control)

[0443] Table 3 shows the bioactivity (ECG) of the compounds in the GLP-1R agonist cAMP stimulation assay. 50 ) Table 3

Claims

1. A compound of formula I: I Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein: X is CR 2 And Z is N, or X is NR. 3 And Z is C; m and s are each independently 1, 2 or 3; q is 0, 1, 2, 3, or 4; Each R 1 It is independently hydrogen, halogen, cyano, or optionally surrounded by 1-6 groups independently selected from halogen, hydroxyl, and C. 1-6 alkoxy substituents of C 1-6 alkyl; Or any two R 1 Each of these is connected to a 4-8 membered ring to provide a fused, bridged, or spiroheterocyclic group comprising 4-11 carbon atoms and 1-3 heteroatoms, wherein the fused, bridged, or spiroheterocyclic group is optionally connected to 1-3 independently selected C atoms. 1-6 Alkyl substitution; R 2 and R 3 Each is independently hydrogen, a halogen group, a cyano group, or optionally surrounded by 1-6 independently selected halogen groups, hydroxyl groups, and C. 1-6 alkoxy substituents of C 1-6 alkyl; Q 1 and Q 5 Each is independently N or CR QA And Q 2 Q 3 and Q 4 Each is independent of N and CR QA or CR QB ;or Q 1 It is a key; and Q 2 Q 3 Q 4 and Q 5 Each is independently O, S, N, NR c CR QA or CR QB ; The condition is that it contains Q. 1 -Q 5 The ring is from the Aromatic tribe; Each R QA Independently, it is hydrogen, halogen, cyano, hydroxyl, -NR c R d C 3-6 cycloalkyl, optionally with 1-6 independently selected R f Replacement C 1-6 Alkyl groups or optionally surrounded by 1-6 groups, each independently selected from hydroxyl, halogen, and C. 1-6 alkoxy substituents of C 1-6 Alkoxy; Or two R atoms on adjacent carbon atoms QA Together with their respective attached atoms, they form a 5-8 membered heterocyclic group or a 5-6 membered heteroaryl group; wherein the 5-8 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally formed by 1-2 independently selected R groups. h replace; Each R QB Independently is -C(O)NR c R d -P(O)R 1a R 1b -C(R) i R j ) n -P(O)R 1a R 1b -S(O)2R 1a -C(R) i R j ) n -S(O)2R 1a -S(O)(=NR) 2a )R 2b -C(R) i R j ) n -S(O)(=NR 2a )R 2b -N=S(O)(R 3a )R 2b -O-(CR) i R j ) n -S(O)(=NR 2a )R 2b Optionally selected by one or more independently chosen from C 1-6 Alkyl and -C(O)(C 1-6 3-12 membered heterocyclic groups substituted with alkyl groups, optionally with 1-3 independently selected -C(O)(C 1-6 alkyl) substituted C 6-10 aryl and optionally 1-6 independently selected R g Substituted 5-10 heteroaryl groups; n is 1, 2, 3, 4, 5, or 6; R 1a and R 1b Selected independently from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally surrounded by 1 to 6 hydroxyl groups, each independently selected from C10, C20, C30, C40, C50, C6 ... 1-6 Alkoxy, C 3-6 Substitution of cycloalkyl and halogen groups; C 3-6 cycloalkyl, the C 3-6 The cycloalkyl group is optionally composed of 1 to 3 independently selected from C10. 1-3 Substitution of alkyl and halogen groups; and C 6-10 Aryl, the C 6-10 The aryl group is optionally selected by 1-3 independently chosen C 1-3 Alkyl substitution; Or R 1a and R 1b Together with the phosphorus atoms to which they are attached, they form a ring containing 5-8 ring atoms, except for those attached to R. 1a and R 1b Apart from phosphorus, 0-2 ring atoms are heteroatoms independently selected from O, S, and N, wherein the ring is optionally separated by 1-3 independently selected C atoms. 1-6 Alkyl substitution; R 2a It is hydrogen, cyano, optionally surrounded by 1-6 groups, each independently selected from halogen, oxo, C 1-6 Alkoxy, C 3-6 C substituents of cycloalkyl and heteroaryl groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected from C 1-3 Substituents of alkyl and halogen groups on C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C 1-3 Alkyl-substituted C 6-10 Aryl; R 2b It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C substituents of cycloalkyl and halogen groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected from C 1-3 Substituents of alkyl and halogen groups on C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C 1-3 Alkyl-substituted C 6-10 Aryl; or R 2a and R 2b Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally separated by 1-3 independently selected carbon atoms. 1-6 Alkyl substitution; or R 2a or R 2b and adjacent R QA Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally separated by 1-2 independently selected R atoms. h replace; R 3a It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C substituents of cycloalkyl and halogen groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected from C 1-3 Substituents of alkyl and halogen groups on C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C 1-3 Alkyl-substituted C 6-10 Aryl; Each R i It can be hydrogen, halogen, or C independently. 1-6 alkyl; or R 2a and R i 、or R 2b and R i Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally separated by 1-3 independently selected carbon atoms. 1-6 Alkyl substitution; Each R j It can be hydrogen, halogen, or C independently. 1-6 alkyl; Or an R i And an R j Together with one or more atoms attached to each of them, they form C 3-6 cycloalkyl groups, wherein the cycloalkyl group is optionally composed of 1-3 independently selected C atoms. 1-6 Alkyl substitution; L 2 R is arbitrarily selected by 1-2 independent choices h Replacement C 6-10 aryl, optionally selected by 1-2 independent R h Replaced 5-10 aryl groups, , , , or , where aa represents the combination with Q 1 -Q 5 The attachment point of the ring; n1 is 1, 2, or 3; L 2A Is it a key or C? 1-10 Alkylene; R La It is hydrogen, C 1-6 Alkyl or -C(O)C 1-6 alkyl; R Lb and R Lc Each of them is independently hydrogen or C. 1-6 alkyl; Ring A is C 6-10 Aryl, C 5-7 Cycloalkyl, 5-7-membered heterocyclic or 5-10-membered heteroaryl, each optionally consisting of 1-5 independently selected R groups. A replace; Each R A Independently, it is a halogen group, C 1-6 Alkyl, C 1-6 Haloalkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl; L 1 It is -C(O)-, -CH2-, -CH(C 1-6 Alkyl)- or -S(O)2-; Ring B is a phenyl group or a 5-6 fused heteroaryl group having 5 to 8 carbon atoms and 1 to 3 heteroatoms independently selected from O, S, and N; wherein ring B is optionally surrounded by 1 to 5 heteroatoms independently selected from R. 8 halogenated, oxo-substituted and C 1-6 Alkyl substituents; R 8 It is phenyl, 5-6 heteroaryl or The phenyl group or the 5-6 heteroaryl group is optionally R 8c Replace, and optionally further by 1-3 independently selected R h replace; L 3 Is it a key or C? 1-3 Alkylene; L 4 Is it a key or C? 1-5 Alkylene; R 8a and R 8b Each is independently hydrogen or optionally composed of one or more halogen groups and C. 3-15 Cycloalkyl substituents substituted C 1-6 Alkyl; or R 8a and R 8b Together with the carbon atoms to which they are attached, they form C atoms that are optionally selected by 1-3 independent groups. 1-6 Alkyl-substituted C 3-15 cycloalkyl ring; wherein the C 1-6 Alkyl groups are optionally surrounded by 1-6 independently selected R groups. f replace; Each R 8c Independently, they are -C(O)OH, -S(O)2OH, -S(O)2NH2, -L 5 -C 1-6 Alkyl, -L 5 -C 3-6 cycloalkyl, -L 5 -C 6-10 Aryl, -L 5 -5-6 membered heterocyclic group, -L 5 -(5-6 heteroaryl groups), wherein each is optionally surrounded by 1-6 independently selected from hydroxyl, halogen, and C groups. 1-6 Substitution of alkoxy groups; Each L 5 Independently, they are -C(O)-, -C(O)O-, -OC(O)-, and -S(O). 1-2 -、-S(O)2O-、-S(O)2NH- or -NHS(O)2-; R 9 It is -C(O)OR 9a -C(O)NR 9a R 9b R is arbitrarily selected by 1-3 independent choices 9c Substituted 5-6 aryl groups, or ; X 1 Is it O or S? R 9a Is it hydrogen or C? 1-6 alkyl; R 9b It is hydrogen, C 1-6 Alkyl, -C(O)(C 1-6 Alkyl groups), -S(O) 0-2 (C 1-6 Alkyl or cyano groups; Each R 9c Independently hydrogen, oxo group, optionally 1-6 independently selected halogen groups and C 1-6 alkoxy-substituted C 1-6 Alkyl, or -C(O)(C 1-6 alkyl); R C It is C 1-6 Alkyl or cyclic C, wherein the C 1-6 The alkyl group is optionally surrounded by 1-3 independently selected from halogen, cyano, C... 1-6 Haloalkyl, C 1-6 Alkoxy and -NR c R d Substituents of the substituents; Cyclic C is a 3-12 membered heterocyclic group, C 3-15 Cycloalkyl or 5-10 heteroaryl groups, each optionally surrounded by 1-3 R groups. Ca replace; Each R Ca Independently, it is a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c R d ; Or a pair of R atoms on the same or different ring atoms Ca Together with one or more ring atoms to which each ring is attached, they form a carbon ring containing 3 to 8 ring atoms; Each R c and R d Each is independently hydrogen, C 1-6 Alkyl, -C(O)(C 1-6 Alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)O(C 1-6 Alkyl groups), -S(O) 1-2 (C 1-6 Alkyl group or -S(O) 1-2 (C 3-6 cycloalkyl), wherein the C 1-6 Alkyl, -C(O)(C 1-6 Alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)O(C 1-6 Alkyl groups), -S(O) 1-2 (C 1-6 Alkyl groups and -S(O) 1-2 (C 3-6 Each of the cycloalkyl groups is optionally surrounded by 1-6 independently selected from hydroxyl, halogen, and C groups. 1-6 Substitution of alkoxy groups; Each R f Independently, it is a halogen group, hydroxyl group, or -NR group. c R d C 1-6 Alkoxy, C 1-6 Haloalkoxy, or optionally surrounded by 1-4 groups, each independently selected from hydroxyl, C 1-6 3-12-membered heterocyclic groups substituted with alkyl groups and 3-12-membered heterocyclic groups; Each R g C is independent 1-6 Alkyl, C 1-6 Alkoxy, -NR c R d Or optionally selected by one or more independently chosen from C 1-6 Alkyl and C(O)C 1-6 Alkyl substituents of 3 to 12-membered heterocyclic groups; and Each R h Independently, it is a halogen group, cyano group, hydroxyl group, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups.

2. The compound according to claim 1, wherein the compound is represented by formula II: II Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug.

3. The compound according to claim 1, wherein the compound is represented by formula IIA; IIA Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug.

4. The compound according to claim 1, wherein the compound is represented by formula IIB; IIB Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug.

5. The compound according to any one of the preceding claims, wherein Q 1 and Q 5 Each is independently N or CR QA And Q 2 Q 3 and Q 4 Each is independent of N and CR QA or CR QB .

6. The compound according to any one of the preceding claims, wherein Q 1 and Q 5 Each is CR independently QA or CR QB .

7. The compound according to any one of the preceding claims, wherein each R QA Independently, it is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or -NR c R d .

8. The compound according to any one of the preceding claims, wherein Q 2 Q 3 and Q 4 One of them is N.

9. The compound according to any one of the preceding claims, wherein Q 2 Q 3 and Q 4 One of them is R QB .

10. The compound according to claim 9, wherein R QB It is -P(=O)R 1a R 1b .

11. The compound according to claim 10, wherein R 1a and R 1b Each is C independently 1-6 alkyl.

12. The compound according to claim 9, wherein R QB It is -S(O)(=NR) 2a )R 2b or -CH2-S(O)(=NR 2a )R 2b .

13. The compound according to claim 12, wherein R 2a It is hydrogen, cyano, optionally surrounded by 1-6 groups, each independently selected from halogen, oxo, C 1-6 Alkoxy, C 3-6 C substituents of cycloalkyl and heteroaryl groups 1-6 Alkyl; and R 2b It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C substituents of cycloalkyl and halogen groups 1-6 Alkyl; or C 3-6 cycloalkyl; or R 2a and R 2b Together with the atoms to which they are attached, they form 5-8 membered heterocyclic groups.

14. The compound according to any one of the preceding claims, wherein L 2 R is arbitrarily selected by 1-2 independent choices h Replacement C 6-10 Aryl, or Where aa represents the combination with Q. 1 -Q 5 The attachment point of the ring.

15. The compound according to any one of the preceding claims, wherein L 2A It is a key.

16. The compound according to any one of the preceding claims, wherein R 2 It is hydrogen.

17. The compound according to any one of the preceding claims, wherein R 3 It is C 1-6 alkyl.

18. The compound according to any of the preceding claims, wherein ring A is optionally surrounded by 1 to 5 groups independently selected from halogen groups, C... 1-6 Alkyl, C 1-6 Haloalkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 Cycloalkyl substituents substituted C 6-10 Aryl.

19. The compound according to any of the preceding claims, wherein ring A is a phenyl group, said phenyl group optionally being surrounded by 1 to 3 groups, each independently selected from a halogen group, C... 1-6 Alkyl group, -S(O)2C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 Substitution of cycloalkyl groups.

20. The compound according to any one of the preceding claims, wherein ring B is: , , , , , , , , , , , , , , , , , , , or ; Where bb represents L 1 The attachment point; and R 4 R 5 R 6 and R 7 Each is independently hydrogen, halogen, or C. 1-6 alkyl.

21. The compound according to claim 20, wherein ring B is: ; where bb represents the relationship with L 1 Attachment point.

22. The compound according to claim 20, wherein ring B is: ; where bb represents the relationship with L 1 Attachment point.

23. The compound according to any one of the preceding claims, wherein R 8 yes .

24. The compound according to any one of claims 1-19, wherein ring B is: or ; where bb represents the relationship with L 1 Attachment point.

25. The compound according to any one of claims 20-24, wherein R 4 It is hydrogen.

26. The compound according to any one of claims 20-25, wherein R 5 R 6 and R 7 Each is hydrogen.

27. The compound according to any of the preceding claims, wherein q is 0.

28. The compound according to claim 1, wherein the compound is represented by formula IIC: IIC Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug; wherein p is 0, 1, 2, 3, 4, or 5.

29. The compound according to any one of the preceding claims, wherein L 3 It is a key and L 4 It is a key.

30. The compound according to claim 1, wherein the compound is represented by formula IID: IID Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein p is 0, 1, 2, 3, 4, or 5; and v is 0, 1, 2, or 3.

31. The compound according to any one of the preceding claims, wherein R 8a and R 8b Each is hydrogen on its own.

32. The compound according to any one of the preceding claims, wherein R 8a and R 8b Together with the carbon atoms to which they are attached, they form a group that is optionally C 1-6 Alkyl-substituted C 3-15 Cycloalkyl rings.

33. The compound according to any one of the preceding claims, wherein R 9 R is arbitrarily selected by 1-3 independent choices 9c Substituted 5-6 aryl groups, or .

34. The compound according to any one of the preceding claims, wherein R 9 It is a 6-membered heteroaryl group.

35. The compound according to any one of the preceding claims, wherein R 9 yes or .

36. The compound according to any one of the preceding claims, wherein R C Or ring C is arbitrarily bounded by 1-3 R Ca Substituted 3-12 membered heterocyclic groups.

37. The compound according to any one of the preceding claims, wherein each R Ca It is C 1-6 alkyl.

38. The compound according to any one of the preceding claims, wherein the ring C is , , , , or .

39. A compound selected from Table 1 or Table 2, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof.

40. A pharmaceutical composition comprising a compound according to any of the preceding claims or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a pharmaceutically acceptable excipient.

41. A method for treating GLP-1-related diseases, disorders, or conditions, the method comprising administering to a patient in need an effective amount of a compound according to any one of claims 1-39 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutical composition according to claim 40.

42. The method of claim 41, 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), juvenile-onset atypical diabetes (YOAD), adolescent-onset adult-onset diabetes (MODY), latent autoimmune diabetes in adults (LADA), obesity, weight gain due to the use of other medications, gout, excessive sugar consumption, 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 artery 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, etc. Pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, essential polydipsia, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof.

43. A method of treating type 2 diabetes in a patient in need, the method comprising administering to the patient in need an effective amount of the compound of any one of claims 1-39 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, or the pharmaceutical composition of claim 40.

44. A method for regulating insulin levels in a patient requiring such regulation, the method comprising administering to the patient in need an effective amount of a compound according to any one of claims 1-39 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutical composition according to claim 40.

45. A method for regulating glucose levels in a patient requiring such regulation, the method comprising administering to the patient in need an effective amount of a compound according to any one of claims 1-39 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug, or a pharmaceutical composition according to claim 40.

46. ​​The method according to any one of claims 41-45, the method further comprising administering an additional therapy or treatment agent to the patient.

47. The method of claim 46, wherein the additional therapy or treatment agent is selected from antidiabetic agents, antiobesity agents, GLP-1 receptor agonists, antiemetics, agents for treating nonalcoholic steatohepatitis (NASH), gastric electrical stimulation, dietary monitoring, physical activity, or combinations thereof.

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