Heterocyclic GLP-1 agonists

Abstract

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

Description

[0001] Cross-references to related applications

[0002] This application claims the benefits of International Patent Application No. PCT / CN2023 / 076495, filed February 16, 2023; International Patent Application No. PCT / CN2023 / 113565, filed August 17, 2023; and International Patent Application No. PCT / CN2023 / 141034, filed December 22, 2023, each of which is incorporated herein by reference in its entirety. Technical Field

[0003] This disclosure relates to GLP-1 agonists, pharmaceutical compositions, and methods of use thereof. Background Technology

[0004] Incretin metabolism hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), play an important role in the regulation of glucose homeostasis. Drugs targeting this intestinal peptide family, such as GLP-1 agonists, have been shown to inhibit glucagon production, reduce gastric motility, and increase satiety.

[0005] 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.

[0006] In healthy individuals, the incretin hormones glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-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

[0007] 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.

[0008] On one hand, compounds of formula I are provided:

[0009] 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 R 1 R 2 R 3 and R QB Each is defined independently as described in this article.

[0010] 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.

[0011] 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.

[0012] 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.

[0013] 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.

[0014] 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.

[0015] 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 about 30 kg / m². 2 .

[0016] 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.

[0017] 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%.

[0018] In some implementations, the method for treating type 2 diabetes includes lowering glucagon levels.

[0019] In some implementations, the method for treating type 2 diabetes includes increasing insulin levels.

[0020] 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 .

[0021] 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.

[0022] 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, dulaglutide, albiglutide, taspoglutide, lixisenatide, semaglutide, or any combination thereof. In some embodiments, the agent for treating NASH is selected from FXR agonists, PF-05221304, synthetic fatty acid-bile conjugates, anti-lysyl oxidase homolog 2 (LOXL2) monoclonal antibodies, caspase inhibitors, MAPK5 inhibitors, galactolectin 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 thereof, a stereoisomer, a mixture of stereoisomers, or a prodrug, or a pharmaceutical composition thereof, and the additional therapeutic agent thereof are administered sequentially as separate doses in any order.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] 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 incorporated by reference. Where a publication or 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

[0027] Before describing the compounds and methods, it should be understood that this disclosure is not limited to the methods, protocols, cell lines, assays, and reagents used, as these can 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.

[0028] definition

[0029] 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.

[0030] Before describing the compounds and methods, it should be understood that this disclosure is not limited to the methods, protocols, cell lines, assays, and reagents used, as these can 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.

[0031] definition

[0032] The following description illustrates exemplary embodiments of the present invention. However, it should be understood that such description is not intended to be a limitation on the scope of this disclosure, but is provided as a description of exemplary embodiments.

[0033] 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.

[0034] 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. Dashes at the beginning or end of chemical groups are for convenience; chemical groups may or may not be depicted with one or more dashes without losing their general meaning. Wavy or dashed lines drawn through the structure indicate the designated attachment point of a group. Unless chemically or structurally required, the order in which chemical groups are written or named does not indicate or imply directionality or stereochemistry.

[0035] prefix "C" u-v "Indicates that the following groups have u to v carbon atoms. For example, "C 1-6 "alkyl" indicates that an alkyl group has 1 to 6 carbon atoms.

[0036] References to the term "about" in this document include (and describe) 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, references to the term "about x" include a description of "x". Additionally, unless the context clearly specifies otherwise, the singular forms "an" and "the" include plural indicators. Thus, for example, references to "the compound" include a plurality of such compounds, and references to "the assay" include references to one or more assays known to those skilled in the art and their equivalents.

[0037] "alkyl" refers to an unbranched saturated hydrocarbon chain or a 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) 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, all positional isomers with that number of carbons can be included; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -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).

[0038] "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., C40, C50, C60, C7 ... 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 groups. Examples of alkenyl groups include, for example, vinyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0039] "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., C36, C46, ​​C56, C6 ... 2-20 alkynyl group), 2 to 12 carbon atoms (i.e., C12-C12). 2-12 acetylsyl), 2 to 8 carbon atoms (i.e., C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 2-8 acetylsyl), 2 to 6 carbon atoms (i.e., C10, C20, C30, C40, C50, C60, C7 ... 2-6 (alkynyl group) or 2 to 4 carbon atoms (i.e., C46) 2-4 (Alkynyl). The term "alkynyl" also includes those groups that have one triple bond and one double bond.

[0040] Some commonly used alternative chemical names can be used. For example, divalent groups such as divalent "alkyl" groups and divalent "aryl" groups can also be called "alkylene" groups or "alkylenyl" groups, "arylene" groups or "arylenyl" groups, respectively.

[0041] "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.

[0042] "Thioalkoxy" refers to the "alkyl-S-" group.

[0043] "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, in the case where 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.

[0044] "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.

[0045] "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.

[0046] "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.

[0047] "Alkylthio" refers to the "alkyl-S-" group.

[0048] "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.

[0049] "Amide group" refers to the "C-amide group" (which refers to the group -C(O)NR). y Rz ) and "N-amide" group (which refers to the -NR group) y C(O)R z Of the two, 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.

[0050] "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.

[0051] "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.

[0052] "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., C64 carbon atoms). 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl group) or 6 to 10 carbon ring atoms (i.e., C46, ​​C56, C6 ... 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 group, regardless of the attachment point. If one or more aryl groups are fused with a heterocyclic group, the resulting ring system is a heterocyclic group, regardless of the attachment point. If one or more aryl groups are fused with a cycloalkyl group, the resulting ring system is a cycloalkyl group, regardless of the attachment point.

[0053] "Carbamoyl" refers to the "O-carbamoyl" group (which refers to -OC(O)NR). y R z (group) and "N-carbamoyl" group (which refers to the group -NR) y C(O)ORz (groups) both, of which 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.

[0054] "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.

[0055] "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 Carbon-cyclic fused-ring systems (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., C1456 ... 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., C14 and C24). 3-10 cycloalkyl groups), 3 to 8 cyclic carbon atoms (i.e., C1646-C ... 3-8 cycloalkyl groups or 3 to 6 cyclic carbon atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 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.

[0056] "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.

[0057] "Halogen" or "halogenated group" refers to an atom that occupies Group VIIA of the periodic table, such as fluorine, chlorine, bromine, or iodine.

[0058] "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.

[0059] "Hybrid alkylene" refers to a divalent heteroalkyl group. A "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. By way of 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. 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 yCH2-、-CH(CH3)NR y 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.

[0060] "Heteroaryl" refers to an aromatic group having a monocyclic or multiple fused rings, wherein one or more cyclic heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl groups comprise 1 to 20 cyclic 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 3-8(Heteroaryl); and 1 to 5 cyclic heteroatoms, 1 to 4 cyclic heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatomum, 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 heteroatomum, 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-oxopyridyl, 1-oxopyrimidinyl, 1-oxopyrazinyl, 1-oxopyridazinyl, 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 aryl as defined above or overlap with aryl as defined above.

[0061] "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 monocyclic or polycyclic, wherein the polycyclic group 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 decahydroquinolinyl, 1,2,3,4-tetrahydroquinolinyl, and 5,6,7,8-tetrahydroquinolinyl are heterocyclic groups regardless of their attachment (i.e., whether 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, azirrocyclopentenyl, benzo[b][1,4]dioxanyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranoneyl, benzofuranoneyl, dioxopentyl, dihydropyranyl, hydropyranyl, thiophene[1,3]dithiaalkyl, decahydroisoquinolinyl, furanoneyl, imidazolinyl, imidazoalkyl, indololinyl, indolazinyl, isoindololinyl, isothiazolyl, isoxazolyl Morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidylyl, oxazolylyl, ethylene oxide, oxacyclobutyl, phenothiazinyl, phenothiazinyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolylyl, pyrazolylyl, quininecycloyl, thiazolyl, tetrahydrofuranyl, tetrahydropyranyl, trithiaalkyl, tetrahydroquinolinyl, thiomorpholinyl, thio-morpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. When there are two substitution positions on the same carbon atom, the term "heterocyclic group" also includes "spiroheterocyclic group". Examples of spirocyclic 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 R QB The sulfoxide imine moiety (e.g., when R...) QB R a and R b With Q 1 -Q 5 When rings fuse, for example when R a With R QA Or R b With R QA When forming a ring, 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-thiazopyroxene 1-oxide, etc. See, for example, Cram et al., J.Org.Chem., 1973, 38(1), 20-26.

[0062] "Sulfonyl" refers to the group -S(O)2R y , 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. Examples of sulfonyl groups are methanesulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0063] "alkylsulfonyl" refers to the group -S(O)2R, where R is an alkyl group.

[0064] "alkyl sulfinyl" refers to the group -S(O)R, where R is an alkyl group.

[0065] The terms “optional” or “optionally” mean that the event or situation described below may or may not occur, and the description includes both scenarios in which the event or situation occurs and scenarios in which the event or situation 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.

[0066] As used herein, the term "compound" is intended to include any or all stereoisomers, geometric isomers, tautomers, and isotopically enriched analogs (e.g., deuterated analogs) of the described structure. Unless otherwise stated, compounds identified herein by name or structure as a particular tautomer form are intended to include other tautomer forms.

[0067] Some compounds exist as tautomers. These tautomers exist in equilibrium with each other. For example, compounds containing amides can exist in equilibrium with their 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 a compound includes both its 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.

[0068] Any compound or structure described herein is 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 can 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 (e.g., 3 H and 14 Those compounds in C). Such isotopically 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 determination), or in the treatment of patients with radiotherapy.

[0069] The term “isotope-enriched analogues” includes “deuterated analogues” of the compounds described herein, wherein one or more hydrogen atoms (such as hydrogen on carbon atoms) are replaced by deuterium. 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.

[0070] 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 greater metabolic stability, such as increased in vivo half-life, reduced dose requirement, and / or improved therapeutic index. 18 F, 3 H, 11 C-labeled compounds can be used in 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 performing the procedures disclosed in the scheme or in the examples and preparations described below. It should be understood that, in this context, deuterium is considered a substituent in the compounds described herein.

[0071] The concentration of such heavier isotopes (particularly deuterium) can be defined by isotope enrichment factors. In the compounds of this disclosure, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of said atom. Unless otherwise stated, when a position is explicitly designated as “H” or “hydrogen,” said 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.

[0072] 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.

[0073] 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.

[0074] 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 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 (For example, HN) + (R N )3 or (alkyl)N + (R N )3) salts of amines, wherein each R N Independently, it is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein each is optionally substituted, such as by one or more (e.g., 1-5 or 1-3) substituents (e.g., halogroup, cyanogroup, hydroxyl group, amino group, alkyl group, alkenyl group, alkynyl group, alkoxy group, or haloalkoxy group). 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.

[0075] The term "substituted" 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, haloyl, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclic, hydroxyl, hydrazyl, 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, haloyl, haloalkyl, hydroxyalkyl, haloalkoxy, haloalkoxyalkyl, heteroalkyl, heteroaryl, heterocyclic, hydroxy, hydrazine, imino, imide, oxo, nitro, sulfinyl, sulfonic acid, sulfonyl, thiocyanate, thiol, thion, or combinations thereof.

[0076] 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, said substituted alkyl groups being substituted by themselves, said substituted aryl groups being further substituted by substituted heteroalkyl groups, 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 an aryl group substituted by 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 by 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, when a group is described as optionally substituted, any substituted element of said group is itself unsubstituted. For example, in some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents, including hydroxyl, haloyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups. In other embodiments, the one or more substituents may be further substituted with a haloyl, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl group, each of which is unsubstituted. In other embodiments, the substituents may be further substituted with a haloyl, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group, each of which is unsubstituted.

[0077] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutical acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption-delaying agents, etc. The use of such media and reagents 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. Additional active ingredients may also be incorporated into the composition.

[0078] "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.

[0079] As used herein, when a ring is described as “aromatic,” it means that the ring has a continuous system of delocalized π electrons. 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.

[0080] As used herein, when a ring is described as “partially unsaturated,” this 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,” this 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.

[0081] 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 by name or structure as a particular tautomer form are intended to include other tautomer forms.

[0082] As used herein, the term "tautomer" refers to a compound whose structure is significantly different in terms of atomic arrangement but is in an easy and rapid equilibrium. It should be understood that the compounds provided herein can be described as different tautomers, and when compounds have tautomer forms, all tautomer forms are intended to fall within the scope of this disclosure, and the naming of the compounds does not exclude any tautomer.

[0083] 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, isotypes, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and their active fragments.

[0084] 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 regulation of glucagon-like peptide-1 (GLP-1) receptor signaling can alter the pathology and / or symptoms and / or progression of the disease, disorder or condition.

[0085] As used herein, the term “GLP-1 agonist” or “GLP-1RA” refers to an agonist of the glucagon-like peptide-1 (GLP-1) receptor. GLP-1RAs enhance glucose-dependent insulin secretion; suppress inappropriately elevated glucagon levels in both fasting and postprandial states; and 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-1RAs have been shown to be effective in treating type 2 diabetes. Examples of GLP-1RAs include, but are not limited to, abiglutide ( ), duraglutide (LY2189265, ), efpeglenatide, exenatide ( Exendin-4, liraglutide NN2211), Lixisenatide ( ), Smegglutinin ( ), tirzepatide, ZP2929, NNC0113-0987, BPI-3016 and TT401.

[0086] As used herein, the term “pharmaceutically acceptable” means that the 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.

[0087] 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.

[0088] 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 mitigation of 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.

[0089] 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 "pharmaceutically acceptable" in the sense that it is compatible with other components of the pharmaceutical formulation and suitable for 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.

[0090] 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.

[0091] In the context of treating a disease, disorder, or condition, the terms “treat,” “treating,” and “treatment” are intended to include relieving or eradicating a disorder, disease, or condition or one or more symptoms associated with said disorder, disease, or condition; or slowing the progression, spread, or worsening of a disease, disorder, or condition or one or more symptoms thereof.

[0092] As used herein, the term “prevention” refers to the complete or partial prevention of the onset, recurrence, or spread of a disease or condition or its symptoms as described herein.

[0093] 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.

[0094] The terms “treatment regimen” and “dosage regimen” are used interchangeably to refer to the dosage and timing of administration of each therapeutic agent in a combination.

[0095] 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.

[0096] 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.

[0097] As used herein, the terms “modulate,” “modulating,” or “modulation” refer to regulation or adjustment (e.g., increasing or decreasing) and may include, for example, agonistic, partial agonistic, or antagonistic effects.

[0098] compound

[0099] This article provides compounds of formula I:

[0100] 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 R 1 R 2 R 3 and R QB Each is defined independently as described in this article.

[0101] On the one hand, this article provides compounds of formula I:

[0102] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein:

[0103] X is C and Z is N, or X is N and Z is C;

[0104] 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 The condition is Q 2 Q 3 and Q 4 At least one of them is CR QB ;or

[0105] Q 1 It is a key; and Q 2 Q 3 Q 4 and Q 5 Each of the following is independently O, S, N, NH, NR c CR QA or CR QB The condition is Q 2 Q 3 Q 4 and Q 5 At least one of them is CR QB ;

[0106] The condition is that it contains Q. 1 -Q 5 The ring is from the Aromatic tribe;

[0107] R QB It is -S(O)(=NR) a )R b 、-(CR i R j ) n -S(O)(=NR a )R b -N=S(O)(R 1a )R b or -O-(CR) i R j ) n -S(O)(=NR a )R b ;

[0108] R1a It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C-substitution of cycloalkyl and halogenated groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl;

[0109] R a 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 C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl;

[0110] R b It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C-substitution of cycloalkyl and halogenated groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl;

[0111] Or R a and R b Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally composed of 1-3 independently selected carbon atoms. 1-6 Alkyl substitution;

[0112] n is 1, 2, 3, 4, 5, or 6;

[0113] Each R i It is independently hydrogen, halogenated or C 1-6 alkyl;

[0114] Or R a and R i Or R b and R iTogether with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally composed of 1-3 independently selected carbon atoms. 1-6 Alkyl substitution;

[0115] Each R j It is independently hydrogen, halogenated or C 1-6 alkyl;

[0116] 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;

[0117] Or an R on an adjacent carbon atom i And an R j Together with one or more atoms to which each is attached, they form olefins, wherein the olefins are optionally bonded by one to three independently selected C atoms. 1-6 Alkyl substitution;

[0118] Each R QA Independently, it is hydrogen, halogroup, cyano, hydroxyl, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e Optionally selected from 1 to 6 independently chosen R f Replacement C 1-6 Alkyl group, optionally surrounded by 1-6 groups, each independently selected from hydroxyl, halogroup and C. 1-6 alkoxy substituents of C 1-6 Alkyl groups, optionally composed of one or more independently selected from C 1-6 Alkyl and -C(O)(C 1-6 A 3-12 membered heterocyclic group substituted with an alkyl group, optionally with 1-3 independently selected -C(O)(C) groups. 1-6 alkyl) substituted C 6-10 Aryl, and optionally 1-6 independently selected R g Substituted 5-10 heteroaryl groups;

[0119] Or two R atoms on adjacent carbon atoms QA Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the rings are optionally separated by 1-2 independently selected R atoms. h replace;

[0120] Or R a Or R band 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;

[0121] L 2 R is arbitrarily selected by 1-2 independently selected factors. h Replacement C 6-10 Aryl, optionally selected by 1-2 independently chosen R h Replaced 5-10 aryl groups, Where aa represents the combination containing Q 1 -Q 5 The attachment point of the ring;

[0122] n1 is 1, 2, or 3;

[0123] L 2A Is it a key or C? 1-10 Alkylene;

[0124] R La It is hydrogen, C 1-6 Alkyl or -C(O)(C 1-6 alkyl);

[0125] R Lb and R Lc Each of them is independently hydrogen or C. 1-6 alkyl;

[0126] 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;

[0127] Each R A Independently, it is a halogenated group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl;

[0128] R 1 R 2 and R 3 Each is independently hydrogen or optionally surrounded by 1-6 independently selected halogen groups, hydroxyl groups, and C. 1-6 alkoxy substituents of C 1-6 alkyl;

[0129] L 1 It is -C(O)-, -CH2-, -CH(C 1-6Alkyl)- or -S(O)2-;

[0130] Cycle 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 substitution is optionally made by one to four independently selected groups: halogenated group, oxo group, and C. 1-6 Alkyl substituents;

[0131] R 8 It is phenyl, 5-6 heteroaryl or The phenyl group or the 5-6 heteroaryl group is R 8c Replaced, and optionally further selected by 1-3 independently chosen R h replace;

[0132] L 3 Is it a key or C? 1-3 Alkylene;

[0133] L 4 Is it a key or C? 1-5 Alkylene;

[0134] R 8a and R 8b Each is independently hydrogen or optionally composed of one or more halogenated groups and C. 3-15 Cycloalkyl substituents substituted C 1-6 Alkyl; or

[0135] R 8a and R 8b Together with their respective attached carbon atoms, they form 1-3 independently selected carbon atoms. 1-6 Alkyl-substituted C 3-15 cycloalkyl ring, wherein the C 1-6 Alkyl groups are optionally separated by 1-6 independently selected R groups. f replace;

[0136] 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, halogenated and C- groups. 1-6 Substitution of alkoxy groups;

[0137] 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-;

[0138] R 9 It is -C(O)OR 9a -C(O)NR 9a R 9b Optionally selected by 1-3 independently chosen R 9c The substituted 5-6 heteroaryl group, optionally with 1-3 independently selected R groups. 9c Substituted 4-6 membered heterocyclic groups, or

[0139] X 1 Is it O or S?

[0140] R 9a Is it hydrogen or C? 1-6 alkyl;

[0141] 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;

[0142] Each R 9c Independently, it consists of hydrogen, oxy 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);

[0143] 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;

[0144] Each R Ca Independently, it is a halogenated group, a cyano group, or a C group. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c R d ;

[0145] 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;

[0146] Each Rc 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;

[0147] R e It is hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0148] Each R f Independently, it is a halogenated group, a hydroxyl group, or -NR. 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;

[0149] 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

[0150] Each R h Independently, it is a halogenated group, a cyano group, a hydroxyl group, or a C group. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3Alkyl)2, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups.

[0151] On the one hand, this article provides compounds of formula I:

[0152] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein:

[0153] X is C and Z is N, or X is N and Z is C;

[0154] 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 The condition is Q 2 Q 3 and Q 4 At least one of them is CR QB ;or

[0155] Q 1 It is a key; and Q 2 Q 3 Q 4 and Q 5 Each of the following is independently O, S, N, NH, NR c CR QA or CR QB The condition is Q 2 Q 3 Q 4 and Q 5 At least one of them is CR QB ;

[0156] The condition is that it contains Q. 1 -Q 5 The ring is from the Aromatic tribe;

[0157] R QB It is -S(O)(=NR) a )R b or -(CR) i R j ) n -S(O)(=NR a )R b ;

[0158] R aIt 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 C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl;

[0159] R b It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C-substitution of cycloalkyl and halogenated groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl;

[0160] Or R a and R b Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally composed of 1-3 independently selected carbon atoms. 1-6 Alkyl substitution;

[0161] n is 1, 2, 3, 4, 5, or 6;

[0162] Each R i It is independently hydrogen, halogenated or C 1-6 alkyl;

[0163] Or R a and R i Or R b and R i Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally composed of 1-3 independently selected carbon atoms. 1-6 Alkyl substitution;

[0164] Each R j It is independently hydrogen, halogenated or C 1-6 alkyl;

[0165] 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;

[0166] Each R QA Independently, it is hydrogen, halogroup, cyano, hydroxyl, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e Optionally selected from 1 to 6 independently chosen R f Replacement C 1-6 Alkyl group, optionally surrounded by 1-6 groups, each independently selected from hydroxyl, halogroup and C. 1-6 alkoxy substituents of C 1-6 Alkyl groups, optionally composed of one or more independently selected from C 1-6 Alkyl and -C(O)(C 1-6 A 3-12 membered heterocyclic group substituted with an alkyl group, optionally with 1-3 independently selected -C(O)(C) groups. 1-6 alkyl) substituted C 6-10 Aryl, and optionally 1-6 independently selected R g Substituted 5-10 heteroaryl groups;

[0167] Or two R atoms on adjacent carbon atoms QA Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the rings are optionally separated by 1-2 independently selected R atoms. h replace;

[0168] Or R a Or R b 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;

[0169] L 2 R is arbitrarily selected by 1-2 independently selected factors. h Replacement C 6-10 Aryl, optionally selected by 1-2 independently chosen R h Replaced 5-10 aryl groups, Where aa represents the combination containing Q 1 -Q 5 The attachment point of the ring;

[0170] n1 is 1, 2, or 3;

[0171] L 2A Is it a key or C? 1-10 Alkylene;

[0172] R La It is hydrogen, C 1-6 Alkyl or -C(O)(C 1-6 alkyl);

[0173] R Lb and R Lc Each of them is independently hydrogen or C. 1-6 alkyl;

[0174] 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;

[0175] Each R A Independently, it is a halogenated group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl;

[0176] R 1 R 2 and R 3 Each is independently hydrogen or optionally surrounded by 1-6 independently selected halogen groups, hydroxyl groups, and C. 1-6 alkoxy substituents of C 1-6 alkyl;

[0177] L 1 It is -C(O)-, -CH2-, -CH(C 1-6 Alkyl)- or -S(O)2-;

[0178] Cycle 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 substitution is optionally made by one to four independently selected groups: halogenated group, oxo group, and C. 1-6 Alkyl substituents;

[0179] R 8 It is phenyl, 5-6 heteroaryl or The phenyl group or the 5-6 heteroaryl group is R 8c Replaced, and optionally further selected by 1-3 independently chosen R h replace;

[0180] L 3 Is it a key or C? 1-3 Alkylene;

[0181] L 4Is it a key or C? 1-5 Alkylene;

[0182] R 8a and R 8b Each is independently hydrogen or optionally composed of one or more halogenated groups and C. 3-15 Cycloalkyl substituents substituted C 1-6 Alkyl; or

[0183] R 8a and R 8b Together with their respective attached carbon atoms, they form 1-3 independently selected carbon atoms. 1-6 Alkyl-substituted C 3-15 cycloalkyl ring, wherein the C 1-6 Alkyl groups are optionally separated by 1-6 independently selected R groups. f replace;

[0184] 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, halogenated and C- groups. 1-6 Substitution of alkoxy groups;

[0185] 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-;

[0186] R 9 It is -C(O)OR 9a -C(O)NR 9a R 9b Optionally selected by 1-3 independently chosen R 9c The substituted 5-6 heteroaryl group, optionally with 1-3 independently selected R groups. 9c Substituted 4-6 membered heterocyclic groups, or

[0187] X 1 Is it O or S?

[0188] R 9a Is it hydrogen or C? 1-6alkyl;

[0189] 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;

[0190] Each R 9c Independently, it consists of hydrogen, oxy 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] 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;

[0192] Each R Ca Independently, it is a halogenated group, a cyano group, or a C group. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c R d ;

[0193] 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;

[0194] 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 3-6Each of the cycloalkyl groups is optionally surrounded by 1-6 independently selected from hydroxyl, halogen, and C groups. 1-6 Substitution of alkoxy groups;

[0195] R e It is hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0196] Each R f Independently, it is a halogenated group, a hydroxyl group, or -NR. 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;

[0197] 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

[0198] Each R h Independently, it is a halogenated group, a cyano group, a hydroxyl group, or a C group. 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.

[0199] On the one hand, this article provides compounds of formula I:

[0200] Or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0201] X is C and Z is N, or X is N and Z is C;

[0202] 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 QBThe condition is Q 2 Q 3 and Q 4 At least one of them is CR QB ;or

[0203] Q 1 It is a key; and Q 2 Q 3 Q 4 and Q 5 Each of the following is independently O, S, N, NH, NR c CR QA or CR QB The condition is Q 2 Q 3 Q 4 and Q 5 At least one of them is CR QB ;

[0204] The condition is that it contains Q. 1 -Q 5 The ring is from the Aromatic tribe;

[0205] R QB It is -S(O)(=NR) a )R b or -(CR) i R j ) n -S(O)(=NR a )R b ;

[0206] R a 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 C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl;

[0207] R b It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C-substitution of cycloalkyl and halogenated groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms.1-3 Alkyl-substituted C 6-10 Aryl;

[0208] Or R a and R b Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the rings are optionally separated by 1-3 independently selected carbon atoms. 1-6 Alkyl substitution;

[0209] n is 1, 2, 3, 4, 5, or 6;

[0210] Each R i It is independently hydrogen, halogenated or C 1-6 alkyl;

[0211] Or R a and R i Or R b and R i Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the rings are optionally separated by 1-3 independently selected carbon atoms. 1-6 Alkyl substitution;

[0212] Each R j It is independently hydrogen, halogenated or C 1-6 alkyl;

[0213] Each R QA Independently, it is hydrogen, halogroup, cyano, hydroxyl, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e Optionally selected from 1 to 6 independently chosen R f Replacement C 1-6 Alkyl group, optionally surrounded by 1-6 groups, each independently selected from hydroxyl, halogroup and C. 1-6 alkoxy substituents of C 1-6 Alkyl groups, optionally composed of one or more independently selected from C 1-6 Alkyl and -C(O)(C 1-6 A 3-12 membered heterocyclic group substituted with an alkyl group, optionally with 1-3 independently selected -C(O)(C) groups. 1-6 alkyl) substituted C 6-10 Aryl, and optionally 1-6 independently selected R g Substituted 5-10 heteroaryl groups;

[0214] Or two R atoms on adjacent carbon atoms QATogether with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the rings are optionally separated by 1-2 independently selected R atoms. h replace;

[0215] Or R a Or R b and adjacent R QA Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the rings are optionally separated by 1-2 independently selected R atoms. h replace;

[0216] L 2 R is arbitrarily selected by 1-2 independently selected factors. h Replacement C 6-10 Aryl, optionally selected by 1-2 independently chosen R h Replaced 5-10 aryl groups, Where aa represents the combination containing Q 1 -Q 5 The attachment point of the ring;

[0217] n1 is 1, 2, or 3;

[0218] L 2A Is it a key or C? 1-10 Alkylene;

[0219] R La It is hydrogen, C 1-6 Alkyl or -C(O)(C 1-6 alkyl);

[0220] R Lb and R Lc Each of them is independently hydrogen or C. 1-6 alkyl;

[0221] 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;

[0222] Each R A Independently, it is a halogenated group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl;

[0223] R 1 R 2 and R 3 Each is independently hydrogen or optionally surrounded by 1-6 independently selected halogen groups, hydroxyl groups, and C.1-6 alkoxy substituents of C 1-6 alkyl;

[0224] L 1 It is -C(O)-, -CH2-, -CH(C 1-6 Alkyl)- or -S(O)2-;

[0225] Cycle 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 substitution is optionally made by one to four independently selected groups: halogenated group, oxo group, and C. 1-6 Alkyl substituents;

[0226] R 8 It is phenyl, 5-6 heteroaryl or Wherein the phenyl or 5-6-membered heteroaryl group is R 8c Replaced, and optionally further selected by 1-3 independently chosen R h replace;

[0227] L 3 Is it a key or C? 1-3 Alkylene;

[0228] L 4 Is it a key or C? 1-5 Alkylene;

[0229] R 8a and R 8b Each is independently hydrogen or optionally composed of one or more halogenated groups and C. 3-15 Cycloalkyl substituents substituted C 1-6 Alkyl; or

[0230] R 8a and R 8b Together with their respective attached carbon atoms, they form 1-3 independently selected carbon atoms. 1-6 Alkyl-substituted C 3-15 cycloalkyl ring, wherein the C 1-6 Alkyl groups are optionally separated by 1-6 independently selected R groups. f replace;

[0231] 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, halogenated and C- groups. 1-6 Substitution of alkoxy groups;

[0232] 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-;

[0233] R 9 It is -C(O)OR 9a -C(O)NR 9a R 9b Optionally selected by 1-3 independently chosen R 9c Substituted 5-6 aryl groups, or

[0234] X 1 Is it O or S?

[0235] R 9a Is it hydrogen or C? 1-6 alkyl;

[0236] 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;

[0237] Each R 9c Independently, it consists of hydrogen, oxy 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);

[0238] 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;

[0239] Each R Ca Independently, it is a halogenated group, a cyano group, or a C group. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c R d ;

[0240] Or a pair of R atoms on the same or different ring atoms CaTogether with one or more ring atoms to which each ring is attached, they form a carbon ring containing 3 to 8 ring atoms;

[0241] 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;

[0242] R e It is hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0243] Each R f Independently, it is a halogenated group, a hydroxyl group, or -NR. 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;

[0244] 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

[0245] Each R h Independently, it is a halogenated group, a cyano group, a hydroxyl group, or a C group. 1-6 Alkyl, C1-6 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.

[0246] On the one hand, this article provides compounds of formula I:

[0247] Or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0248] X is C and Z is N, or X is N and Z is C;

[0249] 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 The condition is Q 2 Q 3 and Q 4 At least one of them is CR QB ;or

[0250] Q 1 It is a key; and Q 2 Q 3 Q 4 and Q 5 Each of the following is independently O, S, N, NH, NR c CR QA or CR QB The condition is Q 2 Q 3 Q 4 and Q 5 At least one of them is CR QB ;

[0251] The condition is that it contains Q. 1 -Q 5 The ring is from the Aromatic tribe;

[0252] R QB It is -S(O)(=NR) a )R b or -(CR) i R j ) n -S(O)(=NR a )R b ;

[0253] R a 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 C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl;

[0254] R b It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C-substitution of cycloalkyl and halogenated groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl;

[0255] Or R a and R b Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the rings are optionally separated by 1-3 independently selected carbon atoms. 1-6 Alkyl substitution;

[0256] n is 1, 2, 3, 4, 5, or 6;

[0257] Each R i It is independently hydrogen, halogenated or C 1-6 alkyl;

[0258] Or R a and R i Or R b and R i Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the rings are optionally separated by 1-3 independently selected carbon atoms. 1-6 Alkyl substitution;

[0259] Each R j It is independently hydrogen, halogenated or C 1-6 alkyl;

[0260] Each R QA Independently, it is hydrogen, halogroup, cyano, hydroxyl, -NR c R d , -C(O)NRc R d , -S(O) 0-2 R e Optionally selected from 1 to 6 independently chosen R f Replacement C 1-6 Alkyl group, optionally surrounded by 1-6 groups, each independently selected from hydroxyl, halogroup and C. 1-6 alkoxy substituents of C 1-6 Alkyl groups, optionally composed of one or more independently selected from C 1-6 Alkyl and -C(O)(C 1-6 A 3-12 membered heterocyclic group substituted with an alkyl group, optionally with 1-3 independently selected -C(O)(C) groups. 1-6 alkyl) substituted C 6-10 Aryl, and optionally 1-6 independently selected R g Substituted 5-10 heteroaryl groups;

[0261] Or two R atoms on adjacent carbon atoms QA Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the rings are optionally separated by 1-2 independently selected R atoms. h replace;

[0262] Or R a Or R b and adjacent R QA Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the rings are optionally separated by 1-2 independently selected R atoms. h replace;

[0263] L 2 R is arbitrarily selected by 1-2 independently selected factors. h Replacement C 6-10 Aryl, optionally selected by 1-2 independently chosen R h Replaced 5-10 aryl groups, Where aa represents the combination containing Q 1 -Q 5 The attachment point of the ring;

[0264] n1 is 1, 2, or 3;

[0265] L 2A Is it a key or C? 1-10 Alkylene;

[0266] R La It is hydrogen, C 1-6 Alkyl or -C(O)(C 1-6 alkyl);

[0267] R Lband R Lc Each of them is independently hydrogen or C. 1-6 alkyl;

[0268] 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;

[0269] Each R A Independently, it is a halogenated group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl;

[0270] R 1 R 2 and R 3 Each is independently hydrogen or optionally surrounded by 1-6 independently selected halogen groups, hydroxyl groups, and C. 1-6 alkoxy substituents of C 1-6 alkyl;

[0271] L 1 It is -C(O)-, -CH2-, -CH(C 1-6 Alkyl)- or -S(O)2-;

[0272] Cycle 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 optionally surrounded by 1 to 4 heteroatoms independently selected from halogen groups, oxo groups, and C. 1-6 Alkyl substituents;

[0273] Where bb represents L 1 Attachment point;

[0274] R 4 R 5 R 6 and R 7 Each is independently hydrogen, halogroup, or C. 1-6 alkyl;

[0275] R 8 It is phenyl, 5-6 heteroaryl or Wherein the phenyl or 5-6-membered heteroaryl group is R 8c Replaced, and optionally further selected by 1-3 independently chosen R h replace;

[0276] L 3 Is it a key or C? 1-3 Alkylene;

[0277] L 4 Is it a key or C? 1-5 Alkylene;

[0278] R 8a and R 8b Each is independently hydrogen or optionally composed of one or more halogenated groups and C. 3-15 Cycloalkyl substituents substituted C 1-6 Alkyl; or

[0279] R 8a and R 8b Together with their respective attached carbon atoms, they form 1-3 independently selected carbon atoms. 1-6 Alkyl-substituted C 3-15 cycloalkyl ring, wherein the C 1-6 Alkyl groups are optionally separated by 1-6 independently selected R groups. f replace;

[0280] 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, halogenated and C- groups. 1-6 Substitution of alkoxy groups;

[0281] 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-;

[0282] R 9 It is -C(O)OR 9a -C(O)NR 9a R 9b Optionally selected by 1-3 independently chosen R 9c Substituted 5-6 aryl groups, or

[0283] X 1 Is it O or S?

[0284] R 9a Is it hydrogen or C? 1-6 alkyl;

[0285] 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;

[0286] Each R 9c Independently, it consists of hydrogen, oxy 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);

[0287] 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;

[0288] Each R Ca Independently, it is a halogenated group, a cyano group, or a C group. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c R d ;

[0289] 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;

[0290] 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. 1-6Substitution of alkoxy groups;

[0291] R e It is hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0292] Each R f Independently, it is a halogenated group, a hydroxyl group, or -NR. 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;

[0293] 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

[0294] Each R h Independently, it is a halogenated group, a cyano group, a hydroxyl group, or a C group. 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.

[0295] In some embodiments, compounds of formula II are provided herein:

[0296] 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 R 1 R 2 R 3 and R QB Each is defined independently as described in this article.

[0297] In some embodiments, compounds of formula III are provided herein:

[0298] 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 R 1 R 2 R 3 and R QB Each is defined independently as described in this article.

[0299] 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 The condition is Q 2 Q 3 and Q 4 At least one of them is CR QB .

[0300] In some implementation schemes, Q 1 and Q 5 Each is independently N or CR QA And Q 2 and Q 3 Each is independently N or CR QA And Q 4 It is CR QB In some implementations, 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 QB In some implementations, Q 1 and Q 5 Each is independently N or CR QA And Q 3 and Q 4 Each is independently N or CR QA And Q2 It is CR QB .

[0301] In some implementation schemes, Q 1 and Q 5 Each is CR independently QA And Q 2 and Q 3 Each is independently N or CR QA And Q 4 It is CR QB In some implementations, 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 QB In some implementations, Q 1 and Q 5 Each is CR independently QA And Q 3 and Q 4 Each is independently N or CR QA And Q 2 It is CR QB .

[0302] In some implementation schemes, part yes

[0303] In some implementations, each R QA Independently, it is hydrogen, halogenated group, C 1-6 Alkyl, C 1-6 alkoxy or -NR c R d .

[0304] In some implementation schemes, R c and R d Each is independently hydrogen or C 1-6 alkyl.

[0305] In some implementation schemes, Q 1 and Q 5 Each is CR independently QA ; where each R QA It can be either hydrogen or a halogenated group.

[0306] In some implementation schemes, Q 2 Q 3 and Q 4 One of them is N.

[0307] In some implementation schemes, Q 2 Q 3 and Q 4 Each is CR independently QA or CR QB The condition is Q 2 Q 3 and Q 4 At least one of them is CR QB .

[0308] In some implementation schemes, R QB It is -S(O)(=NR) a )R b .

[0309] In some implementation schemes, R QB It is -S(O)(=NR) a )R b ;R a 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 C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl; and R b It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C-substitution of cycloalkyl and halogenated groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl.

[0310] In some implementation schemes, R QB It is -S(O)(=NR) a )R b And R a and R b Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally composed of 1-3 independently selected carbon atoms. 1-6 Alkyl substitution.

[0311] In some implementation schemes, R QBIt is -S(O)(=NR) a )R b And R a Or R b 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.

[0312] In some implementation schemes, R QB It is -S(O)(=NR) a )R b And R a 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.

[0313] In some implementation schemes, R QB It is -S(O)(=NR) a )R b And R b 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.

[0314] In some implementation schemes, R QB Yes - (CR) i R j ) n -S(O)(=NR a )R b .

[0315] In some implementation schemes, R QB Yes - (CR) i R j ) n -S(O)(=NR a )R b n is 1, 2, 3, 4, 5, or 6; R a 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 C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C6-10 Aryl; and R b It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C-substitution of cycloalkyl and halogenated groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl.

[0316] In some implementation schemes, R QB Yes - (CR) i R j ) n -S(O)(=NR a )R b And R a and R b Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally composed of 1-3 independently selected carbon atoms. 1-6 Alkyl substitution.

[0317] In some implementation schemes, R QB Yes - (CR) i R j ) n -S(O)(=NR a )R b n is 1, 2, 3, 4, 5, or 6; and each R i It is independently hydrogen, halogenated or C 1-6 Alkyl groups; and each R j It is independently hydrogen, halogenated or C 1-6 alkyl.

[0318] In some implementation schemes, R QB Yes - (CR) i R j ) n -S(O)(=NR a )R b ; and 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.

[0319] In some implementation schemes, R QB Yes - (CR) i Rj ) n -S(O)(=NR a )R b n is 1, 2, 3, 4, 5, or 6; and R a and R i Or R b and R i Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally composed of 1-3 independently selected carbon atoms. 1-6 Alkyl substitution.

[0320] In some implementation schemes, R QB Yes - (CR) i R j ) n -S(O)(=NR a )R b And R a Or R b 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.

[0321] In some implementation schemes, R QB Yes - (CR) i R j ) n -S(O)(=NR a )R b ;R a Or R b 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 Substitution; and an R on an adjacent carbon atom i And an R j Together with one or more atoms to which each is attached, they form olefins, wherein the olefins are optionally bonded by one to three independently selected C atoms. 1-6 Alkyl substitution.

[0322] In some implementation schemes, R QB Yes - (CR) i R j ) n -S(O)(=NR a )R b And R a 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.

[0323] In some implementation schemes, R QB Yes - (CR) i R j ) n -S(O)(=NR a )R b And R b 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.

[0324] In some implementation schemes, R QB It is -N = S(O)(R 1a )R b .

[0325] In some implementation schemes, R QB It is -N = S(O)(R 1a )R b ;R 1a It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C-substitution of cycloalkyl and halogenated groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl; and R a 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 C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl.

[0326] In some implementation schemes, R QB It is -O-(CR) i R j ) n -S(O)(=NR a )R b .

[0327] In some implementation schemes, R QB It is -O-(CR) i R j ) n -S(O)(=NR a )R b n is 1, 2, 3, 4, 5, or 6; R a 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 C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl; and R b It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C-substitution of cycloalkyl and halogenated groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl.

[0328] In some implementation schemes, R QB It is -O-(CR) i R j ) n -S(O)(=NR a )R b And R a and R b Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally composed of 1-3 independently selected carbon atoms. 1-6 Alkyl substitution.

[0329] In some implementation schemes, R QB It is -O-(CR) i R j ) n -S(O)(=NR a )R b n is 1, 2, 3, 4, 5, or 6; and each R i It is independently hydrogen, halogenated or C 1-6 Alkyl groups; and each R j It is independently hydrogen, halogenated or C1-6 alkyl.

[0330] In some implementation schemes, R QB It is -O-(CR) i R j ) n -S(O)(=NR a )R b ; and 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.

[0331] In some implementation schemes, R QB It is -O-(CR) i R j ) n -S(O)(=NR a )R b n is 1, 2, 3, 4, 5, or 6; and R a and R i Or R b and R i Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally composed of 1-3 independently selected carbon atoms. 1-6 Alkyl substitution.

[0332] In some implementation schemes, R QB It is -O-(CR) i R j ) n -S(O)(=NR a )R b And R a Or R b 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.

[0333] In some implementation schemes, R QB It is -O-(CR) i R j ) n -S(O)(=NR a )R b And R a 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.

[0334] In some implementation schemes, R QB It is -O-(CR) i R j ) n -S(O)(=NR a )R b And R b 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.

[0335] In some implementation schemes, R QB It is -S(O)(=NR) a )R b or -C 1-6 Alkyl-S(O)(=NR) a )R b .

[0336] In some implementation schemes, R QB It is -C 1-6 Alkyl-S(O)(=NR) a )R b .

[0337] In some implementation schemes, R QB It is -S(O)(=NR) a )R b or -CH2-S(O)(=NR a )R b .

[0338] In some implementation schemes, R QB It is -CH2-S(O)(=NR) a )R b .

[0339] In some implementation schemes, part yes In some implementation schemes, part yes

[0340] In some implementation schemes, part yes In some implementation schemes, part yes

[0341] In some implementation schemes, part yes

[0342] In some implementation schemes, part yes In some implementation schemes, part yes

[0343] In some implementation schemes, part yes

[0344] In some implementation schemes, part yes

[0345] In some implementation schemes, part yes

[0346] In some implementation schemes, R a 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.

[0347] In some implementation schemes, R b It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C-substitution of cycloalkyl and halogenated groups 1-6 Alkyl, or C 3-6 Cycloalkyl.

[0348] In some implementation schemes, R a and R b Together with the atoms to which they are attached, they form 5-8 membered heterocyclic groups. In some embodiments, R a and R b Together with their respective attached atoms, they form a 5-membered heterocyclic group. In some embodiments, part of... yes

[0349] In some implementation schemes, R a Or R b and adjacent R QATogether with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the rings are optionally separated by 1-2 independently selected R atoms. h Replacement. In some implementations, part of yes

[0350] In some implementation schemes, R a and R i Or R b and R i Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the rings are optionally separated by 1-3 independently selected carbon atoms. 1-6 Alkyl substitution.

[0351] In some implementations, L 2 R is arbitrarily selected by 1-2 independently selected factors. h Replacement C 6-10 Aryl, optionally selected by 1-2 independently chosen R h Replaced 5-10 aryl groups, Where aa represents the combination containing Q 1 -Q 5 The attachment point of the ring.

[0352] In some implementations, L 2 R is arbitrarily selected by 1-2 independently selected factors. h Replacement C 6-10 Aryl, Where aa represents the combination containing Q 1 -Q 5 The attachment point of the ring.

[0353] In some implementations, L 2 R is arbitrarily selected by 1-2 independently selected factors. h Replacement C 6-10 Aryl.

[0354] In some implementations, L 2 R is arbitrarily selected by 1-2 independently selected factors. h Substituted 5-10 heteroaryl groups.

[0355] In some implementations, L 2 yes Where aa represents the combination containing Q 1 -Q 5 The attachment point of the ring. In some implementations, L 2 yes Where aa represents the combination containing Q 1 -Q 5The attachment point of the ring. In some implementations, L 2 yes Where aa represents the combination containing Q 1 -Q 5 The attachment point of the ring.

[0356] In some implementations, L 2A It is a key.

[0357] In some implementation schemes, R 1 It is hydrogen. In some implementations, R 2 It is hydrogen. In some implementations, R 1 and R 2 Each is hydrogen.

[0358] 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 methyl. In some embodiments, R 3 It is a methyl group and is attached to the ring in the (S)-configuration. In some embodiments, R 3 It is hydrogen or methyl, wherein the methyl group is attached to the ring to which it is attached in the (S)- configuration.

[0359] In some implementations, L 1 It is -C(O)-.

[0360] In some implementations, ring A is optionally composed of 1-5 independently selected R... A Replacement C 6-10 Aryl. In some embodiments, ring A is optionally composed of 1-5 independently selected R... A Replacement C 5-7 Cycloalkyl. In some embodiments, ring A is optionally composed of 1-5 independently selected R groups. A The 5-7 membered heterocyclic group is replaced. In some embodiments, ring A is optionally replaced by 1-5 independently selected R groups. A Substituted 5-10 heteroaryl groups.

[0361] In some implementations, each R A Independently, it is a halogenated group, C 1-6 Alkyl or C 3-6 Cycloalkyl.

[0362] In some implementations, ring A is optionally composed of 1-5 independently selected halogenated groups, C... 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-6 Cycloalkyl substituents substituted C 6-10 Aryl.

[0363] In some implementations, ring A is composed of 2-3 independently selected halogenated groups, C... 1-6 Alkyl and C 3-6 A phenyl group substituted with a cycloalkyl substituent.

[0364] 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 substitution is optionally made by one to four independently selected groups: halogenated group, oxo group, 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 bonded by R 8 The substitution is optionally made by one to four independently selected groups: halogenated group, oxo group, 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.

[0365] 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 4 heteroatoms independently selected from halogen groups, oxo groups, 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 surrounded by 1 to 4 heteroatoms independently selected from halogen groups, oxo groups, 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.

[0366] In some implementation schemes, ring B is:

[0367] Where bb represents L 1 Attachment point;

[0368] R 4 R 5 R 6 and R 7 Each is independently hydrogen, halogroup, or C. 1-6 alkyl;

[0369] R 8 It is phenyl, 5-6 heteroaryl or Wherein the phenyl or 5-6-membered heteroaryl group is R 8c Replaced, and optionally further selected by 1-3 independently chosen R h replace;

[0370] L 3 Is it a key or C? 1-3 Alkylene;

[0371] L 4 Is it a key or C? 1-5 Alkylene;

[0372] R 8a and R 8b Each is independently hydrogen or optionally composed of one or more halogenated groups and C. 3-15 Cycloalkyl substituents substituted C 1-6 Alkyl; or

[0373] R 8a and R 8b Together with their respective attached carbon atoms, they form 1-3 independently selected carbon atoms. 1-6 Alkyl-substituted C 3-15 cycloalkyl ring, wherein the C 1-6 Alkyl groups are optionally separated by 1-6 independently selected R groups. f replace;

[0374] 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, halogenated and C- groups. 1-6 Substitution of alkoxy groups;

[0375] 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-;

[0376] R 9 It is -C(O)OR 9a -C(O)NR 9a R 9b Optionally selected by 1-3 independently chosen R 9c Substituted 5-6 aryl groups, or

[0377] X 1 Is it O or S?

[0378] R 9a Is it hydrogen or C? 1-6 alkyl;

[0379] 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;

[0380] Each R 9c Independently, it consists of hydrogen, oxy 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).

[0381] In some implementation schemes, ring B is Where bb represents L 1 Attachment point.

[0382] In some implementation schemes, ring B is Where bb represents L 1 Attachment point.

[0383] In some implementation schemes, ring B is Where bb represents L 1 Attachment point.

[0384] In some implementation schemes, ring B is Where bb represents L 1 Attachment point.

[0385] In some implementation schemes, ring B is Where bb represents L 1 Attachment point.

[0386] In some implementation schemes, ring B is Where bb represents L 1 Attachment point.

[0387] In some implementation schemes, ring B is Where bb represents L 1 Attachment point.

[0388] In some implementation schemes, ring B is:

[0389] Where bb represents L 1 Attachment point.

[0390] In some implementation schemes, R 8 It was R 8c Substituted phenyl groups. In some embodiments, 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.

[0391] In some implementation schemes, R 8 yes

[0392] In some implementation schemes, ring B is: Where bb represents L 1 Attachment point.

[0393] In some implementation schemes, ring B is:

[0394] Where bb represents L 1 Attachment point.

[0395] In some implementation schemes, ring B is Where bb represents L 1 Attachment point.

[0396] In some implementation schemes, ring B is Where bb represents L 1 Attachment point.

[0397] In some implementation schemes, ring B is Where bb represents L 1 Attachment point.

[0398] In some implementation schemes, ring B is Where bb represents L 1 Attachment point.

[0399] In some implementations, L 3 It is a key.

[0400] In some implementations, L 4 It is a key.

[0401] In some implementations, L 3 It is a key and L 4 It is a key.

[0402] In some implementation schemes, R 8 It was R 8c Substituted phenyl, R 8c Substituted 5-6 aryl groups, or

[0403] In some embodiments, compounds of formula IIA are provided herein:

[0404] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein q is 0, 1, 2, 3, 4, or 5; and ring B, ring C, Q 2 L 2 R A R 3 R QA and R QB Each is defined independently as described in this article.

[0405] In some embodiments, compounds of formula IIB are provided herein:

[0406] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein q is 0, 1, 2, 3, 4, or 5; and ring B, ring C, Q 2 L 2 R A R 3 R QA and R QB Each is defined independently as described in this article.

[0407] In some embodiments, this document provides a compound of formula IIA-(S):

[0408] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein q is 0, 1, 2, 3, 4, or 5; and ring B, ring C, Q 2 L 2 R A R 3 R QA and R QB Each is defined independently as described in this article.

[0409] In some embodiments, this document provides a compound of formula IIB-(S):

[0410] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein q is 0, 1, 2, 3, 4, or 5; and ring B, ring C, Q 2 L 2 R A R 3 R QA and R QB Each is defined independently as described in this article.

[0411] In some implementation schemes, ring B is Where bb represents L 1 Attachment point.

[0412] In some implementation schemes, R 4 It is either hydrogen or a halogroup.

[0413] In some implementation schemes, R 5 R 6 and R 7 Each is hydrogen.

[0414] In some implementation schemes, R 8a and R 8b Each is hydrogen on its own.

[0415] In some implementation schemes, R 8a and R 8b Together with their respective attached carbon atoms, they form optionally carbon-bound... 1-6 Alkyl-substituted C 3-15 Cycloalkyl rings.

[0416] In some implementation schemes, R 9 R is arbitrarily selected by 1-3 independently chosen factors. 9c Substituted 5-6 aryl groups, or In some implementation schemes, R 9R is arbitrarily selected by 1-3 independently chosen factors. 9c Substituted 5-6 membered heteroaryl groups. In some embodiments, R 9 yes

[0417] In some implementation schemes, R 9 It is a 6-membered heteroaryl group.

[0418] In some implementation schemes, R 9 yes

[0419] 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.

[0420] In some implementations, each R Ca It is C 1-6 alkyl.

[0421] In some implementations, ring C is

[0422] In some implementations, ring C is And some yes:

[0423] In some implementations, ring C is And some yes:

[0424] In some implementations, compounds of formula IIC are provided herein:

[0425] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein q is 0, 1, 2, 3, 4, or 5; Z 1 Is it N or CR? 5 Z 2 Is it N or CR? 6 Z 3 Is it N or CR? 7 ;R 4 R 5 R 6 and R 7 Each is independently hydrogen, halogroup, or C. 1-6 Alkyl groups; and cyclic C, R 8a R 8bL 4 R 9 R A R 3 Q 2 R QA and R QB Each is defined independently as described in this article.

[0426] In some embodiments, this document provides a compound of formula IIC-(S):

[0427] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein q is 0, 1, 2, 3, 4, or 5; Z 1 Is it N or CR? 5 Z 2 Is it N or CR? 6 Z 3 Is it N or CR? 7 ;R 4 R 5 R 6 and R 7 Each is independently hydrogen, halogroup, or C. 1-6 Alkyl groups; and cyclic C, R 8a R 8b L 4 R 9 R A R 3 Q 2 R QA and R QB Each is defined independently as described in this article.

[0428] On the one hand, this paper provides compounds of formula IIC-(S):

[0429] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein:

[0430] Q 2 Is it N or CR? QA ;

[0431] R QB It is -S(O)(=NR) a )R b 、-(CR i R j ) n -S(O)(=NR a )R b -N=S(O)(R1a )R b or -O-(CR) i R j ) n -S(O)(=NR a )R b ;

[0432] R 1a It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C-substitution of cycloalkyl and halogenated groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl;

[0433] R a 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 C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl;

[0434] R b It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C-substitution of cycloalkyl and halogenated groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl;

[0435] Or R a and R b Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally composed of 1-3 independently selected carbon atoms. 1-6 Alkyl substitution;

[0436] n is 1, 2, 3, 4, 5, or 6;

[0437] Each R i It is independently hydrogen, halogenated or C 1-6 alkyl;

[0438] Or R a and R i Or R b and R i Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally composed of 1-3 independently selected carbon atoms. 1-6 Alkyl substitution;

[0439] Each R j It is independently hydrogen, halogenated or C 1-6 alkyl;

[0440] 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;

[0441] Each R QA Independently, it is hydrogen, halogroup, cyano, hydroxyl, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e Optionally selected from 1 to 6 independently chosen R f Replacement C 1-6 Alkyl group, optionally surrounded by 1-6 groups, each independently selected from hydroxyl, halogroup and C. 1-6 alkoxy substituents of C 1-6 Alkyl groups, optionally composed of one or more independently selected from C 1-6 Alkyl and -C(O)(C 1-6 A 3-12 membered heterocyclic group substituted with an alkyl group, optionally with 1-3 independently selected -C(O)(C) groups. 1-6 alkyl) substituted C 6-10 Aryl, and optionally 1-6 independently selected R g Substituted 5-10 heteroaryl groups;

[0442] Or R a Or R b 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;

[0443] q is 0, 1, 2, 3, 4, or 5;

[0444] Each R A Independently, it is a halogenated group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl;

[0445] R 3 It is hydrogen or optionally surrounded by 1-6 independently selected halogen groups, hydroxyl groups, and C. 1-6 alkoxy substituents of C 1-6 alkyl;

[0446] Z 1 Is it N or CR? 5 ;

[0447] Z 2 Is it N or CR? 6 ;

[0448] Z 3 Is it N or CR? 7 ;

[0449] R 4 R 5 R 6 and R 7 Each is independently hydrogen, halogroup, or C. 1-6 alkyl;

[0450] L 4 Is it a key or C? 1-5 Alkylene;

[0451] R 8a and R 8b Each is independently hydrogen or optionally composed of one or more halogenated groups and C. 3-15 Cycloalkyl substituents substituted C 1-6 Alkyl; or

[0452] R 8a and R 8b Together with their respective attached carbon atoms, they form 1-3 independently selected carbon atoms. 1-6 Alkyl-substituted C 3-15 cycloalkyl ring, wherein the C 1-6 Alkyl groups are optionally separated by 1-6 independently selected R groups. f replace;

[0453] R 9 It is -C(O)OR 9a -C(O)NR 9a R 9b Optionally selected by 1-3 independently chosen R9c The substituted 5-6 heteroaryl group, optionally with 1-3 independently selected R groups. 9c Substituted 4-6 membered heterocyclic groups, or

[0454] X 1 Is it O or S?

[0455] R 9a Is it hydrogen or C? 1-6 alkyl;

[0456] 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;

[0457] Each R 9c Independently, it consists of hydrogen, oxy 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);

[0458] 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;

[0459] Each R Ca Independently, it is a halogenated group, a cyano group, or a C group. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c R d ;

[0460] 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;

[0461] 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 C1-6 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;

[0462] Each R e Independently, it is hydrogen and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0463] Each R f Independently, it is a halogenated group, a hydroxyl group, or -NR. 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;

[0464] 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

[0465] Each R h Independently, it is a halogenated group, a cyano group, a hydroxyl group, or a C group. 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.

[0466] On the one hand, this paper provides compounds of formula IIC-(S):

[0467] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein:

[0468] Q 2 Is it N or CR? QA ;

[0469] R QB It is -S(O)(=NR) a )R b or -(CR) i R j ) n -S(O)(=NR a )R b ;

[0470] R a 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 C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl;

[0471] R b It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C-substitution of cycloalkyl and halogenated groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl;

[0472] Or R a and R b Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally composed of 1-3 independently selected carbon atoms. 1-6 Alkyl substitution;

[0473] n is 1, 2, 3, 4, 5, or 6;

[0474] Each R i It is independently hydrogen, halogenated or C 1-6 alkyl;

[0475] Or R a and R i Or R b and R iTogether with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally composed of 1-3 independently selected carbon atoms. 1-6 Alkyl substitution;

[0476] Each R j It is independently hydrogen, halogenated or C 1-6 alkyl;

[0477] 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;

[0478] Each R QA Independently, it is hydrogen, halogroup, cyano, hydroxyl, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e Optionally selected from 1 to 6 independently chosen R f Replacement C 1-6 Alkyl group, optionally surrounded by 1-6 groups, each independently selected from hydroxyl, halogroup and C. 1-6 alkoxy substituents of C 1-6 Alkyl groups, optionally composed of one or more independently selected from C 1-6 Alkyl and -C(O)(C 1-6 A 3-12 membered heterocyclic group substituted with an alkyl group, optionally with 1-3 independently selected -C(O)(C) groups. 1-6 alkyl) substituted C 6-10 Aryl, and optionally 1-6 independently selected R g Substituted 5-10 heteroaryl groups;

[0479] Or R a Or R b 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;

[0480] q is 0, 1, 2, 3, 4, or 5;

[0481] Each R A Independently, it is a halogenated group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6cycloalkyl;

[0482] R 3 It is hydrogen or optionally surrounded by 1-6 independently selected halogen groups, hydroxyl groups, and C. 1-6 alkoxy substituents of C 1-6 alkyl;

[0483] Z 1 Is it N or CR? 5 ;

[0484] Z 2 Is it N or CR? 6 ;

[0485] Z 3 Is it N or CR? 7 ;

[0486] R 4 R 5 R 6 and R 7 Each is independently hydrogen, halogroup, or C. 1-6 alkyl;

[0487] L 4 Is it a key or C? 1-5 Alkylene;

[0488] R 8a and R 8b Each is independently hydrogen or optionally composed of one or more halogenated groups and C. 3-15 Cycloalkyl substituents substituted C 1-6 Alkyl; or

[0489] R 8a and R 8b Together with their respective attached carbon atoms, they form 1-3 independently selected carbon atoms. 1-6 Alkyl-substituted C 3-15 cycloalkyl ring, wherein the C 1-6 Alkyl groups are optionally separated by 1-6 independently selected R groups. f replace;

[0490] R 9 It is -C(O)OR 9a -C(O)NR 9a R 9b Optionally selected by 1-3 independently chosen R 9c The substituted 5-6 heteroaryl group, optionally with 1-3 independently selected R groups. 9c Substituted 4-6 membered heterocyclic groups, or

[0491] X 1 Is it O or S?

[0492] R 9a Is it hydrogen or C? 1-6 alkyl;

[0493] 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;

[0494] Each R 9c Independently, it consists of hydrogen, oxy 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);

[0495] 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;

[0496] Each R Ca Independently, it is a halogenated group, a cyano group, or a C group. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c R d ;

[0497] 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;

[0498] 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 1-6Alkyl 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;

[0499] Each R e Independently, it is hydrogen and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0500] Each R f Independently, it is a halogenated group, a hydroxyl group, or -NR. 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;

[0501] 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

[0502] Each R h Independently, it is a halogenated group, a cyano group, a hydroxyl group, or a C group. 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.

[0503] In some implementation schemes, R 4 It is hydrogen. In some implementations, R 4 R 5 R 6 and R 7 Each is hydrogen.

[0504] In some implementation schemes, Z 1 It is CH. In some implementations, Z 1 It is N.

[0505] In some implementation schemes, Z 2 It is CH. In some implementations, Z 2 It is N.

[0506] In some implementation schemes, Z 3 It is CH. In some implementations, Z 3 It is N.

[0507] In some implementation schemes, Z 1 Z 2 and Z 3 One of them is N or CH, and Z 1 Z 2 and Z 3 The other two are CH. In some implementations, Z 1 Z 2 and Z 3 One of them is N, and Z 1 Z 2 and Z 3 The other two are CH. In some implementations, Z 1 Z 2 and Z 3 Each is CH.

[0508] In some implementation schemes, R 4 It is hydrogen; and Z 1 Z 2 and Z 3 One of them is N or CH, and Z 1 Z 2 and Z 3 The other two are CH. In some implementations, R 4 It is hydrogen; and Z 1 Z 2 and Z 3 One of them is N, and Z 1 Z 2 and Z 3 The other two are CH. In some implementations, R 4 It is hydrogen; and Z 1 Z 2 and Z 3 Each is CH.

[0509] In some implementation schemes, R QB It is -S(O)(=NR) a )R b .

[0510] In some implementations, compounds of formula IID are provided herein:

[0511] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein q is 0, 1, 2, 3, 4, or 5; v is 0, 1, 2, or 3; and R a R b R Ca R 8a R 8b R 9 R A R 3 Q 2 and R QA Each is defined independently as described in this article.

[0512] In some embodiments, this document provides a compound of formula IID-(S):

[0513] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein q is 0, 1, 2, 3, 4, or 5; v is 0, 1, 2, or 3; and R a R b R Ca R 8a R 8b R 9 R A R 3 Q 2 and R QA Each is defined independently as described in this article.

[0514] On the one hand, this paper provides compounds of formula IID-(S):

[0515] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein:

[0516] Q 2 Is it N or CR? QA ;

[0517] R a 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 C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C6-10 Aryl;

[0518] R b It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C-substitution of cycloalkyl and halogenated groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl;

[0519] Or R a and R b Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally composed of 1-3 independently selected carbon atoms. 1-6 Alkyl substitution;

[0520] Each R QA Independently, it is hydrogen, halogroup, cyano, hydroxyl, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e Optionally selected from 1 to 6 independently chosen R f Replacement C 1-6 Alkyl group, optionally surrounded by 1-6 groups, each independently selected from hydroxyl, halogroup and C. 1-6 alkoxy substituents of C 1-6 Alkyl groups, optionally composed of one or more independently selected from C 1-6 Alkyl and -C(O)(C 1-6 A 3-12 membered heterocyclic group substituted with an alkyl group, optionally with 1-3 independently selected -C(O)(C) groups. 1-6 alkyl) substituted C 6-10 Aryl, and optionally 1-6 independently selected R g Substituted 5-10 heteroaryl groups;

[0521] Or R a Or R b 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;

[0522] q is 0, 1, 2, 3, 4, or 5;

[0523] Each R A Independently, it is a halogenated group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl;

[0524] R 3 It is hydrogen or optionally surrounded by 1-6 independently selected halogen groups, hydroxyl groups, and C. 1-6 alkoxy substituents of C 1-6 alkyl;

[0525] R 8a and R 8b Each is independently hydrogen or optionally composed of one or more halogenated groups and C. 3-15 Cycloalkyl substituents substituted C 1-6 Alkyl; or

[0526] R 8a and R 8b Together with their respective attached carbon atoms, they form 1-3 independently selected carbon atoms. 1-6 Alkyl-substituted C 3-15 cycloalkyl ring, wherein the C 1-6 Alkyl groups are optionally separated by 1-6 independently selected R groups. f replace;

[0527] R 9 It is -C(O)OR 9a -C(O)NR 9a R 9b Optionally selected by 1-3 independently chosen R 9c The substituted 5-6 heteroaryl group, optionally with 1-3 independently selected R groups. 9c Substituted 4-6 membered heterocyclic groups, or

[0528] X 1 Is it O or S?

[0529] R 9a Is it hydrogen or C? 1-6 alkyl;

[0530] 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;

[0531] Each R 9c Independently, it consists of hydrogen, oxy group, optionally 1-6 independently selected halogen groups, and C. 1-6alkoxy-substituted C 1-6 Alkyl, or -C(O)(C 1-6 alkyl);

[0532] v is 0, 1, 2, or 3;

[0533] Each R Ca Independently, it is a halogenated group, a cyano group, or a C group. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c R d ;

[0534] 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;

[0535] 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;

[0536] Each R e Independently, it is hydrogen and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0537] Each R f Independently, it is a halogenated group, a hydroxyl group, or -NR. c R d C 1-6 Alkoxy, C 1-6 Haloalkoxy, or optionally surrounded by 1-4 groups, each independently selected from hydroxyl, C 1-63-12-membered heterocyclic groups substituted with alkyl groups and 3-12-membered heterocyclic groups;

[0538] 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

[0539] Each R h Independently, it is a halogenated group, a cyano group, a hydroxyl group, or a C group. 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.

[0540] In some implementations, compounds of formula IIE are provided herein:

[0541] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein q is 0, 1, 2, 3, 4, or 5; v is 0, 1, 2, or 3; w is 0, 1, 2, or 3; each R 1f C is independent 1-6 Alkyl, wherein each C 1-6 Alkyl groups are independently and optionally selected by 1-6 independently chosen R groups. f Replace; and R a R b R Ca R 9 R A R 3 Q 2 and R QA Each is defined independently as described in this article.

[0542] In some embodiments, this document provides a compound of formula IIE-(S):

[0543] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein q is 0, 1, 2, 3, 4, or 5; v is 0, 1, 2, or 3; w is 0, 1, 2, or 3; R 1f C is independent1-6 Alkyl, wherein each C 1-6 Alkyl groups are independently and optionally selected by 1-6 independently chosen R groups. f Replace; and R a R b R Ca R 9 R A R 3 Q 2 and R QA Each is defined independently as described in this article.

[0544] On the one hand, this paper provides compounds of formula IIE-(S):

[0545] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein:

[0546] Q 2 Is it N or CR? QA ;

[0547] R a 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 C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl;

[0548] R b It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C-substitution of cycloalkyl and halogenated groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl;

[0549] Or R a and R b Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally composed of 1-3 independently selected carbon atoms. 1-6 Alkyl substitution;

[0550] Each R QA Independently, it is hydrogen, halogroup, cyano, hydroxyl, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e Optionally selected from 1 to 6 independently chosen R f Replacement C 1-6 Alkyl group, optionally surrounded by 1-6 groups, each independently selected from hydroxyl, halogroup and C. 1-6 alkoxy substituents of C 1-6 Alkyl groups, optionally composed of one or more independently selected from C 1-6 Alkyl and -C(O)(C 1-6 A 3-12 membered heterocyclic group substituted with an alkyl group, optionally with 1-3 independently selected -C(O)(C) groups. 1-6 alkyl) substituted C 6-10 Aryl, and optionally 1-6 independently selected R g Substituted 5-10 heteroaryl groups;

[0551] Or R a Or R b 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;

[0552] q is 0, 1, 2, 3, 4, or 5;

[0553] Each R A Independently, it is a halogenated group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl;

[0554] R 3 It is hydrogen or optionally surrounded by 1-6 independently selected halogen groups, hydroxyl groups, and C. 1-6 alkoxy substituents of C 1-6 alkyl;

[0555] R 9 It is -C(O)OR 9a -C(O)NR 9a R 9b Optionally selected by 1-3 independently chosen R 9c The substituted 5-6 heteroaryl group, optionally with 1-3 independently selected R groups. 9cSubstituted 4-6 membered heterocyclic groups, or

[0556] X 1 Is it O or S?

[0557] R 9a Is it hydrogen or C? 1-6 alkyl;

[0558] 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;

[0559] Each R 9c Independently, it consists of hydrogen, oxy 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);

[0560] v is 0, 1, 2, or 3;

[0561] Each R Ca Independently, it is a halogenated group, a cyano group, or a C group. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c R d ;

[0562] 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;

[0563] 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 (C1-6 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;

[0564] Each R e Independently, it is hydrogen and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0565] w is 0, 1, 2, or 3;

[0566] Each R 1f C is independent 1-6 Alkyl, wherein each C 1-6 Alkyl groups are independently and optionally selected by 1-6 independently chosen R groups. f replace;

[0567] Each R f Independently, it is a halogenated group, a hydroxyl group, or -NR. 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;

[0568] 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

[0569] Each R h Independently, it is a halogenated group, a cyano group, a hydroxyl group, or a C group. 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.

[0570] In some implementation schemes, R QB Yes - (CR) i R j ) n -S(O)(=NR a )Rb In some implementations, n is 1 or 2. In some implementations, n is 1. In some implementations, n is 2.

[0571] In some implementation schemes, R a 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.

[0572] In some implementations, compounds of formula IIF are provided herein:

[0573] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein Y is -(CR i R j ) n -; q is 0, 1, 2, 3, 4, or 5; v is 0, 1, 2, or 3; and n, R b R i R j R Ca R 8a R 8b R 9 R A R 3 Q 2 and R QA Each is defined independently as described in this article.

[0574] In some embodiments, this document provides a compound of the formula IIF-(S):

[0575] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein Y is -(CR i R j ) n -; q is 0, 1, 2, 3, 4, or 5; v is 0, 1, 2, or 3; and n, R b R i R j R Ca R 8a R 8b R 9 R A R 3 Q 2 and R QA Each is defined independently as described in this article.

[0576] On the one hand, this paper provides compounds of formula IIF-(S):

[0577] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein:

[0578] Q 2 Is it N or CR? QA ;

[0579] Y is -(CR) i R j ) n -;

[0580] R b It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C-substitution of cycloalkyl and halogenated groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl;

[0581] n is 1, 2, 3, 4, 5, or 6;

[0582] Each R i It is independently hydrogen, halogenated or C 1-6 alkyl;

[0583] Each R j It is independently hydrogen, halogenated or C 1-6 alkyl;

[0584] Or an R on an adjacent carbon atom i And an R j Together with one or more atoms to which each is attached, they form olefins, wherein the olefins are optionally bonded by one to three independently selected C atoms. 1-6 Alkyl substitution;

[0585] Each R QA Independently, it is hydrogen, halogroup, cyano, hydroxyl, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e Optionally selected from 1 to 6 independently chosen R f Replacement C 1-6Alkyl group, optionally surrounded by 1-6 groups, each independently selected from hydroxyl, halogroup and C. 1-6 alkoxy substituents of C 1-6 Alkyl groups, optionally composed of one or more independently selected from C 1-6 Alkyl and -C(O)(C 1-6 A 3-12 membered heterocyclic group substituted with an alkyl group, optionally with 1-3 independently selected -C(O)(C) groups. 1-6 alkyl) substituted C 6-10 Aryl, and optionally 1-6 independently selected R g Substituted 5-10 heteroaryl groups;

[0586] q is 0, 1, 2, 3, 4, or 5;

[0587] Each R A Independently, it is a halogenated group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl;

[0588] R 3 It is hydrogen or optionally surrounded by 1-6 independently selected halogen groups, hydroxyl groups, and C. 1-6 alkoxy substituents of C 1-6 alkyl;

[0589] R 8a and R 8b Each is independently hydrogen or optionally composed of one or more halogenated groups and C. 3-15 Cycloalkyl substituents substituted C 1-6 Alkyl; or

[0590] R 8a and R 8b Together with their respective attached carbon atoms, they form 1-3 independently selected carbon atoms. 1-6 Alkyl-substituted C 3-15 cycloalkyl ring, wherein the C 1-6 Alkyl groups are optionally separated by 1-6 independently selected R groups. f replace;

[0591] R 9 It is -C(O)OR 9a -C(O)NR 9a R 9b Optionally selected by 1-3 independently chosen R 9c The substituted 5-6 heteroaryl group, optionally with 1-3 independently selected R groups. 9c Substituted 4-6 membered heterocyclic groups, or

[0592] X 1 Is it O or S?

[0593] R 9a Is it hydrogen or C? 1-6 alkyl;

[0594] 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;

[0595] Each R 9c Independently, it consists of hydrogen, oxy 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);

[0596] v is 0, 1, 2, or 3;

[0597] Each R Ca Independently, it is a halogenated group, a cyano group, or a C group. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c R d ;

[0598] 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;

[0599] 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 (C3-6 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;

[0600] Each R e Independently, it is hydrogen and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0601] Each R f Independently, it is a halogenated group, a hydroxyl group, or -NR. 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;

[0602] 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

[0603] Each R h Independently, it is a halogenated group, a cyano group, a hydroxyl group, or a C group. 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.

[0604] In some embodiments, compounds of formula IIG are provided herein:

[0605] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein Y is -(CR i R j ) n -; q is 0, 1, 2, 3, 4, or 5; w is 0, 1, 2, or 3; v is 0, 1, 2, or 3; each R 1f C is independent 1-6 Alkyl, wherein each C 1-6 Alkyl groups are independently and optionally selected by 1-6 independently chosen R groups.f Replace; and n, R b R i R j R Ca R 9 R A R 3 Q 2 and R QA Each is defined independently as described in this article.

[0606] In some embodiments, this document provides a compound of formula IIG-(S):

[0607] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein Y is -(CR i R j ) n -; q is 0, 1, 2, 3, 4, or 5; w is 0, 1, 2, or 3; v is 0, 1, 2, or 3; each R 1f C is independent 1-6 Alkyl, wherein each C 1-6 Alkyl groups are independently and optionally selected by 1-6 independently chosen R groups. f Replace; and n, R b R i R j R Ca R 9 R A R 3 Q 2 and R QA Each is defined independently as described in this article.

[0608] On the one hand, this paper provides compounds of formula IIG-(S):

[0609] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein:

[0610] Q 2 Is it N or CR? QA ;

[0611] Y is -(CR) i R j ) n -;

[0612] R b It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C3-6 C-substitution of cycloalkyl and halogenated groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl;

[0613] n is 1, 2, 3, 4, 5, or 6;

[0614] Each R i It is independently hydrogen, halogenated or C 1-6 alkyl;

[0615] Each R j It is independently hydrogen, halogenated or C 1-6 alkyl;

[0616] Or an R on an adjacent carbon atom i And an R j Together with one or more atoms to which each is attached, they form olefins, wherein the olefins are optionally bonded by one to three independently selected C atoms. 1-6 Alkyl substitution;

[0617] Each R QA Independently, it is hydrogen, halogroup, cyano, hydroxyl, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e Optionally selected from 1 to 6 independently chosen R f Replacement C 1-6 Alkyl group, optionally surrounded by 1-6 groups, each independently selected from hydroxyl, halogroup and C. 1-6 alkoxy substituents of C 1-6 Alkyl groups, optionally composed of one or more independently selected from C 1-6 Alkyl and -C(O)(C 1-6 A 3-12 membered heterocyclic group substituted with an alkyl group, optionally with 1-3 independently selected -C(O)(C) groups. 1-6 alkyl) substituted C 6-10 Aryl, and optionally 1-6 independently selected R g Substituted 5-10 heteroaryl groups;

[0618] q is 0, 1, 2, 3, 4, or 5;

[0619] Each R A Independently, it is a halogenated group, C 1-6Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl;

[0620] R 3 It is hydrogen or optionally surrounded by 1-6 independently selected halogen groups, hydroxyl groups, and C. 1-6 alkoxy substituents of C 1-6 alkyl;

[0621] R 9 It is -C(O)OR 9a -C(O)NR 9a R 9b Optionally selected by 1-3 independently chosen R 9c The substituted 5-6 heteroaryl group, optionally with 1-3 independently selected R groups. 9c Substituted 4-6 membered heterocyclic groups, or

[0622] X 1 Is it O or S?

[0623] R 9a Is it hydrogen or C? 1-6 alkyl;

[0624] 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;

[0625] Each R 9c Independently, it consists of hydrogen, oxy 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);

[0626] v is 0, 1, 2, or 3;

[0627] Each R Ca Independently, it is a halogenated group, a cyano group, or a C group. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c R d ;

[0628] 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;

[0629] 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;

[0630] Each R e Independently, it is hydrogen and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0631] w is 0, 1, 2, or 3;

[0632] Each R 1f C is independent 1-6 Alkyl, wherein each C 1-6 Alkyl groups are independently and optionally selected by 1-6 independently chosen R groups. f replace;

[0633] Each R f Independently, it is a halogenated group, a hydroxyl group, or -NR. 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;

[0634] 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)C1-6 Alkyl substituents of 3 to 12-membered heterocyclic groups; and

[0635] Each R h Independently, it is a halogenated group, a cyano group, a hydroxyl group, or a C group. 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.

[0636] In some embodiments, compounds of formula IIH are provided herein:

[0637] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein Y 1 It is C 1-3 alkylene or C2-olefin, wherein the C 1-3 The alkylene or C2-olefinic group is optionally represented by one or two independently selected R groups. h Substitution; q is 0, 1, 2, 3, 4, or 5; v is 0, 1, 2, or 3; and R b R Ca R 8a R 8b R 9 R A R 3 Q 2 and R QA Each is defined independently as described in this article.

[0638] In some embodiments, this document provides a compound of formula IIH-(S):

[0639] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein Y 1 It is C 1-3 alkylene or C2-olefin, wherein the C 1-3 The alkylene or C2-olefinic group is optionally represented by one or two independently selected R groups. h Substitution; q is 0, 1, 2, 3, 4, or 5; v is 0, 1, 2, or 3; and R b R Ca R 8a R 8b R 9 R A R 3Q 2 and R QA Each is defined independently as described in this article.

[0640] On the one hand, this article provides compounds of formula IIH-(S):

[0641] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein:

[0642] Q 2 Is it N or CR? QA ;

[0643] Y 1 It is C 1-3 alkylene or C2-olefin, wherein C 1-3 The alkylene or C2-olefinic group is optionally represented by one or two independently selected R groups. h replace;

[0644] R b It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C-substitution of cycloalkyl and halogenated groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl;

[0645] Each R QA Independently, it is hydrogen, halogroup, cyano, hydroxyl, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e Optionally selected from 1 to 6 independently chosen R f Replacement C 1-6 Alkyl group, optionally surrounded by 1-6 groups, each independently selected from hydroxyl, halogroup and C. 1-6 alkoxy substituents of C 1-6 Alkyl groups, optionally composed of one or more independently selected from C 1-6 Alkyl and -C(O)(C 1-6 A 3-12 membered heterocyclic group substituted with an alkyl group, optionally with 1-3 independently selected -C(O)(C) groups. 1-6 alkyl) substituted C 6-10Aryl, and optionally 1-6 independently selected R g Substituted 5-10 heteroaryl groups;

[0646] q is 0, 1, 2, 3, 4, or 5;

[0647] Each R A Independently, it is a halogenated group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl;

[0648] R 3 It is hydrogen or optionally surrounded by 1-6 independently selected halogen groups, hydroxyl groups, and C. 1-6 alkoxy substituents of C 1-6 alkyl;

[0649] R 8a and R 8b Each is independently hydrogen or optionally composed of one or more halogenated groups and C. 3-15 Cycloalkyl substituents substituted C 1-6 Alkyl; or

[0650] R 8a and R 8b Together with their respective attached carbon atoms, they form 1-3 independently selected carbon atoms. 1-6 Alkyl-substituted C 3-15 cycloalkyl ring, wherein the C 1-6 Alkyl groups are optionally separated by 1-6 independently selected R groups. f replace;

[0651] R 9 It is -C(O)OR 9a -C(O)NR 9a R 9b Optionally selected by 1-3 independently chosen R 9c The substituted 5-6 heteroaryl group, optionally with 1-3 independently selected R groups. 9c Substituted 4-6 membered heterocyclic groups, or

[0652] X 1 Is it O or S?

[0653] R 9a Is it hydrogen or C? 1-6 alkyl;

[0654] 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;

[0655] Each R 9c Independently, it consists of hydrogen, oxy 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);

[0656] v is 0, 1, 2, or 3;

[0657] Each R Ca Independently, it is a halogenated group, a cyano group, or a C group. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c R d ;

[0658] 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;

[0659] 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;

[0660] Each R e Independently, it is hydrogen and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0661] Each R f Independently, it is a halogenated group, a hydroxyl group, or -NR.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;

[0662] 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

[0663] Each R h Independently, it is a halogenated group, a cyano group, a hydroxyl group, or a C group. 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.

[0664] In some embodiments, compounds of formula IIJ are provided herein:

[0665] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein Y 1 It is C 1-3 alkylene or C2-olefin, wherein the C 1-3 The alkylene or C2-olefinic group is optionally represented by one or two independently selected R groups. h Replacement; q is 0, 1, 2, 3, 4, or 5; w is 0, 1, 2, or 3; v is 0, 1, 2, or 3; each R 1f C is independent 1-6 Alkyl, wherein each C 1-6 Alkyl groups are independently and optionally selected by 1-6 independently chosen R groups. f Replace; and R b R Ca R 9 R A R 3 Q 2 and R QA Each is defined independently as described in this article.

[0666] In some embodiments, this document provides a compound of formula IIJ-(S):

[0667] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein Y 1 It is C 1-3 alkylene or C2-olefin, wherein the C 1-3 The alkylene or C2-olefinic group is optionally represented by one or two independently selected R groups. h Replacement; q is 0, 1, 2, 3, 4, or 5; w is 0, 1, 2, or 3; v is 0, 1, 2, or 3; each R 1f C is independent 1-6 Alkyl, wherein each C 1-6 Alkyl groups are independently and optionally selected by 1-6 independently chosen R groups. f Replace; and R b R Ca R 9 R A R 3 Q 2 and R QA Each is defined independently as described in this article.

[0668] On the one hand, this paper provides compounds of formula IIJ-(S):

[0669] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein:

[0670] Q 2 Is it N or CR? QA ;

[0671] Y 1 It is C 1-3 alkylene or C2-olefin, wherein C 1-3 The alkylene or C2-olefinic group is optionally represented by one or two independently selected R groups. h replace;

[0672] R b It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C-substitution of cycloalkyl and halogenated groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3Alkyl-substituted C 6-10 Aryl;

[0673] n is 1, 2, 3, 4, 5, or 6;

[0674] Each R i It is independently hydrogen, halogenated or C 1-6 alkyl;

[0675] Each R j It is independently hydrogen, halogenated or C 1-6 alkyl;

[0676] Or an R on an adjacent carbon atom i And an R j Together with one or more atoms to which each is attached, they form olefins, wherein the olefins are optionally bonded by one to three independently selected C atoms. 1-6 Alkyl substitution;

[0677] Each R QA Independently, it is hydrogen, halogroup, cyano, hydroxyl, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e Optionally selected from 1 to 6 independently chosen R f Replacement C 1-6 Alkyl group, optionally surrounded by 1-6 groups, each independently selected from hydroxyl, halogroup and C. 1-6 alkoxy substituents of C 1-6 Alkyl groups, optionally composed of one or more independently selected from C 1-6 Alkyl and -C(O)(C 1-6 A 3-12 membered heterocyclic group substituted with an alkyl group, optionally with 1-3 independently selected -C(O)(C) groups. 1-6 alkyl) substituted C 6-10 Aryl, and optionally 1-6 independently selected R g Substituted 5-10 heteroaryl groups;

[0678] q is 0, 1, 2, 3, 4, or 5;

[0679] Each R A Independently, it is a halogenated group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl;

[0680] R 3 It is hydrogen or optionally surrounded by 1-6 independently selected halogen groups, hydroxyl groups, and C.1-6 alkoxy substituents of C 1-6 alkyl;

[0681] R 9 It is -C(O)OR 9a -C(O)NR 9a R 9b Optionally selected by 1-3 independently chosen R 9c The substituted 5-6 heteroaryl group, optionally with 1-3 independently selected R groups. 9c Substituted 4-6 membered heterocyclic groups, or

[0682] X 1 Is it O or S?

[0683] R 9a Is it hydrogen or C? 1-6 alkyl;

[0684] 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;

[0685] Each R 9c Independently, it consists of hydrogen, oxy 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);

[0686] v is 0, 1, 2, or 3;

[0687] Each R Ca Independently, it is a halogenated group, a cyano group, or a C group. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c R d ;

[0688] 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;

[0689] 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 1-6Alkyl 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;

[0690] Each R e Independently, it is hydrogen and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0691] w is 0, 1, 2, or 3;

[0692] Each R 1f C is independent 1-6 Alkyl, wherein each C 1-6 Alkyl groups are independently and optionally selected by 1-6 independently chosen R groups. f replace;

[0693] Each R f Independently, it is a halogenated group, a hydroxyl group, or -NR. 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;

[0694] 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

[0695] Each R h Independently, it is a halogenated group, a cyano group, a hydroxyl group, or a C group. 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.

[0696] In some implementation schemes, R QB It is -O-(CR) i R j ) n -S(O)(=NR a )R b In some implementations, n is 3. In some implementations, R b and R i Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally composed of 1-3 independently selected carbon atoms. 1-6 Alkyl substitution.

[0697] In some implementations, compounds of formula IIK are provided herein:

[0698] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein q is 0, 1, 2, 3, 4, or 5; v is 0, 1, 2, or 3; and R a R Ca R 8a R 8b R 9 R A R 3 Q 2 and R QA Each is defined independently as described in this article.

[0699] In some embodiments, this document provides a compound of formula IIK-(S):

[0700] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein q is 0, 1, 2, 3, 4, or 5; v is 0, 1, 2, or 3; and R a R Ca R 8a R 8b R 9 R A R 3 Q 2 and R QA Each is defined independently as described in this article.

[0701] On the one hand, this paper provides compounds of formula IIF-(S):

[0702] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein:

[0703] Q 2 Is it N or CR? QA ;

[0704] R a 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 C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl;

[0705] Each R QA Independently, it is hydrogen, halogroup, cyano, hydroxyl, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e Optionally selected from 1 to 6 independently chosen R f Replacement C 1-6 Alkyl group, optionally surrounded by 1-6 groups, each independently selected from hydroxyl, halogroup and C. 1-6 alkoxy substituents of C 1-6 Alkyl groups, optionally composed of one or more independently selected from C 1-6 Alkyl and -C(O)(C 1-6 A 3-12 membered heterocyclic group substituted with an alkyl group, optionally with 1-3 independently selected -C(O)(C) groups. 1-6 alkyl) substituted C 6-10 Aryl, and optionally 1-6 independently selected R g Substituted 5-10 heteroaryl groups;

[0706] q is 0, 1, 2, 3, 4, or 5;

[0707] Each R A Independently, it is a halogenated group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6Alkoxy or C 3-6 cycloalkyl;

[0708] R 3 It is hydrogen or optionally surrounded by 1-6 independently selected halogen groups, hydroxyl groups, and C. 1-6 alkoxy substituents of C 1-6 alkyl;

[0709] R 8a and R 8b Each is independently hydrogen or optionally composed of one or more halogenated groups and C. 3-15 Cycloalkyl substituents substituted C 1-6 Alkyl; or

[0710] R 8a and R 8b Together with their respective attached carbon atoms, they form 1-3 independently selected carbon atoms. 1-6 Alkyl-substituted C 3-15 cycloalkyl ring, wherein the C 1-6 Alkyl groups are optionally separated by 1-6 independently selected R groups. f replace;

[0711] R 9 It is -C(O)OR 9a -C(O)NR 9a R 9b Optionally selected by 1-3 independently chosen R 9c The substituted 5-6 heteroaryl group, optionally with 1-3 independently selected R groups. 9c Substituted 4-6 membered heterocyclic groups, or

[0712] X 1 Is it O or S?

[0713] R 9a Is it hydrogen or C? 1-6 alkyl;

[0714] 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;

[0715] Each R 9c Independently, it consists of hydrogen, oxy 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);

[0716] v is 0, 1, 2, or 3;

[0717] Each R Ca Independently, it is a halogenated group, a cyano group, or a C group. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c R d ;

[0718] 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;

[0719] 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;

[0720] Each R e Independently, it is hydrogen and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0721] Each R f Independently, it is a halogenated group, a hydroxyl group, or -NR. 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;

[0722] Each R g C is independent1-6 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

[0723] Each R h Independently, it is a halogenated group, a cyano group, a hydroxyl group, or a C group. 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.

[0724] In some implementations, compounds of formula IIL are provided herein:

[0725] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein each R 1f C is independent 1-6 Alkyl, wherein each C 1-6 Alkyl groups are independently and optionally selected by 1-6 independently chosen R groups. f Substitute; q is 0, 1, 2, 3, 4, or 5; v is 0, 1, 2, or 3; w is 0, 1, 2, or 3; and R a R Ca R f R 9 R A R 3 Q 2 and R QA Each is defined independently as described in this article.

[0726] In some embodiments, this document provides a compound of formula IIL-(S):

[0727] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein each R 1f C is independent 1-6 Alkyl, wherein each C 1-6 Alkyl groups are independently and optionally selected by 1-6 independently chosen R groups. f Substitute; q is 0, 1, 2, 3, 4, or 5; v is 0, 1, 2, or 3; w is 0, 1, 2, or 3; and Ra R Ca R f R 9 R A R 3 Q 2 and R QA Each is defined independently as described in this article.

[0728] On the one hand, this article provides compounds of formula IIL-(S):

[0729] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein:

[0730] Q 2 Is it N or CR? QA ;

[0731] R a 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 C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl;

[0732] Each R QA Independently, it is hydrogen, halogroup, cyano, hydroxyl, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e Optionally selected from 1 to 6 independently chosen R f Replacement C 1-6 Alkyl group, optionally surrounded by 1-6 groups, each independently selected from hydroxyl, halogroup and C. 1-6 alkoxy substituents of C 1-6 Alkyl groups, optionally composed of one or more independently selected from C 1-6 Alkyl and -C(O)(C 1-6 A 3-12 membered heterocyclic group substituted with an alkyl group, optionally with 1-3 independently selected -C(O)(C) groups. 1-6 alkyl) substituted C 6-10 Aryl, and optionally 1-6 independently selected R gSubstituted 5-10 heteroaryl groups;

[0733] q is 0, 1, 2, 3, 4, or 5;

[0734] Each R A Independently, it is a halogenated group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl;

[0735] R 3 It is hydrogen or optionally surrounded by 1-6 independently selected halogen groups, hydroxyl groups, and C. 1-6 alkoxy substituents of C 1-6 alkyl;

[0736] R 9 It is -C(O)OR 9a -C(O)NR 9a R 9b Optionally selected by 1-3 independently chosen R 9c The substituted 5-6 heteroaryl group, optionally with 1-3 independently selected R groups. 9c Substituted 4-6 membered heterocyclic groups, or

[0737] X 1 Is it O or S?

[0738] R 9a Is it hydrogen or C? 1-6 alkyl;

[0739] 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;

[0740] Each R 9c Independently, it consists of hydrogen, oxy 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);

[0741] v is 0, 1, 2, or 3;

[0742] Each R Ca Independently, it is a halogenated group, a cyano group, or a C group. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c R d ;

[0743] 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;

[0744] 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;

[0745] Each R e Independently, it is hydrogen and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0746] w is 0, 1, 2, or 3;

[0747] Each R 1f C is independent 1-6 Alkyl, wherein each C 1-6 Alkyl groups are independently and optionally selected by 1-6 independently chosen R groups. f replace;

[0748] Each R f Independently, it is a halogenated group, a hydroxyl group, or -NR. 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;

[0749] Each R g C is independent1-6 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

[0750] Each R h Independently, it is a halogenated group, a cyano group, a hydroxyl group, or a C group. 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.

[0751] In some implementation schemes, R 3 It is a methyl group.

[0752] In some implementations, q is 2 or 3.

[0753] In some implementations, each R A Independently, it is a halogenated group, C 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, each R A It can be fluorine, chlorine, methyl, or cyclopropyl.

[0754] In some implementations, q is 2 or 3; and each R A Independently, it is a halogenated group, C 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, q is 2 or 3; and each R A It can be fluorine, chlorine, methyl, or cyclopropyl.

[0755] In some implementation schemes, Q 2 It is N. In some implementations, Q 2 It is CR QA .

[0756] In some implementations, each R QA Independently, it is hydrogen, halogenated group, -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.

[0757] In some implementation schemes, Q2 It is CR QA And each R QA Independently, it is hydrogen, halogenated group, -NH(C) 1-6 Alkyl), C 1-6 Alkyl or C 1-6 Alkyl group.

[0758] In some implementation schemes, Q 2 It is CR QA And R a Or R b and R QA Together with their respective attached atoms, they form 5-7 membered heterocyclic groups, wherein the heterocyclic groups are optionally separated by 1-2 independently selected R atoms. h replace.

[0759] In some implementation schemes, R a It is hydrogen, cyano, C 1-6 Alkyl or C 3-6 Cycloalkyl.

[0760] In some implementation schemes, R b It is arbitrarily C 3-6 Cycloalkyl-substituted C 1-6 Alkyl, or C 3-6 Cycloalkyl. In some embodiments, R b It is C 1-6 Alkyl group. In some embodiments, R b It was C 3-6 Cycloalkyl-substituted C 1-6 Alkyl group. In some embodiments, R b It is C 3-6 Cycloalkyl.

[0761] In some implementation schemes, R a It is hydrogen, cyano, C 1-6 Alkyl or C 3-6 cycloalkyl; and R b It is arbitrarily C 3-6 Cycloalkyl-substituted C 1-6 Alkyl, or C 3-6 Cycloalkyl. In some embodiments, R a It is hydrogen, cyano, methyl, or cyclopropyl; and R b It is methyl, ethyl, -CH2-cyclopropyl, cyclopropyl or cyclobutyl.

[0762] In some implementation schemes, R a and R b Together with the atoms to which they are attached, they form 5-8 membered heterocyclic groups.

[0763] In some implementation schemes, Ra Or R b and adjacent R QA Together with their respective attached atoms, they form 5-7 membered heterocyclic groups, wherein the heterocyclic groups are optionally separated by 1-2 independently selected R atoms. h replace.

[0764] In some implementations, w is 0 or 1. In some implementations, w is 0. In some implementations, w is 1. In some implementations, each R f C is independent 1-6 alkyl.

[0765] In some implementations, w is 0 or 1; and R f It is a methyl group.

[0766] In some implementation schemes, R a It is hydrogen, cyano, C 1-6 Alkyl or C 3-6 cycloalkyl; and R b It is arbitrarily C 3-6 Cycloalkyl-substituted C 1-6 Alkyl, or C 3-6 cycloalkyl; or R a and R b Together with the atoms to which they are attached, they form 5-8 membered heterocyclic groups; or

[0767] R a It is hydrogen, cyano, C 1-6 Alkyl or C 3-6 cycloalkyl; and R b and adjacent R QA Together with their respective attached atoms, they form 5-7 membered heterocyclic groups, wherein the heterocyclic groups are optionally separated by 1-2 independently selected R atoms. h Replace; or

[0768] R a and adjacent R QA Together with their respective attached atoms, they form 5-7 membered heterocyclic groups, wherein the heterocyclic groups are optionally separated by 1-2 independently selected R atoms. h Replace; and R b It is arbitrarily C 3-6 Cycloalkyl-substituted C 1-6 Alkyl, or C 3-6 Cycloalkyl.

[0769] In some implementations, each R h C is independent 1-6 Alkyl group. In some embodiments, each R h It is methyl on its own.

[0770] In some implementations, each R i and each R j It is hydrogen; or R a Or R b and R i Together with the atoms to which they are attached, they form 5-8 membered heterocyclic groups; 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.

[0771] In some implementation schemes, R 3 It is methyl;

[0772] q is 2 or 3;

[0773] Each R A Independently, it is a halogenated group, C 1-6 Alkyl or C 3-6 cycloalkyl;

[0774] Each R QA Independently, it is hydrogen, halogenated group, -NH(C) 1-6 Alkyl), C 1-6 Alkyl or C 1-6 Alkoxy;

[0775] R a It is hydrogen, cyano, C 1-6 Alkyl or C 3-6 cycloalkyl; and R b It is arbitrarily C 3-6 Cycloalkyl-substituted C 1-6 Alkyl, or C 3-6 cycloalkyl; or R a and R b Together with the atoms to which they are attached, they form 5-8 membered heterocyclic groups; or

[0776] R a It is hydrogen, cyano, C 1-6 Alkyl or C 3-6 cycloalkyl; and R b and adjacent R QA Together with their respective attached atoms, they form 5-7 membered heterocyclic groups, wherein the heterocyclic groups are optionally separated by 1-2 independently selected R atoms. h Replace; or

[0777] R a and adjacent R QA Together with their respective attached atoms, they form 5-7 membered heterocyclic groups, wherein the heterocyclic groups are optionally separated by 1-2 independently selected R atoms. h Replace; and R b It is arbitrarily C3-6 Cycloalkyl-substituted C 1-6 Alkyl, or C 3-6 cycloalkyl;

[0778] Each R h C is independent 1-6 Alkyl; and

[0779] Each R i and each R j It is hydrogen; or R a and R i Or R b and R i Together with the atoms to which they are attached, they form 5-8 membered heterocyclic groups; 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.

[0780] On the one hand, this article provides compounds of formula IIIA:

[0781] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein:

[0782] Q 2 Is it N or CR? QA ;

[0783] R a 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 C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl;

[0784] R b It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C-substitution of cycloalkyl and halogenated groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C6-10 Aryl;

[0785] Or R a and R b Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally composed of 1-3 independently selected carbon atoms. 1-6 Alkyl substitution;

[0786] Each R QA Independently, it is hydrogen, halogroup, cyano, hydroxyl, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e Optionally selected from 1 to 6 independently chosen R f Replacement C 1-6 Alkyl group, optionally surrounded by 1-6 groups, each independently selected from hydroxyl, halogroup and C. 1-6 alkoxy substituents of C 1-6 Alkyl groups, optionally composed of one or more independently selected from C 1-6 Alkyl and -C(O)(C 1-6 A 3-12 membered heterocyclic group substituted with an alkyl group, optionally with 1-3 independently selected -C(O)(C) groups. 1-6 alkyl) substituted C 6-10 Aryl, and optionally 1-6 independently selected R g Substituted 5-10 heteroaryl groups;

[0787] Or R a Or R b 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;

[0788] Each R Ca C is independent 1-6 alkyl;

[0789] q is 0, 1, 2, 3, 4, or 5;

[0790] Each R A Independently, it is a halogenated group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl;

[0791] R 3 It is hydrogen or optionally surrounded by 1-6 independently selected halogen groups, hydroxyl groups, and C.1-6 alkoxy substituents of C 1-6 alkyl;

[0792] R 9 It is -C(O)OR 9a -C(O)NR 9a R 9b Optionally selected by 1-3 independently chosen R 9c The substituted 5-6 heteroaryl group, optionally with 1-3 independently selected R groups. 9c Substituted 4-6 membered heterocyclic groups, or

[0793] X 1 Is it O or S?

[0794] R 9a Is it hydrogen or C? 1-6 alkyl;

[0795] 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;

[0796] Each R 9c Independently, it consists of hydrogen, oxy 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);

[0797] 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 3-6Each of the cycloalkyl groups is optionally surrounded by 1-6 independently selected from hydroxyl, halogen, and C groups. 1-6 Substitution of alkoxy groups;

[0798] Each R e Independently, it is hydrogen and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0799] w is 0, 1, 2, or 3;

[0800] Each R 1f C is independent 1-6 Alkyl, wherein each C 1-6 Alkyl groups are independently and optionally selected by 1-6 independently chosen R groups. f replace;

[0801] Each R f Independently, it is a halogenated group, a hydroxyl group, or -NR. 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;

[0802] 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

[0803] Each R h Independently, it is a halogenated group, a cyano group, a hydroxyl group, or a C group. 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.

[0804] On the one hand, this article provides compounds of formula IIIB:

[0805] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein:

[0806] Q 2 Is it N or CR? QA ;

[0807] R a 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 C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl;

[0808] R b It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C-substitution of cycloalkyl and halogenated groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl;

[0809] Or R a and R b Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally composed of 1-3 independently selected carbon atoms. 1-6 Alkyl substitution;

[0810] Each R QA Independently, it is hydrogen, halogroup, cyano, hydroxyl, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e Optionally selected from 1 to 6 independently chosen R f Replacement C 1-6 Alkyl group, optionally surrounded by 1-6 groups, each independently selected from hydroxyl, halogroup and C. 1-6 alkoxy substituents of C 1-6 Alkyl groups, optionally composed of one or more independently selected from C 1-6 Alkyl and -C(O)(C 1-6 A 3-12 membered heterocyclic group substituted with an alkyl group, optionally with 1-3 independently selected -C(O)(C) groups. 1-6alkyl) substituted C 6-10 Aryl, and optionally 1-6 independently selected R g Substituted 5-10 heteroaryl groups;

[0811] Or R a Or R b 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;

[0812] q is 0, 1, 2, 3, 4, or 5;

[0813] Each R A Independently, it is a halogenated group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl;

[0814] R 3 It is hydrogen or optionally surrounded by 1-6 independently selected halogen groups, hydroxyl groups, and C. 1-6 alkoxy substituents of C 1-6 alkyl;

[0815] R 9 It is -C(O)OR 9a -C(O)NR 9a R 9b Optionally selected by 1-3 independently chosen R 9c The substituted 5-6 heteroaryl group, optionally with 1-3 independently selected R groups. 9c Substituted 4-6 membered heterocyclic groups, or

[0816] X 1 Is it O or S?

[0817] R 9a Is it hydrogen or C? 1-6 alkyl;

[0818] 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;

[0819] Each R 9c Independently, it consists of hydrogen, oxy group, optionally 1-6 independently selected halogen groups, and C. 1-6 alkoxy-substituted C 1-6 Alkyl, or -C(O)(C1-6 alkyl);

[0820] 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;

[0821] Each R e Independently, it is hydrogen and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0822] w is 0, 1, 2, or 3;

[0823] Each R 1f C is independent 1-6 Alkyl, wherein each C 1-6 Alkyl groups are independently and optionally selected by 1-6 independently chosen R groups. f replace;

[0824] Each R f Independently, it is a halogenated group, a hydroxyl group, or -NR. 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;

[0825] Each R g C is independent 1-6 Alkyl, C 1-6 Alkoxy, -NR c R dOr 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

[0826] Each R h Independently, it is a halogenated group, a cyano group, a hydroxyl group, or a C group. 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.

[0827] On the one hand, this article provides compounds of formula IIIC:

[0828] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein:

[0829] Q 2 Is it N or CR? QA ;

[0830] R a 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 C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl;

[0831] R b It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C-substitution of cycloalkyl and halogenated groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl;

[0832] Or R a and R bTogether with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally composed of 1-3 independently selected carbon atoms. 1-6 Alkyl substitution;

[0833] Each R QA Independently, it is hydrogen, halogroup, cyano, hydroxyl, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e Optionally selected from 1 to 6 independently chosen R f Replacement C 1-6 Alkyl group, optionally surrounded by 1-6 groups, each independently selected from hydroxyl, halogroup and C. 1-6 alkoxy substituents of C 1-6 Alkyl groups, optionally composed of one or more independently selected from C 1-6 Alkyl and -C(O)(C 1-6 A 3-12 membered heterocyclic group substituted with an alkyl group, optionally with 1-3 independently selected -C(O)(C) groups. 1-6 alkyl) substituted C 6-10 Aryl, and optionally 1-6 independently selected R g Substituted 5-10 heteroaryl groups;

[0834] q is 0, 1, 2, 3, 4, or 5;

[0835] Each R A Independently, it is a halogenated group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl;

[0836] R 3 It is hydrogen or optionally surrounded by 1-6 independently selected halogen groups, hydroxyl groups, and C. 1-6 alkoxy substituents of C 1-6 alkyl;

[0837] R 9 It is -C(O)OR 9a -C(O)NR 9a R 9b Optionally selected by 1-3 independently chosen R 9c The substituted 5-6 heteroaryl group, optionally with 1-3 independently selected R groups. 9c Substituted 4-6 membered heterocyclic groups, or

[0838] X 1 Is it O or S?

[0839] R 9a Is it hydrogen or C? 1-6 alkyl;

[0840] 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;

[0841] Each R 9c Independently, it consists of hydrogen, oxy 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);

[0842] 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;

[0843] Each R e Independently, it is hydrogen and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0844] w is 0, 1, 2, or 3;

[0845] Each R 1f C is independent 1-6 Alkyl, wherein each C 1-6 Alkyl groups are independently and optionally selected by 1-6 independently chosen R groups. f replace;

[0846] Each R f Independently, it is a halogenated group, a hydroxyl group, or -NR. 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; and

[0847] 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 are 3 to 12-membered heterocyclic groups.

[0848] In some embodiments, such as Formula IIIA or IIIB, R 3 It is C 1-6 Alkyl group. In some embodiments such as formula IIIA or IIIB, R 3 It is a methyl group.

[0849] In some implementations, such as Formula IIIA or IIIB, Q 2 It is CH. Such as formula IIIA or IIIB, R 3 It is a methyl group.

[0850] In some embodiments, such as formula IIIA or IIIB, q is 2 or 3.

[0851] In some embodiments, such as Formula IIIA or IIIB, R 9 yes

[0852] On the one hand, this paper provides compounds of formula IIID:

[0853] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein:

[0854] R a 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 1-6Alkyl groups, optionally composed of 1-3 independently selected C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl;

[0855] R b It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C-substitution of cycloalkyl and halogenated groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl;

[0856] R QA It contains hydrogen, halogenated group, cyano group, hydroxyl group, and -NR. c R d , -C(O)NR c R d , -S(O) 0-2 R e Optionally selected from 1 to 6 independently chosen R f Replacement C 1-6 Alkyl group, optionally surrounded by 1-6 groups, each independently selected from hydroxyl, halogroup and C. 1-6 alkoxy substituents of C 1-6 Alkyl groups, optionally composed of one or more independently selected from C 1-6 Alkyl and -C(O)(C 1-6 A 3-12 membered heterocyclic group substituted with an alkyl group, optionally with 1-3 independently selected -C(O)(C) groups. 1-6 alkyl) substituted C 6-10 Aryl, and optionally 1-6 independently selected R g Substituted 5-10 heteroaryl groups;

[0857] 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 (C3-6 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;

[0858] Each R e Independently, it is hydrogen and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; and

[0859] 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 are 3 to 12-membered heterocyclic groups.

[0860] In some embodiments, such as formulas IIIA, IIIB, or IIIC, R QA It is hydrogen, halogenated group, -NR c R d Or C 1-6 Alkyl. In some embodiments, such as formula IIIA, IIIB, or IIIC, R QA It can be hydrogen, a halogenated group, -NHCH3, or a methyl group.

[0861] In some embodiments, such as formulas IIIA, IIIB, or IIIC, R a Is it hydrogen or C? 1-6 Alkyl. In some embodiments, such as formula IIIA, IIIB, or IIIC, R a It is hydrogen, methyl, or ethyl.

[0862] In some embodiments, such as formulas IIIA, IIIB, or IIIC, R b It is C 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, such as formula IIIA, IIIB, or IIIC, R b It is methyl, ethyl, cyclopropyl, or cyclobutyl.

[0863] In some embodiments, such as formulas IIIA, IIIB, or IIIC, R a Is it hydrogen or C? 1-6 Alkyl; and R b It is C 1-6 Alkyl or C 3-6 Cycloalkyl.

[0864] In some embodiments, such as formulas IIIA, IIIB, or IIIC, R a It is hydrogen, methyl, or ethyl; and R b It is methyl, ethyl, cyclopropyl, or cyclobutyl.

[0865] On the one hand, this paper provides compounds of formula IIID:

[0866] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein: R QA It is hydrogen, halogenated group, -NR c R d Or C 1-6 Alkyl; R a Is it hydrogen or C? 1-6 Alkyl; and R b It is C 1-6 Alkyl or C 3-6 Cycloalkyl.

[0867] On the one hand, this paper provides compounds of formula IIID:

[0868] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein: R QA It is hydrogen, a halogroup, -NHCH3, or a methyl group; R a It is hydrogen, methyl, or ethyl; and R b It is methyl, ethyl, cyclopropyl, or cyclobutyl.

[0869] On the one hand, this paper provides compounds of formula IIID:

[0870] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein: R QA It is hydrogen, a halogroup, -NHCH3, or a methyl group; R a It is methyl or ethyl; and R b It is ethyl, cyclopropyl, or cyclobutyl.

[0871] 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:

[0872] Table 1

[0873] 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:

[0874] Table 2

[0875] Compounds of Formula I include their pharmaceutically acceptable salts. Furthermore, compounds of Formula I also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts and may be used as intermediates for the preparation and / or purification of compounds of Formula I and / or for the isolation of enantiomers of compounds of Formula I. Non-limiting examples of pharmaceutically acceptable salts of compounds of Formula I include trifluoroacetate salts.

[0876] It should be further understood that compounds of Formula I or their salts can be separated in solvated form, 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 both non-solvated and solvated forms with pharmaceutically acceptable solvents (such as water, ethanol, etc.).

[0877] Pharmaceutical composition and administration

[0878] 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, or injection or infusion; or intracranial (e.g., intrathecal or intraventricular) administration. Parenteral administration can be in the form of a single bolus dose or, 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, powdered, or oily bases, thickeners, etc., may be necessary or desired.

[0879] 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 compositions are 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 following forms: tablets, pills, powders, lozenges, capsules, flat capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), ointments containing, for example, up to 10% by weight of an 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.

[0880] 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.

[0881] 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.

[0882] Methods for preparing pharmaceutical compositions have been described in numerous publications, such as Pharmaceutical Dosage Forms: Tablets, 2nd Edition, Revised Edition, Volumes 1-3, edited by Lieberman et al.; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al.; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al. and published by Marcel Dekker, Inc.

[0883] 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 acid metaglycerides; 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 the compounds described 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 covered may contain 0.001% to 100% of the chemical entities provided herein, 0.1% to 95% in one embodiment, 75% to 85% in another embodiment, and 20% to 80% in yet another embodiment. 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).

[0884] 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, intrasinus, trachea, intestine, epidural, interstitial, intraperitoneal, intraarterial, intrabronchial, intracystic, intracerebral, intracisary, intracoronary, intradermal, intracatheter, duodenal, intradural, intraepithelial, intraepithelial, esophageal, intragastric, intragingival, intraileum, intraileum, intralymphatic, intramedullary, 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).

[0885] 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. Such compositions can be prepared as injectable formulations, as liquid solutions or suspensions; they can also be prepared in solid forms suitable for preparing solutions or suspensions after the addition of liquid prior to injection; and emulsified formulations are also possible. 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. Such devices can include, for example, needle injectors, microneedle injectors, needle-free injectors, and infusion techniques.

[0886] 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 microbial contamination (such as bacteria and fungi).

[0887] 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, appropriate flowability can be maintained, for example, by using a coating (e.g., lecithin), in the case of a dispersion, by maintaining the 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 a delayed-absorption agent (e.g., aluminum monostearate and gelatin) in the composition.

[0888] 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, a sterile powder is used to prepare a 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.

[0889] 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 ethylenediaminetetraacetate, sodium benzoate, potassium metasulfite, grapefruit seed extract, methanesulfonylmethane (MSM), lactic acid, glycine, vitamins (such as vitamins A and E), and potassium acetate.

[0890] 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.

[0891] In some embodiments, a compound of Formula I as described herein, 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 formulated for local delivery to the digestive or gastrointestinal (GI) tract by means of oral administration (e.g., solid or liquid dosage form).

[0892] In some embodiments, 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, stereoisomer, 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 silicic acid; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucralose, etc. The ingredients include: c) sugars and gum arabic; d) humectants such as glycerin; e) disintegrants such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; f) solution blockers such as paraffin; g) absorption enhancers such as quaternary ammonium compounds; h) wetting agents such as cetyl alcohol and glyceryl monostearate; d) 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.

[0893] 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, marume, solution, or suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) as another solid dosage form will be encapsulated in a capsule (gelatin or cellulose matrix capsule). 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 coating or delayed-release oral dosage forms have also been considered.

[0894] In some embodiments, other physiologically acceptable compounds may include wetting agents, emulsifiers, dispersants, or preservatives specifically designed to prevent microbial growth or activity. For example, a variety of preservatives are well known and include, for instance, phenol and ascorbic acid.

[0895] 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.

[0896] 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.)).

[0897] 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 water-washable and contains an oil phase, an emulsifier, and an aqueous phase. For example, the oil phase, sometimes also referred to as the "internal" phase, typically includes paraffin esters 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.

[0898] 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.

[0899] The amount of compounds in a pharmaceutical composition or formulation can vary within a 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.

[0900] Formulation Example 1 - Tablet Formulation

[0901] Mix the following ingredients thoroughly and compress them into a single-score tablet. Element Dosage per tablet, mg The compounds in this disclosure text 400 corn starch 50 Cross-linked carboxymethyl cellulose sodium 25 lactose 120 magnesium stearate 5

[0902] Example 2 of formulation - capsule formulation

[0903] Mix the following ingredients thoroughly and fill them into hard-shell gelatin capsules. Element Dosage per capsule, mg The compounds in this disclosure text 200 Lactose, spray dried 148 magnesium stearate 2

[0904] Formulation Example 3 - Suspension Formulation

[0905] Mix the following ingredients to form a suspension for oral administration. Element quantity The compounds in this disclosure text 1.0g fumaric acid 0.5g Sodium chloride 2.0g Methylparaben 0.15g propylparaben 0.05g granulated sugar 25.0g Sorbitol (70% solution) 13.00g Veegum K (Vanderbilt Co.) 1.0g Flavorings 0.035mL Colorant 0.5mg distilled water Add to a final volume of 100mL

[0906] Example 4 of the formulation - injectable formulation

[0907] Mix the following ingredients to form an injectable formulation. Element quantity The compounds in this disclosure text 0.2mg-20mg Sodium acetate buffer solution, 0.4M 2.0mL HCl (1N) or NaOH (1N) Replenish to the appropriate pH Water (distilled, sterile) Add to a final volume of 20 mL

[0908] Example 5 of formulation - Suppository formulation

[0909] By combining the compounds in this disclosure with H-15 (triglycerides of saturated vegetable fatty acids; Riches-Nelson, Inc., New York) was mixed to prepare a suppository with a total weight of 2.5g, and the suppository had the following composition:

[0910] 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.

[0911] In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof is administered in doses from about 0.01 mg to about 1000 mg. For example, doses from about 0.1 mg to about 30 mg, from about 10 mg to about 80 mg, from about 0.5 mg to about 15 mg, from about 50 mg to about 200 mg, from about 100 mg to about 300 mg, from about 200 mg to about 400 mg, from about 300 mg to about 500 mg, from about 400 mg to about 600 mg, from about 500 mg to about 800 mg, from about 600 mg to about 900 mg, or from about 700 mg to about 1000 mg. In some embodiments, the dose is a therapeutically effective amount.

[0912] In some embodiments, a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a mixture of stereoisomers, or a prodrug, is administered at a dose 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 10 mg / kg; about 0.001 mg / kg to Approximately 5 mg / kg; approximately 0.001 mg / kg to approximately 1 mg / kg; approximately 0.001 mg / kg to approximately 0.5 mg / kg; approximately 0.001 mg / kg to approximately 0.1 mg / kg; approximately 0.01 mg / kg to approximately 50 mg / kg; approximately 0.01 mg / kg to approximately 25 mg / kg; approximately 0.01 mg / kg to approximately 10 mg / kg; approximately 0.01 mg / kg to approximately 5 mg / kg; approximately 0.01 mg / kg to approximately 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; 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.

[0913] 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 fractionated 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).

[0914] 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 weeks, 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 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 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 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer.

[0915] 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).

[0916] 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.

[0917] 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.

[0918] Treatment

[0919] 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.

[0920] 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.

[0921] 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).

[0922] 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.

[0923] 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.

[0924] In some embodiments, the compounds and pharmaceutical compositions and methods used to treat the patients described herein 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 the patients 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.

[0925] 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.

[0926] Indications

[0927] obesity

[0928] 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).

[0929] 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), bone 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 both obesity and insulin deficiency.

[0930] diabetes

[0931] 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).

[0932] 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.

[0933] 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.

[0934] 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.

[0935] 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.

[0936] 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.

[0937] 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.

[0938] 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.

[0939] 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.

[0940] 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.

[0941] 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.

[0942] 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.

[0943] 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.

[0944] Metabolic barriers

[0945] 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.

[0946] 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.

[0947] 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; 17Suppl: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, First LR. 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 less than two years old, two years old to less than 12 years old, or 12 years old to 21 years old (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 less than one year old, one month old to less than four months old, three months old to less than seven months old, six months old to less than one year old, one year old to less than two years old, two years old to less than three years old, two years old to less than seven years old, three years old to less than five years old, five years old to less than ten years old, six years old to less than 13 years old, ten years old to less than 15 years old, or 15 years old to less than 22 years old. In some implementations, patients are adult patients.

[0948] 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, protection against fractures, 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.

[0949] Cardiovascular and vascular diseases

[0950] 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 fibrinogen or plasminogen activator inhibitor levels in the blood).

[0951] 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.

[0952] Nervous system diseases

[0953] In some implementations, the condition, 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). See, for example, US2006 / 0275288 A1.

[0954] Non-limiting examples of mental disorders include substance dependence / addiction (narcotic drugs and amphetamines) and attention deficit / hyperactivity disorder (ADHD). The compounds and pharmaceutical compositions described herein can be used to improve behavioral responses to addictive substances, reduce substance dependence, prevent relapse into substance abuse, and alleviate anxiety caused by the absence of a given addictive substance. See, for example, US2012 / 0021979A1.

[0955] 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.

[0956] Insulin-related conditions and disorders

[0957] In some implementations, the symptoms, diseases, or impairments are impaired fasting glucose (IFG), impaired fasting glucose parameters (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.

[0958] 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.

[0959] Autoimmune disorders

[0960] 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, US20120148586 A1.

[0961] Gastrointestinal disorders

[0962] In some implementations, the symptom, disease, or disorder is a gastrointestinal-related disorder. Non-limiting examples of such disorders include ulcers of any etiology (e.g., peptic ulcers, Zollinger-Ellison syndrome, drug-induced ulcers, ulcers associated with infection or other pathogens), digestive disorders, malabsorption, short bowel syndrome, cul-de-sac syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), stomatitis, 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).

[0963] weight

[0964] In some embodiments, the compounds and pharmaceutical compositions described herein can be used to reduce (e.g., excess weight) in a patient (e.g., a patient 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 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 an obese patient. In some embodiments, the weight gain may also be drug-induced weight gain or weight gain following cessation of smoking.

[0965] In some implementations, the symptom, disease, or disorder is an eating disorder, such as overeating, binge eating, bulimia, or compulsive eating.

[0966] Inflammatory diseases

[0967] 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).

[0968] cancer

[0969] 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 colorectal cancer (e.g., stomach cancer). Gastrointestinal stromal tumors (GISTs), colorectal cancers (e.g., familial colorectal cancer, hereditary nonpolyposis colorectal cancer, GISTs), small bowel cancers (e.g., non-Hodgkin's lymphoma, GISTs), 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). Cancers include: parathyroid carcinoma, nasal cavity carcinoma, sinus carcinoma, bone tumors (e.g., osteosarcoma, Ewing's tumor, uterine sarcoma, soft tissue sarcoma), angiofibroma, retinal sarcoma, penile cancer, testicular tumors, pediatric solid tumors (e.g., nephroblastoma, pediatric kidney tumors), Kaposi's sarcoma, Kaposi's sarcoma caused by AIDS, maxillary sinus tumors, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemias (e.g., acute myeloid leukemia, acute lymphoblastic leukemia).

[0970] Hypothalamic-pituitary disorders

[0971] 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.

[0972] In some implementations, conditions, diseases, or disorders associated with diabetes are linked to the hypothalamic-pituitary-gonadal axis.

[0973] pulmonary disease

[0974] 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).

[0975] In some implementations, the condition, disease, or disorder associated with diabetes is lung disease.

[0976] Combination therapy

[0977] In some implementations, this disclosure considers both monotherapy regimens and combination therapy regimens.

[0978] 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.

[0979] 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, and gastric electrical stimulation (e.g., And dietary changes.

[0980] 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.

[0981] 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.

[0982] 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, sibutramine, mazindol, fluoxetine, tesofensine), serotonin 2C receptor agonists (e.g., lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptor modulators, GABA modulators (e.g., topiramate) (including GABA receptor agonists (e.g., gabapentin, pregabalin)), and neuropeptide Y antagonists (e.g., virifibrate). Cannabinoid receptor antagonists (e.g., rimonabant, taranabant), orexin antagonists, orexin receptor antagonists, orexin acylase 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), and pancreatic lipase inhibitors (e.g., orlistat). istat), cetilistat), β3 agonists (e.g., N-5984), diacylglycerol acyltransferase 1 (DGAT1) inhibitors, acetyl-CoA carboxylase (ACC) inhibitors, stearoyl-CoA 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 fenofibrate), phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate, trodusquemin), GPR119 agonists (e.g., PSN-821, MBX-2982, APD597), glucoskinase 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., metriptin), leptin resistance modifiers, CNTF (ciliary neurotrophic factor), BDNF ( Brain-derived neurotrophic factor), cholecystokinin agonists, amylin preparations (e.g., pramlinide, 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). 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.

[0983] 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 Escherichia 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., roximately 2999), and agents that antagonize the action of glucagon or reduce glucagon secretion; sulfonylurea ... 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, liximabide, 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.

[0984] 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. Extracts), 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.

[0985] 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 WO 01 / 14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole), compounds described in WO 2004 / 039365), and PKC inhibitors (e.g., rubostaurin). Mesylate, AGE inhibitors (e.g., ALT946, N-benzoylthiazolium bromide (ALT766), EXO-226, pyridorin, pyridoxine), 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.

[0986] 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)) and squalene synthase inhibitors (e.g., WO3). Compounds described in 97 / 10224, such as N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazon-3-yl]acetyl]piperidin-4-acetic acid), fibrates (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate), anion exchange resins (e.g., colestyramine), nicotinic acid drugs (e.g., nicomol, niceritrol, niaspan), phytosterols (e.g., daidzein, gamma-oryzanol). (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).

[0987] 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).

[0988] 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)), anti-aldosterone preparations (e.g., spironolactone, triamterene)), carbonic anhydrase inhibitors (e.g., acetazolamide) and chlorobenzenesulfonamide preparations (e.g., chlortalidone, mefruside, indapamide)).

[0989] 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).

[0990] In some embodiments, the one or more additional therapeutic agents include those that can be used as, for example, antithrombin 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).

[0991] 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.

[0992] Other exemplary therapeutic agents include agents that regulate hepatic glucose balance (e.g., fructose-1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glycogen synthase kinase inhibitors, glucokinase activators), agents designed to treat complications of long-term hyperglycemia (e.g., aldose reductase inhibitors (e.g., epalrestat and ranisitar)), agents for treating complications associated with microangiopathy, anti-dyslipidemia agents (e.g., HMG-CoA reductase inhibitors (statins, such as rosuvastatin), cholesterol-lowering drugs, bile acid sequestrants (e.g., cholestyramine), cholesterol absorption inhibitors (e.g., phytosterols), cholesterol ester transfer protein (CETP) inhibitors, and ileal bile duct inhibitors. Inhibitors of the bile acid transport system (IBAT inhibitors), bile acid conjugating resins, niacin (nicotinic acid) and its analogues, antioxidants (e.g., probucol), omega-3 fatty acids), antihypertensive drugs (including adrenergic receptor antagonists (such as beta blockers (e.g., atenolol), alpha blockers (e.g., doxazosin), and mixed alpha / beta blockers (e.g., labetalol)), adrenergic receptor agonists (including alpha-2 agonists (e.g., clonidine)), angiotensin-converting enzyme (ACE) inhibitors (e.g., lisinopril), calcium channel blockers (such as dihydropyridines (e.g., nifedipine), phenylalkylamines (e.g., verapamil), and benzothiazazepines (e.g., diltiazem)), blood Angiotensin II receptor antagonists (e.g., candesartan), 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)), adenosine diphosphate (ADP) receptor inhibitors (e.g., clopidogrel), phosphate Diesterase inhibitors (e.g., cilostazol), glycoprotein IIB / IIA inhibitors (e.g., tirofiban), adenosine reuptake inhibitors (e.g., dipyridamole), norepinephrine agents (e.g., phenbutazone), serotonergic agents (e.g., sibutramine), diacylglycerol acyltransferase (DGAT) inhibitors, feeding behavior modulators, pyruvate dehydrogenase kinase (PDK) modulators, serotonin receptor modulators, 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.,Toloxacin and amifugamide), compounds described in WO 0007 / 013694, WO 2007 / 018314, WO 2008 / 093639 and WO 2008 / 099794, GPR40 agonists (e.g., fasiglifam or its hydrate, compounds described in WO 2004 / 041266, WO 2004 / 106276, WO 2005 / 063729, WO 2005 / 063725, WO 2005 / 087710, WO 2005 / 095338, WO 2007 / 013689 and WO Compounds listed in 2008 / 001931), SGLT1 inhibitors, adiponectin or its agonists, IKK inhibitors (e.g., AS-2868), somatostatin receptor agonists, ACC2 inhibitors, cachexia modifiers (e.g., cyclooxygenase inhibitors (e.g., indomethacin), progesterone derivatives (e.g., megestrol acetate), glucocorticoids (e.g., dexamethasone), metoclopramide agents, tetrahydrocannabinol agents, agents that improve lipid metabolism (e.g., eicosapentaenoic acid), growth hormone, IGF-1, antibodies against cachexia-inducing factors TNF-α, LIF, IL-6 and oncogene M, metabolic regulatory proteins or peptides (e.g., glucokinase (GK), glucokinase regulatory protein (GKRP), uncoupling proteins 2 and 3 (UCP2 and UCP3), peroxisome proliferator-activated receptor α (PPARα), MC4r agonists, insulin receptor agonists, PDEs) 5. Inhibitors, glycosylation inhibitors (e.g., ALT-711), neurotrophic agents (e.g., Y-128, VX853, neurotrophic peptides), antidepressants (e.g., desipramine, amitriptyline, imipramine), antiepileptic drugs (e.g., lamotrigine, trileptal, keppra, zonegran, pregabalin, harkoseride, carbamazepine), antiarrhythmic drugs (e.g., mexiletine), and acetylcholine receptor ligands (e.g., ABT-594). Endothelin receptor antagonists (e.g., ABT-627), narcotic analgesics (e.g., morphine), α2 receptor agonists (e.g., clonidine), local analgesics (e.g., capsaicin), anxiolytics (e.g., benzothiazazepine), phosphodiesterase inhibitors (e.g., sildenafil), dopamine receptor agonists (e.g., apomorphine), cytotoxic antibodies (e.g., T-cell receptor and IL-2 receptor specific antibodies), B-cell depletion therapy (e.g., anti-CD20 antibodies (e.g., rituxana), i-BLyS antibodies), drugs affecting T-cell migration (e.g., anti-integrin α4 / β1 antibodies (e.g., ...).Natazumab (tysabri), drugs acting on immunoaffinity (e.g., cyclosporine, tacrolimus, sirolimus, rapamycin), interferons (e.g., IFN-β), immunomodulators (e.g., glatiramer), TNF-binding proteins (e.g., circulating receptors), immunosuppressants (e.g., mycophenolate mofetil), and metaglidasen, AMG-131, bagliflozin, MBX-2044, linaglidasen, agliflozin Zanthoxylate, chiglitazar, lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, exenatide, kinin-4, memantine, midazolam, ketoconazole, ethyl eicosapentaenoate, clonidine, azosemi, isosorbide, ethacrylic acid, pyrrolitanide, bumetanide, etoposide, piroxicam, NO donor agents (e.g., organic nitrates) and NO promoters (e.g., phosphodiesterase inhibitors).

[0993] 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 resists (e.g., reduces or eliminates) nausea or 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. While not 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.

[0994] Non-limiting examples of antiemetics include 5HT3 receptor antagonists (serotonin receptor antagonists), neuroleptics / antipsychotics, antihistamines, anticholinergics, sterols (e.g., corticosteroids), NK1 receptor antagonists (neurokine 1P substance receptor antagonists), antidopaminergics / dopamine receptor antagonists, benzodiazepines, and cannabinoids.

[0995] For example, antiemetics can be selected from neuroleptics, antihistamines, anticholinergics, sterols, 5HT3 receptor antagonists, NK1 receptor antagonists, antidopaminergics / dopamine receptor antagonists, benzodiazepines, and non-psychoactive cannabinoids.

[0996] In some implementations, 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 (+netostitan), quetiapine, qamosetron, ramosteron, licastron, risperidone, ziprasidone, and zatosetron.

[0997] In some implementations, the 5HT3 receptor antagonist is granisetron, dolasetron, ondansetron, hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemyrosetron, zatisetron, batapirde, MDL-73147EF, metoclopramide, N-3389, Y-25130 hydrochloride, MDL 72222, tropyl-3,5-dimethylbenzoic acid, 3-(4-allylpiperazin-1-yl)-2-quinoxaloline carboxylate maleic acid, zacopride hydrochloride, and mirtazapine.

[0998] In some implementations, the 5HT3 receptor antagonist is granisetron, dolasetron, ondansetron, hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemyrosetron, or zatisetron.

[0999] In some implementations, the 5HT3 receptor antagonist is granisetron, dolasetron, or ondansetron.

[1000] In some implementations, the 5HT3 receptor antagonist is granisetron.

[1001] In some implementations, the 5HT3 receptor antagonist is ondansetron.

[1002] In some implementations, the ...

Claims

1. A compound of formula I: Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein: X is C and Z is N, or X is N and Z is C; 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 The condition is Q 2 Q 3 and Q 4 At least one of them is CR QB ; or Q 1 It is a key; and Q 2 Q 3 Q 4 and Q 5 Each of the following is independently O, S, N, NH, NR c CR QA or CR QB The condition is Q 2 Q 3 Q 4 and Q 5 At least one of them is CR QB ; The condition is that it contains Q. 1 -Q 5 The ring is from the Aromatic tribe; R QB is -S(O)(=NR a )R b 、-(CR i R j ) n -S(O)(=NR a )R b 、-N=S(O)(R 1a )R b or -O-(CR i R j ) n -S(O)(=NR a )R b ; R 1a It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C-substitution of cycloalkyl and halogenated groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl; R a 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 C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl; R b It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C-substitution of cycloalkyl and halogenated groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl; Or R a and R b Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally composed of 1-3 independently selected carbon atoms. 1-6 Alkyl substitution; n is 1, 2, 3, 4, 5, or 6; Each R i It is independently hydrogen, halogenated or C 1-6 alkyl; Or R a and R i Or R b and R i Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally composed of 1-3 independently selected carbon atoms. 1-6 Alkyl substitution; Each R j It is independently hydrogen, halogenated or C 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; Or an R on an adjacent carbon atom i And an R j Together with one or more atoms to which each is attached, they form olefins, wherein the olefins are optionally bonded by one to three independently selected C atoms. 1-6 Alkyl substitution; Each R QA Independently, it is hydrogen, halogroup, cyano, hydroxyl, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e Optionally selected from 1 to 6 independently chosen R f Replacement C 1-6 Alkyl group, optionally surrounded by 1-6 groups, each independently selected from hydroxyl, halogroup and C. 1-6 alkoxy substituents of C 1-6 Alkyl groups, optionally composed of one or more independently selected from C 1-6 Alkyl groups and -C(O)(C 1-6 A 3-12 membered heterocyclic group substituted with an alkyl group, optionally with 1-3 independently selected -C(O)(C) groups. 1-6 alkyl) substituted C 6-10 Aryl, and optionally 1-6 independently selected R g Substituted 5-10 heteroaryl groups; Or two R atoms on adjacent carbon atoms QA Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the rings are optionally separated by 1-2 independently selected R atoms. h replace; Or R a or R b 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; L 2 R is arbitrarily selected by 1-2 independently selected factors. h Replacement C 6-10 Aryl, optionally selected by 1-2 independently chosen R h Replaced 5-10 aryl groups, Where aa represents the combination containing 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 halogenated group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl; R 1 R 2 and R 3 Each is independently hydrogen or optionally surrounded by 1-6 independently selected halogen groups, hydroxyl groups, and C. 1-6 alkoxy substituents of C 1-6 alkyl; L 1 It is -C(O)-, -CH2-, -CH(C 1-6 Alkyl)- or -S(O)2-; Cycle 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 substitution is optionally made by one to four independently selected groups: halogenated group, oxo group, 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 R 8c Replaced, and optionally further selected by 1-3 independently chosen 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 halogenated groups and C. 3-15 Cycloalkyl substituents substituted C 1-6 Alkyl; or R 8a and R 8b Together with their respective attached carbon atoms, they form 1-3 independently selected carbon atoms. 1-6 Alkyl-substituted C 3-15 cycloalkyl ring, wherein the C 1-6 Alkyl groups are optionally separated 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, halogenated 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 Optionally selected by 1-3 independently chosen R 9c The substituted 5-6 heteroaryl group, optionally with 1-3 independently selected R groups. 9c Substituted 4-6 membered heterocyclic 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, it consists of hydrogen, oxy 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 halogenated 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; R e It is hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Each R f Independently, it is a halogenated group, a hydroxyl group, or -NR. 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 halogenated group, a cyano group, a hydroxyl group, or a C group. 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; 3. The compound according to claim 1, wherein the compound is represented by formula III; 4. 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 The condition is Q 2 Q 3 and Q 4 At least one of them is CR QB .

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

6. The compound according to any one of the preceding claims, wherein Q 1 and Q 5 Each is CR independently QA ; where each R QA It can be either hydrogen or a halogenated group.

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

8. The compound according to any one of the preceding claims, wherein R QB It is -S(O)(=NR) a )R b or -CH2-S(O)(=NR a )R b .

9. The compound according to any one of claims 1-7, wherein R QB It is -O-(CR) i R j ) n -S(O)(=NR a )R b .

10. The compound according to any one of the preceding claims, wherein R a 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.

11. The compound according to any one of the preceding claims, wherein R b It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C-substitution of cycloalkyl and halogenated groups 1-6 Alkyl, or C 3-6 Cycloalkyl.

12. The compound according to any one of claims 1-9, wherein R a and R b Together with the atoms to which they are attached, they form 5-8 membered heterocyclic groups.

13. The compound according to any one of claims 1-9, wherein R a or R b 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.

14. The compound according to any one of the preceding claims, wherein L 2 R is arbitrarily selected by 1-2 independently selected factors. h Replacement C 6-10 Aryl, Where aa represents the combination containing 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 1 and R 2 Each 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 one of the preceding claims, wherein L 1 It is -C(O)-.

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

20. The compound according to any of the preceding claims, wherein ring A is separated by 2-3 groups independently selected from halogenated groups, C... 1-6 Alkyl and C 3-6 A phenyl group substituted with a cycloalkyl substituent.

21. The compound according to any of the preceding claims, wherein ring B is: Where bb represents L 1 Attachment point.

22. The compound according to any one of the preceding claims, wherein R 8 It was R 8c Substituted phenyl groups.

23. The compound according to any one of the preceding claims, wherein R 8 It was R 8c Substituted 5-6 aryl groups.

24. The compound according to any one of the preceding claims, wherein ring B is: Where bb represents L 1 Attachment point.

25. The compound according to any of the preceding claims, wherein ring B is: Where bb represents L 1 Attachment point.

26. The compound according to any one of claims 1-21 or 24-25, wherein L 3 It is a key.

27. The compound according to any one of claims 1-21 or 24-25, wherein L 4 It is a key.

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

29. The compound according to any of the preceding claims, wherein ring B is Where bb represents L 1 Attachment point.

30. The compound according to any one of the preceding claims, wherein R 4 It is either hydrogen or a halogroup.

31. The compound according to any one of the preceding claims, wherein R 5 R 6 and R 7 Each is hydrogen.

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

33. The compound according to any one of the preceding claims, wherein R 8a and R 8b Together with their respective attached carbon atoms, they form optionally carbon-bound... 1-6 Alkyl-substituted C 3-15 Cycloalkyl rings.

34. The compound according to any one of the preceding claims, wherein R 9 R is arbitrarily selected by 1-3 independently chosen factors. 9c Substituted 5-6 aryl groups, or 35. The compound according to any one of the preceding claims, wherein R 9 It is a 6-membered heteroaryl group.

36. The compound according to any one of the preceding claims, wherein R 9 yes 37. The compound according to any one of the preceding claims, wherein the ring C is optionally surrounded by 1-3 R... Ca Substituted 3-12 membered heterocyclic groups.

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

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

40. The compound according to claim 1, wherein the compound is a compound of formula IIIA: Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, wherein: Q 2 Is it N or CR? QA ; R a 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 C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl; R b It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C-substitution of cycloalkyl and halogenated groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl; Or R a and R b Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally composed of 1-3 independently selected carbon atoms. 1-6 Alkyl substitution; Each R QA Independently, it is hydrogen, halogroup, cyano, hydroxyl, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e Optionally selected from 1 to 6 independently chosen R f Replacement C 1-6 Alkyl group, optionally surrounded by 1-6 groups, each independently selected from hydroxyl, halogroup and C. 1-6 alkoxy substituents of C 1-6 Alkyl groups, optionally composed of one or more independently selected from C 1-6 Alkyl groups and -C(O)(C 1-6 A 3-12 membered heterocyclic group substituted with an alkyl group, optionally with 1-3 independently selected -C(O)(C) groups. 1-6 alkyl) substituted C 6-10 Aryl, and optionally 1-6 independently selected R g Substituted 5-10 heteroaryl groups; Or R a or R b 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 Ca C is independent 1-6 alkyl; q is 0, 1, 2, 3, 4, or 5; Each R A Independently, it is a halogenated group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl; R 3 It is hydrogen or optionally surrounded by 1-6 independently selected halogen groups, hydroxyl groups, and C. 1-6 alkoxy substituents of C 1-6 alkyl; R 9 It is -C(O)OR 9a -C(O)NR 9a R 9b Optionally selected by 1-3 independently chosen R 9c The substituted 5-6 heteroaryl group, optionally with 1-3 independently selected R groups. 9c Substituted 4-6 membered heterocyclic 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, it consists of hydrogen, oxy 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); 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 e Independently, it is hydrogen and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; w is 0, 1, 2, or 3; Each R 1f C is independent 1-6 Alkyl, wherein each C 1-6 Alkyl groups are independently and optionally selected by 1-6 independently chosen R groups. f replace; Each R f Independently, it is a halogenated group, a hydroxyl group, or -NR. 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 halogenated group, a cyano group, a hydroxyl group, or a C group. 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.

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

42. A compound, said compound being selected from: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug.

43. A compound, said compound being selected from: Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug.

44. 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.

45. 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 1-43 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutical composition according to claim 44.

46. ​​The method of claim 45, 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.

47. 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 a compound according to any one of claims 1-43 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug, or a pharmaceutical composition according to claim 44.

48. 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 1-40 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutical composition according to claim 44.

49. 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 1-43 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutical composition according to claim 44.

50. The method according to any one of claims 45-49, the method further comprising administering an additional therapy or treatment agent to the patient.

51. The method of claim 50, 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.

52. A method for preparing a compound of formula I: A method comprising, or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer thereof, a mixture of stereoisomers thereof, or a prodrug thereof, said method comprising, subjecting a compound of formula I-1: Compounds of formula 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: LG is a leaving group; X is C and Z is N, or X is N and Z is C; 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 The condition is Q 2 Q 3 and Q 4 At least one of them is CR QB ; or Q 1 It is a key; and Q 2 Q 3 Q 4 and Q 5 Each of the following is independently O, S, N, NH, NR c CR QA or CR QB The condition is Q 2 Q 3 Q 4 and Q 5 At least one of them is CR QB ; The condition is that it contains Q. 1 -Q 5 The ring is from the Aromatic tribe; R QB is -S(O)(=NR a )R b 、-(CR i R j ) n -S(O)(=NR a )R b 、-N=S(O)(R 1a )R b or -O-(CR i R j ) n -S(O)(=NR a )R b ; R 1a It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C-substitution of cycloalkyl and halogenated groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl; R a 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 C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl; R b It is arbitrarily selected from 1 to 6 independently chosen from C. 1-6 Alkoxy, C 3-6 C-substitution of cycloalkyl and halogenated groups 1-6 Alkyl groups, optionally composed of 1-3 independently selected C14 groups. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl, or optionally composed of 1-3 independently selected C atoms. 1-3 Alkyl-substituted C 6-10 Aryl; Or R a and R b Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally composed of 1-3 independently selected carbon atoms. 1-6 Alkyl substitution; n is 1, 2, 3, 4, 5, or 6; Each R i It is independently hydrogen, halogenated or C 1-6 alkyl; Or R a and R i Or R b and R i Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the heterocyclic groups are optionally composed of 1-3 independently selected carbon atoms. 1-6 Alkyl substitution; Each R j It is independently hydrogen, halogenated or C 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; Or an R on an adjacent carbon atom i And an R j Together with one or more atoms to which each is attached, they form olefins, wherein the olefins are optionally bonded by one to three independently selected C atoms. 1-6 Alkyl substitution; Each R QA Independently, it is hydrogen, halogroup, cyano, hydroxyl, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e Optionally selected from 1 to 6 independently chosen R f Replacement C 1-6 Alkyl group, optionally surrounded by 1-6 groups, each independently selected from hydroxyl, halogroup and C. 1-6 alkoxy substituents of C 1-6 Alkyl groups, optionally composed of one or more independently selected from C 1-6 Alkyl groups and -C(O)(C 1-6 A 3-12 membered heterocyclic group substituted with an alkyl group, optionally with 1-3 independently selected -C(O)(C) groups. 1-6 alkyl) substituted C 6-10 Aryl, and optionally 1-6 independently selected R g Substituted 5-10 heteroaryl groups; Or two R atoms on adjacent carbon atoms QA Together with their respective attached atoms, they form 5-8 membered heterocyclic groups, wherein the rings are optionally separated by 1-2 independently selected R atoms. h replace; Or R a or R b 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; L 2 R is arbitrarily selected by 1-2 independently selected factors. h Replacement C 6-10 Aryl, optionally selected by 1-2 independently chosen R h Replaced 5-10 aryl groups, Where aa represents the combination containing 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 halogenated group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl; R 1 R 2 and R 3 Each is independently hydrogen or optionally surrounded by 1-6 independently selected halogen groups, hydroxyl groups, and C. 1-6 alkoxy substituents of C 1-6 alkyl; L 1 It is -C(O)-, -CH2-, -CH(C 1-6 Alkyl)- or -S(O)2-; Cycle 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 substitution is optionally made by one to four independently selected groups: halogenated group, oxo group, 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 R 8c Replaced, and optionally further selected by 1-3 independently chosen 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 halogenated groups and C. 3-15 Cycloalkyl substituents substituted C 1-6 Alkyl; or R 8a and R 8b Together with their respective attached carbon atoms, they form 1-3 independently selected carbon atoms. 1-6 Alkyl-substituted C 3-15 cycloalkyl ring, wherein the C 1-6 Alkyl groups are optionally separated 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, halogenated 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 Optionally selected by 1-3 independently chosen R 9c The substituted 5-6 heteroaryl group, optionally with 1-3 independently selected R groups. 9c Substituted 4-6 membered heterocyclic 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, it consists of hydrogen, oxy 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 halogenated 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; R e It is hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Each R f Independently, it is a halogenated group, a hydroxyl group, or -NR. 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 halogenated group, a cyano group, a hydroxyl group, or a C group. 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.

53. The method of claim 52, wherein the method further comprises a hydrolysis or transesterification step before or after the contact.

54. The method according to claim 52 or 53, wherein the method comprises an alkali and optionally an increased temperature.

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