Heterocyclic GLP-1 agonists

Abstract

FIELD OF THE DISCLOSURE The present disclosure relates generally to GLP-1 agonists and pharmaceutical compositions comprising same, as well as methods of treating GLP-1-related diseases, disorders or conditions.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit 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.

[0002] FIELD OF THE INVENTION The present disclosure relates to GLP-1 agonists, pharmaceutical compositions, and methods of use thereof. [Background technology]

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

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

[0005] In healthy individuals, the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) provide tandem regulation of the insulin secretory response to glucose ingestion. This incretin effect is significantly reduced (if present) in T2DM, but GLP-1 retains its insulinotropic properties even when the pancreatic endocrine response to GIP is effectively abolished. Therefore, incretin mimetics and other GLP-1-based therapies may be useful in stimulating insulin production in T2DM patients. Summary of the Invention

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

[0007] In one embodiment, a compound of formula I: [ka] I or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein: 1 , Q 2 , Q 3 , Q 4 , Q 5 , L 1 , L 2 , R 1 , R 2 , R 3 and R QB are each independently as defined herein.

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

[0009] Also provided is a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0010] Also provided is a method of treating type 2 diabetes in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, or a pharmaceutical composition thereof.

[0011] Also provided is a method of treating type 2 diabetes in a patient, comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, or a pharmaceutical composition thereof, to a patient identified or diagnosed with type 2 diabetes.

[0012] Also provided is a method for treating diabetes in a patient, 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 analogue, stereoisomer, mixture of stereoisomers or prodrug thereof, or a pharmaceutical composition thereof. In some embodiments, determining that the patient has type 2 diabetes comprises performing an assay to determine the level of an analyte in a sample from the patient, wherein the analyte is selected from the group consisting of hemoglobin A1c (HbA1c), fasting plasma glucose, non-fasting plasma glucose, or any combination thereof. In some embodiments, the level of HbA1c is about 6.5% or higher. In some embodiments, the level of fasting plasma glucose is about 126 mg / dL or higher. In some embodiments, the level of non-fasting plasma glucose is about 200 mg / dL or higher.

[0013] In some embodiments, the method further comprises obtaining a sample from the patient. In some embodiments, the sample is a bodily fluid sample. In some embodiments, the patient is about 40 to about 70 years old and is overweight or obese. In some embodiments, the patient has a body mass index (BMI) of about 22 kg / m 2 In some embodiments, the patient's BMI is about 30 kg / m or greater. 2 That's all.

[0014] In some embodiments, treating type 2 diabetes comprises lowering fasting plasma glucose levels. In some embodiments, fasting plasma glucose levels are lowered to about 100 mg / dL or less.

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

[0016] In some embodiments, the treatment of type 2 diabetes comprises lowering glucagon levels.

[0017] In some embodiments, the treatment of type 2 diabetes comprises increasing insulin levels.

[0018] In some embodiments, treating type 2 diabetes involves lowering BMI. In some embodiments, BMI is about 25 kg / m 2 It drops to the following:

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

[0020] In some embodiments, the method for treating type 2 diabetes further comprises administering an additional treatment or therapeutic agent to the patient. In some embodiments, the additional treatment or therapeutic agent is selected from the group consisting of an antidiabetic agent, an antiobesity agent, a GLP-1 receptor agonist, a nonalcoholic steatohepatitis (NASH) therapeutic agent, an antiemetic agent, gastric electrical stimulation, dietary monitoring, physical activity, or any combination thereof. In some embodiments, the antidiabetic agent is selected from the group consisting of a biguanide, a sulfonylurea, a glitazar, a thiazolidinedione, a dipeptidyl peptidase 4 (DPP-4) inhibitor, a meglitinide, a sodium-glucose-coupled transporter 2 (SGLT2) inhibitor, a glitazone, a GRP40 agonist, a glucose-dependent insulinotropic peptide (GIP), insulin or an insulin analog, an alpha-glucosidase inhibitor, a sodium-glucose-coupled transporter 1 (SGLT1) inhibitor, or any combination thereof. In some embodiments, the biguanide is metformin. In some embodiments, the anti-obesity agent is selected from the group consisting of a neuropeptide Y receptor type 2 (NPYR2) agonist, an NPYR1 or NPYR5 antagonist, human islet-activating peptide (HIP), a cannabinoid receptor type 1 (CB1R) antagonist, a lipase inhibitor, a melanocortin receptor 4 agonist, a farnesoid X receptor (FXR) agonist, phentermine, zonisamide, a norepinephrine / dopamine reuptake inhibitor, a GDF-15 analog, an opioid receptor antagonist, a cholecystokinin agonist, a serotonergic agent, a methionine aminoptidase 2 (MetAP2) inhibitor, diethylpropion, phendimetrazine, benzphetamine, a fibroblast growth factor receptor (FGFR) modulator, an AMP-activated protein kinase (AMPK) activator, or any combination thereof. In some embodiments, the GLP-1 receptor agonist is selected from the group consisting of liraglutide, exenatide, dulaglutide, albiglutide, taspoglutide, lixisenatide, semaglutide, or any combination thereof.In some embodiments, the NASH therapeutic agent is selected from the group consisting of FXR agonists, PF-05221304, synthetic fatty acid bile acid conjugates, anti-lysine oxidase homolog 2 (LOXL2) monoclonal antibodies, caspase inhibitors, MAPK5 inhibitors, galectin 3 inhibitors, fibroblast growth factor 21 (FGF21) agonists, niacin analogs, leukotriene D4 (LTD4) receptor antagonists, acetyl-CoA carboxylase (ACC) inhibitors, ketohexokinase (KHK) inhibitors, ileal bile acid transporter (IBAT) inhibitors, apoptosis signal-regulating kinase 1 (ASK1) inhibitors, or any combination thereof. In some embodiments, the compound of Formula I, or its pharmaceutically acceptable salt, isotope-enriched analog, stereoisomer, mixture of stereoisomers or prodrug, or pharmaceutical composition thereof, and the additional therapeutic agent are administered sequentially in any order as separate administrations.

[0021] Also provided is a method of modulating insulin levels in a patient in need thereof, comprising administering to the patient an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutical composition thereof. In some embodiments, the modulation results in increased insulin levels.

[0022] Also provided are methods for modulating glucose levels in a patient in need thereof, comprising administering to the patient an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutical composition thereof. In some embodiments, the modulation results in a decrease in glucose levels.

[0023] Also provided are methods for treating a GLP-1-associated disease, disorder, or condition, comprising administering to a patient in need of treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutical composition thereof. In some embodiments, the disease, disorder, or condition is selected from the group consisting of type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), early-onset atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of adults (LADA), obesity, weight gain due to use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, lipid Cellular dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial cell dysfunction, impaired vascular compliance, vascular restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial lipemia, metabolism In some embodiments, the disease is selected from the group consisting of: chronic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, treatment of addiction, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulceration, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof.In some embodiments, the disease, disorder or condition is type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, renal disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, arteriosclerotic cardiovascular disease, hyperglycemia, postprandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders. , insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulceration, psoriasis, primary polydipsia, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS), or any combination thereof. In some embodiments, the disease, disorder, or condition includes, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat deposition, myocardial infarction, peripheral arterial disease, stroke, transient ischemic attack, hyperglycemia, postprandial 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 ulceration, or any combination thereof.

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

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

[0026] (definition) Provided herein are heterocyclic GLP-1 agonists for use in the management of T2DM and other conditions in which activation of GLP-1 activity is beneficial.

[0027] Before describing the present compounds and methods, it is to be understood that this disclosure is not limited to the methodology, procedures, cell lines, assays, and reagents described, as these may vary. It is also to be understood that the terminology used herein is intended to describe embodiments of the disclosure, and is not intended to limit the scope of the disclosure, which is set forth in the appended claims.

[0028] (definition) The following description describes exemplary embodiments of the present technology, however, it should be recognized that such description is not intended as a limitation on the scope of the present disclosure, but instead is provided as a description of exemplary embodiments.

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

[0030] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment of a substituent. For example, -C(O)NH2 is attached through a carbon atom. Dashes at the beginning or end of a chemical group are for convenience, and a chemical group may be shown with or without one or more dashes without loss of normal meaning. Wavy or dashed lines drawn through lines in a structure indicate a particular point of attachment of a group. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implied by the order in which chemical groups are written or named.

[0031] Prefix “C” uv " indicates that the following group has u to v carbon atoms. For example, "C 1-6 "Alkyl" indicates that the alkyl group has from 1 to 6 carbon atoms.

[0032] References herein to "about" a value or parameter include (and describe) embodiments that are directed to the value or parameter itself. In certain embodiments, the term "about" includes the stated amount ±10%. In other embodiments, the term "about" includes the stated amount ±5%. In other specific embodiments, the term "about" includes the stated amount ±1%. Also, the term "about x" includes the reference to "x". Additionally, the singular forms "a" and "the" include plural references unless the context clearly indicates otherwise. Thus, for example, reference to "the compound" includes a plurality of such compounds, and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those of skill in the art.

[0033] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to an alkyl group having 1 to 20 carbon atoms (i.e., C 1-20alkyl), 1 to 12 carbon atoms (i.e., C 1-12 alkyl), 1 to 8 carbon atoms (i.e., C 1-8 alkyl), 1 to 6 carbon atoms (i.e., C 1-6 alkyl), or 1 to 4 carbon atoms (i.e., C 1-4 alkyl). Examples of alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbon atoms is named by a chemical name or specified by a molecular formula, all positional isomers having that number of carbon atoms 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).

[0034] "Alkenyl" refers to an alkyl group containing at least one (e.g., 1 to 3 or 1) carbon-carbon double bond and 2 to 20 carbon atoms (i.e., C 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 It refers to an alkyl group having an alkenyl group. Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0035] "Alkynyl" refers to an alkyl group containing at least one (e.g., 1 to 3 or 1) carbon-carbon triple bond and 2 to 20 carbon atoms (i.e., C2-20 alkynyl), 2 to 12 carbon atoms (i.e., C 2-12 alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 alkynyl), 2 to 6 carbon atoms (i.e., C 2-6 alkynyl) or 2 to 4 carbon atoms (i.e., C 2-4 The term "alkynyl" also includes groups having one triple bond and one double bond.

[0036] Certain commonly used alternative chemical names may be used, for example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, etc. may also be referred to as "alkylene" or "alkylenyl" groups, "arylene" or "arylenyl" groups, respectively.

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

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

[0039] "Haloalkyl" refers to an unbranched or branched alkyl group, as defined above, in which one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms have been replaced with halogen. For example, if a residue is substituted with 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 substituted with two ("di") or three ("tri") halo groups, which may, but need not, be the same halogen. Examples of haloalkyl include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

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

[0041] "Hydroxyalkyl" refers to an alkyl group, as defined above, in which one or more (eg, 1 to 6 or 1 to 3) hydrogen atoms have been replaced with hydroxy groups.

[0042] "Cyanoalkyl" refers to an alkyl group, as defined above, in which one or more (eg, 1 to 6 or 1 to 3) hydrogen atoms have been replaced with a hydroxy group.

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

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

[0045] "Amide" is -C(O)NR y R z The "C-amido" group and -NR refer to the group y C(O)R z The "N-amido" group refers to both the y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein, or R y and R z taken together form a cycloalkyl or heterocyclyl; each of which can be optionally substituted as defined herein.

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

[0047] "Amidino" is -C(NR y )(NR z 2), where R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which can be optionally substituted as defined herein.

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

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

[0050] "Carboxyl ester" or "ester" is -OC(O)R x and -C(O)OR x Refers to both R x is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which can be optionally substituted as defined herein.

[0051] "Cycloalkyl" refers to saturated or partially unsaturated cyclic alkyl groups having single or multiple rings, including fused, bridged, and spiro ring systems. The term "cycloalkyl" refers to cycloalkenyl groups (i.e., ring groups having at least one double bond) and at least one sp 3As used herein, cycloalkyl includes carbocyclic fused ring systems having 3 to 20 ring carbon atoms (i.e., at least one non-aromatic ring). 3-20 cycloalkyl), 3 to 14 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. The term cycloalkyl is also intended to encompass any non-aromatic ring that may be fused to an aryl ring, regardless of attachment to the rest of the molecule. Furthermore, cycloalkyl also includes "spirocycloalkyl" when the two substitution positions are on the same carbon atom, such as spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.

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

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

[0054] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatom groups. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms. By way of example, one, two, or three carbon atoms can be independently replaced with the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O)-, and the like, where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted. Examples of heteroalkyl groups include -OCH, -CHOCH, -SCH, -CHSCH, -NRCH, and -CHNRCH, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which is optionally substituted. As used herein, heteroalkyl includes 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0055] "Heteroalkylene" refers to a divalent heteroalkyl group. A "heteroalkylene" group must have at least one carbon and at least one heteroatom group within the chain. The term "heteroalkylene" includes unbranched or branched saturated chains containing carbon and heteroatoms. For example, one, two, or three carbon atoms can be independently replaced with the same or different heteroatom groups. Heteroatom groups include -NR y -, -O-, -S-, -S(O)-, -S(O)2-, and the like, wherein R yis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which can be optionally 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)2CH2CH2OCH2-, and -CH2NR y CH2-, -CH(CH3)NR y CH2-, -CH2CH2NR y CH2-, -CH2CH2NR y CH2CH2NR y CH2-, where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which can be optionally substituted as defined herein. As used herein, heteroalkylene includes 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 amide or other functional groups having oxo present on one or more carbon atoms.

[0056] "Heteroaryl" refers to an aromatic group having a single ring or multiple fused rings containing one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to a heteroaryl having 1 to 20 ring carbon atoms (i.e., C 1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-12 heteroaryl) or 3 to 8 ring carbon atoms (i.e., C 3-8Heteroaryl) and includes 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. In certain cases, heteroaryl includes 5- to 10-, 5- to 7-, or 5- to 6-membered ring systems each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothienyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, and isoquinolyl. , isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, thienyl, triazolyl, tetrazolyl and triazinyl. Fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thienyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, and the heteroaryl may be bonded via any ring of the fused system. Any aromatic ring having a single or multiple fused rings containing at least one heteroatom is considered heteroaryl, regardless of the bond to the rest of the molecule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with the aryl defined above.

[0057] "Heterocyclyl" refers to a saturated or partially unsaturated cyclic alkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bridged heterocyclyl groups, fused heterocyclyl groups, and spiroheterocyclyl groups. Heterocyclyls can be monocyclic or polycyclic, which may be fused, bridged, or spiro, and may contain one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O - ) moiety. Any non-aromatic ring or fused ring system containing at least one heteroatom and one non-aromatic ring is considered heterocyclyl, regardless of attachment to the rest of the molecule. For example, fused ring systems such as decahydroquinazolinyl, 1,2,3,4-tetrahydroquinazolinyl, and 5,6,7,8-tetrahydroquinazolinyl are heterocyclyl (i.e., may be attached via a carbon atom or a heteroatom), regardless of attachment to the rest of the molecule. Additionally, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to a cycloalkyl, aryl, or heteroaryl ring, regardless of attachment to the rest of the molecule. As used herein, heterocyclyl refers to a ring having from 2 to 20 ring carbon atoms (i.e., C 2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C 2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C 2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C 2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C 3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C 3-8 heterocyclyl) or 3 to 6 ring carbon atoms (i.e., C 3-6Heterocyclyl) having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclyl groups include, for example, azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindoline, and the like. Heterocyclyl groups include aryl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term "heterocyclyl" also includes "spiroheterocyclyl" when there are two positions for substitution on the same carbon atom. Examples of spiro-heterocyclyl rings include, for example, bicyclic and tricyclic ring systems such as oxabicyclo[2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, and the heterocyclyl may be attached via either ring of the fused system. The term "heterocyclyl" also refers to R QB The sulfoximine moiety (e.g., R QB R a and Rb But, Q 1 -Q 5 When fused to a ring containing, for example, R a and R QA , or R b and R QA forms a ring), for example, 3,4-dihydro-1λ 6 ,2-Thiazine 1-oxide, 1λ 6 ,2-Thiazine 1-oxide, 4,5-dihydro-3H-1λ 6 -Isothiazole 1-oxide, 1-(imino)tetrahydro-1H-1λ 6 -Thiophene 1-oxide, 4,5-dihydro-3H-1λ 6 , 2-thiazepine 1-oxide, etc. See, for example, Cram, et al., J. Org. Chem., 1973, 38(1), 20-26.

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

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

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

[0061] The term "desired" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where said event or circumstance occurs and cases where it does not occur. Also, the term "optionally substituted" refers to any one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms on a given atom or group that may or may not be replaced by a non-hydrogen moiety.

[0062] As used herein, the term "compound" is meant to include any and all stereoisomers, geometric isomers, tautomers, and isotopically enriched analogs (e.g., deuterated analogs) of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0063] Some compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with an imidic acid tautomer. Regardless of which tautomer is shown and the nature of the equilibrium between the tautomers, it is understood by those skilled in the art that the compound includes both the amide and imidic acid tautomers. Thus, amide-containing compounds are understood to include their imidic acid tautomers. Similarly, imidic acid-containing compounds are understood to include their amide tautomers.

[0064] Any compound or structure shown herein is also intended to represent the unlabeled form and isotopically labeled form of the compound.These forms of compounds are also referred to as "isotopically enriched analogs".Isotopically labeled compounds have the structure shown herein, except that one or more atoms are replaced by atoms with 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, each of which is, for example, 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 of the present disclosure, such as 3 H and 14 Those incorporating a radioactive isotope such as C. Such isotopically labeled compounds may be useful 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 substrate tissue distribution assays), or in radiation treatment of patients.

[0065] The term "isotopically enriched analog" includes "deuterated analogs" of the compounds described herein, in which one or more hydrogen atoms have been replaced by deuterium atoms, such as hydrogen atoms on a carbon atom. Such compounds exhibit increased resistance to metabolism and are therefore useful for increasing 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 atoms.

[0066] Therapeutic compounds of the present disclosure that are labeled or substituted with deuterium may have improved DMPK (drug metabolism and pharmacokinetic) properties with respect to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes, such as deuterium, may confer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. 18 F, 3 H, 11 Compounds labeled with C may be useful for PET or SPECT or other imaging studies. The isotopically labeled compounds of the present disclosure and their prodrugs can generally be prepared by carrying out the procedures disclosed in the following schemes or examples and preparations, substituting readily available isotopically labeled reagents for non-isotopically labeled reagents. It is understood that deuterium in this context is considered a substituent in the compounds described herein.

[0067] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," that position is understood to have hydrogen at its natural abundance isotopic composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0068] In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0069] Pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that are useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0070] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and organic acids. Also, when a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, when the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from bases include, for example, acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include salts of NH3, or primary, secondary, and tertiary amines, such as salts derived from N-containing heterocycles, N-containing heteroaryls, or salts of the formula N(R N )3 (e.g., HN + (R N )3 or (alkyl)N + (R N ) 3) salts derived from amines represented by the formula: Nare independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be optionally substituted, for example, with one or more (e.g., 1 to 5 or 1 to 3) substituents (e.g., halo, cyano, hydroxy, amino, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, or haloalkoxy). Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0071] The term "substituted" means that any one or more hydrogen atoms on the specified atom or group are replaced with one or more non-hydrogen substituents, provided that the replacement 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, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonate, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. In some embodiments, the one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, acyl, amino, amido, amidino, aryl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanidino, halo, haloalkyl, hydroxyalkyl, haloalkoxy, haloalkoxyalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, imido, oxo, nitro, sulfinyl, sulfonic acid, sulfonyl, thiocyanate, thiol, thione, or a combination thereof.

[0072] Polymers or similar undefined structures resulting from defining a substituent with an infinite number of additional substituents (e.g., a substituted aryl having a substituted alkyl, itself substituted with a substituted aryl group, further substituted with a substituted heteroalkyl group) are not intended to be included herein. Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definition is not intended to include impermissible substitution patterns (e.g., a methyl substituted with five fluorines or a heteroaryl group with two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term "substituted" may describe other chemical groups defined herein. Unless otherwise specified, when a group is described as being optionally substituted, any substituent of that group is itself not substituted. For example, in some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents, including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, one or more of the substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted.

[0073] As used herein, "pharmaceutically acceptable carriers" or "pharmaceutically acceptable additives" include any solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonicity agents and adsorption retardants, etc. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic composition is contemplated. Additional active ingredients may also be incorporated into the composition.

[0074] A "solvate" is formed by the interaction of a solvent and a compound. Solvates of the salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0075] As used herein, when a ring is described as "aromatic," it means that the ring has a continuous, delocalized π-electron system. Typically, the number of out-of-plane π-electrons corresponds to Hückel's rule (4n+2). Examples of such rings include benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thiazole, isoxazole, isothiazole, and the like. When a ring system containing at least two rings is described as "aromatic," it means that the ring system contains one or more aromatic rings. Thus, when a ring system containing at least two rings is described as "non-aromatic," it means that none of the constituent rings of the ring system are aromatic.

[0076] As used herein, when a ring is described as "partially unsaturated," it is meant that the ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation due to the ring itself, e.g., one or more double bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like. When a ring system containing at least two rings is described as "partially unsaturated," it is meant that the ring system contains one or more partially unsaturated rings, provided that none of the constituent rings of the ring system are aromatic.

[0077] As used herein, the term "compound" is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0078] As used herein, the term "tautomer" refers to compounds whose structures differ significantly in the arrangement of atoms but which exist in ready and rapid equilibrium; the compounds provided herein may be represented as different tautomers; it is understood that when a compound has tautomeric forms, all tautomeric forms are intended to be within the scope of the present disclosure, and the naming of a compound does not exclude any tautomer.

[0079] As used herein, the term "GLP-1R" or "GLP-1 receptor" is meant to include, but is not limited to, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and / or orthologous GLP-1R molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.

[0080] As used herein, the term "GLP-1 associated disease" is meant to include, but is not limited to, any disease, disorder, or condition in which modulation of glucagon-like peptide-1 (GLP-1) receptor signaling can alter the pathology and / or symptoms and / or progression of the disease, disorder, or condition.

[0081] As used herein, the term "GLP-1 agonist" or "GLP-1 RA" refers to an agonist of the glucagon-like peptide-1 (GLP-1) receptor. GLP-1 RAs enhance glucose-dependent insulin secretion, suppress inappropriately elevated glucagon levels in both fasting and postprandial states, and delay gastric emptying. Karla et al., Glucagon-like peptide-1 receptor agonists in the treatment of type 2 diabetes: Past, present, and future, Indian J Endocrinol Metab. 2016 Mar-Apr; 20(2): 254-267. GLP-1 RAs have been shown to treat type 2 diabetes. Examples of GLP-1 RAs include, but are not limited to, albiglutide (Tanzeum®), dulaglutide (LY2189265, Trulicity®), efpeglenatide, exenatide (Byetta®, Bydureon®, Exendin-4), liraglutide (Victoza®, NN2211), lixisenatide (Lyxumia®), semaglutide (Ozempic®), tirzepatide, ZP2929, NNC0113-0987, BPI-3016, and TT401.

[0082] As used herein, the term "pharmaceutically acceptable" indicates that a compound or a salt thereof or composition is chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the subject being treated therewith.

[0083] The term "administration" or "administering" refers to a method of providing a dosage of a compound or pharmaceutical composition to a vertebrate or invertebrate, including a mammal, bird, fish, or amphibian. The method of administration can vary depending on various factors, such as the components of the pharmaceutical composition, the site of the disease, and the severity of the disease.

[0084] As used herein, the term "effective amount" or "effective dosage" or "pharmaceutically effective amount" or "therapeutically effective amount" refers to a sufficient amount of the administered chemical substance (e.g., a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof) that will alleviate to some extent one or more of the symptoms of the disease or condition being treated, and may include curing the disease. "Cure" means that the symptoms of active disease are eliminated. The result includes the reduction and / or alleviation of the signs, symptoms, or causes of disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein that is required to provide a clinically significant reduction in disease symptoms. The appropriate "effective" amount in any individual case can be determined using any suitable technique, such as a dose escalation study. In some embodiments, the "therapeutically effective amount" of a compound provided herein refers to the amount of the compound that is effective as a monotherapy or combination therapy.

[0085] The term "excipient" or "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid excipient, diluent, carrier, solvent, or encapsulating material. In some embodiments, each component is "pharmaceutically acceptable" in the sense of being compatible with the other components of the pharmaceutical formulation, suitable for use in contact with the tissues or organs of humans and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problems or complications, and commensurate with a reasonable benefit / risk ratio. For example, Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical See Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0086] The term "pharmaceutical composition" refers to a mixture of a compound of Formula I provided herein or a pharmaceutically acceptable salt or solvate thereof 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 a compound to an organism. Multiple techniques for administering a compound exist in the art, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0087] The terms "treat," "treating," and "treatment," in the context of treating a disease, disorder, or condition, are meant to include alleviating or arresting the disorder, disease, or condition, or one or more symptoms associated with the disorder, disease, or condition, or slowing the progression, spread, or worsening of the disease, disorder, or condition, or one or more symptoms thereof.

[0088] As used herein, the term "preventing" refers to the prevention, in whole or in part, of the onset, recurrence or spread of a disease or condition described herein, or a symptom thereof.

[0089] As used herein, the terms "subject," "patient," or "individual" are used interchangeably and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, the term refers to a subject, particularly a mammalian subject, for whom diagnosis, prognosis, or treatment is desired or required. In some embodiments, the subject is a human. In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of the disease, disorder, or condition to be treated and / or prevented.

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

[0091] As used herein, the term "pharmaceutical combination" refers to a pharmaceutical treatment resulting from the mixing or combining of two or more active ingredients and includes both fixed and loose combinations of the active ingredients.

[0092] As used herein, the term "combination therapy" refers to a dosing regimen of two different therapeutically active agents (i.e., components of a combination or combination partners), which are administered together or separately in a manner prescribed by a healthcare professional or in accordance with regulatory agencies as defined herein.

[0093] As used herein, the terms "modulate," "modulating," or "modulation" refer to regulation or modulation (e.g., increase or decrease) and can include, for example, agonism, partial agonism, or antagonism.

[0094] (compound) Formula I: [ka] I or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein: 1 , Q 2 , Q 3 , Q 4 , Q 5 , L 1 , L 2 , R 1 , R 2 , R 3 and R QB are each independently as defined herein.

[0095] In one embodiment, a compound of formula I: [ka] I or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein: X is C and Z is N, or X is N and Z is C; Q 1 and Q 5 are each independently N or CR QA and;Q 2 , Q 3 and Q 4 are each independently N, CR QA or CR QB where Q 2 , Q 3 and Q 4 At least one of the following is CR QB is; or Q1 is a bond;Q 2 , Q 3 , Q 4 and Q 5 are each independently O, S, N, NH, or NR c , C.R. QA or CR QB where Q 2 , Q 3 , Q 4 and Q 5 At least one of the following is CR QB and; However, Q 1 -Q 5 The ring containing is aromatic; 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 and; R 1a are each independently C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and halo 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; R a are hydrogen, cyano, each independently halo, oxo, C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and heteroaryl1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; R b are each independently C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and halo 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; Or, R a and R b are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 3 independently selected C 1-6 optionally substituted with alkyl; n is 1, 2, 3, 4, 5 or 6; Each R i are independently hydrogen, halo, or C 1-6 is alkyl; Or, R a and R i , or R b and R i are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 3 independently selected C 1-6 optionally substituted with alkyl; Each R j are independently hydrogen, halo, or C 1-6 is alkyl; Or, one R i and one R j together with the atoms to which they are bonded, form C3-6 Form a cycloalkyl, wherein the cycloalkyl is selected from 1 to 3 independently selected C 1-6 optionally substituted with alkyl; Or, one R on an adjacent carbon atom i and one R j each taken together with the atom to which it is attached forms an alkene, and the alkene is selected from 1 to 3 independently selected C 1-6 optionally substituted with alkyl; Each R QA are independently hydrogen, halo, cyano, hydroxy, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e , 1 to 6 independently selected R f C optionally substituted with 1-6 alkyl, each independently hydroxy, halo and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 Alkoxy, each independently C 1-6 Alkyl and -C(O)(C 1-6 alkyl), 3- to 12-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of 1 to 3 independently selected —C(O)(C 1-6 C optionally substituted with alkyl 6-10 aryl, and 1 to 6 independently selected R g is a 5- to 10-membered heteroaryl optionally substituted with Or, two R on adjacent carbon atoms QA are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl ring, which ring is joined by 1 to 2 independently selected R h may be substituted with; Or, R a or R b and adjacent R QA are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 2 independently selected R hmay be substituted with; L 2 is one to two independently selected R h C optionally substituted with 6-10 aryl, 1 to 2 independently selected R h 5- to 10-membered heteroaryl optionally substituted by [ka] where aa is Q 1 -Q 5 represents the point of attachment to the ring containing n1 is 1, 2 or 3; L 2A is a bond or C 1-10 is alkylene; R La is hydrogen, C 1-6 Alkyl or -C(O)(C 1-6 alkyl); R Lb and R Lc each independently represents hydrogen or C 1-6 is alkyl; Ring A is C 6-10 Aryl, C 5-7 cycloalkyl, 5- to 7-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is selected from 1 to 5 independently selected R A may be substituted with; Each R A independently, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 is cycloalkyl; R 1 , R 2 and R 3 are each independently hydrogen, or independently halo, hydroxy, and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 is alkyl; L 1 -C(O)-, -CH2-, -CH(C 1-6alkyl)- or -S(O)2-; Ring B is a 5,6-fused heteroaryl having 5 to 8 carbon atoms and 1 to 3 heteroatoms independently selected from O, S, and N, and said ring B is R 8 and independently substituted with halo, oxo, and C 1-6 optionally substituted with 1 to 4 substituents selected from alkyl; R 8 is phenyl, 5- to 6-membered heteroaryl, or [ka] and the phenyl or 5- to 6-membered heteroaryl is R 8c and 1 to 3 independently selected R h may be substituted with; L 3 is a bond or C 1-3 is alkylene; L 4 is a bond or C 1-5 is alkylene; R 8a and R 8b are each independently hydrogen, or independently halo and C 3-15 C optionally substituted with one or more substituents selected from the group consisting of cycloalkyl 1-6 is alkyl; or R 8a and R 8b Each of these, together with the carbon atom to which it is attached, is one to three independently selected C 1-6 C optionally substituted with alkyl 3-15 Forms a cycloalkyl ring, 1-6 Alkyl is 1 to 6 independently selected R f may be substituted with; Each R 8c are independently -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- to 6-membered heterocyclyl, -L 5 -(5- to 6-membered heteroaryl), each of which is independently hydroxy, halo, and C 1-6 optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy; Each L 5 are independently -C(O)-, -C(O)O-, -OC(O)-, -S(O) 1-2 -, -S(O)2O-, -S(O)2NH- or -NHS(O)2-; R 9 is -C(O)OR 9a , -C(O)NR 9a R 9b , 1 to 3 independently selected R 9c 5-6 membered heteroaryl optionally substituted with 1 to 3 independently selected R 9c 4- to 6-membered heterocyclyl optionally substituted by [ka] and; X 1 is O or S; R 9a is hydrogen or C 1-6 is alkyl; R 9b is hydrogen, C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -S(O) 0-2 (C 1-6 alkyl) or cyano; Each R 9c are independently selected from hydrogen, oxo, 1 to 6 independently selected halo, and C 1-6 C optionally substituted with alkoxy 1-6 Alkyl, or -C(O)(C 1-6 alkyl); Ring C is a 3- to 12-membered heterocyclyl, C 3-15 cycloalkyl or 5- to 10-membered heteroaryl, each of which is selected from 1 to 3 R Ca may be substituted with; Each R Ca are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c R d and; or a pair of R on the same or different ring atoms Ca each together with the ring atom to which it is attached forms a carbocyclic ring containing 3 to 8 ring atoms; Each R c and R d are each 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), -S(O) 1-2 (C 1-6 alkyl) or -S(O) 1-2 (C 3-6 cycloalkyl), and the C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)O(C 1-6 alkyl), -S(O) 1-2 (C 1-6 alkyl) and -S(O) 1-2 (C 3-6 cycloalkyl) are each independently selected from hydroxy, halo, and C 1-6 optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy; R e is hydrogen, C 1-6 Alkyl or C 1-6 is haloalkyl; Each R f are independently halo, hydroxy, -NR c R d , C 1-6 Alkoxy, C 1-6 haloalkoxy, or each independently hydroxy, C 1-6a 3- to 12-membered heterocyclyl optionally substituted by 1 to 4 substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; Each R g independently, C 1-6 Alkyl, C 1-6 Alkoxy, -NR c R d , or each independently C 1-6 Alkyl and -C(O)C 1-6 alkyl; and Each R h are independently halo, cyano, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 Alkyl)2, C 1-3 Alkoxy or C 1-3 It is haloalkoxy.

[0096] In one embodiment, a compound of formula I: [ka] I or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein: X is C and Z is N, or X is N and Z is C; Q 1 and Q 5 are each independently N or CR QA and;Q 2 , Q 3 and Q 4 are each independently N, CR QA or CR QB where Q 2 , Q 3 and Q 4 At least one of the following is CR QB is; or Q 1 is a bond;Q 2 , Q3 , Q 4 and Q 5 are each independently O, S, N, NH, or NR c , C.R. QA or CR QB where Q 2 , Q 3 , Q 4 and Q 5 At least one of the following is CR QB and; However, Q 1 -Q 5 The ring containing is aromatic; R QB is -S(O)(=NR a )R b or -(CR i R j ) n -S(O)(=NR a )R b and; R a are hydrogen, cyano, each independently halo, oxo, C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and heteroaryl 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; R b are each independently C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and halo 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; Or, R a and R b are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 3 independently selected C 1-6 optionally substituted with alkyl; n is 1, 2, 3, 4, 5 or 6; Each R i are independently hydrogen, halo, or C 1-6 is alkyl; Or, R a and R i , or R b and R i are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 3 independently selected C 1-6 optionally substituted with alkyl; Each R j are independently hydrogen, halo, or C 1-6 is alkyl; Or, one R i and one R j together with the atoms to which they are bonded, form C 3-6 Form a cycloalkyl, wherein the cycloalkyl is selected from 1 to 3 independently selected C 1-6 optionally substituted with alkyl; Each R QA are independently hydrogen, halo, cyano, hydroxy, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e , 1 to 6 independently selected R f C optionally substituted with 1-6 alkyl, each independently hydroxy, halo and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 Alkoxy, each independently C 1-6 Alkyl and -C(O)(C 1-6alkyl), 3- to 12-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of 1 to 3 independently selected —C(O)(C 1-6 C optionally substituted with alkyl 6-10 aryl, and 1 to 6 independently selected R g is a 5- to 10-membered heteroaryl optionally substituted with Or, two R on adjacent carbon atoms QA are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl ring, which ring is joined by 1 to 2 independently selected R h may be substituted with; Or, R a or R b and adjacent R QA are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 2 independently selected R h may be substituted with; L 2 is one to two independently selected R h C optionally substituted with 6-10 aryl, 1 to 2 independently selected R h 5- to 10-membered heteroaryl optionally substituted by [ka] where aa is Q 1 -Q 5 represents the point of attachment to the ring containing n1 is 1, 2 or 3; L 2A is a bond or C 1-10 is alkylene; R La is hydrogen, C 1-6 Alkyl or -C(O)(C 1-6 alkyl); R Lb and R Lc each independently represents hydrogen or C 1-6 is alkyl; Ring A is C 6-10 Aryl, C5-7 cycloalkyl, 5- to 7-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is selected from 1 to 5 independently selected R A may be substituted with; Each R A independently, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 is cycloalkyl; R 1 , R 2 and R 3 are each independently hydrogen, or independently halo, hydroxy, and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 is alkyl; L 1 -C(O)-, -CH2-, -CH(C 1-6 alkyl)- or -S(O)2-; Ring B is a 5,6-fused heteroaryl having 5 to 8 carbon atoms and 1 to 3 heteroatoms independently selected from O, S, and N, and said ring B is R 8 and independently substituted with halo, oxo, and C 1-6 optionally substituted with 1 to 4 substituents selected from alkyl; R 8 is phenyl, 5- to 6-membered heteroaryl, or [ka] and the phenyl or 5- to 6-membered heteroaryl is R 8c and 1 to 3 independently selected R h may be substituted with; L 3 is a bond or C 1-3 is alkylene; L 4 is a bond or C 1-5 is alkylene; R 8a and R 8bare each independently hydrogen, or independently halo and C 3-15 C optionally substituted with one or more substituents selected from the group consisting of cycloalkyl 1-6 is alkyl; or R 8a and R 8b Each of these, together with the carbon atom to which it is attached, is one to three independently selected C 1-6 C optionally substituted with alkyl 3-15 Forms a cycloalkyl ring, 1-6 Alkyl is 1 to 6 independently selected R f may be substituted with; Each R 8c are independently -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- to 6-membered heterocyclyl, -L 5 -(5- to 6-membered heteroaryl), each of which is independently hydroxy, halo, and C 1-6 optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy; Each L 5 are independently -C(O)-, -C(O)O-, -OC(O)-, -S(O) 1-2 -, -S(O)2O-, -S(O)2NH- or -NHS(O)2-; R 9 is -C(O)OR 9a , -C(O)NR 9a R 9b , 1 to 3 independently selected R 9c 5-6 membered heteroaryl optionally substituted with 1 to 3 independently selected R 9c 4- to 6-membered heterocyclyl optionally substituted by [ka] and; X 1is O or S; R 9a is hydrogen or C 1-6 is alkyl; R 9b is hydrogen, C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -S(O) 0-2 (C 1-6 alkyl) or cyano; Each R 9c are independently selected from hydrogen, oxo, 1 to 6 independently selected halo, and C 1-6 C optionally substituted with alkoxy 1-6 Alkyl, or -C(O)(C 1-6 alkyl); Ring C is a 3- to 12-membered heterocyclyl, C 3-15 cycloalkyl or 5- to 10-membered heteroaryl, each of which is selected from 1 to 3 R Ca may be substituted with; Each R Ca are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c R d and; or a pair of R on the same or different ring atoms Ca each together with the ring atom to which it is attached forms a carbocyclic ring containing 3 to 8 ring atoms; Each R c and R d are each 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), -S(O) 1-2 (C 1-6 alkyl) or -S(O) 1-2 (C 3-6 cycloalkyl), and the C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)O(C1-6 alkyl), -S(O) 1-2 (C 1-6 alkyl) and -S(O) 1-2 (C 3-6 cycloalkyl) are each independently selected from hydroxy, halo, and C 1-6 optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy; R e is hydrogen, C 1-6 Alkyl or C 1-6 is haloalkyl; Each R f are independently halo, hydroxy, -NR c R d , C 1-6 Alkoxy, C 1-6 haloalkoxy, or each independently hydroxy, C 1-6 a 3- to 12-membered heterocyclyl optionally substituted by 1 to 4 substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; Each R g independently, C 1-6 Alkyl, C 1-6 Alkoxy, -NR c R d , or each independently C 1-6 Alkyl and -C(O)C 1-6 alkyl; and Each R h are independently halo, cyano, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 Alkyl)2, C 1-3 Alkoxy or C 1-3 It is haloalkoxy.

[0097] In one embodiment, a compound of formula I: [ka] I or a pharmaceutically acceptable salt or solvate thereof, wherein: X is C and Z is N, or X is N and Z is C; Q 1 and Q 5 are each independently N or CR QA and;Q 2 , Q 3 and Q 4 are each independently N, CR QA or CR QB where Q 2 , Q 3 and Q 4 At least one of the following is CR QB is; or Q 1 is a bond;Q 2 , Q 3 , Q 4 and Q 5 are each independently O, S, N, NH, or NR c , C.R. QA or CR QB where Q 2 , Q 3 , Q 4 and Q 5 At least one of the following is CR QB and; However, Q 1 -Q 5 The ring containing is aromatic; R QB is -S(O)(=NR a )R b or -(CR i R j ) n -S(O)(=NR a )R b and; R a are hydrogen, cyano, each independently halo, oxo, C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and heteroaryl 1-6 alkyl, each independently C 1-3C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; R b are each independently C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and halo 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; Or, R a and R b are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, the ring being joined to one or more independently selected C 1-6 optionally substituted with alkyl; n is 1, 2, 3, 4, 5 or 6; Each R i are independently hydrogen, halo, or C 1-6 is alkyl; Or, R a and R i , or R b and R i are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, the ring being joined to one or more independently selected C 1-6 optionally substituted with alkyl; Each R j are independently hydrogen, halo, or C 1-6 is alkyl; Each R QA are independently hydrogen, halo, cyano, hydroxy, -NR c R d , -C(O)NR c R d , -S(O)0-2 R e , 1 to 6 independently selected R f C optionally substituted with 1-6 alkyl, each independently hydroxy, halo and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 Alkoxy, each independently C 1-6 Alkyl and -C(O)(C 1-6 alkyl), 3- to 12-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of 1 to 3 independently selected —C(O)(C 1-6 C optionally substituted with alkyl 6-10 aryl, and 1 to 6 independently selected R g is a 5- to 10-membered heteroaryl optionally substituted with Or, two R on adjacent carbon atoms QA are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl ring, which ring is joined by 1 to 2 independently selected R h may be substituted with; Or, R a or R b and adjacent R QA are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl ring, which ring is joined by 1 to 2 independently selected R h may be substituted with; L 2 is one to two independently selected R h C optionally substituted with 6-10 aryl, 1 to 2 independently selected R h 5- to 10-membered heteroaryl optionally substituted by [ka] where aa is Q 1 -Q 5 represents the point of attachment to the ring containing n1 is 1, 2 or 3; L 2A is a bond or C 1-10is alkylene; R La is hydrogen, C 1-6 Alkyl or -C(O)(C 1-6 alkyl); R Lb and R Lc each independently represents hydrogen or C 1-6 is alkyl; Ring A is C 6-10 Aryl, C 5-7 cycloalkyl, 5- to 7-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is selected from 1 to 5 independently selected R A may be substituted with; Each R A independently, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 is cycloalkyl; R 1 , R 2 and R 3 are each independently hydrogen, or independently halo, hydroxy, and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 is alkyl; L 1 -C(O)-, -CH2-, -CH(C 1-6 alkyl)- or -S(O)2-; Ring B is a 5,6-fused heteroaryl having 5 to 8 carbon atoms and 1 to 3 heteroatoms independently selected from O, S, and N, and Ring B is R 8 and independently substituted with halo, oxo, and C 1-6 optionally substituted with 1 to 4 substituents selected from alkyl; R 8 is phenyl, 5- to 6-membered heteroaryl, or [ka] and the phenyl or 5- to 6-membered heteroaryl is R 8cand 1 to 3 independently selected R h may be substituted with; L 3 is a bond or C 1-3 is alkylene; L 4 is a bond or C 1-5 is alkylene; R 8a and R 8b are each independently hydrogen, or independently halo and C 3-15 C optionally substituted with one or more substituents selected from the group consisting of cycloalkyl 1-6 is alkyl; or R 8a and R 8b Each of these, together with the carbon atom to which it is attached, is one to three independently selected C 1-6 C optionally substituted with alkyl 3-15 Forms a cycloalkyl ring, 1-6 Alkyl is 1 to 6 independently selected R f may be substituted with; Each R 8c are independently -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- to 6-membered heterocyclyl, -L 5 -(5- to 6-membered heteroaryl), each of which is independently hydroxy, halo, and C 1-6 optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy; Each L 5 are independently -C(O)-, -C(O)O-, -OC(O)-, -S(O) 1-2 -, -S(O)2O-, -S(O)2NH- or -NHS(O)2-; R 9 is -C(O)OR 9a , -C(O)NR 9a R9b , 1 to 3 independently selected R 9c 5- to 6-membered heteroaryl optionally substituted with [ka] and; X 1 is O or S; R 9a is hydrogen or C 1-6 is alkyl; R 9b is hydrogen, C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -S(O) 0-2 (C 1-6 alkyl) or cyano; Each R 9c are independently selected from hydrogen, oxo, 1 to 6 independently selected halo, and C 1-6 C optionally substituted with alkoxy 1-6 Alkyl, or -C(O)(C 1-6 alkyl); Ring C is a 3- to 12-membered heterocyclyl, C 3-15 cycloalkyl or 5- to 10-membered heteroaryl, each of which is selected from 1 to 3 R Ca may be substituted with; Each R Ca are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c R d and; or a pair of R on the same or different ring atoms Ca each together with the ring atom to which it is attached forms a carbocyclic ring containing 3 to 8 ring atoms; Each R c and R d are each 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), -S(O)1-2 (C 1-6 alkyl) or -S(O) 1-2 (C 3-6 cycloalkyl), and the C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)O(C 1-6 alkyl), -S(O) 1-2 (C 1-6 alkyl) and -S(O) 1-2 (C 3-6 cycloalkyl) are each independently selected from hydroxy, halo, and C 1-6 optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy; R e is hydrogen, C 1-6 Alkyl or C 1-6 is haloalkyl; Each R f are independently halo, hydroxy, -NR c R d , C 1-6 Alkoxy, C 1-6 haloalkoxy, or each independently hydroxy, C 1-6 a 3- to 12-membered heterocyclyl optionally substituted by 1 to 4 substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; Each R g independently, C 1-6 Alkyl, C 1-6 Alkoxy, -NR c R d , or each independently C 1-6 Alkyl and -C(O)C 1-6 alkyl; and Each R h are independently halo, cyano, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 Alkyl)2, C 1-3 Alkoxy or C1-3 It is haloalkoxy.

[0098] In one embodiment, a compound of formula I: [ka] I or a pharmaceutically acceptable salt or solvate thereof, wherein: X is C and Z is N, or X is N and Z is C; Q 1 and Q 5 are each independently N or CR QA and;Q 2 , Q 3 and Q 4 are each independently N, CR QA or CR QB where Q 2 , Q 3 and Q 4 At least one of the following is CR QB is; or Q 1 is a bond;Q 2 , Q 3 , Q 4 and Q 5 are each independently O, S, N, NH, or NR c , C.R. QA or CR QB where Q 2 , Q 3 , Q 4 and Q 5 At least one of the following is CR QB and; However, Q 1 -Q 5 The ring containing is aromatic; R QB is -S(O)(=NR a )R b or -(CR i R j ) n -S(O)(=NR a )R b and; R aare hydrogen, cyano, each independently halo, oxo, C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and heteroaryl 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; R b are each independently C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and halo 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; Or, R a and R b are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, the ring being joined to one or more independently selected C 1-6 optionally substituted with alkyl; n is 1, 2, 3, 4, 5 or 6; Each R i are independently hydrogen, halo, or C 1-6 is alkyl; Or, R a and R i , or R b and R i are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, the ring being joined to one or more independently selected C 1-6 optionally substituted with alkyl; Each R j are independently hydrogen, halo, or C1-6 is alkyl; Each R QA are independently hydrogen, halo, cyano, hydroxy, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e , 1 to 6 independently selected R f C optionally substituted with 1-6 alkyl, each independently hydroxy, halo and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 Alkoxy, each independently C 1-6 Alkyl and -C(O)(C 1-6 alkyl), 3- to 12-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of 1 to 3 independently selected —C(O)(C 1-6 C optionally substituted with alkyl 6-10 aryl, and 1 to 6 independently selected R g is a 5- to 10-membered heteroaryl optionally substituted with Or, two R on adjacent carbon atoms QA are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl ring, which ring is joined by 1 to 2 independently selected R h may be substituted with; Or, R a or R b and adjacent R QA are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl ring, which ring is joined by 1 to 2 independently selected R h may be substituted with; L 2 is one to two independently selected R h C optionally substituted with 6-10 aryl, 1 to 2 independently selected R h 5- to 10-membered heteroaryl optionally substituted by [ka] where aa is Q 1 -Q 5 represents the point of attachment to the ring containing n1 is 1, 2 or 3; L 2A is a bond or C 1-10 is alkylene; R La is hydrogen, C 1-6 Alkyl or -C(O)(C 1-6 alkyl); R Lb and R Lc each independently represents hydrogen or C 1-6 is alkyl; Ring A is C 6-10 Aryl, C 5-7 cycloalkyl, 5- to 7-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is selected from 1 to 5 independently selected R A may be substituted with; Each R A independently, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 is cycloalkyl; R 1 , R 2 and R 3 are each independently hydrogen, or independently halo, hydroxy, and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 is alkyl; L 1 -C(O)-, -CH2-, -CH(C 1-6 alkyl)- or -S(O)2-; Ring B is a 5,6-fused heteroaryl having 5 to 8 carbon atoms and 1 to 3 heteroatoms independently selected from O, S, and N; Ring B is independently selected from halo, oxo, and C 1-6 optionally substituted with 1 to 4 substituents selected from alkyl; bb is L 1 represents the attachment point to; R 4 , R 5 , R 6 and R 7 are each independently hydrogen, halo, or C 1-6 is alkyl; R 8 is phenyl, 5- to 6-membered heteroaryl, or [ka] and the phenyl or 5- to 6-membered heteroaryl is R 8c and 1 to 3 independently selected R h may be substituted with; L 3 is a bond or C 1-3 is alkylene; L 4 is a bond or C 1-5 is alkylene; R 8a and R 8b are each independently hydrogen, or independently halo and C 3-15 C optionally substituted with one or more substituents selected from the group consisting of cycloalkyl 1-6 is alkyl; or R 8a and R 8b Each of these, together with the carbon atom to which it is attached, is one to three independently selected C 1-6 C optionally substituted with alkyl 3-15 Forms a cycloalkyl ring, 1-6 Alkyl is 1 to 6 independently selected R f may be substituted with; Each R 8c are independently -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- to 6-membered heterocyclyl, -L 5-(5- to 6-membered heteroaryl), each of which is independently hydroxy, halo, and C 1-6 optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy; Each L 5 are independently -C(O)-, -C(O)O-, -OC(O)-, -S(O) 1-2 -, -S(O)2O-, -S(O)2NH- or -NHS(O)2-; R 9 is -C(O)OR 9a , -C(O)NR 9a R 9b , 1 to 3 independently selected R 9c 5- to 6-membered heteroaryl optionally substituted with [ka] and; X 1 is O or S; R 9a is hydrogen or C 1-6 is alkyl; R 9b is hydrogen, C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -S(O) 0-2 (C 1-6 alkyl) or cyano; Each R 9c are independently selected from hydrogen, oxo, 1 to 6 independently selected halo, and C 1-6 C optionally substituted with alkoxy 1-6 Alkyl, or -C(O)(C 1-6 alkyl); Ring C is a 3- to 12-membered heterocyclyl, C 3-15 cycloalkyl or 5- to 10-membered heteroaryl, each of which is selected from 1 to 3 R Ca may be substituted with; Each R Ca are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c Rd and; or a pair of R on the same or different ring atoms Ca each together with the ring atom to which it is attached forms a carbocyclic ring containing 3 to 8 ring atoms; Each R c and R d are each 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), -S(O) 1-2 (C 1-6 alkyl) or -S(O) 1-2 (C 3-6 cycloalkyl), and the C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)O(C 1-6 alkyl), -S(O) 1-2 (C 1-6 alkyl) and -S(O) 1-2 (C 3-6 cycloalkyl) are each independently selected from hydroxy, halo, and C 1-6 optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy; R e is hydrogen, C 1-6 Alkyl or C 1-6 is haloalkyl; Each R f are independently halo, hydroxy, -NR c R d , C 1-6 Alkoxy, C 1-6 haloalkoxy, or each independently hydroxy, C 1-6 a 3- to 12-membered heterocyclyl optionally substituted by 1 to 4 substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; Each R g independently, C 1-6 Alkyl, C 1-6 Alkoxy, -NR c R d, or each independently C 1-6 Alkyl and -C(O)C 1-6 alkyl; and Each R h are independently halo, cyano, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 Alkyl)2, C 1-3 Alkoxy or C 1-3 It is haloalkoxy.

[0099] In some embodiments, a compound of Formula II: [ka] II or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein: 1 , Q 2 , Q 3 , Q 4 , Q 5 , L 1 , L 2 , R 1 , R 2 , R 3 and R QB are each independently as defined herein.

[0100] In some embodiments, the compound of formula III: [ka] III or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein: 1 , Q 2 , Q 3 , Q 4 , Q 5 , L 1 , L2 , R 1 , R 2 , R 3 and R QB are each independently as defined herein.

[0101] In some embodiments, Q 1 and Q 5 are each independently N or CR QA and;Q 2 , Q 3 and Q 4 are each independently N, CR QA or CR QB where Q 2 , Q 3 and Q 4 At least one of the following is CR QB is.

[0102] In some embodiments, Q 1 and Q 5 are each independently N or CR QA and;Q 2 and Q 3 are each independently N or CR QA and Q 4 is CR QB In some embodiments, Q 1 and Q 5 are each independently N or CR QA and;Q 2 and Q 4 are each independently N or CR QA and Q 3 is CR QB In some embodiments, Q 1 and Q 5 are each independently N or CR QA and;Q 3 and Q 4 are each independently N or CR QA and Q 2 is CR QB is.

[0103] In some embodiments, Q1 and Q 5 are each independently QA and;Q 2 and Q 3 are each independently N or CR QA and Q 4 is CR QB In some embodiments, Q 1 and Q 5 are each independently QA and;Q 2 and Q 4 are each independently N or CR QA and Q 3 is CR QB In some embodiments, Q 1 and Q 5 are each independently QA and;Q 3 and Q 4 are each independently N or CR QA and Q 2 is CR QB is.

[0104] In some embodiments, the moiety [ka] teeth, [ka] is.

[0105] In some embodiments, each R QA are independently hydrogen, halo, or C 1-6 Alkyl, C 1-6 Alkoxy or -NR c R d is.

[0106] In some embodiments, R c and R d are each independently hydrogen or C 1-6 It is alkyl.

[0107] In some embodiments, Q 1 and Q 5 are each independently QA and each R QA are independently hydrogen or halo.

[0108] In some embodiments, Q 2 , Q 3 and Q 4 One of them is N.

[0109] In some embodiments, Q 2 , Q 3 and Q 4 are each independently QA or CR QB where Q 2 , Q 3 and Q 4 At least one of the following is CR QB is.

[0110] In some embodiments, R QB is -S(O)(=NR a )R b is.

[0111] In some embodiments, R QB is -S(O)(=NR a )R b and;R a are hydrogen, cyano, each independently halo, oxo, C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and heteroaryl 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 aryl; R b are each independently C 1-6 Alkoxy, C 3-6C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and halo 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 It is aryl.

[0112] In some embodiments, R QB is -S(O)(=NR a )R b and;R a and R b are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 3 independently selected C 1-6 It may be substituted with alkyl.

[0113] In some embodiments, R QB is -S(O)(=NR a )R b and;R a or R b and adjacent R QA are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 2 independently selected R h may be substituted with.

[0114] In some embodiments, R QB is -S(O)(=NR a )R b and;R a and adjacent R QA are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 2 independently selected R h may be substituted with.

[0115] In some embodiments, R QB is -S(O)(=NRa )R b and;R b and adjacent R QA are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 2 independently selected R h may be substituted with.

[0116] In some embodiments, R QB is -(CR i R j ) n -S(O)(=NR a )R b is.

[0117] In some embodiments, R QB is -(CR i R j ) n -S(O)(=NR a )R b n is 1, 2, 3, 4, 5 or 6; R a are hydrogen, cyano, each independently halo, oxo, C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and heteroaryl 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 aryl; R b are each independently C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and halo 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3C optionally substituted with alkyl 6-10 It is aryl.

[0118] In some embodiments, R QB is -(CR i R j ) n -S(O)(=NR a )R b and;R a and R b are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 3 independently selected C 1-6 It may be substituted with alkyl.

[0119] In some embodiments, R QB is -(CR i R j ) n -S(O)(=NR a )R b n is 1, 2, 3, 4, 5, or 6; and each R i are independently hydrogen, halo, or C 1-6 alkyl; each R j are independently hydrogen, halo, or C 1-6 It is alkyl.

[0120] In some embodiments, R QB is -(CR i R j ) n -S(O)(=NR a )R b and one R i and one R j together with the atoms to which they are bonded, form C 3-6 Form a cycloalkyl, wherein the cycloalkyl is selected from 1 to 3 independently selected C 1-6 It may be substituted with alkyl.

[0121] In some embodiments, R QB is -(CR i R j ) n-S(O)(=NR a )R b n is 1, 2, 3, 4, 5 or 6; R a and R i , or R b and R i are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 3 independently selected C 1-6 It may be substituted with alkyl.

[0122] In some embodiments, R QB is -(CR i R j ) n -S(O)(=NR a )R b and;R a or R b and adjacent R QA are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 2 independently selected R h may be substituted with.

[0123] In some embodiments, R QB is -(CR i R j ) n -S(O)(=NR a )R b and;R a or R b and adjacent R QA are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 2 independently selected R h and one R on adjacent carbon atoms. i and one R j each taken together with the atom to which it is attached forms an alkene, and the alkene is selected from 1 to 3 independently selected C 1-6 It may be substituted with alkyl.

[0124] In some embodiments, R QB is -(CRi R j ) n -S(O)(=NR a )R b and;R a and adjacent R QA are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 2 independently selected R h may be substituted with.

[0125] In some embodiments, R QB is -(CR i R j ) n -S(O)(=NR a )R b and;R b and adjacent R QA are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 2 independently selected R h may be substituted with.

[0126] In some embodiments, R QB is -N=S(O)(R 1a )R b is.

[0127] In some embodiments, R QB is -N=S(O)(R 1a )R b and;R 1a are each independently C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and halo 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 aryl; R a are hydrogen, cyano, each independently halo, oxo, C1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and heteroaryl 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 It is aryl.

[0128] In some embodiments, R QB is -O-(CR i R j ) n -S(O)(=NR a )R b is.

[0129] In some embodiments, R QB is -O-(CR i R j ) n -S(O)(=NR a )R b n is 1, 2, 3, 4, 5 or 6; R a are hydrogen, cyano, each independently halo, oxo, C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and heteroaryl 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 aryl; R b are each independently C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and halo 1-6 alkyl, each independently C1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 It is aryl.

[0130] In some embodiments, R QB is -O-(CR i R j ) n -S(O)(=NR a )R b and;R a and R b are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 3 independently selected C 1-6 It may be substituted with alkyl.

[0131] In some embodiments, R QB 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 are independently hydrogen, halo, or C 1-6 alkyl; each R j are independently hydrogen, halo, or C 1-6 It is alkyl.

[0132] In some embodiments, R QB is -O-(CR i R j ) n -S(O)(=NR a )R b and one R i and one R j together with the atoms to which they are bonded, form C 3-6 Form a cycloalkyl, wherein the cycloalkyl is selected from 1 to 3 independently selected C 1-6 It may be substituted with alkyl.

[0133] In some embodiments, R QB is -O-(CR i R j ) n -S(O)(=NR a )R b n is 1, 2, 3, 4, 5 or 6; R a and R i , or R b and R i are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 3 independently selected C 1-6 It may be substituted with alkyl.

[0134] In some embodiments, R QB is -O-(CR i R j ) n -S(O)(=NR a )R b and;R a or R b and adjacent R QA are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 2 independently selected R h may be substituted with.

[0135] In some embodiments, R QB is -O-(CR i R j ) n -S(O)(=NR a )R b and;R a and adjacent R QA are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 2 independently selected R h may be substituted with.

[0136] In some embodiments, R QB is -O-(CR i Rj ) n -S(O)(=NR a )R b and;R b and adjacent R QA are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 2 independently selected R h may be substituted with.

[0137] In some embodiments, R QB is -S(O)(=NR a )R b or -C 1-6 Alkyl-S(O)(=NR a )R b is.

[0138] In some embodiments, R QB -C 1-6 Alkyl-S(O)(=NR a )R b is.

[0139] In some embodiments, R QB is -S(O)(=NR a )R b or -CH2-S(O)(=NR a )R b is.

[0140] In some embodiments, R QB is -CH2-S(O)(=NR a )R b is.

[0141] In some embodiments, the moiety [ka] teeth, [ka] In some embodiments, the moiety [ka] teeth, [ka] [ka] is.

[0142] In some embodiments, the moiety [ka] teeth, [ka] In some embodiments, the moiety [ka] teeth, [ka] is.

[0143] In some embodiments, the moiety [ka] teeth, [ka] is.

[0144] In some embodiments, the moiety [ka] teeth, [ka] In some embodiments, the moiety [ka] teeth, [ka] is.

[0145] In some embodiments, the moiety [ka] teeth, [ka] is.

[0146] In some embodiments, the moiety [ka] teeth, [ka] is.

[0147] In some embodiments, the moiety [ka] teeth, [ka] is.

[0148] In some embodiments, R a are hydrogen, cyano, each independently halo, oxo, C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and heteroaryl 1-6 It is alkyl.

[0149] In some embodiments, R b are each independently C 1-6 Alkoxy, C 3-6C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and halo 1-6 Alkyl, or C 3-6 It is cycloalkyl.

[0150] In some embodiments, R a and R b are taken together with the atom to which each is attached to form a 5- to 8-membered heterocyclyl. a and R b are taken together with the atom to which each is attached to form a 5-membered heterocyclyl. [ka] teeth, [ka] is.

[0151] In some embodiments, R a or R b and adjacent R QA are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl ring, which ring is joined by 1 to 2 independently selected R h In some embodiments, the moiety [ka] teeth, [ka] is.

[0152] In some embodiments, R a and R i , or R b and R i are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, the ring being joined to one or more independently selected C 1-6 It may be substituted with alkyl.

[0153] In some embodiments, L 2 is one to two independently selected R h C optionally substituted with 6-10 aryl, 1 to 2 independently selected R h 5- to 10-membered heteroaryl optionally substituted by [ka] where aa is Q 1 -Q 5 represents the point of attachment to the ring containing

[0154] In some embodiments, L 2 is one to two independently selected R h C optionally substituted with 6-10 aryl, [ka] where aa is Q 1 -Q 5 represents the point of attachment to the ring containing

[0155] In some embodiments, L 2 is one to two independently selected R h C optionally substituted with 6-10 It is aryl.

[0156] In some embodiments, L 2 is one to two independently selected R h and optionally substituted 5- to 10-membered heteroaryl.

[0157] In some embodiments, L 2 teeth, [ka] where aa is Q 1 -Q 5In some embodiments, L 2 teeth, [ka] where aa is Q 1 -Q 5 In some embodiments, L 2 teeth, [ka] where aa is Q 1 -Q 5 represents the point of attachment to the ring containing

[0158] In some embodiments, L 2A is a bond.

[0159] In some embodiments, R 1 is hydrogen. In some embodiments, R 2 is hydrogen. In some embodiments, R 1 and R 2 are each hydrogen.

[0160] In some embodiments, R 3 is hydrogen or C 1-6 In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is C 1-6 In some embodiments, R 3 is hydrogen or methyl. In some embodiments, R 3 is methyl. In some embodiments, R 3 is methyl and is attached to the ring to which it is bonded in the (S)-configuration. 3 is hydrogen or methyl, and said methyl is attached to the ring to which it is attached in the (S)-configuration.

[0161] In some embodiments, L 1 is -C(O)-.

[0162] In some embodiments, ring A is selected from 1 to 5 independently selected R A C optionally substituted with 6-10 In some embodiments, ring A is aryl. In some embodiments, ring A is aryl. A C optionally substituted with 5-7 In some embodiments, ring A is cycloalkyl. ... A In some embodiments, ring A is a 5- to 7-membered heterocyclyl optionally substituted with 1 to 5 independently selected R A and optionally substituted 5- to 10-membered heteroaryl.

[0163] In some embodiments, each R A independently, halo, C 1-6 Alkyl, or C 3-6 It is cycloalkyl.

[0164] In some embodiments, ring A is independently halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-6 C optionally substituted with 1 to 5 substituents selected from the group consisting of cycloalkyl 6-10 It is aryl.

[0165] In some embodiments, ring A is independently halo, C 1-6 Alkyl and C 3-6 and phenyl substituted with 2 to 3 substituents selected from the group consisting of cycloalkyl.

[0166] In some embodiments, Ring B is a 5,6-fused heteroaryl having 5 to 8 carbon atoms and 1 to 3 heteroatoms independently selected from O, S, and N, and Ring B is R 8and independently substituted with halo, oxo, and C 1-6 The 5-membered ring of the 5,6-fused heteroaryl may be substituted with 1 to 4 substituents selected from alkyl; 1 In some embodiments, Ring B is a 5,6-fused heteroaryl having 5 to 8 carbon atoms and 1 to 3 heteroatoms independently selected from O, S, and N, and Ring B is linked to R 8 and independently substituted with halo, oxo, and C 1-6 The 5-membered ring of the 5,6-fused heteroaryl may be substituted with 1 to 4 substituents selected from alkyl; 1 and Ring C is attached to the 6-membered ring of the 5,6-fused heteroaryl.

[0167] In some embodiments, Ring B is a 5,6-fused heteroaryl having 5 to 8 carbon atoms and 1 to 3 heteroatoms independently selected from O, S, and N, and Ring B is independently selected from halo, oxo, and C 1-6 and the 5-membered ring of the 5,6-fused heteroaryl is optionally substituted with 1 to 4 substituents selected from L 1 In some embodiments, Ring B is a 5,6-fused heteroaryl having 5 to 8 carbon atoms and 1 to 3 heteroatoms independently selected from O, S, and N, and Ring B is independently selected from halo, oxo, and C 1-6 The 5-membered ring of the 5,6-fused heteroaryl may be substituted with 1 to 4 substituents selected from alkyl; 1 and Ring C is attached to the 6-membered ring of the 5,6-fused heteroaryl.

[0168] In some embodiments, ring B is [ka] wherein: bb is L 1 represents the attachment point to; R 4 , R5 , R 6 and R 7 are each independently hydrogen, halo, or C 1-6 is alkyl; R 8 is phenyl, 5- to 6-membered heteroaryl, or [ka] and the phenyl or 5- to 6-membered heteroaryl is R 8c and 1 to 3 independently selected R h may be substituted with; L 3 is a bond or C 1-3 is alkylene; L 4 is a bond or C 1-5 is alkylene; R 8a and R 8b are each independently hydrogen, or independently halo and C 3-15 C optionally substituted with one or more substituents selected from the group consisting of cycloalkyl 1-6 is alkyl; or R 8a and R 8b Each of these, together with the carbon atom to which it is attached, is one to three independently selected C 1-6 C optionally substituted with alkyl 3-15 Forms a cycloalkyl ring, 1-6 Alkyl is 1 to 6 independently selected R f may be substituted with; Each R 8c are independently -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- to 6-membered heterocyclyl, -L 5 -(5- to 6-membered heteroaryl), each of which is independently hydroxy, halo, and C1-6 optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy; Each L 5 are independently -C(O)-, -C(O)O-, -OC(O)-, -S(O) 1-2 -, -S(O)2O-, -S(O)2NH- or -NHS(O)2-; R 9 is -C(O)OR 9a , -C(O)NR 9a R 9b , 1 to 3 independently selected R 9c 5- to 6-membered heteroaryl optionally substituted with [ka] and; X 1 is O or S; R 9a is hydrogen or C 1-6 is alkyl; R 9b is hydrogen, C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -S(O) 0-2 (C 1-6 alkyl) or cyano; Each R 9c are independently selected from hydrogen, oxo, 1 to 6 independently selected halo, and C 1-6 C optionally substituted with alkoxy 1-6 Alkyl, or -C(O)(C 1-6 alkyl).

[0169] In some embodiments, ring B is [ka] where bb is L 1 Represents the attachment point to

[0170] In some embodiments, ring B is [ka] where bb is L 1 Represents the attachment point to

[0171] In some embodiments, ring B is [ka] where bb is L 1 Represents the attachment point to

[0172] In some embodiments, ring B is [ka] where bb is L 1 Represents the attachment point to

[0173] In some embodiments, ring B is [ka] where bb is L 1 Represents the attachment point to

[0174] In some embodiments, ring B is [ka] where bb is L 1 Represents the attachment point to

[0175] In some embodiments, ring B is [ka] where bb is L 1 Represents the attachment point to

[0176] In some embodiments, ring B is [ka] where bb is L 1 Represents the attachment point to

[0177] In some embodiments, R 8 is R 8c In some embodiments, R 8 is R 8c In some embodiments, R is a substituted 5- to 6-membered heteroaryl. 8 is R 8c In some embodiments, R is substituted pyridyl. 8 is R 8c substituted phenyl, or R 8c It is a substituted pyridyl.

[0178] In some embodiments, R 8 teeth, [ka] is.

[0179] In some embodiments, ring B is [ka] where bb is L 1 Represents the attachment point to

[0180] In some embodiments, ring B is [ka] where bb is L 1 Represents the attachment point to

[0181] In some embodiments, ring B is [ka] where bb is L 1 Represents the attachment point to

[0182] In some embodiments, ring B is [ka] where bb is L 1 Represents the attachment point to

[0183] In some embodiments, ring B is [ka] where bb is L 1 Represents the attachment point to

[0184] In some embodiments, ring B is [ka] where bb is L 1 Represents the attachment point to

[0185] In some embodiments, L 3 is a bond.

[0186] In some embodiments, L 4 is a bond.

[0187] In some embodiments, L 3 is a bond, L 4 is a bond.

[0188] In some embodiments, R 8 is R 8c phenyl substituted with R 8c a 5- to 6-membered heteroaryl substituted with [ka] is.

[0189] In some embodiments, the compound of formula IIA: [ka] 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; 2 , L 2 , R A , R 3 , R QA and R QB are each independently as defined herein.

[0190] In some embodiments, the compound of formula IIB: [ka] IIB 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; 2 , L 2 , R A , R 3 , R QA and R QB are each independently as defined herein.

[0191] In some embodiments, the compound of formula IIA-(S): [ka] IIA-(S) 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; 2 , L 2 , R A , R 3 , R QA and R QB are each independently as defined herein.

[0192] In some embodiments, the compound of formula IIB-(S): [ka] IIB-(S) 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; 2 , L 2 , R A , R 3 , R QA and R QB are each independently as defined herein.

[0193] In some embodiments, ring B is [ka] where bb is L 1 Represents the attachment point to

[0194] In some embodiments, R 4 is hydrogen or halo.

[0195] In some embodiments, R 5 , R 6 and R 7 are each hydrogen.

[0196] In some embodiments, R 8a and R 8b are each independently hydrogen.

[0197] In some embodiments, R 8a and R 8b together with the carbon atoms to which they are attached, form C 1-6 Optionally alkyl-substituted C 3-15 Forms a cycloalkyl ring.

[0198] In some embodiments, R 9 is one to three independently selected R 9c 5- to 6-membered heteroaryl optionally substituted with [ka] In some embodiments, R 9 is one to three independently selected R 9c In some embodiments, R 9 teeth, [ka] is.

[0199] In some embodiments, R 9 is a six-membered heteroaryl.

[0200] In some embodiments, R 9 teeth, [ka] is.

[0201] In some embodiments, ring C is selected from 1 to 3 R Ca In some embodiments, ring C is a 3- to 12-membered heterocyclyl optionally substituted with 1 to 3 R Ca is a 6-membered heterocyclyl optionally substituted by

[0202] In some embodiments, each R Ca is C 1-6 It is alkyl.

[0203] In some embodiments, ring C is [ka] is.

[0204] In some embodiments, ring C is [ka] and part [ka] teeth, [ka] is.

[0205] In some embodiments, ring C is [ka] and part [ka] teeth, [ka] is.

[0206] In some embodiments, the compound of formula IIC: [ka] IIC 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; Z 1 is N or CR 5 and Z 2 is N or CR 6 and Z 3 is N or CR 7 and;R 4 , R 5 , R 6 and R 7 are each independently hydrogen, halo, or C 1-6 alkyl; ring C, R 8a , R 8b , L 4 , R 9 , R A , R 3 , Q 2 , R QA and R QBare each independently as defined herein.

[0207] In some embodiments, the compound of formula IIC-(S): [ka] IIC-(S) 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; Z 1 is N or CR 5 and Z 2 is N or CR 6 and Z 3 is N or CR 7 and;R 4 , R 5 , R 6 and R 7 are each independently hydrogen, halo, or C 1-6 alkyl; ring C, R 8a , R 8b , L 4 , R 9 , R A , R 3 , Q 2 , R QA and R QB are each independently as defined herein.

[0208] In one embodiment, a compound of formula IIC-(S): [ka] IIC-(S) or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein: Q 2 is N or CR QA and; 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 and; R 1a are each independently C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and halo 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; R a are hydrogen, cyano, each independently halo, oxo, C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and heteroaryl 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; R b are each independently C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and halo 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3C optionally substituted with alkyl 6-10 is aryl; Or, R a and R b are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 3 independently selected C 1-6 optionally substituted with alkyl; n is 1, 2, 3, 4, 5 or 6; Each R i are independently hydrogen, halo, or C 1-6 is alkyl; Or, R a and R i , or R b and R i are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 3 independently selected C 1-6 optionally substituted with alkyl; Each R j are independently hydrogen, halo, or C 1-6 is alkyl; Or, one R i and one R j together with the atoms to which they are bonded, form C 3-6 Form a cycloalkyl, wherein the cycloalkyl is selected from 1 to 3 independently selected C 1-6 optionally substituted with alkyl; Each R QA are independently hydrogen, halo, cyano, hydroxy, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e , 1 to 6 independently selected R f C optionally substituted with 1-6 alkyl, each independently hydroxy, halo and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 Alkoxy, each independently C 1-6 Alkyl and -C(O)(C1-6 alkyl), 3- to 12-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of 1 to 3 independently selected —C(O)(C 1-6 C optionally substituted with alkyl 6-10 aryl, and 1 to 6 independently selected R g is a 5- to 10-membered heteroaryl optionally substituted with Or, R a or R b and adjacent R QA are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 2 independently selected R h may be substituted with; q is 0, 1, 2, 3, 4 or 5; Each R A independently, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 is cycloalkyl; R 3 are hydrogen, or independently halo, hydroxy and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 is alkyl; Z 1 is N or CR 5 and; Z 2 is N or CR 6 and; Z 3 is N or CR 7 and; R 4 , R 5 , R 6 and R 7 are each independently hydrogen, halo, or C 1-6 is alkyl; L 4 is a bond or C 1-5 is alkylene; R 8a and R 8bare each independently hydrogen, or independently halo and C 3-15 C optionally substituted with one or more substituents selected from the group consisting of cycloalkyl 1-6 is alkyl; or R 8a and R 8b Each of these, together with the carbon atom to which it is attached, is one to three independently selected C 1-6 C optionally substituted with alkyl 3-15 Forms a cycloalkyl ring, 1-6 Alkyl is 1 to 6 independently selected R f may be substituted with; R 9 is -C(O)OR 9a , -C(O)NR 9a R 9b , 1 to 3 independently selected R 9c 5-6 membered heteroaryl optionally substituted with 1 to 3 independently selected R 9c 4- to 6-membered heterocyclyl optionally substituted by [ka] and; X 1 is O or S; R 9a is hydrogen or C 1-6 is alkyl; R 9b is hydrogen, C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -S(O) 0-2 (C 1-6 alkyl) or cyano; Each R 9c are independently selected from hydrogen, oxo, 1 to 6 independently selected halo, and C 1-6 C optionally substituted with alkoxy 1-6 Alkyl, or -C(O)(C 1-6 alkyl); Ring C is a 3- to 12-membered heterocyclyl, C 3-15cycloalkyl or 5- to 10-membered heteroaryl, each of which is selected from 1 to 3 R Ca may be substituted with; Each R Ca are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c R d and; or a pair of R on the same or different ring atoms Ca each together with the ring atom to which it is attached forms a carbocyclic ring containing 3 to 8 ring atoms; Each R c and R d are each 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), -S(O) 1-2 (C 1-6 alkyl) or -S(O) 1-2 (C 3-6 cycloalkyl), and the C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)O(C 1-6 alkyl), -S(O) 1-2 (C 1-6 alkyl) and -S(O) 1-2 (C 3-6 cycloalkyl) are each independently selected from hydroxy, halo, and C 1-6 optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy; Each R e are independently hydrogen, C 1-6 Alkyl or C 1-6 is haloalkyl; Each R f are independently halo, hydroxy, -NR c R d , C 1-6 Alkoxy, C 1-6 haloalkoxy, or each independently hydroxy, C1-6 a 3- to 12-membered heterocyclyl optionally substituted by 1 to 4 substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; Each R g independently, C 1-6 Alkyl, C 1-6 Alkoxy, -NR c R d , or each independently C 1-6 Alkyl and -C(O)C 1-6 alkyl; and Each R h are independently halo, cyano, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 Alkyl)2, C 1-3 Alkoxy or C 1-3 It is haloalkoxy.

[0209] In one embodiment, a compound of formula IIC-(S): [ka] IIC-(S) or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein: Q 2 is N or CR QA and; R QB is -S(O)(=NR a )R b or -(CR i R j ) n -S(O)(=NR a )R b and; R a are hydrogen, cyano, each independently halo, oxo, C 1-6 Alkoxy, C 3-6C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and heteroaryl 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; R b are each independently C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and halo 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; Or, R a and R b are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 3 independently selected C 1-6 optionally substituted with alkyl; n is 1, 2, 3, 4, 5 or 6; Each R i are independently hydrogen, halo, or C 1-6 is alkyl; Or, R a and R i , or R b and R i are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 3 independently selected C 1-6 optionally substituted with alkyl; Each R j are independently hydrogen, halo, or C 1-6 is alkyl; Or, one Ri and one R j together with the atoms to which they are bonded, form C 3-6 Form a cycloalkyl, wherein the cycloalkyl is selected from 1 to 3 independently selected C 1-6 optionally substituted with alkyl; Each R QA are independently hydrogen, halo, cyano, hydroxy, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e , 1 to 6 independently selected R f C optionally substituted with 1-6 alkyl, each independently hydroxy, halo and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 Alkoxy, each independently C 1-6 Alkyl and -C(O)(C 1-6 alkyl), 3- to 12-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of 1 to 3 independently selected —C(O)(C 1-6 C optionally substituted with alkyl 6-10 aryl, and 1 to 6 independently selected R g is a 5- to 10-membered heteroaryl optionally substituted with Or, R a or R b and adjacent R QA are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 2 independently selected R h may be substituted with; q is 0, 1, 2, 3, 4 or 5; Each R A independently, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 is cycloalkyl; R 3are hydrogen, or independently halo, hydroxy and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 is alkyl; Z 1 is N or CR 5 and; Z 2 is N or CR 6 and; Z 3 is N or CR 7 and; R 4 , R 5 , R 6 and R 7 are each independently hydrogen, halo, or C 1-6 is alkyl; L 4 is a bond or C 1-5 is alkylene; R 8a and R 8b are each independently hydrogen, or independently halo and C 3-15 C optionally substituted with one or more substituents selected from the group consisting of cycloalkyl 1-6 is alkyl; or R 8a and R 8b Each of these, together with the carbon atom to which it is attached, is one to three independently selected C 1-6 C optionally substituted with alkyl 3-15 Forms a cycloalkyl ring, 1-6 Alkyl is 1 to 6 independently selected R f may be substituted with; R 9 is -C(O)OR 9a , -C(O)NR 9a R 9b , 1 to 3 independently selected R 9c 5-6 membered heteroaryl optionally substituted with 1 to 3 independently selected R 9c 4- to 6-membered heterocyclyl optionally substituted by [ka] and; X 1 is O or S; R 9a is hydrogen or C 1-6 is alkyl; R 9b is hydrogen, C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -S(O) 0-2 (C 1-6 alkyl) or cyano; Each R 9c are independently selected from hydrogen, oxo, 1 to 6 independently selected halo, and C 1-6 C optionally substituted with alkoxy 1-6 Alkyl, or -C(O)(C 1-6 alkyl); Ring C is a 3- to 12-membered heterocyclyl, C 3-15 cycloalkyl or 5- to 10-membered heteroaryl, each of which is selected from 1 to 3 R Ca may be substituted with; Each R Ca are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c R d and; or a pair of R on the same or different ring atoms Ca each together with the ring atom to which it is attached forms a carbocyclic ring containing 3 to 8 ring atoms; Each R c and R d are each 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), -S(O) 1-2 (C 1-6 alkyl) or -S(O) 1-2 (C 3-6 cycloalkyl), and the C 1-6 Alkyl, -C(O)(C 1-6alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)O(C 1-6 alkyl), -S(O) 1-2 (C 1-6 alkyl) and -S(O) 1-2 (C 3-6 cycloalkyl) are each independently selected from hydroxy, halo, and C 1-6 optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy; Each R e are independently hydrogen, C 1-6 Alkyl or C 1-6 is haloalkyl; Each R f are independently halo, hydroxy, -NR c R d , C 1-6 Alkoxy, C 1-6 haloalkoxy, or each independently hydroxy, C 1-6 a 3- to 12-membered heterocyclyl optionally substituted by 1 to 4 substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; Each R g independently, C 1-6 Alkyl, C 1-6 Alkoxy, -NR c R d , or each independently C 1-6 Alkyl and -C(O)C 1-6 alkyl; and Each R h are independently halo, cyano, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 Alkyl)2, C 1-3 Alkoxy or C 1-3 It is haloalkoxy.

[0210] In some embodiments, R 4 is hydrogen. In some embodiments, R4 , R 5 , R 6 , and R 7 are each hydrogen.

[0211] In some embodiments, Z 1 is CH. In some embodiments, Z 1 is N.

[0212] In some embodiments, Z 2 is CH. In some embodiments, Z 2 is N.

[0213] In some embodiments, Z 3 is CH. In some embodiments, Z 3 is N.

[0214] In some embodiments, Z 1 , Z 2 and Z 3 One of the groups is N or CH, and Z 1 , Z 2 and Z 3 The other two of Z are CH. 1 , Z 2 and Z 3 One of them is N and the other is Z. 1 , Z 2 and Z 3 The other two of Z are CH. 1 , Z 2 and Z 3 are CH, respectively.

[0215] In some embodiments, R 4 is hydrogen; Z 1 , Z 2 and Z 3 One of the groups is N or CH, and Z 1 , Z 2 and Z 3 The other two of R are CH. 4is hydrogen; Z 1 , Z 2 and Z 3 One of them is N and the other is Z. 1 , Z 2 and Z 3 The other two of R are CH. 4 is hydrogen; Z 1 , Z 2 and Z 3 are CH, respectively.

[0216] In some embodiments, R QB is -S(O)(=NR a )R b is.

[0217] In some embodiments, the compound of formula IID: [ka] IID 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; 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 are each independently as defined herein.

[0218] In some embodiments, the compound of formula IID-(S): [ka] IID-(S) 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; v is 0, 1, 2, or 3; and Ra , R b , R Ca , R 8a , R 8b , R 9 , R A , R 3 , Q 2 and R QA are each independently as defined herein.

[0219] In one embodiment, a compound of formula IID-(S): [ka] IID-(S) or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein: Q 2 is N or CR QA and; R a are hydrogen, cyano, each independently halo, oxo, C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and heteroaryl 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; R b are each independently C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and halo 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl6-10 is aryl; Or, R a and R b are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 3 independently selected C 1-6 optionally substituted with alkyl; Each R QA are independently hydrogen, halo, cyano, hydroxy, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e , 1 to 6 independently selected R f C optionally substituted with 1-6 alkyl, each independently hydroxy, halo and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 Alkoxy, each independently C 1-6 Alkyl and -C(O)(C 1-6 alkyl), 3- to 12-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of 1 to 3 independently selected —C(O)(C 1-6 C optionally substituted with alkyl 6-10 aryl, and 1 to 6 independently selected R g is a 5- to 10-membered heteroaryl optionally substituted with Or, R a or R b and adjacent R QA are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 2 independently selected R h may be substituted with; q is 0, 1, 2, 3, 4 or 5; Each R A independently, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 is cycloalkyl; R3 are hydrogen, or independently halo, hydroxy and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 is alkyl; R 8a and R 8b are each independently hydrogen, or independently halo and C 3-15 C optionally substituted with one or more substituents selected from the group consisting of cycloalkyl 1-6 is alkyl; or R 8a and R 8b Each of these, together with the carbon atom to which it is attached, is one to three independently selected C 1-6 C optionally substituted with alkyl 3-15 Forms a cycloalkyl ring, 1-6 Alkyl is 1 to 6 independently selected R f may be substituted with; R 9 is -C(O)OR 9a , -C(O)NR 9a R 9b , 1 to 3 independently selected R 9c 5-6 membered heteroaryl optionally substituted with 1 to 3 independently selected R 9c 4- to 6-membered heterocyclyl optionally substituted by [ka] and; X 1 is O or S; R 9a is hydrogen or C 1-6 is alkyl; R 9b is hydrogen, C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -S(O) 0-2 (C 1-6 alkyl) or cyano; Each R 9c are independently selected from hydrogen, oxo, 1 to 6 independently selected halo, and C 1-6C optionally substituted with alkoxy 1-6 Alkyl, or -C(O)(C 1-6 alkyl); v is 0, 1, 2 or 3; Each R Ca are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c R d and; or a pair of R on the same or different ring atoms Ca each together with the ring atom to which it is attached forms a carbocyclic ring containing 3 to 8 ring atoms; Each R c and R d are each 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), -S(O) 1-2 (C 1-6 alkyl) or -S(O) 1-2 (C 3-6 cycloalkyl), and the C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)O(C 1-6 alkyl), -S(O) 1-2 (C 1-6 alkyl) and -S(O) 1-2 (C 3-6 cycloalkyl) are each independently selected from hydroxy, halo, and C 1-6 optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy; Each R e are independently hydrogen, C 1-6 Alkyl or C 1-6 is haloalkyl; Each R f are independently halo, hydroxy, -NR c R d , C 1-6 Alkoxy, C1-6 haloalkoxy, or each independently hydroxy, C 1-6 a 3- to 12-membered heterocyclyl optionally substituted by 1 to 4 substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; Each R g independently, C 1-6 Alkyl, C 1-6 Alkoxy, -NR c R d , or each independently C 1-6 Alkyl and -C(O)C 1-6 alkyl; and Each R h are independently halo, cyano, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 Alkyl)2, C 1-3 Alkoxy or C 1-3 It is haloalkoxy.

[0220] In some embodiments, the compound of formula IIE: [ka] NO 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; v is 0, 1, 2, or 3; w is 0, 1, 2, or 3; and each R 1f independently, C 1-6 alkyl, and each C 1-6 Alkyl is independently 1 to 6 independently selected R f may be substituted with R a , R b , R Ca , R 9 , R A , R 3 , Q 2 and R QAare each independently as defined herein.

[0221] In some embodiments, the compound of formula IIE-(S): [ka] IIE-(S) 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; v is 0, 1, 2, or 3; w is 0, 1, 2, or 3; 1f independently, C 1-6 alkyl, and each C 1-6 Alkyl is independently 1 to 6 independently selected R f may be substituted with R a , R b , R Ca , R 9 , R A , R 3 , Q 2 and R QA are each independently as defined herein.

[0222] In one embodiment, a compound of formula IIE-(S): [ka] IIE-(S) or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein: Q 2 is N or CR QA and; R a are hydrogen, cyano, each independently halo, oxo, C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and heteroaryl 1-6 alkyl, each independently C 1-3C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; R b are each independently C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and halo 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; Or, R a and R b are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 3 independently selected C 1-6 optionally substituted with alkyl; Each R QA are independently hydrogen, halo, cyano, hydroxy, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e , 1 to 6 independently selected R f C optionally substituted with 1-6 alkyl, each independently hydroxy, halo and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 Alkoxy, each independently C 1-6 Alkyl and -C(O)(C 1-6 alkyl), 3- to 12-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of 1 to 3 independently selected —C(O)(C 1-6 C optionally substituted with alkyl6-10 aryl, and 1 to 6 independently selected R g is a 5- to 10-membered heteroaryl optionally substituted with Or, R a or R b and adjacent R QA are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 2 independently selected R h may be substituted with; q is 0, 1, 2, 3, 4 or 5; Each R A independently, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 is cycloalkyl; R 3 are hydrogen, or independently halo, hydroxy and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 is alkyl; R 9 is -C(O)OR 9a , -C(O)NR 9a R 9b , 1 to 3 independently selected R 9c 5-6 membered heteroaryl optionally substituted with 1 to 3 independently selected R 9c 4- to 6-membered heterocyclyl optionally substituted by [ka] and; X 1 is O or S; R 9a is hydrogen or C 1-6 is alkyl; R 9b is hydrogen, C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -S(O) 0-2 (C 1-6 alkyl) or cyano; Each R 9c are independently selected from hydrogen, oxo, 1 to 6 independently selected halo, and C 1-6 C optionally substituted with alkoxy 1-6 Alkyl, or -C(O)(C 1-6 alkyl); v is 0, 1, 2 or 3; Each R Ca are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c R d and; or a pair of R on the same or different ring atoms Ca each together with the ring atom to which it is attached forms a carbocyclic ring containing 3 to 8 ring atoms; Each R c and R d are each 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), -S(O) 1-2 (C 1-6 alkyl) or -S(O) 1-2 (C 3-6 cycloalkyl), and the C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)O(C 1-6 alkyl), -S(O) 1-2 (C 1-6 alkyl) and -S(O) 1-2 (C 3-6 cycloalkyl) are each independently selected from hydroxy, halo, and C 1-6 optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy; Each R e are independently hydrogen, C 1-6 Alkyl or C 1-6 is haloalkyl; w is 0, 1, 2 or 3; Each R 1f independently, C 1-6 alkyl, and each C 1-6 Alkyl is independently 1 to 6 independently selected R f may be substituted with; Each R f are independently halo, hydroxy, -NR c R d , C 1-6 Alkoxy, C 1-6 haloalkoxy, or each independently hydroxy, C 1-6 a 3- to 12-membered heterocyclyl optionally substituted by 1 to 4 substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; Each R g independently, C 1-6 Alkyl, C 1-6 Alkoxy, -NR c R d , or each independently C 1-6 Alkyl and -C(O)C 1-6 alkyl; and Each R h are independently halo, cyano, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 Alkyl)2, C 1-3 Alkoxy or C 1-3 It is haloalkoxy.

[0223] In some embodiments, R QB is -(CR i R j ) n -S(O)(=NR a )R b In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2.

[0224] In some embodiments, Ra and adjacent R QA are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 2 independently selected R h may be substituted with.

[0225] In some embodiments, the compound of formula IIF: [ka] IIF or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein Y is -(CR i R j ) n -; q is 0, 1, 2, 3, 4 or 5; v is 0, 1, 2 or 3; n, R b , R i , R j , R Ca , R 8a , R 8b , R 9 , R A , R 3 , Q 2 and R QA are each independently as defined herein.

[0226] In some embodiments, the compound of formula IIF-(S): [ka] IIF-(S) or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein Y is -(CR i R j ) n -; q is 0, 1, 2, 3, 4 or 5; v is 0, 1, 2 or 3; n, R b , R i , R j , R Ca , R 8a , R 8b , R9 , R A , R 3 , Q 2 and R QA are each independently as defined herein.

[0227] In one embodiment, a compound of formula IIF-(S): [ka] IIF-(S) or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein: Q 2 is N or CR QA and; Y is -(CR i R j ) n - and; R b are each independently C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and halo 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; n is 1, 2, 3, 4, 5 or 6; Each R i are independently hydrogen, halo, or C 1-6 is alkyl; Each R j are independently hydrogen, halo, or C 1-6 is alkyl; Or, one R on an adjacent carbon atom i and one R j each taken together with the atom to which it is attached forms an alkene, and the alkene is selected from 1 to 3 independently selected C 1-6optionally substituted with alkyl; Each R QA are independently hydrogen, halo, cyano, hydroxy, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e , 1 to 6 independently selected R f C optionally substituted with 1-6 alkyl, each independently hydroxy, halo and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 Alkoxy, each independently C 1-6 Alkyl and -C(O)(C 1-6 alkyl), 3- to 12-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of 1 to 3 independently selected —C(O)(C 1-6 C optionally substituted with alkyl 6-10 aryl, and 1 to 6 independently selected R g is a 5- to 10-membered heteroaryl optionally substituted with q is 0, 1, 2, 3, 4 or 5; Each R A independently, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 is cycloalkyl; R 3 are hydrogen, or independently halo, hydroxy and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 is alkyl; R 8a and R 8b are each independently hydrogen, or independently halo and C 3-15 C optionally substituted with one or more substituents selected from the group consisting of cycloalkyl 1-6 is alkyl; or R 8a and R 8bEach of these, together with the carbon atom to which it is attached, is one to three independently selected C 1-6 C optionally substituted with alkyl 3-15 Forms a cycloalkyl ring, 1-6 Alkyl is 1 to 6 independently selected R f may be substituted with; R 9 is -C(O)OR 9a , -C(O)NR 9a R 9b , 1 to 3 independently selected R 9c 5-6 membered heteroaryl optionally substituted with 1 to 3 independently selected R 9c 4- to 6-membered heterocyclyl optionally substituted by [ka] and; X 1 is O or S; R 9a is hydrogen or C 1-6 is alkyl; R 9b is hydrogen, C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -S(O) 0-2 (C 1-6 alkyl) or cyano; Each R 9c are independently selected from hydrogen, oxo, 1 to 6 independently selected halo, and C 1-6 C optionally substituted with alkoxy 1-6 Alkyl, or -C(O)(C 1-6 alkyl); v is 0, 1, 2 or 3; Each R Ca are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c R d and; or a pair of R on the same or different ring atoms Caeach together with the ring atom to which it is attached forms a carbocyclic ring containing 3 to 8 ring atoms; Each R c and R d are each 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), -S(O) 1-2 (C 1-6 alkyl) or -S(O) 1-2 (C 3-6 cycloalkyl), and the C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)O(C 1-6 alkyl), -S(O) 1-2 (C 1-6 alkyl) and -S(O) 1-2 (C 3-6 cycloalkyl) are each independently selected from hydroxy, halo, and C 1-6 optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy; Each R e are independently hydrogen, C 1-6 Alkyl or C 1-6 is haloalkyl; Each R f are independently halo, hydroxy, -NR c R d , C 1-6 Alkoxy, C 1-6 haloalkoxy, or each independently hydroxy, C 1-6 a 3- to 12-membered heterocyclyl optionally substituted by 1 to 4 substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; Each R g independently, C 1-6 Alkyl, C 1-6 Alkoxy, -NR c R d , or each independently C 1-6 Alkyl and -C(O)C 1-6alkyl; and Each R h are independently halo, cyano, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 Alkyl)2, C 1-3 Alkoxy or C 1-3 It is haloalkoxy.

[0228] In some embodiments, the compound of formula IIG: [ka] IIG or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, 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; and each R 1f independently, C 1-6 alkyl, and each C 1-6 Alkyl is independently 1 to 6 independently selected R f n, R b , R i , R j , R Ca , R 9 , R A , R 3 , Q 2 and R QA are each independently as defined herein.

[0229] In some embodiments, the compound of formula IIG-(S): [ka] IIG-(S) or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, 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; and each R 1f independently, C 1-6 alkyl, and each C 1-6 Alkyl is independently 1 to 6 independently selected R f n, R b , R i , R j , R Ca , R 9 , R A , R 3 , Q 2 and R QA are each independently as defined herein.

[0230] In one embodiment, a compound of formula IIG-(S): [ka] IIG-(S) or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein: Q 2 is N or CR QA and; Y is -(CR i R j ) n - and; R b are each independently C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and halo 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C1-3 C optionally substituted with alkyl 6-10 is aryl; n is 1, 2, 3, 4, 5 or 6; Each R i are independently hydrogen, halo, or C 1-6 is alkyl; Each R j are independently hydrogen, halo, or C 1-6 is alkyl; Or, one R on an adjacent carbon atom i and one R j each taken together with the atom to which it is attached forms an alkene, and the alkene is selected from 1 to 3 independently selected C 1-6 optionally substituted with alkyl; Each R QA are independently hydrogen, halo, cyano, hydroxy, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e , 1 to 6 independently selected R f C optionally substituted with 1-6 alkyl, each independently hydroxy, halo and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 Alkoxy, each independently C 1-6 Alkyl and -C(O)(C 1-6 alkyl), 3- to 12-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of 1 to 3 independently selected —C(O)(C 1-6 C optionally substituted with alkyl 6-10 aryl, and 1 to 6 independently selected R g is a 5- to 10-membered heteroaryl optionally substituted with q is 0, 1, 2, 3, 4 or 5; Each R A independently, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6Alkoxy or C 3-6 is cycloalkyl; R 3 are hydrogen, or independently halo, hydroxy and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 is alkyl; R 9 is -C(O)OR 9a , -C(O)NR 9a R 9b , 1 to 3 independently selected R 9c 5-6 membered heteroaryl optionally substituted with 1 to 3 independently selected R 9c 4- to 6-membered heterocyclyl optionally substituted by [ka] and; X 1 is O or S; R 9a is hydrogen or C 1-6 is alkyl; R 9b is hydrogen, C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -S(O) 0-2 (C 1-6 alkyl) or cyano; Each R 9c are independently selected from hydrogen, oxo, 1 to 6 independently selected halo, and C 1-6 C optionally substituted with alkoxy 1-6 Alkyl, or -C(O)(C 1-6 alkyl); v is 0, 1, 2 or 3; Each R Ca are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c R d and; or a pair of R on the same or different ring atoms Caeach together with the ring atom to which it is attached forms a carbocyclic ring containing 3 to 8 ring atoms; Each R c and R d are each 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), -S(O) 1-2 (C 1-6 alkyl) or -S(O) 1-2 (C 3-6 cycloalkyl), and the C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)O(C 1-6 alkyl), -S(O) 1-2 (C 1-6 alkyl) and -S(O) 1-2 (C 3-6 cycloalkyl) are each independently selected from hydroxy, halo, and C 1-6 optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy; Each R e are independently hydrogen, C 1-6 Alkyl or C 1-6 is haloalkyl; w is 0, 1, 2 or 3; Each R 1f independently, C 1-6 alkyl, and each C 1-6 Alkyl is independently 1 to 6 independently selected R f may be substituted with; Each R f are independently halo, hydroxy, -NR c R d , C 1-6 Alkoxy, C 1-6 haloalkoxy, or each independently hydroxy, C 1-6 a 3- to 12-membered heterocyclyl optionally substituted by 1 to 4 substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; Each Rg independently, C 1-6 Alkyl, C 1-6 Alkoxy, -NR c R d , or each independently C 1-6 Alkyl and -C(O)C 1-6 alkyl; and Each R h are independently halo, cyano, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 Alkyl)2, C 1-3 Alkoxy or C 1-3 It is haloalkoxy.

[0231] In some embodiments, the compound of formula IIH: [ka] IIH or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein Y 1 is C 1-3 alkylene or C2 alkenylene, 1-3 Alkylene or C2 alkenylene is one to two independently selected R h q is 0, 1, 2, 3, 4, or 5; v is 0, 1, 2, or 3; R b , R Ca , R 8a , R 8b , R 9 , R A , R 3 , Q 2 and R QA are each independently as defined herein.

[0232] In some embodiments, the compound of formula IIH-(S): [ka] IIH-(S) or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein Y 1 is C 1-3 alkylene or C2 alkenylene, 1-3 Alkylene or C2 alkenylene is one to two independently selected R h q is 0, 1, 2, 3, 4, or 5; v is 0, 1, 2, or 3; R b , R Ca , R 8a , R 8b , R 9 , R A , R 3 , Q 2 and R QA are each independently as defined herein.

[0233] In one embodiment, a compound of formula IIH-(S): [ka] IIH-(S) or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein: Q 2 is N or CR QA and; Y 1 is C 1-3 alkylene or C2 alkenylene, 1-3 Alkylene or C2 alkenylene is one to two independently selected R h may be substituted with; R b are each independently C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and halo 1-6 alkyl, each independently C 1-3C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; Each R QA are independently hydrogen, halo, cyano, hydroxy, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e , 1 to 6 independently selected R f C optionally substituted with 1-6 alkyl, each independently hydroxy, halo and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 Alkoxy, each independently C 1-6 Alkyl and -C(O)(C 1-6 alkyl), 3- to 12-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of 1 to 3 independently selected —C(O)(C 1-6 C optionally substituted with alkyl 6-10 aryl, and 1 to 6 independently selected R g is a 5- to 10-membered heteroaryl optionally substituted with q is 0, 1, 2, 3, 4 or 5; Each R A independently, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 is cycloalkyl; R 3 are hydrogen, or independently halo, hydroxy and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 is alkyl; R 8a and R 8b are each independently hydrogen, or independently halo and C3-15 C optionally substituted with one or more substituents selected from the group consisting of cycloalkyl 1-6 is alkyl; or R 8a and R 8b Each of these, together with the carbon atom to which it is attached, is one to three independently selected C 1-6 C optionally substituted with alkyl 3-15 Forms a cycloalkyl ring, 1-6 Alkyl is 1 to 6 independently selected R f may be substituted with; R 9 is -C(O)OR 9a , -C(O)NR 9a R 9b , 1 to 3 independently selected R 9c 5-6 membered heteroaryl optionally substituted with 1 to 3 independently selected R 9c 4- to 6-membered heterocyclyl optionally substituted by [ka] and; X 1 is O or S; R 9a is hydrogen or C 1-6 is alkyl; R 9b is hydrogen, C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -S(O) 0-2 (C 1-6 alkyl) or cyano; Each R 9c are independently selected from hydrogen, oxo, 1 to 6 independently selected halo, and C 1-6 C optionally substituted with alkoxy 1-6 Alkyl, or -C(O)(C 1-6 alkyl); v is 0, 1, 2 or 3; Each R Ca are independently halo, cyano, C 1-6 Alkyl, C 1-6Haloalkyl, C 1-6 Alkoxy or NR c R d and; or a pair of R on the same or different ring atoms Ca each together with the ring atom to which it is attached forms a carbocyclic ring containing 3 to 8 ring atoms; Each R c and R d are each 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), -S(O) 1-2 (C 1-6 alkyl) or -S(O) 1-2 (C 3-6 cycloalkyl), and the C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)O(C 1-6 alkyl), -S(O) 1-2 (C 1-6 alkyl) and -S(O) 1-2 (C 3-6 cycloalkyl) are each independently selected from hydroxy, halo, and C 1-6 optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy; Each R e are independently hydrogen, C 1-6 Alkyl or C 1-6 is haloalkyl; Each R f are independently halo, hydroxy, -NR c R d , C 1-6 Alkoxy, C 1-6 haloalkoxy, or each independently hydroxy, C 1-6 a 3- to 12-membered heterocyclyl optionally substituted by 1 to 4 substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; Each R g independently, C 1-6 Alkyl, C1-6 Alkoxy, -NR c R d , or each independently C 1-6 Alkyl and -C(O)C 1-6 alkyl; and Each R h are independently halo, cyano, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 Alkyl)2, C 1-3 Alkoxy or C 1-3 It is haloalkoxy.

[0234] In some embodiments, the compound of formula IIJ: [ka] IIJ or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein Y 1 is C 1-3 alkylene or C2 alkenylene, 1-3 Alkylene or C2 alkenylene is one to two independently selected R h q is 0, 1, 2, 3, 4, or 5; w is 0, 1, 2, or 3; v is 0, 1, 2, or 3; and each R 1f independently, C 1-6 alkyl, and each C 1-6 Alkyl is independently 1 to 6 independently selected R f may be substituted with R b , R Ca , R 9 , R A , R 3 , Q 2 and R QA are each independently as defined herein.

[0235] In some embodiments, the compound of formula IIJ-(S): [ka] IIJ-(S) or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein Y 1 is C 1-3 alkylene or C2 alkenylene, 1-3 Alkylene or C2 alkenylene is one to two independently selected R h q is 0, 1, 2, 3, 4, or 5; w is 0, 1, 2, or 3; v is 0, 1, 2, or 3; and each R 1f independently, C 1-6 alkyl, and each C 1-6 Alkyl is independently 1 to 6 independently selected R f may be substituted with R b , R Ca , R 9 , R A , R 3 , Q 2 and R QA are each independently as defined herein.

[0236] In one embodiment, a compound of formula IIJ-(S): [ka] IIJ-(S) or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein: Q 2 is N or CR QA and; Y 1 is C 1-3 alkylene or C2 alkenylene, 1-3 Alkylene or C2 alkenylene is one to two independently selected R h may be substituted with; Rb are each independently C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and halo 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; n is 1, 2, 3, 4, 5 or 6; Each R i are independently hydrogen, halo, or C 1-6 is alkyl; Each R j are independently hydrogen, halo, or C 1-6 is alkyl; Or, one R on an adjacent carbon atom i and one R j each taken together with the atom to which it is attached forms an alkene, and the alkene is selected from 1 to 3 independently selected C 1-6 optionally substituted with alkyl; Each R QA are independently hydrogen, halo, cyano, hydroxy, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e , 1 to 6 independently selected R f C optionally substituted with 1-6 alkyl, each independently hydroxy, halo and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 Alkoxy, each independently C 1-6 Alkyl and -C(O)(C 1-6 alkyl), 3- to 12-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of 1 to 3 independently selected —C(O)(C 1-6C optionally substituted with alkyl 6-10 aryl, and 1 to 6 independently selected R g is a 5- to 10-membered heteroaryl optionally substituted with q is 0, 1, 2, 3, 4 or 5; Each R A independently, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 is cycloalkyl; R 3 are hydrogen, or independently halo, hydroxy and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 is alkyl; R 9 is -C(O)OR 9a , -C(O)NR 9a R 9b , 1 to 3 independently selected R 9c 5-6 membered heteroaryl optionally substituted with 1 to 3 independently selected R 9c 4- to 6-membered heterocyclyl optionally substituted by [ka] and; X 1 is O or S; R 9a is hydrogen or C 1-6 is alkyl; R 9b is hydrogen, C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -S(O) 0-2 (C 1-6 alkyl) or cyano; Each R 9c are independently selected from hydrogen, oxo, 1 to 6 independently selected halo, and C 1-6 C optionally substituted with alkoxy 1-6 Alkyl, or -C(O)(C 1-6 alkyl); v is 0, 1, 2 or 3; Each R Ca are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c R d and; or a pair of R on the same or different ring atoms Ca each together with the ring atom to which it is attached forms a carbocyclic ring containing 3 to 8 ring atoms; Each R c and R d are each 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), -S(O) 1-2 (C 1-6 alkyl) or -S(O) 1-2 (C 3-6 cycloalkyl), and the C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)O(C 1-6 alkyl), -S(O) 1-2 (C 1-6 alkyl) and -S(O) 1-2 (C 3-6 cycloalkyl) are each independently selected from hydroxy, halo, and C 1-6 optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy; Each R e are independently hydrogen, C 1-6 Alkyl or C 1-6 is haloalkyl; w is 0, 1, 2 or 3; Each R 1f independently, C 1-6 alkyl, and each C 1-6 Alkyl is independently 1 to 6 independently selected R f may be substituted with; Each Rf are independently halo, hydroxy, -NR c R d , C 1-6 Alkoxy, C 1-6 haloalkoxy, or each independently hydroxy, C 1-6 a 3- to 12-membered heterocyclyl optionally substituted by 1 to 4 substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; Each R g independently, C 1-6 Alkyl, C 1-6 Alkoxy, -NR c R d , or each independently C 1-6 Alkyl and -C(O)C 1-6 alkyl; and Each R h are independently halo, cyano, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 Alkyl)2, C 1-3 Alkoxy or C 1-3 It is haloalkoxy.

[0237] In some embodiments, R QB is -O-(CR i R j ) n -S(O)(=NR a )R b In some embodiments, n is 3. In some embodiments, R b and R i are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 3 independently selected C 1-6 It may be substituted with alkyl.

[0238] In some embodiments, the compound of formula IIK: [ka] IIK 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; 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 are each independently as defined herein.

[0239] In some embodiments, the compound of formula IIK-(S): [ka] IIK-(S) 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; 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 are each independently as defined herein.

[0240] In one embodiment, a compound of formula IIF-(S): [ka] IIK-(S) or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein: Q 2 is N or CR QA and; R aare hydrogen, cyano, each independently halo, oxo, C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and heteroaryl 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; Each R QA are independently hydrogen, halo, cyano, hydroxy, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e , 1 to 6 independently selected R f C optionally substituted with 1-6 alkyl, each independently hydroxy, halo and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 Alkoxy, each independently C 1-6 Alkyl and -C(O)(C 1-6 alkyl), 3- to 12-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of 1 to 3 independently selected —C(O)(C 1-6 C optionally substituted with alkyl 6-10 aryl, and 1 to 6 independently selected R g is a 5- to 10-membered heteroaryl optionally substituted with q is 0, 1, 2, 3, 4 or 5; Each R A independently, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 is cycloalkyl; R 3 are hydrogen, or independently halo, hydroxy and C1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 is alkyl; R 8a and R 8b are each independently hydrogen, or independently halo and C 3-15 C optionally substituted with one or more substituents selected from the group consisting of cycloalkyl 1-6 is alkyl; or R 8a and R 8b Each of these, together with the carbon atom to which it is attached, is one to three independently selected C 1-6 C optionally substituted with alkyl 3-15 Forms a cycloalkyl ring, 1-6 Alkyl is 1 to 6 independently selected R f may be substituted with; R 9 is -C(O)OR 9a , -C(O)NR 9a R 9b , 1 to 3 independently selected R 9c 5-6 membered heteroaryl optionally substituted with 1 to 3 independently selected R 9c 4- to 6-membered heterocyclyl optionally substituted by [ka] and; X 1 is O or S; R 9a is hydrogen or C 1-6 is alkyl; R 9b is hydrogen, C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -S(O) 0-2 (C 1-6 alkyl) or cyano; Each R 9c are independently selected from hydrogen, oxo, 1 to 6 independently selected halo, and C 1-6 C optionally substituted with alkoxy 1-6Alkyl, or -C(O)(C 1-6 alkyl); v is 0, 1, 2 or 3; Each R Ca are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c R d and; or a pair of R on the same or different ring atoms Ca each together with the ring atom to which it is attached forms a carbocyclic ring containing 3 to 8 ring atoms; Each R c and R d are each 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), -S(O) 1-2 (C 1-6 alkyl) or -S(O) 1-2 (C 3-6 cycloalkyl), and the C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)O(C 1-6 alkyl), -S(O) 1-2 (C 1-6 alkyl) and -S(O) 1-2 (C 3-6 cycloalkyl) are each independently selected from hydroxy, halo, and C 1-6 optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy; Each R e are independently hydrogen, C 1-6 Alkyl or C 1-6 is haloalkyl; Each R f are independently halo, hydroxy, -NR c R d , C 1-6 Alkoxy, C 1-6 haloalkoxy, or each independently hydroxy, C1-6 a 3- to 12-membered heterocyclyl optionally substituted by 1 to 4 substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; Each R g independently, C 1-6 Alkyl, C 1-6 Alkoxy, -NR c R d , or each independently C 1-6 Alkyl and -C(O)C 1-6 alkyl; and Each R h are independently halo, cyano, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 Alkyl)2, C 1-3 Alkoxy or C 1-3 It is haloalkoxy.

[0241] In some embodiments, the compound of formula IIL: [ka] IIL or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R 1f independently, C 1-6 alkyl, and each C 1-6 Alkyl is independently 1 to 6 independently selected R f q is 0, 1, 2, 3, 4, or 5; v is 0, 1, 2, or 3; w is 0, 1, 2, or 3; R a , R Ca , R f , R 9 , R A , R 3 , Q 2 and R QA are each independently as defined herein.

[0242] In some embodiments, the compound of formula II-(S): [ka] IIL-(S) or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R 1f independently, C 1-6 alkyl, and each C 1-6 Alkyl is independently 1 to 6 independently selected R f q is 0, 1, 2, 3, 4, or 5; v is 0, 1, 2, or 3; w is 0, 1, 2, or 3; R a , R Ca , R f , R 9 , R A , R 3 , Q 2 and R QA are each independently as defined herein.

[0243] In one embodiment, a compound of formula II-(S): [ka] IIL-(S) or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein: Q 2 is N or CR QA and; R a are hydrogen, cyano, each independently halo, oxo, C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and heteroaryl 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; Each R QA are independently hydrogen, halo, cyano, hydroxy, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e , 1 to 6 independently selected R f C optionally substituted with 1-6 alkyl, each independently hydroxy, halo and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 Alkoxy, each independently C 1-6 Alkyl and -C(O)(C 1-6 alkyl), 3- to 12-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of 1 to 3 independently selected —C(O)(C 1-6 C optionally substituted with alkyl 6-10 aryl, and 1 to 6 independently selected R g is a 5- to 10-membered heteroaryl optionally substituted with q is 0, 1, 2, 3, 4 or 5; Each R A independently, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 is cycloalkyl; R 3 are hydrogen, or independently halo, hydroxy and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 is alkyl; R 9 is -C(O)OR 9a , -C(O)NR 9a R 9b , 1 to 3 independently selected R 9c5-6 membered heteroaryl optionally substituted with 1 to 3 independently selected R 9c 4- to 6-membered heterocyclyl optionally substituted by [ka] and; X 1 is O or S; R 9a is hydrogen or C 1-6 is alkyl; R 9b is hydrogen, C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -S(O) 0-2 (C 1-6 alkyl) or cyano; Each R 9c are independently selected from hydrogen, oxo, 1 to 6 independently selected halo, and C 1-6 C optionally substituted with alkoxy 1-6 Alkyl, or -C(O)(C 1-6 alkyl); v is 0, 1, 2 or 3; Each R Ca are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c R d and; or a pair of R on the same or different ring atoms Ca each together with the ring atom to which it is attached forms a carbocyclic ring containing 3 to 8 ring atoms; Each R c and R d are each 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), -S(O) 1-2 (C 1-6 alkyl) or -S(O) 1-2 (C 3-6cycloalkyl), and the C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)O(C 1-6 alkyl), -S(O) 1-2 (C 1-6 alkyl) and -S(O) 1-2 (C 3-6 cycloalkyl) are each independently selected from hydroxy, halo, and C 1-6 optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy; Each R e are independently hydrogen, C 1-6 Alkyl or C 1-6 is haloalkyl; w is 0, 1, 2 or 3; Each R 1f independently, C 1-6 alkyl, and each C 1-6 Alkyl is independently 1 to 6 independently selected R f may be substituted with; Each R f are independently halo, hydroxy, -NR c R d , C 1-6 Alkoxy, C 1-6 haloalkoxy, or each independently hydroxy, C 1-6 a 3- to 12-membered heterocyclyl optionally substituted by 1 to 4 substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; Each R g independently, C 1-6 Alkyl, C 1-6 Alkoxy, -NR c R d , or each independently C 1-6 Alkyl and -C(O)C 1-6 alkyl; and Each R h are independently halo, cyano, hydroxy, C 1-6 Alkyl, C 1-6Haloalkyl, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 Alkyl)2, C 1-3 Alkoxy or C 1-3 It is haloalkoxy.

[0244] In some embodiments, R 3 is methyl.

[0245] In some embodiments, q is 2 or 3.

[0246] In some embodiments, each R A independently, halo, C 1-6 Alkyl or C 3-6 In some embodiments, each R A is independently fluoro, chloro, methyl or cyclopropyl.

[0247] In some embodiments, q is 2 or 3; A independently, halo, C 1-6 Alkyl or C 3-6 In some embodiments, q is 2 or 3; A is independently fluoro, chloro, methyl or cyclopropyl.

[0248] In some embodiments, Q 2 is N. In some embodiments, Q 2 is CR QA is.

[0249] In some embodiments, each R QA are independently hydrogen, halo, -NH(C 1-6 alkyl), C 1-6 Alkyl or C 1-6 In some embodiments, each R QA are independently hydrogen, fluoro, chloro, -NHCH3, methyl, isopropyl, or -OCH3.

[0250] In some embodiments, Q 2 is CR QA and each R QA are independently hydrogen, halo, -NH(C 1-6 alkyl), C 1-6 Alkyl or C 1-6 It is an alkoxy.

[0251] In some embodiments, Q 2 is CR QA and;R a or R b and R QA are taken together with the atom to which they are attached to form a 5- to 7-membered heterocyclyl, and the heterocyclyl is selected from 1 to 2 independently selected R h may be substituted with.

[0252] In some embodiments, R a is hydrogen, cyano, C 1-6 Alkyl or C 3-6 It is cycloalkyl.

[0253] In some embodiments, R b is C 3-6 C optionally substituted with cycloalkyl 1-6 Alkyl, or C 3-6 In some embodiments, R b is C 1-6 In some embodiments, R b is C 3-6 Cycloalkyl-substituted C 1-6 In some embodiments, R b is C 3-6 It is cycloalkyl.

[0254] In some embodiments, R a is hydrogen, cyano, C 1-6 Alkyl or C 3-6 is cycloalkyl; R b is C 3-6C optionally substituted with cycloalkyl 1-6 Alkyl, or C 3-6 In some embodiments, R a is hydrogen, cyano, methyl or cyclopropyl; R b is methyl, ethyl, -CH2-cyclopropyl, cyclopropyl, or cyclobutyl.

[0255] In some embodiments, R a and R b are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl.

[0256] In some embodiments, R a or R b and adjacent R QA are taken together with the atom to which they are attached to form a 5- to 7-membered heterocyclyl, and the heterocyclyl is selected from 1 to 2 independently selected R h may be substituted with.

[0257] In some embodiments, w is 0 or 1. In some embodiments, w is 0. In some embodiments, w is 1. In some embodiments, each R f independently, C 1-6 It is alkyl.

[0258] In some embodiments, w is 0 or 1; R f is methyl.

[0259] In some embodiments, R a is hydrogen, cyano, C 1-6 Alkyl, or C 3-6 is cycloalkyl; R b is C 3-6 C optionally substituted with cycloalkyl 1-6 Alkyl, or C 3-6 is cycloalkyl; or R a and R beach taken together with the atom to which it is attached forms a 5- to 8-membered heterocyclyl; or R a is hydrogen, cyano, C 1-6 Alkyl, or C 3-6 is cycloalkyl; R b and adjacent R QA are taken together with the atom to which they are attached to form a 5- to 7-membered heterocyclyl, and the heterocyclyl is selected from 1 to 2 independently selected R h may be substituted with; or R a and adjacent R QA are taken together with the atom to which they are attached to form a 5- to 7-membered heterocyclyl, and the heterocyclyl is selected from 1 to 2 independently selected R h may be substituted with R b is C 3-6 C optionally substituted with cycloalkyl 1-6 Alkyl, or C 3-6 It is cycloalkyl.

[0260] In some embodiments, each R h independently, C 1-6 In some embodiments, each R h are independently methyl.

[0261] In some embodiments, each R i and each R j is hydrogen; or R a Or R b and R i each together with the atom to which it is attached forms a 5- to 8-membered heterocyclyl; or one R i and one R j together with the atoms to which they are bonded, form C 3-6 Forms a cycloalkyl.

[0262] In some embodiments, R 3 is methyl; q is 2 or 3; Each RA independently, halo, C 1-6 Alkyl or C 3-6 is cycloalkyl; Each R QA are independently hydrogen, halo, -NH(C 1-6 alkyl), C 1-6 Alkyl or C 1-6 is alkoxy; R a is hydrogen, cyano, C 1-6 Alkyl, or C 3-6 is cycloalkyl; R b is C 3-6 C optionally substituted with cycloalkyl 1-6 Alkyl, or C 3-6 is cycloalkyl; or R a and R b each taken together with the atom to which it is attached forms a 5- to 8-membered heterocyclyl; or R a is hydrogen, cyano, C 1-6 Alkyl, or C 3-6 is cycloalkyl; R b and adjacent R QA are taken together with the atom to which they are attached to form a 5- to 7-membered heterocyclyl, and the heterocyclyl is selected from 1 to 2 independently selected R h may be substituted with; or R a and adjacent R QA are taken together with the atom to which they are attached to form a 5- to 7-membered heterocyclyl, and the heterocyclyl is selected from 1 to 2 independently selected R h may be substituted with R b is C 3-6 C optionally substituted with cycloalkyl 1-6 Alkyl, or C 3-6 is cycloalkyl; Each R h independently, C 1-6 is alkyl; and Each R i and each R j is hydrogen; or R a and Ri , or R b and R i each together with the atom to which it is attached forms a 5- to 8-membered heterocyclyl; or one R i and one R j together with the atoms to which they are bonded, form C 3-6 Forms a cycloalkyl.

[0263] In one embodiment, a compound of formula IIIA: [ka] IIIA or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein: Q 2 is N or CR QA and; R a are hydrogen, cyano, each independently halo, oxo, C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and heteroaryl 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; R b are each independently C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and halo 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10is aryl; Or, R a and R b are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 3 independently selected C 1-6 optionally substituted with alkyl; Each R QA are independently hydrogen, halo, cyano, hydroxy, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e , 1 to 6 independently selected R f C optionally substituted with 1-6 alkyl, each independently hydroxy, halo and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 Alkoxy, each independently C 1-6 Alkyl and -C(O)(C 1-6 alkyl), 3- to 12-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of 1 to 3 independently selected —C(O)(C 1-6 C optionally substituted with alkyl 6-10 aryl, and 1 to 6 independently selected R g is a 5- to 10-membered heteroaryl optionally substituted with Or, R a or R b and adjacent R QA are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 2 independently selected R h may be substituted with; Each R Ca independently, C 1-6 is alkyl; q is 0, 1, 2, 3, 4 or 5; Each R A independently, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6Alkoxy or C 3-6 is cycloalkyl; R 3 are hydrogen, or independently halo, hydroxy and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 is alkyl; R 9 is -C(O)OR 9a , -C(O)NR 9a R 9b , 1 to 3 independently selected R 9c 5-6 membered heteroaryl optionally substituted with 1 to 3 independently selected R 9c 4- to 6-membered heterocyclyl optionally substituted by [ka] and; X 1 is O or S; R 9a is hydrogen or C 1-6 is alkyl; R 9b is hydrogen, C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -S(O) 0-2 (C 1-6 alkyl) or cyano; Each R 9c are independently selected from hydrogen, oxo, 1 to 6 independently selected halo, and C 1-6 C optionally substituted with alkoxy 1-6 Alkyl, or -C(O)(C 1-6 alkyl); Each R c and R d are each 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), -S(O) 1-2 (C 1-6 alkyl) or -S(O) 1-2 (C3-6 cycloalkyl), and the C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)O(C 1-6 alkyl), -S(O) 1-2 (C 1-6 alkyl) and -S(O) 1-2 (C 3-6 cycloalkyl) are each independently selected from hydroxy, halo, and C 1-6 optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy; Each R e are independently hydrogen, C 1-6 Alkyl or C 1-6 is haloalkyl; w is 0, 1, 2 or 3; Each R 1f independently, C 1-6 alkyl, and each C 1-6 Alkyl is independently 1 to 6 independently selected R f may be substituted with; Each R f are independently halo, hydroxy, -NR c R d , C 1-6 Alkoxy, C 1-6 haloalkoxy, or each independently hydroxy, C 1-6 a 3- to 12-membered heterocyclyl optionally substituted by 1 to 4 substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; Each R g independently, C 1-6 Alkyl, C 1-6 Alkoxy, -NR c R d , or each independently C 1-6 Alkyl and -C(O)C 1-6 alkyl; and Each R h are independently halo, cyano, hydroxy, C 1-6 Alkyl, C1-6 Haloalkyl, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 Alkyl)2, C 1-3 Alkoxy or C 1-3 It is haloalkoxy.

[0264] In one embodiment, a compound of formula IIIB: [ka] IIIB or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein: Q 2 is N or CR QA and; R a are hydrogen, cyano, each independently halo, oxo, C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and heteroaryl 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; R b are each independently C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and halo 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; Or, R a and R bare taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 3 independently selected C 1-6 optionally substituted with alkyl; Each R QA are independently hydrogen, halo, cyano, hydroxy, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e , 1 to 6 independently selected R f C optionally substituted with 1-6 alkyl, each independently hydroxy, halo and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 Alkoxy, each independently C 1-6 Alkyl and -C(O)(C 1-6 alkyl), 3- to 12-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of 1 to 3 independently selected —C(O)(C 1-6 C optionally substituted with alkyl 6-10 aryl, and 1 to 6 independently selected R g is a 5- to 10-membered heteroaryl optionally substituted with Or, R a or R b and adjacent R QA are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 2 independently selected R h may be substituted with; q is 0, 1, 2, 3, 4 or 5; Each R A independently, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 is cycloalkyl; R 3 are hydrogen, or independently halo, hydroxy and C 1-6C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 is alkyl; R 9 is -C(O)OR 9a , -C(O)NR 9a R 9b , 1 to 3 independently selected R 9c 5-6 membered heteroaryl optionally substituted with 1 to 3 independently selected R 9c 4- to 6-membered heterocyclyl optionally substituted by [ka] and; X 1 is O or S; R 9a is hydrogen or C 1-6 is alkyl; R 9b is hydrogen, C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -S(O) 0-2 (C 1-6 alkyl) or cyano; Each R 9c are independently selected from hydrogen, oxo, 1 to 6 independently selected halo, and C 1-6 C optionally substituted with alkoxy 1-6 Alkyl, or -C(O)(C 1-6 alkyl); Each R c and R d are each 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), -S(O) 1-2 (C 1-6 alkyl) or -S(O) 1-2 (C 3-6 cycloalkyl), and the C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -C(O)(C 3-6cycloalkyl), -C(O)O(C 1-6 alkyl), -S(O) 1-2 (C 1-6 alkyl) and -S(O) 1-2 (C 3-6 cycloalkyl) are each independently selected from hydroxy, halo, and C 1-6 optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy; Each R e are independently hydrogen, C 1-6 Alkyl or C 1-6 is haloalkyl; w is 0, 1, 2 or 3; Each R 1f independently, C 1-6 alkyl, and each C 1-6 Alkyl is independently 1 to 6 independently selected R f may be substituted with; Each R f are independently halo, hydroxy, -NR c R d , C 1-6 Alkoxy, C 1-6 haloalkoxy, or each independently hydroxy, C 1-6 a 3- to 12-membered heterocyclyl optionally substituted by 1 to 4 substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; Each R g independently, C 1-6 Alkyl, C 1-6 Alkoxy, -NR c R d , or each independently C 1-6 Alkyl and -C(O)C 1-6 alkyl; and Each R h are independently halo, cyano, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 Alkyl)2, C 1-3 Alkoxy or C1-3 It is haloalkoxy.

[0265] In one embodiment, a compound of formula IIIC: [ka] IIIC or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein: Q 2 is N or CR QA and; R a are hydrogen, cyano, each independently halo, oxo, C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and heteroaryl 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; R b are each independently C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and halo 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; Or, R a and R b are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 3 independently selected C 1-6 optionally substituted with alkyl; Each R QA are independently hydrogen, halo, cyano, hydroxy, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e , 1 to 6 independently selected R f C optionally substituted with 1-6 alkyl, each independently hydroxy, halo and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 Alkoxy, each independently C 1-6 Alkyl and -C(O)(C 1-6 alkyl), 3- to 12-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of 1 to 3 independently selected —C(O)(C 1-6 C optionally substituted with alkyl 6-10 aryl, and 1 to 6 independently selected R g is a 5- to 10-membered heteroaryl optionally substituted with q is 0, 1, 2, 3, 4 or 5; Each R A independently, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 is cycloalkyl; R 3 are hydrogen, or independently halo, hydroxy and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 is alkyl; R 9 is -C(O)OR 9a , -C(O)NR 9a R 9b , 1 to 3 independently selected R 9c 5-6 membered heteroaryl optionally substituted with 1 to 3 independently selected R 9c 4- to 6-membered heterocyclyl optionally substituted by [ka] and; X 1 is O or S; R 9a is hydrogen or C 1-6 is alkyl; R 9b is hydrogen, C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -S(O) 0-2 (C 1-6 alkyl) or cyano; Each R 9c are independently selected from hydrogen, oxo, 1 to 6 independently selected halo, and C 1-6 C optionally substituted with alkoxy 1-6 Alkyl, or -C(O)(C 1-6 alkyl); Each R c and R d are each 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), -S(O) 1-2 (C 1-6 alkyl) or -S(O) 1-2 (C 3-6 cycloalkyl), and the C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)O(C 1-6 alkyl), -S(O) 1-2 (C 1-6 alkyl) and -S(O) 1-2 (C 3-6 cycloalkyl) are each independently selected from hydroxy, halo, and C 1-6 optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy; Each R e are independently hydrogen, C 1-6 Alkyl or C 1-6 is haloalkyl; w is 0, 1, 2 or 3; Each R 1f independently, C 1-6 alkyl, and each C 1-6 Alkyl is independently 1 to 6 independently selected R f may be substituted with; Each R f are independently halo, hydroxy, -NR c R d , C 1-6 Alkoxy, C 1-6 haloalkoxy, or each independently hydroxy, C 1-6 a 3- to 12-membered heterocyclyl optionally substituted with 1 to 4 substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; and Each R g independently, C 1-6 Alkyl, C 1-6 Alkoxy, -NR c R d , or each independently C 1-6 Alkyl and -C(O)C 1-6 and 3- to 12-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of alkyl.

[0266] In certain embodiments, such as of formula IIIA or IIIB, R 3 is C 1-6 In certain embodiments, such as of formula IIIA or IIIB, R 3 is methyl.

[0267] In certain embodiments, such as those of formula IIIA or IIIB, Q 2 is CH. In Formula IIIA or IIIB, etc., R 3 is methyl.

[0268] In certain embodiments, such as of formula IIIA or IIIB, q is 2 or 3.

[0269] In certain embodiments, such as of formula IIIA or IIIB, R9 teeth, [ka] is.

[0270] In one embodiment, a compound of formula IIID: [ka] IIID or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein: R a are hydrogen, cyano, each independently halo, oxo, C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and heteroaryl 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; R b are each independently C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and halo 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; R QA is hydrogen, halo, cyano, hydroxy, -NR c R d , -C(O)NR c R d , -S(O) 0-2 Re , 1 to 6 independently selected R f C optionally substituted with 1-6 alkyl, each independently hydroxy, halo and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 Alkoxy, each independently C 1-6 Alkyl and -C(O)(C 1-6 alkyl), 3- to 12-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of 1 to 3 independently selected —C(O)(C 1-6 C optionally substituted with alkyl 6-10 aryl, and 1 to 6 independently selected R g is a 5- to 10-membered heteroaryl optionally substituted with Each R c and R d are each 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), -S(O) 1-2 (C 1-6 alkyl) or -S(O) 1-2 (C 3-6 cycloalkyl), and the C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)O(C 1-6 alkyl), -S(O) 1-2 (C 1-6 alkyl) and -S(O) 1-2 (C 3-6 cycloalkyl) are each independently selected from hydroxy, halo, and C 1-6 optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy; Each R e are independently hydrogen, C 1-6 Alkyl or C 1-6 is haloalkyl; and Each R g independently, C1-6 Alkyl, C 1-6 Alkoxy, -NR c R d , or each independently C 1-6 Alkyl and -C(O)C 1-6 and 3- to 12-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of alkyl.

[0271] In certain embodiments, such as those of formula IIIA, IIIB, or IIIC, R QA -NR c R d or C 1-6 In certain embodiments, such as of formula IIIA, IIIB, or IIIC, R QA is hydrogen, halo, -NHCH-3 or methyl.

[0272] In certain embodiments, such as those of formula IIIA, IIIB, or IIIC, R a is hydrogen or C 1-6 In certain embodiments, such as of formula IIIA, IIIB, or IIIC, R a is hydrogen, methyl or ethyl.

[0273] In certain embodiments, such as those of formula IIIA, IIIB, or IIIC, R b is C 1-6 Alkyl or C 3-6 In certain embodiments, such as of formula IIIA, IIIB, or IIIC, R b is methyl, ethyl, cyclopropyl or cyclobutyl.

[0274] In certain embodiments, such as those of formula IIIA, IIIB, or IIIC, R a is hydrogen or C 1-6 alkyl; R b is C 1-6 Alkyl or C 3-6 It is cycloalkyl.

[0275] In certain embodiments, such as those of formula IIIA, IIIB, or IIIC, R a is hydrogen, methyl or ethyl; R b is methyl, ethyl, cyclopropyl or cyclobutyl.

[0276] In one embodiment, a compound of formula IIID: [ka] IIID or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein R QA -NR c R d , or C 1-6 alkyl; R a is hydrogen or C 1-6 alkyl; R b is C 1-6 Alkyl or C 3-6 It is cycloalkyl.

[0277] In one embodiment, a compound of formula IIID: [ka] IIID or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein R QA is hydrogen, halo, -NHCH-3, or methyl; R a is hydrogen, methyl or ethyl; R b is methyl, ethyl, cyclopropyl or cyclobutyl.

[0278] In one embodiment, a compound of formula IIID: [ka] IIID or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein R QA is hydrogen, halo, -NHCH-3, or methyl; R a is methyl or ethyl; R b is ethyl or cyclopropyl or cyclobutyl.

[0279] In certain embodiments, Table 1: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 [Table 1-31] [Table 1-32] [Table 1-33] [Table 1-34] [Table 1-35] [Table 1-36] [Table 1-37] [Table 1-38] The present invention provides a compound selected from the following: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0280] In certain embodiments, Table 2: [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17 Table 2-18 Table 2-19 Table 2-20 Table 2-21 Table 2-22 Table 2-23 Table 2-24 Table 2-25 Table 2-26 Table 2-27 Table 2-28 Table 2-29 Table 2-30 Table 2-31 Table 2-32 Table 2-33 Table 2-34 Table 2-35 Table 2-36 Table 2-37 Table 2-38 Table 2-39 Table 2-40 Table 2-41 [Table 2-42] [Table 2-43] [Table 2-44] [Table 2-45] [Table 2-46] The present invention provides a compound selected from the following: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0281] The compounds of Formula I include pharmaceutically acceptable salts thereof. The compounds of Formula I also include other salts of such compounds that are not necessarily pharmaceutically acceptable salts but may be useful as intermediates for preparing and / or purifying compounds of Formula I and / or for separating enantiomers of compounds of Formula I. Non-limiting examples of pharmaceutically acceptable salts of compounds of Formula I include trifluoroacetate salts.

[0282] It is further understood that the compounds of formula I or their salts may be isolated in the form of solvates, and therefore, all such solvates are included within the scope of the present disclosure. For example, the compounds of formula I and their salts can exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.

[0283] Pharmaceutical Compositions and Administration When used as pharmaceuticals, the compounds described herein (e.g., compounds of Formula I, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof) can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical arts and can be administered by 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, epithelial, ocular, and mucosal membranes, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral, or parenteral. Oral administration can include dosage forms formulated for once-daily or twice-daily (BID) administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or for example, by continuous perfusion pump.The pharmaceutical compositions and preparations for topical administration can include transdermal patch, ointment, lotion, cream, gel, drop, suppository, spray, liquid and powder.Traditional pharmaceutical carriers, aqueous, powder or oily base, thickener, etc. may be necessary or desirable.

[0284] Also provided are pharmaceutical compositions comprising a compound of Formula I, or its pharmaceutically acceptable salt, isotope-enriched analog, stereoisomer, stereoisomer mixture, or prodrug, as an active ingredient, in combination with one or more pharmaceutically acceptable excipients (carriers). For example, pharmaceutical compositions are prepared using a compound of Formula I, or its pharmaceutically acceptable salt, isotope-enriched analog, stereoisomer, stereoisomer mixture, or prodrug. In some embodiments, the composition is suitable for topical administration. In preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed in such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When an excipient functions as a diluent, it can be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), for example, ointments containing up to 10% by weight of 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.

[0285] Further provided is a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, together with a pharmaceutically acceptable excipient. Pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, as an active ingredient can be prepared by thoroughly mixing a pharmaceutical carrier with a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, according to conventional pharmaceutical compounding techniques. The carrier can take a variety of forms depending on the desired route of administration (e.g., oral, parenteral). In some embodiments, the composition is a solid oral composition.

[0286] Suitable pharmaceutically acceptable carriers are well known in the art, and a description 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.

[0287] Methods for formulating pharmaceutical compositions are described in numerous publications, such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, Lieberman et al.; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, Avis et al.; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, Lieberman et al., Marcel Dekker, Inc.

[0288] In some embodiments, compound or pharmaceutical compositions can be administered in combination with one or more conventional pharmaceutical additives.Pharmaceutically acceptable additives include but are not limited to ion exchanger, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery system (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 matrix, serum protein, such as human serum albumin, buffer substances, such as phosphate, Tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substance, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene block polymer and wool fat. Cyclodextrins, such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives, such as hydroxyalkylcyclodextrins, e.g., 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilizing derivatives, may also be used to enhance delivery of the compounds described herein. Forms or compositions may be prepared containing 0.005% to 100% of the chemicals described herein, with the remainder consisting of non-toxic additives. Contemplated compositions may contain 0.001% to 100% of the chemicals provided herein, and in one embodiment, 0.1 to 95%, in another embodiment, 75 to 85%, and in a further embodiment, 20 to 80%. Actual methods for preparing such dosage forms are known or apparent to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy, 22 nd Edition (Pharmaceutical Press, London, UK. 2012).

[0289] In some embodiments, the compounds and pharmaceutical compositions described herein or pharmaceutical compositions thereof may be administered to a patient in need thereof by any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, intracervical, intrasinus, intratracheal, enteral, epidural, intrainterstitial, intraperitoneal, intra-arterial, intrabronchial, intrasynovial, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinus, intraspinal, intraspinal, intrasynovial, intratesticular, intrathecal, intraductal, intratumoral, intrauterine, intravascular, intravenous, nasal (e.g., intranasal), nasogastric, oral, parenteral, transdermal, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and vaginal. In some embodiments, the route of administration is parenteral (eg, intratumoral).

[0290] In some embodiments, the compound of Formula I described herein, or its pharmaceutically acceptable salt, isotope-enriched analog, stereoisomer, stereoisomer mixture or prodrug, or pharmaceutical composition thereof, can be formulated for parenteral administration, for example, can be formulated for injection by intraarterial, intrasternal, intracranial, intravenous, intramuscular, subcutaneous or intraperitoneal route.For example, such compositions can be prepared as injections as either liquid solution or suspension, and can also be prepared as solid forms suitable for preparing solution or suspension by adding liquid before injection, and the preparation can also be emulsified.The preparation of such preparations is known to those skilled in the art in light of the present disclosure.In some embodiments, a device is used for parenteral administration.For example, such a device can include needle injectors, microneedle injectors, needle-free injectors and infusion technology.

[0291] In some embodiments, the pharmaceutical forms suitable for injection include sterile aqueous solution or dispersion; formulations containing sesame oil, peanut oil or aqueous propylene glycol; and sterile powder for the immediate preparation of sterile injectable solution or dispersion.In some embodiments, the form must be sterile and fluid enough to be easily injected.In some embodiments, the form must be stable under the conditions of manufacture and storage, and must be protected against the contaminating action of microorganisms, such as bacteria and fungi.

[0292] In some embodiments, the carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. In some embodiments, proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. In some embodiments, the prevention of microbial action can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In some embodiments, isotonic agents, such as sugars or sodium chloride, are included. In some embodiments, prolonged absorption of the injectable composition can be brought about by the use in the composition of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0293] In some embodiments, sterile injectable solution is prepared by incorporating the required amount of the compound of Formula I or its pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture or prodrug in a suitable solvent with various other ingredients as listed above, if necessary, followed by filtration sterilization.In some embodiments, dispersion is prepared by incorporating various sterile active ingredients into a sterile vehicle that contains a basic dispersion medium and other required ingredients from those listed above.In some embodiments, sterile powder is used to prepare sterile injectable solution.In some embodiments, preparation method is vacuum drying and freeze-drying technology, which obtains powder of active ingredient and any additional desired ingredients from its previously sterile-filtered solution.

[0294] In some embodiments, pharmaceutically acceptable excipients that can be used in rectal compositions as gels, creams, enemas, or rectal suppositories include cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (e.g., PEG ointment), glycerin, glycerinated gelatin, hydrogenated vegetable oils, poloxamer, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxide SBN, vanilla essential oil, aerosol, and phenoxyethanol. Ingredients that may be added include, but are not limited to, one or more of: parabens, sodium methylparaben, sodium propylparaben, diethylamine, carbomer, carbopol, methylparaben, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxymetabisulfite, disodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins such as vitamins A and E, and potassium acetate.

[0295] In some embodiments, suppositories can be prepared by mixing the compound of Formula I described herein, or its pharmaceutically acceptable salt, isotope-enriched analog, stereoisomer, mixture of stereoisomers or prodrug, or pharmaceutical composition, 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 therefore melts in the rectum to release the active compound.In some embodiments, the composition for rectal administration is in the form of an enema.

[0296] In some embodiments, a compound of Formula I described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutical composition thereof, is formulated for local delivery to the gastrointestinal or GI tract by oral administration (e.g., in a solid or liquid dosage form).

[0297] In some embodiments, the solid dosage form for oral administration includes capsules, tablets, pills, powders and granules.In some embodiments, the compound of Formula I or its pharmaceutically acceptable salt, isotope-enriched analog, stereoisomer, stereoisomer mixture or prodrug can be added with one or more pharmaceutically acceptable additives, such as sodium citrate or dicalcium phosphate, and / or: a) excipients or fillers, such as starch, lactose, sucrose, glucose, mannitol and silicic acid; b) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose and acacia; c) wetting agents, such as glycerol In some embodiments, the solid composition of the present invention is mixed with the following additives: d) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) dissolution retardants such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and their mixtures.For example, in the case of capsules, tablets, and pills, dosage forms can also contain buffering agents.In some embodiments, similar type of solid composition can also be used as a filler in soft and hard-filled gelatin capsules, using additives such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0298] In some embodiments, the pharmaceutical composition is in the form of a unit dosage form, for example, a pill or tablet. Thus, the composition may contain a compound of Formula I provided herein, or its pharmaceutically acceptable salt, isotope-enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, together with a diluent such as lactose, sucrose, dicalcium phosphate, etc.; a lubricant such as magnesium stearate, etc.; and a binder such as starch, acacia gum, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, etc. In some embodiments, another solid dosage form is a powder, quince, solution, or suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglyceride) encapsulated in a capsule (gelatin or cellulose-based capsule). In some embodiments, a unit dosage form in which one or more compounds provided herein and a pharmaceutical composition or additional active agent are physically separated is also contemplated; for example, a capsule (or a tablet in a capsule) containing granules of each drug; a two-layer tablet; a two-compartment gel cap, etc. In some embodiments, enteric coated or sustained release oral dosage forms are also contemplated.

[0299] In some embodiments, other physiologically acceptable compounds may include wetting agents, emulsifying agents, dispersing agents, or preservatives that are particularly useful for preventing the growth or action of microorganisms. For example, various preservatives are well known and include, for example, phenol and ascorbic acid.

[0300] In some embodiments, the additive is sterile and generally does not contain undesirable substances.For example, these compositions can be sterilized by conventional and well-known aseptic techniques.In some embodiments, the additives for various oral dosage forms, such as tablets and capsules, do not require sterility.For example, United States Pharmacopeia / National Formulary (USP / NF) standards may be sufficient.

[0301] In some embodiments, the compound of Formula I described herein, or its pharmaceutically acceptable salt, isotope-enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, or pharmaceutical composition thereof, is formulated for ocular administration. In some embodiments, the ophthalmic composition includes, but is not limited to, one or more of the following: viscosity enhancers (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol), stabilizers (e.g., Pluronic (triblock copolymer), cyclodextrin), preservatives (e.g., benzalkonium chloride, EDTA, SofZia (boric acid, propylene glycol, sorbitol, zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychlorocomplex; Allergan, Inc.).

[0302] In some embodiments, the compound of Formula I described herein, or its pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, or pharmaceutical composition thereof, is formulated for topical administration to the skin or mucosa (e.g., dermal or transdermal). In some embodiments, topical compositions can include ointments and creams. In some embodiments, ointments are typically semi-solid formulations based on petrolatum or other petroleum derivatives. In some embodiments, creams containing selected active ingredients are typically viscous liquid or semi-solid emulsions, often either oil-in-water or water-in-oil. For example, cream bases are typically water-washable and contain an oil phase, an emulsifier, and an aqueous phase. For example, the oil phase, also known as the "internal" phase, is generally composed of petrolatum and a fatty alcohol, such as cetyl or stearyl alcohol; the aqueous phase is usually, but not necessarily, larger in volume than the oil phase and generally contains a moisturizer. In some embodiments, the emulsifier in a cream formulation is typically a nonionic, anionic, cationic, or amphoteric surfactant. In some embodiments, the ointment base, as well as other carriers or vehicles, should be inert, stable, non-irritating, and non-sensitizing.

[0303] In any of the above embodiments, the pharmaceutical compositions described herein may comprise one or more of the following: lipids, interbilayer cross-linked multilamellar vesicles, biodegradable poly(D,L-lactic-co-glycolic acid) (PLGA)-based or polyanhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[0304] The amount of the compound in a pharmaceutical composition or formulation can vary within the full range used by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt%) basis, about 0.01 to 99.99 wt% of the compound of the present disclosure based on the total formulation, with the remainder being one or more suitable pharmaceutical excipients. In one embodiment, the compound is present at a level of about 1 to 80 wt%. Representative pharmaceutical formulations are described below.

[0305] Formulation Example 1 - Tablet Formulation The following ingredients are thoroughly mixed and compressed into single scored tablets: [Table 3]

[0306] Formulation Example 2 - Capsule Formulation The following ingredients are thoroughly mixed and loaded into a hard-shell gelatin capsule: [Table 4]

[0307] Formulation Example 3 - Suspension Formulation The following ingredients are mixed to form a suspension for oral administration: [Table 5]

[0308] Formulation Example 4 - Injection Formulation The following ingredients are mixed to form an injectable formulation: [Table 6]

[0309] Formulation Example 5 - Suppository Formulation Suppositories weighing 2.5 g total are prepared by mixing a compound of the present disclosure with Witepsol® H-15 (triglyceride of saturated vegetable fatty acids; Riches-Nelson, Inc., New York) and have the following composition: [Table 7]

[0310] In some embodiments, the dosage of the compound of Formula I or its pharmaceutically acceptable salt, isotope-enriched analog, stereoisomer, stereoisomer mixture or prodrug is determined based on multiple factors, including but not limited to the type of patient, age, weight, sex, condition, severity of patient's condition, route of administration, and the activity of the compound or its pharmaceutically acceptable salt, isotope-enriched analog, stereoisomer, stereoisomer mixture or prodrug.In some embodiments, the dosage suitable for specific circumstances can be determined by those skilled in the medical field.In some embodiments, the total daily dosage can be divided and administered in portions throughout the day or by means of providing continuous delivery.

[0311] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, is administered at a dose of about 0.01 to about 1000 mg, e.g., about 0.1 to about 30 mg, about 10 to about 80 mg, about 0.5 to about 15 mg, about 50 mg to about 200 mg, about 100 mg to about 300 mg, about 200 to about 400 mg, about 300 mg to about 500 mg, about 400 mg to about 600 mg, about 500 mg to about 800 mg, about 600 mg to about 900 mg, or about 700 mg to about 1000 mg. In some embodiments, the dose is a therapeutically effective amount.

[0312] In some embodiments, a compound of Formula I described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, is administered at a dose of from about 0.0002 mg / kg to about 100 mg / kg (e.g., from about 0.0002 mg / kg to about 50 mg / kg; from about 0.0002 mg / kg to about 25 mg / kg; from about 0.0002 mg / kg to about 1 0mg / kg; about 0.0002mg / kg to about 5mg / kg; about 0.0002mg / kg to about 1mg / kg; about 0.0002mg / kg to about 0.5mg / kg; about 0.0002mg / kg ~0.1mg / kg; approx. 0.001mg / kg ~ approx. 50mg / kg; approx. 0.001mg / kg ~ approx. 25mg / kg; approx. 0.001mg / kg ~ approx. 10mg / kg; approx. 0.001mg / kg ~5mg / kg; approx. 0.001mg / kg ~ approx. 1mg / kg; approx. 0.001mg / kg ~ approx. 0.5mg / kg; approx. 0.001mg / kg ~ approx. 0.1mg / kg; approx. 0.01mg / kg ~ Approx. 50mg / kg; Approx. 0.01mg / kg ~ Approx. 25mg / kg; Approx. 0.01mg / kg ~ Approx. 10mg / kg; Approx. 0.01mg / kg ~ Approx. 5mg / kg; Approx. 0.01mg / kg ~ Approx. 1mg / In some embodiments, the compound of Formula I described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, is administered at a dosage of about 100 mg / kg.

[0313] In some embodiments, the above dosages of the compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, may be administered daily (e.g., as a single dose or as two or more divided doses) or non-daily (e.g., every other day, every third day, every third day, weekly, twice weekly, biweekly, monthly).

[0314] In some embodiments, the administration period of a compound of Formula I described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In some embodiments, the period of time during which administration is suspended is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, is administered to a patient for a period of time, followed by another period during which administration of the compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, is suspended. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, is administered for a first period and a second period following the first period, administration is stopped during the second period, followed by administration of the compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, for a third period, and then administration is stopped for a fourth period following the third period. For example, the period of administration of the compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, followed by a period of cessation of administration, may be repeated for a set or indefinite period.In some embodiments, the administration period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In some embodiments, the period of cessation of administration is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

[0315] In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, is orally administered to a patient one or more times daily (e.g., once daily, twice daily, three times daily, four times daily, or in a single daily dose).

[0316] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, is administered parenterally to a patient one or more times daily (e.g., 1 to 4 times daily, once daily, twice daily, three times daily, four times daily, or in a single daily dose).

[0317] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, is administered weekly to a patient by parenteral administration.

[0318] Treatment method In some embodiments, the present disclosure features a method for treating a patient (e.g., a human) with a disease, disorder, or condition in which modulation of GLP-1R (e.g., suppressed or impaired and / or elevated or undesired GLP-1R) is beneficial for treating the underlying pathology and / or symptoms and / or progression of the disease, disorder, or condition. In some embodiments, the methods described herein may include, or may further include, treating one or more conditions associated with, coexisting with, or secondary to any one or more of the conditions described herein.

[0319] Provided are methods for treating a disease, disorder, or condition associated with GLP-1, comprising administering to a patient in need of treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutical composition disclosed herein.

[0320] In some embodiments, the disease, disorder, or condition is selected from the group consisting of type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), early-onset atypical diabetes mellitus (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of adults (LADA), obesity, weight gain due to use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, and kidney disease. Disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial cell dysfunction, impaired vascular compliance, vascular restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial lipemia The conditions that may be treated include, but are not limited to, diabetes, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, treatment of addiction, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulceration, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, and polycystic ovary syndrome (PCOS).

[0321] In some embodiments, the disease, disorder, or condition includes type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, arteriosclerotic cardiovascular disease, hyperglycemia, postprandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, These include, but are not limited to, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulceration, psoriasis, primary polydipsia, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS), or any combination thereof.

[0322] In some embodiments, the disease, disorder, or condition includes, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat deposition, myocardial infarction, peripheral arterial disease, stroke, transient ischemic attack, hyperglycemia, postprandial 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 ulceration, or any combination thereof.

[0323] In some embodiments, the compounds and pharmaceutical compositions and methods for treating patients described herein induce one or more of the following: lowering blood glucose levels, lowering blood hemoglobin A1c (HbA1c) levels, promoting insulin synthesis, stimulating insulin secretion, increasing beta cell mass, regulating gastric acid secretion, regulating gastric emptying, reducing body mass index (BMI), and / or reducing glucagon production (e.g., glucagon level).In certain embodiments, the compounds and pharmaceutical compositions and methods for treating patients described herein stabilize serum glucose and serum insulin levels (e.g., serum glucose and serum insulin concentrations).Also provided is a method for regulating glucose or insulin levels in patients in need of such regulation, comprising administering to the patient an effective amount of a compound of Formula I, or its pharmaceutically acceptable salt, isotope-enriched analog, stereoisomer, stereoisomer mixture or prodrug, or a pharmaceutical composition disclosed herein.

[0324] In some embodiments, provided herein are methods for reducing the risk of major adverse cardiovascular events (MACE) in a patient in need thereof (e.g., by about at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80%), the method comprising administering to the patient an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutical composition disclosed herein. In some of these embodiments, the patient is an adult diagnosed with type 2 diabetes (T2D). In certain embodiments, the patient is an adult diagnosed with heart disease. In certain embodiments, the patient is an adult diagnosed with type 2 diabetes (T2D) and heart disease. In certain embodiments, the patient is an adult with type 2 diabetes (T2D). In certain embodiments, the patient is an adult with heart disease. In certain embodiments, the patient has type 2 diabetes (T2D) and heart disease.

[0325] Indications obesity In some embodiments, the condition, disease or disorder is obesity and the condition, disease or disorder associated with or related to obesity.Non-limiting examples of obesity and obesity-related conditions include symptomatic obesity, simple obesity, childhood obesity, morbid obesity and abdominal obesity (central obesity characterized by abdominal adiposity).Non-limiting examples of symptomatic obesity include endocrine obesity (e.g., Cushing's syndrome, hypothyroidism, insulinoma, obesity type II diabetes, pseudohypoparathyroidism, hypogonadism), hypothalamic obesity, genetic obesity (e.g., Prader-Willi syndrome, Laurence-Moon-Biedl syndrome), and drug-induced obesity (e.g., steroid-, phenothiazine-, insulin-, sulfonylurea-, or beta-blocker-induced obesity).

[0326] In some embodiments, the condition, disease or disorder is related to obesity.Examples of such condition, disease or disorder include but are not limited to impaired glucose tolerance, diabetes (for example, type 2 diabetes, obesity diabetes), dyslipidemia, hyperlipidemia, hypertension, heart failure, hyperuricemia, gout, fatty liver (including non-alcoholic steatohepatitis (NASH)), coronary heart disease (for example, myocardial infarction, angina pectoris), cerebral infarction (for example, cerebral thrombosis, transient ischemic attack), bone or joint disease (for example, knee osteoarthritis, hip osteoarthritis, spondylosis, lower back pain), sleep apnea syndrome, obesity hypoventilation syndrome (Pickwickian syndrome), menstrual disorders (for example, menstrual cycle abnormality, menstrual volume and cycle abnormality, amenorrhea, menstrual symptom abnormality), visceral obesity syndrome and metabolic syndrome.In some embodiments, the compounds and pharmaceutical compositions described herein can be used to treat patients who show both symptoms of obesity and insulin deficiency.

[0327] diabetes In some embodiments, the condition, disease or disorder is diabetes.Non-limiting examples of diabetes include type 1 diabetes, type 2 diabetes (e.g., diet-treated type 2 diabetes, sulfonylurea-treated type 2 diabetes, very advanced stage type 2 diabetes, long-term insulin-treated type 2 diabetes), diabetes (e.g., non-insulin-dependent diabetes, insulin-dependent diabetes), gestational diabetes, obese diabetes, autoimmune diabetes, and borderline diabetes.In some embodiments, the condition, disease or disorder is type 2 diabetes (e.g., diet-treated type 2 diabetes, sulfonylurea-treated type 2 diabetes, very advanced stage type 2 diabetes, long-term insulin-treated type 2 diabetes).

[0328] Provided are methods for treating diabetes in a patient, the methods comprising: (a) determining that the patient has type 2 diabetes; and (b) administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutical composition disclosed herein.

[0329] Provided is a method of treating type 2 diabetes in a patient, comprising administering to a patient identified or diagnosed as having type 2 diabetes a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutical composition disclosed herein.

[0330] Also provided is a method of treating type 2 diabetes in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutical composition disclosed herein.

[0331] In some embodiments, the compounds and pharmaceutical compositions for treating patients with conditions, diseases, or disorders described herein (e.g., type 2 diabetes) reduce fasting plasma glucose levels. In some embodiments, the compounds and pharmaceutical compositions for treating patients with conditions, diseases, or disorders described herein (e.g., type 2 diabetes) reduce non-fasting plasma glucose levels. In some embodiments, the compounds and pharmaceutical compositions for treating patients with conditions, diseases, or disorders described herein (e.g., type 2 diabetes) reduce HbA1c levels. In some embodiments, the compounds and pharmaceutical compositions for treating patients with conditions, diseases, or disorders described herein (e.g., type 2 diabetes) reduce glucagon levels. In some embodiments, the compounds and pharmaceutical compositions for treating patients with conditions, diseases, or disorders described herein (e.g., type 2 diabetes) increase insulin levels. In some embodiments, the compounds and pharmaceutical compositions for treating patients with conditions, diseases, or disorders described herein (e.g., type 2 diabetes) reduce BMI.

[0332] In some embodiments, about a 5% to about 95% reduction in fasting plasma glucose levels indicates treatment of type 2 diabetes. In some embodiments, about a 15% to about 80% reduction in fasting plasma glucose levels indicates treatment of type 2 diabetes. In some embodiments, about a 25% to about 60% reduction in fasting plasma glucose levels indicates treatment of type 2 diabetes. In some embodiments, a reduction in fasting plasma glucose levels to about 126 mg / dL or less, about 110 mg / dL or less, or about 90 mg / dL or less indicates treatment of type 2 diabetes.

[0333] In some embodiments, about a 5% to about 95% reduction in non-fasting plasma glucose levels indicates treatment of type 2 diabetes. In some embodiments, about a 15% to about 80% reduction in non-fasting plasma glucose levels indicates treatment of type 2 diabetes. In some embodiments, about a 25% to about 60% reduction in non-fasting plasma glucose levels indicates treatment of type 2 diabetes. In some embodiments, a reduction in non-fasting plasma glucose levels to about 200 mg / dL or less, about 150 mg / dL or less, or about 130 mg / dL or less indicates treatment of type 2 diabetes.

[0334] In some embodiments, an about 5% to about 95% reduction in HbA1c levels indicates treatment of type 2 diabetes. In some embodiments, an about 15% to about 80% reduction in HbA1c levels indicates treatment of type 2 diabetes. In some embodiments, an about 25% to about 60% reduction in HbA1c levels indicates treatment of type 2 diabetes. In some embodiments, a reduction in HbA1c levels to about 6.5% or less, about 6.0% or less, or about 5.0% or less indicates treatment of type 2 diabetes.

[0335] In some embodiments, a decrease in glucagon levels of about 5% to about 95% indicates treatment of type 2 diabetes. In some embodiments, a decrease in glucagon levels of about 15% to about 80% indicates treatment of type 2 diabetes. In some embodiments, a decrease in glucagon levels of about 25% to about 60% indicates treatment of type 2 diabetes. In some embodiments, an increase in insulin levels of about 5% to about 95% indicates treatment of type 2 diabetes. In some embodiments, an increase in insulin levels of about 15% to about 80% indicates treatment of type 2 diabetes. In some embodiments, an increase in insulin levels of about 25% to about 60% indicates treatment of type 2 diabetes.

[0336] In some embodiments, an about 5% to about 95% reduction in BMI indicates treatment of type 2 diabetes. In some embodiments, an about 15% to about 80% reduction in BMI indicates treatment of type 2 diabetes. In some embodiments, an about 25% to about 60% reduction in BMI indicates treatment of type 2 diabetes. In some embodiments, an 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% reduction in BMI indicates treatment of type 2 diabetes. In some embodiments, a reduction in BMI to about 40 or less, about 30 or less, or about 20 or less indicates treatment of type 2 diabetes.

[0337] In some embodiments, the condition, disease or disorder is related to diabetes (for example, diabetic complications).Non-limiting examples of the disease related to diabetes include obesity, obesity-related disease, metabolic syndrome, neuropathy, nephropathy (for example, diabetic nephropathy), retinopathy, diabetic cardiomyopathy, cataract, macroangiopathy, osteopenia, hyperosmolar diabetic coma, infectious diseases (for example, respiratory infection, urinary tract infection, gastrointestinal infection, skin and soft tissue infection, lower limb infection), diabetic gangrene, xerostomia, hearing impairment, cerebrovascular disease, diabetic cachexia, delayed wound healing, diabetic dyslipidemia, peripheral blood circulation disorder, cardiovascular risk factors (for example, coronary artery disease, peripheral artery disease, cerebrovascular disease, hypertension and uncontrolled cholesterol and / or lipid level and / or inflammation-related risk factors), NASH, fracture, cognitive dysfunction.

[0338] Other non-limiting examples of disorders related to diabetes include prediabetes, hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, hyper-LDL cholesterolemia, hypo-HDL cholesterolemia, postprandial hyperlipidemia), metabolic syndrome (e.g., metabolic syndrome X, a metabolic disorder in which activation of GLP-1R is beneficial), hypertension, impaired glucose tolerance (IGT), insulin resistance, and sarcopenia.

[0339] In some embodiments, the condition, disease, or disorder is diabetes and obesity (diabetic obesity). In some embodiments, the compounds described herein are useful for improving the therapeutic effect of metformin.

[0340] Disorders of metabolically important tissues In some embodiments, the condition, disease, or disorder is a disorder of a metabolically important tissue. Non-limiting examples of metabolically important tissues include the liver, adipose tissue, pancreas, kidney, and intestine.

[0341] In some embodiments, the condition, disease or disorder is fatty liver disease.Fatty liver disease includes but is not limited to non-alcoholic fatty acid liver disease (NAFLD), steatohepatitis, non-alcoholic steatohepatitis (NASH), fatty liver disease caused by hepatitis, fatty liver disease caused by obesity, fatty liver disease caused by diabetes, fatty liver disease caused by insulin resistance, fatty liver disease caused by hypertriglyceridemia, abetalipoproteinemia, glycogen storage disease, Weber-Christian disease, Wolman disease, acute fatty liver of pregnancy and lipodystrophy.

[0342] Non-alcoholic fatty liver disease (NAFLD) represents a group of diseases that occur in the absence of alcohol abuse, and is typically characterized by the presence of steatosis (fat in the liver).NAFLD is thought to be related to various conditions, such as metabolic syndrome (including obesity, diabetes, hypertriglyceridemia) and insulin resistance.It can cause liver disease in adults and children, and 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 macrovesicular steatosis (also known as non-alcoholic fatty liver or NAFL) to non-alcoholic steatohepatitis (NASH) (Angulo et al., J Gastroenterol Hepatol 2002; 17 Suppl:S186-90).In some embodiments, the patient is a pediatric patient. As used herein, the term "pediatric patient" refers to a patient who is under 21 years old at the time of diagnosis or treatment. The term "child" can be further divided into various subgroups, including neonates (birth to 1 month old); infants (1 month to 2 years old); children (2 to 12 years old); and adolescents (12 to 21 years old (up to but not including their 22nd birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WB Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. In some embodiments, the pediatric patient is from birth to 28 days of age, from 29 days to less than 2 years of age, from 2 years to less than 12 years of age, or from 12 years to 21 years of age (up to but not including the 22nd birthday).In some embodiments, the pediatric patient is between birth and 28 days of age, between 29 days and less than 1 year of age, between 1 month and less than 4 months of age, between 3 months and less than 7 months of age, between 6 months and less than 1 year of age, between 1 year and less than 2 years of age, between 2 years and less than 3 years of age, between 2 years and less than 7 years of age, between 3 years and less than 5 years of age, between 5 years and less than 10 years of age, between 6 years and less than 13 years of age, between 10 years and less than 15 years of age, or between 15 years and less than 22 years of age. In some embodiments, the patient is an adult patient.

[0343] Other non-limiting examples of disorders in metabolically important tissues include joint disorders (e.g., osteoarthritis, secondary osteoarthritis), fatty liver (e.g., liver); gallstones: gallbladder disorders; gastroesophageal reflux disease; sleep apnea; hepatitis; fatty liver; bone diseases characterized by altered bone metabolism, such as osteoporosis, e.g., postmenopausal osteoporosis, decreased bone strength, osteopenia, Paget's disease, osteolytic metastases in cancer patients, osteodystrophy in liver disease, and altered bone metabolism due to renal failure or hemodialysis, fractures, bone surgery, aging, pregnancy, protection against fractures, and nutritional disorders 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 may be used to treat surgical trauma by improving post-surgical recovery and / or by preventing the catabolic response caused by surgical trauma.

[0344] Cardiovascular and vascular diseases In some embodiments, the condition, disease or disorder is cardiovascular disease.Non-limiting examples of cardiovascular disease include congestive heart failure, atherosclerosis, arteriosclerosis, coronary heart disease, coronary artery disease, congestive heart failure, coronary heart disease, hypertension, heart failure, cerebrovascular disease (for example, cerebral infarction), vascular dysfunction, myocardial infarction, elevated blood pressure (for example, 130 / 85 mmHg or more) and prothrombotic state (exemplified by high fibrinogen or plasminogen activator inhibitor in blood).

[0345] In some embodiments, the condition, disease or disorder is associated with a vascular disease. Non-limiting examples of vascular diseases include peripheral vascular disease, macrovascular complications (e.g., stroke), vascular dysfunction, peripheral arterial disease, abdominal aortic aneurysm, carotid artery disease, cerebrovascular disease (e.g., cerebral infarction), pulmonary embolism, chronic venous insufficiency, critical limb ischemia, retinopathy, nephropathy, and neuropathy.

[0346] Neurological disorders In some embodiments, the condition, disease or disorder is a neurological disorder (e.g., neurodegenerative disease) or psychiatric disorder.Non-limiting examples of neurological disorders include idiopathic intracranial hypertension (IIH), brain insulin resistance, mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), anxiety, dementia (e.g., senile dementia), traumatic brain injury, Huntington's disease, tardive dyskinesia, hyperactivity disorder, mania, Parkinson's disease, Steele-Richard syndrome, Down syndrome, myasthenia gravis, neurotrauma, brain trauma, vascular amyloidosis, cerebral hemorrhage with amyloidosis type I, encephalitis, Friedrich ataxia, acute confusion disorder, amyotrophic lateral sclerosis (ALS), glaucoma, and apoptosis-mediated degenerative diseases of the central nervous system (e.g., Creutzfeldt-Jakob disease, bovine spongiform encephalopathy (mad cow disease) and chronic wasting syndrome). See, for example, US2006 / 0275288A1.

[0347] Non-limiting examples of psychiatric disorders include drug dependence / addiction (narcotics and amphetamine) and attention deficit / hyperactivity disorder (ADHD).The compounds and pharmaceutical compositions described herein can be useful for improving the behavioral response to addictive drugs, reducing drug dependence, preventing relapse of drug abuse, and reducing the anxiety caused by the absence of certain addictive substances.See, for example, US2012 / 0021979A1.

[0348] In some embodiments, the compounds and pharmaceutical compositions described herein are useful for improving learning and memory by increasing neuronal plasticity and promoting cell differentiation, and also for preserving dopamine neuron and motor function in Parkinson's disease.

[0349] Insulin-Related Conditions and Disorders In some embodiments, the condition, disease or disorder is impaired fasting glucose (IFG), impaired fasting glucose (IFG), hyperglycemia, insulin resistance (impaired glucose homeostasis), hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hypoglycemic conditions, insulin resistance syndrome, paresthesia caused by hyperinsulinemia, hyperlipidemia, hypercholesterolemia, impaired wound healing, leptin resistance, impaired glucose tolerance, elevated fasting glucose, dyslipidemia (e.g., atherosclerotic dyslipidemia characterized by hyperlipidemia, high triglycerides and low HDL cholesterol), glucagonoma, hyperprolactinemia, hypoglycemia (e.g., nocturnal hypoglycemia), and insulin-related concurrent coma endpoints.

[0350] In some embodiments, the compounds and pharmaceutical compositions described herein may reduce or delay the progression of borderline, impaired fasting glucose, or impaired fasting glycemia to diabetes.

[0351] autoimmune disease In some embodiments, said condition, disease or disorder is autoimmune disease.Non-limiting examples of autoimmune disease include multiple sclerosis, experimental autoimmune encephalomyelitis, autoimmune disease associated with immune rejection, graft-versus-host disease, uveitis, optic neuropathy, optic neuritis, transverse myelitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, myasthenia gravis and Graves' disease.See, for example, US20120148586A1.

[0352] Gastrointestinal disorders In some embodiments, the condition, disease or disorder is a stomach or intestinal disorder.Non-limiting examples of these disorders include ulcers of any etiology (e.g., peptic ulcer, Zollinger-Ellison syndrome, drug-induced ulcer, ulcer associated with infection or other pathogen), digestive disorders, malabsorption, short bowel syndrome, appendicitis, inflammatory bowel disease (Crohn's disease and ulcerative colitis), celiac sprue, hypogammaglobulinemia sprue, chemotherapy and / or radiotherapy-induced mucositis and diarrhea, gastroenteritis, 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, tuberculosis cachexia, cachexia associated with blood disorders, cachexia associated with endocrine disorders, cachexia associated with infectious diseases, cachexia caused by acquired immune deficiency syndrome, etc.).

[0353] body weight In some embodiments, the compounds and pharmaceutical compositions described herein can be used to reduce weight (e.g., excess weight), prevent weight gain, induce weight loss, reduce body fat, or reduce food intake in patients (e.g., patients in need thereof). In some embodiments, the patient's weight gain can be due to excessive food intake or an unbalanced diet, or can be due to concomitant medication (e.g., insulin sensitizers with PPARγ agonist-like activity, such as troglitazone, rosiglitazone, englitazone, ciglitazone, pioglitazone, etc.). In some embodiments, the weight gain can be prior to obesity, or can be weight gain in obese patients. In some embodiments, the weight gain can also be drug-induced weight gain or weight gain after smoking cessation.

[0354] In some embodiments, the condition, disease or disorder is an eating disorder, such as hyperphagia, binge eating, bulimia or compulsive eating.

[0355] inflammatory diseases In some embodiments, condition, disease or disorder is inflammatory disorder.Non-limiting examples of inflammatory disease include chronic rheumatoid arthritis, spondylitis deformans, osteoarthritis, lower back pain, gout, post-operative or post-traumatic inflammation, abdominal distension, neuralgia, pharyngitis, cystitis, pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory bowel disease), the inflammation of metabolically important tissues, including liver, fat, pancreas, kidney, intestine, and pro-inflammatory condition (for example, the level of pro-inflammatory cytokine or inflammatory C-reactive protein marker in blood increases).

[0356] cancer In some embodiments, the condition, disease or disorder is cancer. Suitable examples of cancer include breast cancer (e.g., invasive ductal carcinoma, ductal carcinoma in situ, inflammatory breast cancer), prostate cancer (e.g., hormone-dependent prostate cancer, hormone-independent prostate cancer), pancreatic cancer (e.g., pancreatic ductal carcinoma), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), lung cancer (e.g., non-small cell lung cancer, small cell lung carcinoma, malignant mesothelioma), colon cancer (e.g., gastrointestinal stromal tumor), rectal cancer (e.g., gastrointestinal stromal tumor), tumors), colorectal cancer (e.g., familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumors), small intestine cancer (e.g., non-Hodgkin's lymphoma, gastrointestinal stromal tumors), esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer (e.g., nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer), salivary gland cancer, brain tumors (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma), schwannoma, liver cancer (e.g., , primary liver cancer, extrahepatic bile duct cancer), kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter), bile duct cancer, endometrial cancer, cervical cancer, ovarian cancer (e.g., epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, low-grade ovarian tumor), bladder cancer, urethral cancer, skin cancer (e.g., intraocular (eye) melanoma, Merkel cell carcinoma), hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer (e.g., medullary thyroid carcinoma), parathyroid carcinoma , nasal cavity cancer, paranasal sinus cancer, bone tumors (e.g., osteosarcoma, Ewing's tumor, uterine sarcoma, soft tissue sarcoma), angiofibroma, retinal sarcoma, penile cancer, testicular tumor, pediatric solid tumors (e.g., Wilms' tumor, pediatric kidney tumor), Kaposi's sarcoma, AIDS-related Kaposi's sarcoma, maxillary sinus tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia).

[0357] Hypothalamic-pituitary disorders In some embodiments, the condition, disease or disorder is related to the hypothalamic-pituitary-gonadal axis. For example, the condition, disease or disorder is related to the hypothalamic-pituitary-ovarian axis. In another example, the condition, disease or disorder is related to the hypothalamic-pituitary-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.

[0358] In some embodiments, the diabetes-related condition, disease or disorder is associated with the hypothalamic-pituitary-gonadal axis.

[0359] Pulmonary disease In some embodiments, the condition, disease or disorder is associated with a pulmonary disease. Pulmonary diseases include, but are not limited to, asthma, idiopathic pulmonary fibrosis, pulmonary hypertension, obstructive sleep apnea-hypopnea syndrome, and chronic obstructive pulmonary disease (COPD) (e.g., emphysema, chronic bronchitis, refractory (irreversible) asthma).

[0360] In some embodiments, the diabetes-related condition, disease or disorder is a pulmonary disease.

[0361] Combination treatment In some embodiments, the present disclosure contemplates both monotherapy and combination therapy regimens.

[0362] 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 therapeutic regimens) in combination with the administration of the compounds described herein.

[0363] In some embodiments, the methods described herein include administering a compound described herein in combination with one or more of dietary therapy (e.g., dietary monitoring, dietary therapy for diabetes), exercise therapy (e.g., physical activity), blood glucose monitoring, gastric electrical stimulation (e.g., TANTALUS®), and dietary modification.

[0364] In some embodiments, a compound of Formula I described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, may be administered in combination with one or more additional therapeutic agents.

[0365] Representative additional therapeutic agents include, but are not limited to, anti-obesity agents, therapeutic agents for diabetes, therapeutic agents for diabetic complications, therapeutic agents for hyperlipidemia, antihypertensive agents, diuretics, chemotherapy agents, immunotherapeutic agents, anti-inflammatory agents, antithrombotic agents, antioxidants, therapeutic agents for osteoporosis, vitamins, anti-dementia agents, therapeutic agents for erectile dysfunction, therapeutic agents for frequent urination or urinary incontinence, therapeutic agents for NAFLD, therapeutic agents for NASH, therapeutic agents for dysuria, and antiemetic agents.

[0366] In some embodiments, the one or more additional therapeutic agents include, for example, those useful as anti-obesity agents. Non-limiting examples include monoamine uptake inhibitors (e.g., tramadol, phentermine, sibutramine, mazindol, fluoxetine, tesofensine), serotonin 2C receptor agonists (e.g., lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptor modulators, GABA modulators (e.g., topiramate), GABA receptor agonists (e.g., gabapentin, pregabalin), neuropeptide Y antagonists (e.g., velneperit), cannabinoid receptor antagonists, and the like. agonists (e.g., rimonabant, taranabant), ghrelin antagonists, ghrelin receptor antagonists, ghrelin acylation enzyme inhibitors, opioid receptor antagonists (e.g., GSK-1521498, naltrexone), orexin receptor antagonists, melanocortin 4 receptor agonists, 11β-hydroxysteroid dehydrogenase inhibitors (e.g., AZD-4017, BVT-3498, INCB-13739), pancreatic lipase inhibitors (e.g., orlistat, cetilistat), β3 agonists (e.g., diacylglycerol acyltransferase 1 (DGAT1) inhibitors (e.g., N-5984), acetyl-CoA carboxylase (ACC) inhibitors, stearic acid-CoA desaturase inhibitors, microsomal triglyceride transfer protein inhibitors (e.g., R-256918), sodium-glucose transporter 2 (SGLT-2) inhibitors (e.g., JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941), NFK inhibitors (e.g., HE-328 6), PPAR agonists (e.g., GFT-505, DRF-11605, gemfibrozil, and fenofibrate), phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate, trodasquemine), GPR119 agonists (e.g., PSN-821, MBX-2982, APD597), glucokinase activators (e.g., pyragliatin, AZD-1656, AZD6370, TTP-355, WO2006 / 112549, WO2007 / 028135, WO2008 / 047821,compounds described in WO2008 / 050821, WO2008 / 136428 and WO2008 / 156757), leptin, leptin derivatives (e.g., metreleptin), leptin resistance improving agents, CNTF (ciliary neurotrophic factor), BDNF (brain-derived neurotrophic factor), cholecystokinin agonists, amylin preparations (e.g., pramlintide, AC-2307), neuropeptide Y agonists (e.g., PYY3-36, PYY3-36 derivatives, obinineptide, TM-30339, TM-30335), oxyntomodulin (OXM) preparations, appetite suppressants (e.g., ephedrine), FGF21 preparations (e.g., animal steroids extracted from bovine or porcine pancreas, Examples of suitable anti-inflammatory drugs include synthetic FGF21 preparations; human FGF21 preparations genetically synthesized using E. coli or yeast; fragments or derivatives of FGF21, appetite suppressants (e.g., P-57), human islet-activating peptide (HIP), farnesoid X receptor (FXR) agonists, phentermine, zonisamide, norepinephrine / dopamine reuptake inhibitors (e.g., bupropion), GDF-15 analogs, methionine aminopeptidase 2 (MetAP2) inhibitors, diethylpropion, phendimetrazine, benzphetamine, fibroblast growth factor receptor (FGFR) modulators, and AMP-activated protein kinase (AMPK) activators.

[0367] In some embodiments, the one or more additional therapeutic agents include, for example, those useful as antidiabetic agents. Non-limiting examples include insulin and insulin preparations (e.g., animal insulin preparations extracted from bovine or porcine pancreas; human insulin preparations genetically synthesized using E. coli or yeast; zinc insulin; protamine zinc insulin;Fragments or derivatives of insulin (e.g., INS-1), oral insulin preparations, synthetic human insulin), insulin sensitizers (e.g., pioglitazone or a salt thereof), biguanides (e.g., metformin, buformin or a salt thereof (e.g., hydrochloride, fumarate, succinate), glucagon analogues (e.g., any of the glucagon analogues described in WO2010 / 011439), agents that antagonise the action of glucagon or reduce glucagon secretion, sulfonylureas (e.g., chloroquine ... thiazolidinediones (e.g., rosiglitazone or pioglitazone), α-glucosidase inhibitors (e.g., voglibose, acarbose, miglitol, emiglitate), insulin secretagogues, such as prandial glucose regulators (sometimes referred to as "short-acting secretagogues"), e.g., meglibose, thiazolidinediones (e.g., thiazolidinediones ... Antihypertensives (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, albiglutide, dulaglutide, aviglutide, taspoglutide, lixisenatide, semaglutide, AVE-0010, S4P, and Boc5) , and dipeptidyl peptidase IV (DPP-4) inhibitors (e.g., vildagliptin, dutogliptin, gemigliptin, alogliptin, saxagliptin, sitagliptin, linagliptin, berberine, adogliptin, teneligliptin, omarigliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, SK-0403, ALS2-0426, TA-6666, TS-021, KRP-104, trelagliptin);

[0368] In some embodiments, the one or more additional therapeutic agents include, for example, those useful for treating NAFL and NASH. Non-limiting examples include FXR agonists, PF-05221304, synthetic fatty acid bile acid conjugates, anti-lysine oxidase homolog 2 (LOXL2) monoclonal antibodies, caspase inhibitors, MAPK5 inhibitors, galectin 3 inhibitors, fibroblast growth factor 21 (FGF21), niacin analogs, leukotriene D4 (LTD4) receptor antagonists, acetyl-CoA carboxylase (ACC) inhibitors, ketohexokinase (KHK) inhibitors, apoptosis signal-regulating kinase 1 (ASK1) inhibitors, ileal bile acid transporters, and the like. Ingredients include: IBAT inhibitors, glycyrrhizin, Schisandra chinensis extract, ascorbic acid, glutathione, silymarin, lipoic acid, and d-α-tocopherol, ascorbic acid, glutathione, vitamin B complex, glitazones / thiazolidinediones (e.g., troglitazone, rosiglitazone, pioglitazone), metformin, cysteamine, sulfonylureas, α-glucosidase inhibitors, meglitinides, vitamin E, tetrahydrolipstatin, milk thistle protein, antivirals, and antioxidants.

[0369] In some embodiments, the one or more additional therapeutic agents include, for example, those useful for treating diabetic complications. Non-limiting examples include aldose reductase inhibitors (e.g., tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat, lidrestat), neurotrophic factors and their enhancers (e.g., NGF, NT-3, BDNF, neurotrophic factor production / secretion promoters described in WO01 / 14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxyl)propyl]oxazole), compounds described in WO2004 / 039365), PKC inhibitors (e.g., ruthenium phosphate phosphate inhibitors), and the like. Examples of anti-inflammatory drugs include benzodiazepines (e.g., benzodiazepine mesylate), AGE inhibitors (e.g., ALT946, N-phenacylthiazolium bromide (ALT766), EXO-226, pyridoline, pyridoxamine), serotonin and noradrenaline reuptake inhibitors (e.g., duloxetine), sodium channel inhibitors (e.g., lacosamide), reactive oxygen scavengers (e.g., thioctic acid), cerebral vasodilators (e.g., tiapride, mexiletine), somatostatin receptor agonists (e.g., BIM23190), and apoptosis signal-regulating kinase-1 (ASK-1) inhibitors.

[0370] In some embodiments, the one or more additional therapeutic agents include, for example, those useful for treating hyperlipidemia. Non-limiting examples include HMG-COA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or a salt thereof (e.g., sodium salt, calcium salt)), squalene synthase inhibitors (e.g., compounds described in WO97 / 10224, such as N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] [acetyl]piperidine-4-acetic acid), fibrate compounds (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate), anion exchange resins (e.g., cholestyramine), nicotinic acid drugs (e.g., nicomol, niceritrol, niaspan), phytosterols (e.g., soybean sterol, gamma oryzanol (γ-oryzanol)), cholesterol absorption inhibitors (e.g., Zekia), CETP inhibitors (e.g., dalcetrapib, anacetrapib), and omega-3 fatty acid preparations (e.g., omega-3 fatty acid ethyl ester 90).

[0371] In some embodiments, the one or more additional therapeutic agents include, for example, those useful as 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), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine, cilnidipine), and beta-blockers (e.g., metoprolol, atenolol, propranolol, carvedilol, pindolol).

[0372] In some embodiments, the one or more additional therapeutic agents include, for example, those useful as diuretics. Non-limiting examples include xanthine derivatives (e.g., theobromine sodium salicylate, theobromine calcium salicylate), thiazide preparations (e.g., ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penfluthiazide, polythiazide, methyclothiazide), antialdosterone preparations (e.g., spironolactone, triamterene), carbonic anhydrase inhibitors (e.g., acetazolamide), chlorobenzenesulfonamides (e.g., chlorthalidone, mefruside, indapamide).

[0373] In some embodiments, the one or more additional therapeutic agents include, for example, those useful as immunotherapeutic agents. Non-limiting examples include microbial or bacterial compounds (e.g., muramyl dipeptide derivatives, picibanil), polysaccharides with immunopotentiating activity (e.g., lentinan, schizofiran, krestin), cytokines obtained by genetic engineering techniques (e.g., interferons, interleukins (IL), such as IL-1, IL-2, IL-12), and colony-stimulating factors (e.g., granulocyte colony-stimulating factor, erythropoietin).

[0374] In some embodiments, the one or more additional therapeutic agents include those useful as, for example, antithrombotic agents. Non-limiting examples include heparin (e.g., heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarin (e.g., warfarin potassium), antithrombin agents (e.g., aragatroban, dabigatran), FXa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, betrixaban, YM150, WO02 / 06234, WO2004 / 048363, WO2005 / 0307), and the like. 40, compounds described in WO2005 / 058823 and WO2005 / 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 icosapentate, beraprost sodium, sarpogrelate hydrochloride).

[0375] In some embodiments, the one or more additional therapeutic agents include, for example, those useful for treating osteoporosis.Non-limiting examples include alfacalcidol, calcitriol, elcatonin, calcitonin salmon, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium, and risedronate disodium.Suitable examples of vitamins include vitamin B1 and vitamin B12.Suitable examples of erectile dysfunction drugs include apomorphine and sildenafil citrate.Suitable examples of therapeutic agents for urinary frequency or urinary incontinence include flavoxate hydrochloride, oxybutynin hydrochloride, and propiverine hydrochloride.Suitable examples of therapeutic agents for dysuria include acetylcholinesterase inhibitors (e.g., distigmine).Suitable examples of anti-inflammatory agents include nonsteroidal anti-inflammatory drugs, such as aspirin, acetaminophen, and indomethacin.

[0376] Other exemplary additional therapeutic agents include drugs that regulate hepatic glucose balance (e.g., fructose 1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glycogen synthase kinase inhibitors, glucokinase activators), drugs designed to treat complications of long-term hyperglycemia, such as aldose reductase inhibitors (e.g., epalrestat and ranirestat), drugs used to treat complications associated with microangiopathy, anti-dyslipidemic drugs, such as HMG-CoA reductase inhibitors (statins, e.g., rosuvastatin), cin), cholesterol-lowering drugs, bile acid metal sequestering agents (e.g., cholestyramine), cholesterol absorption inhibitors (e.g., plant sterols, e.g., phytosterols), cholesterol ester transfer protein (CETP) inhibitors, inhibitors of the ileal bile acid transport system (IBAT inhibitors), bile acid-binding resins, nicotinic acid (niacin) and its analogs, antioxidants (e.g., probucol), omega-3 fatty acids, antihypertensive agents, e.g., adrenoceptor antagonists, e.g., beta-blockers (e.g., atenolol), alpha-blockers (e.g., doxazosin), mixed alpha / beta-blockers (e.g., alpha-blockers), beta-blockers (e.g., labetalol), adrenergic receptor agonists, e.g., alpha-2 agonists (e.g., clonidine), angiotensin-converting enzyme (ACE) inhibitors (e.g., lisinopril), calcium channel blockers, e.g., dihydropyridines (e.g., nifedipine), phenylalkylamines (e.g., verapamil), benzothiazepines (e.g., diltiazem), angiotensin II receptor antagonists (e.g., candesartan), aldosterone receptor antagonists (e.g., eplerenone), centrally acting adrenergic agents, e.g., central alpha agonists Anticoagulants include steroids (e.g., clonidine), diuretics (e.g., furosemide), hemostatic regulators, such as antithrombotic agents (e.g., fibrinolysis activators), thrombin antagonists, factor VIIa inhibitors, anticoagulants (e.g., vitamin K antagonists, e.g., warfarin), heparin and its low molecular weight analogues, 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), phosphodiesterase inhibitors (e.g.,cilostazol), glycoprotein IIB / IIA inhibitors (e.g., tirofiban), adenosine reuptake inhibitors (e.g., dipyridamole), noradrenergic agonists (e.g., phentermine), serotonergic agents (e.g., sibutramine), diacylglycerol transferase (DGAT) inhibitors, feeding behavior modifiers, pyruvate dehydrogenase kinase (PDK) modulators, serotonin receptor modulators, monoamine transport modulators, e.g., selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine), noradrenergic Narothelin reuptake inhibitors (NARIs), noradrenaline-serotonin reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs) (e.g., toloxatone and amiflamine), compounds described in WO2007 / 013694, WO2007 / 018314, WO2008 / 093639 and WO2008 / 099794, GPR40 agonists (e.g., fasiglifam or its hydrate, WO2004 / 041266, WO2004 / 106276, WO2005 / 063729, WO2005 / 063725, WO2005 / 0 87710, compounds described in WO2005 / 095338, WO2007 / 013689 and WO2008 / 001931), SGLT1 inhibitors, adiponectin or its agonists, IKK inhibitors (e.g., AS-2868), somatostatin receptor agonists, ACC2 inhibitors, anti-cachexia drugs, for example, cyclooxygenase inhibitors (e.g., indomethacin), progesterone derivatives (e.g., megestrol acetate), glucocorticoids (e.g., dexamethasone), metoclopramide drugs, tetrahydrocannabinol drugs, fat metabolism improvers ( e.g., eicosapentaenoic acid), growth hormone, IGF-1, antibodies against cachexia-inducing factors TNF-α, LIF, IL-6 and oncostatin M, metabolism-improving proteins or peptides, e.g., glucokinase (GK), glucokinase regulatory protein (GKRP), uncoupling proteins 2 and 3 (UCP2 and UCP3), peroxisome proliferator-activated receptor α (PPARα), MC4r agonists, insulin receptor agonists, PDE5 inhibitors, glycation inhibitors (e.g., ALT-711), nerve regeneration promoters (e.g., Y-128, VX853,prosaptide), antidepressants (e.g., desipramine, amitriptyline, imipramine), antiepileptics (e.g., lamotrigine, trileptal, keppra, zonegran, pregabalin, halcoceride, carbamazepine), antiarrhythmics (e.g., mexiletine), acetylcholine receptor ligands (e.g., ABT-594), endothelin receptor antagonists (e.g., ABT-627), narcotic analgesics (e.g., morphine), α2 receptor agonists Anti-inflammatory drugs include steroids (e.g., clonidine), topical analgesics (e.g., capsaicin), anxiolytics (e.g., benzothiazepines), phosphodiesterase inhibitors (e.g., sildenafil), dopamine receptor agonists (e.g., apomorphine), cytotoxic antibodies (e.g., T cell receptor and IL-2 receptor-specific antibodies), B cell depletion treatments (e.g., anti-CD20 antibodies (e.g., Rituxan), i-BLyS antibodies), drugs affecting T cell migration (e.g., anti-insulin Tegrin α4 / β1 antibodies (e.g., Tysabri), drugs acting on immunophilins (e.g., cyclosporine, tacrolimus, sirolimus, rapamycin), interferons (e.g., IFN-β), immunomodulatory drugs (e.g., glatiramer), TNF-binding proteins (e.g., circulating receptors), immunosuppressants (e.g., mycophenolic acid), metaglidasen, AMG-131, balaglitazone, MBX-2044, rivoglitazone, aleglitazar, Examples of such anti-inflammatory drugs include tiglitazar, lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, exenatide, exendin-4, memantine, midazolam, ketoconazole, ethyl icosapentate, clonidine, azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, etoposide, piroxicam, NO donors (e.g., nitrates), and NO promoters (e.g., phosphodiesterase inhibitors).

[0377] In some embodiments, one or more additional therapeutic agents include, for example, those useful as antiemetics. As used herein, "antiemetic" refers to any agent that counters (e.g., reduces or eliminates) nausea or vomiting (vomiting). When referring to the therapeutically effective amount of an antiemetic, it is understood that the amount administered is the amount necessary to counter (e.g., reduces or eliminates) nausea or vomiting (vomiting). Without wishing to be bound by theory, it is believed that administering one or more antiemetics in combination with the compound of formula (I) described herein can, for example, allow patients to eat normally, thereby speeding up the response to treatment, and therefore allowing the compound of formula (I) to be administered.

[0378] Non-limiting examples of antiemetic agents include 5HT3 receptor antagonists (serotonin receptor antagonists), neuroleptics / antipsychotics, antihistamines, anticholinergics, steroids (e.g., corticosteroids), NK1 receptor antagonists (e.g., neurokinin 1 substance P receptor antagonists), antidopaminergics / dopamine receptor antagonists, benzodiazepines, and cannabinoids.

[0379] For example, the antiemetic agent may be selected from the group consisting of neuroleptics, antihistamines, anticholinergics, steroids, 5HT-3 receptor antagonists, NK1 receptor antagonists, antidopamines / dopamine receptor antagonists, benzodiazepines and non-psychoactive cannabinoids.

[0380] In some embodiments, the antiemetic agent is a 5HT3 receptor antagonist (serotonin receptor antagonist). Non-limiting examples of 5HT3 receptor antagonists (serotonin receptor antagonists) include granisetron (Kytril), dolasetron, ondansetron (Zofran), tropisetron, ramosetron, palonosetron, alosetron, azasetron, bemesetron, zatisetron, batanopiride, MDL-73147EF; metoclopramide, N-3389 (endo-3,9-dimethyl-3,9-diazabicyclo[3,3,1]non-7-yl-1H-indazole-3-carboxamide dihydrochloride), Y-25130 hydrochloride, MDL 72222, tropanyl-3,5-dimethylbenzoate, 3-(4-allylpiperazin-1-yl)-2-quinoxalinecarbonitrile maleate, zacopride hydrochloride, and mirtazepine. Other non-limiting examples of 5HT3 receptor antagonists (serotonin receptor antagonists) include cilansetron, clozapine, cyproheptadine, dazopride, hydroxyzine, lerisetron, metoclopramide, mianserin, olanzapine, palonosetron (plus netupitant), quetiapine, camosetron, lamosterone, licasetron, risperidone, ziprasidone, and zatosetron.

[0381] In certain embodiments, the 5HT-3 receptor antagonist is granisetron, dolasetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemesetron, zatisetron, batanopiride, MDL-73147EF, metoclopramide, N-3389, Y-25130 hydrochloride, MDL 72222, tropanyl-3,5-dimethylbenzoate, 3-(4-allyl-piperazin-1-yl)-2-quinoxalinecarbonitrile maleate, zacopride hydrochloride, and mirtazepine.

[0382] In certain embodiments, the 5HT-3 receptor antagonist is granisetron, dolasetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemesetron, and zatisetron.

[0383] In certain embodiments, the 5HT-3 receptor antagonist is granisetron, dolasetron, and ondansetron.

[0384] In certain embodiments, the 5HT-3 receptor antagonist is granisetron.

[0385] In certain embodiments, the 5HT-3 receptor antagonist is ondansetron.

[0386] In some embodiments, the antiemetic agent is an antihistamine.Non-limiting examples of antihistamines include piperazine derivatives (e.g., cyclizine, meclizine, and cinnarizine); promethazine; dimenhydrinate (Dramine, Gravol); diphenhydramine; hydroxyzine; buclizine; and meclizine hydrochloride (Bonine, Antivert), doxylamine, and mirtazapine.

[0387] In some embodiments, the antiemetic agent is an anticholinergic agent (an inhibitor of acetylcholine receptors).Non-limiting examples of anticholinergic agents include atropine, scopolamine, glycopyrone, hyoscine, Artan (trihexy-5 trihexyphenidyl hydrochloride), Cogentin (benztropine mesylate), Akineton (biperiden hydrochloride), Dicypal (Norflex orphenadrine citrate), diphenhydramine, hydroxyzine, hyoscyamine, and Chemadrin (procyclidine hydrochloride).

[0388] In some embodiments, the antiemetic agent is a steroid (e.g., a corticosteroid). Non-limiting examples of steroids include betamethasone, dexamethasone, methylprednisolone, Prednisone®, and trimethobenzamide (Tigan).

[0389] In some embodiments, the antiemetic agent is an NK1 receptor antagonist (e.g., a neurokinin 1 substance P receptor antagonist). Non-limiting examples of NK1 receptor antagonists include aprepitant, casopitant, ezlopitant, fosaprepitant, maropitant, netupitant, rolapitant, and vestipitant.

[0390] Other non-limiting examples of NK1 receptor antagonists include MPC-4505, GW597599, MPC-4505, GR205171, L-759274, SR 140333, CP-96,345, BIIF 1149, NKP 608C, NKP 608A, CGP 60829, SR 140333 (norpitantium besylate / chloride), LY 303870 (ranepitant), MDL-105172A, MDL-103896, MEN-11149, MEN-11467, DNK 333A, YM-49244, YM-44778, ZM-274773, MEN-10930, S-19752, Neuronorm, YM-35375, DA-5018, MK-869, L-754030, CJ-11974, L-758298, DNK-33A, 6b-l, CJ-11974 j. Benserazide and carbidopa k. TAK-637 [(aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthyridine-6,13-dione], PD 154075, ([(2-benzofuran)-CHOCO]-(R)-α-MeTrp-(S)-NHCH(CH)Ph), FK888, and (D-Pro, D-Trp, Phe)SP.

[0391] In some embodiments, the antiemetic agent is an antidopamine / dopamine receptor antagonist (e.g., a dopamine receptor antagonist, e.g., a D2 or D3 antagonist).Non-limiting examples include phenothiazines (e.g., promethazine, chlorpromazine, prochlorperazine, perphenazine, hydroxyzine, thiethylperazine, metopimazine); benzamides (e.g., metoclopramide, domperidone), butyrophenones (e.g., haloperidol, droperidol); alizapride, bromopride, clebopride, domperidone, itopride, metoclopramide, trimethobenzamide, and amisulpride.

[0392] In some embodiments, the antiemetic agent is a non-psychoactive cannabinoid (e.g., cannabidiol (CBD), cannabidiol dimethylheptyl (CBD-DMH), tetrahydrocannabinol (THC), a cannabinoid agonist such as WIN 55-212 (a CB1 and CB2 receptor agonist), dronabinol (Marinol®), and nabilone (Cesamet®)).

[0393] Other exemplary antiemetic agents include c-9280 (Merck); benzodiazepines (diazepam, midazolam, lorazepam); neuroleptic / antipsychotics (e.g., dixyrazine, haloperidol, and prochlorperazine (Compazine®)); cerium oxalate; propofol; sodium citrate; dextrose; fructose (Nausene); orthophosphate; fructose; glucose (Emetrol); bismuth subsalicylate (Pepto-Bismol); ephedrine; vitamin B6; essential oils of peppermint, lavender, and lemon; and ginger.

[0394] Still other exemplary antiemetic agents include those described in US20120101089A1; US10,071,088B2; US6,673,792B1; US6,197,329B1; US10,828,297B2; US10,322,106B2; US10,525,033B2; WO2009080351A1; WO2019203753A2; WO2002020001A2; US8,119,697B2; US5,039,528; US20090305964A1; and WO2006 / 111169, each of which is incorporated herein by reference in its entirety.

[0395] In some embodiments, the additional therapeutic agent or regimen is administered to the patient prior to contact or administration of the compound and pharmaceutical composition (e.g., about 1 hour, or about 6 hours, or about 12 hours, or about 24 hours, or about 48 hours, or about 1 week, or about 1 month).

[0396] In some embodiments, the additional therapeutic agent or regimen is administered to the patient at approximately the same time as the contact or administration of the compound and the pharmaceutical composition. For example, the additional therapeutic agent or regimen and the compound and the pharmaceutical composition are provided to the patient simultaneously in the same dosage form. For another example, the additional therapeutic agent or regimen and the compound and the pharmaceutical composition are provided to the patient concurrently in separate dosage forms.

[0397] Patient selection In some embodiments, the methods described herein further comprise identifying a patient (e.g., a subject) in need of such treatment (e.g., by blood assay, body mass index, or other conventional methods known in the art).

[0398] In some embodiments, the methods described herein further include a step of identifying a patient (e.g., a patient) having a disease, disorder, or condition (e.g., a GLP-1-related disease, disorder, or condition) provided herein.

[0399] In some embodiments, the methods described herein further comprise identifying a patient (e.g., a patient) with type 2 diabetes. In some embodiments, determining whether a patient has type 2 diabetes comprises performing an assay to determine the level of hemoglobin A1c (HbA1c), fasting plasma glucose, non-fasting plasma glucose, or any combination thereof. In some embodiments, the level of HbA1c is about 6.5% to about 24.0%. In some embodiments, the level of HbA1c is about 6.5% or greater. In some embodiments, the level of HbA1c is about 8.0% or greater. In some embodiments, the level of HbA1c is about 10.0% or greater. In some embodiments, the level of HbA1c is about 12.0% or greater. In some embodiments, the level of HbA1c is about 14.0% or greater. In some embodiments, the level of HbA1c is about 16.0% or greater. In some embodiments, the level of HbA1c is about 18.0% or greater. In some embodiments, the level of HbA1c is about 20.0% or greater. In some embodiments, the level of HbA1c is about 22.0% or greater. In some embodiments, the level of HbA1c is about 24.0% or greater.

[0400] In some embodiments, the fasting plasma glucose level is about 120 mg / dL or greater to about 750 mg / dL or greater. In some embodiments, the fasting plasma glucose level is about 200 mg / dL or greater to about 500 mg / dL or greater. In some embodiments, the fasting plasma glucose level is about 300 mg / dL or greater to about 700 mg / dL or greater.

[0401] In some embodiments, the non-fasting plasma glucose level is about 190 mg / dL or greater to about 750 mg / dL or greater. In some embodiments, the non-fasting plasma glucose level is about 250 mg / dL or greater to about 450 mg / dL or greater. In some embodiments, the non-fasting plasma glucose level is about 400 mg / dL or greater to about 700 mg / dL or greater.

[0402] In some embodiments, determining whether the patient has type 2 diabetes further comprises determining the patient's BMI. In some embodiments, the patient's BMI is about 22 kg / m 2 More than ~ about 100kg / m 2 In some embodiments, the patient's BMI is about 30 kg / m or greater. 2 More than ~90kg / m 2 In some embodiments, the patient's BMI is about 40 kg / m 2 More than ~about 80kg / m 2 In some embodiments, the patient's BMI is about 50 kg / m or greater. 2 More than ~ about 70kg / m 2 That's all.

[0403] In some embodiments, additional factors (e.g., risk factors) used to determine whether a patient has type 2 diabetes further include the patient's age and ethnicity. In some embodiments, the patient is about 10 years or older. In some embodiments, the patient is about 15 years or older. In some embodiments, the patient is about 20 years or older. In some embodiments, the patient is about 25 years or older. In some embodiments, the patient is about 30 years or older. In some embodiments, the patient is about 35 years or older. In some embodiments, the patient is about 40 years or older. In some embodiments, the patient is about 42 years or older. In some embodiments, the patient is about 44 years or older. In some embodiments, the patient is about 46 years or older. In some embodiments, the patient is about 48 years or older. In some embodiments, the patient is about 50 years or older. In some embodiments, the patient is about 52 years or older. In some embodiments, the patient is about 54 years or older. In some embodiments, the patient is about 56 years or older. In some embodiments, the patient is about 58 years or older. In some embodiments, the patient is about 60 years of age or older. In some embodiments, the patient is about 62 years of age or older. In some embodiments, the patient is about 64 years of age or older. In some embodiments, the patient is about 66 years of age or older. In some embodiments, the patient is about 68 years of age or older. In some embodiments, the patient is about 70 years of age or older. In some embodiments, the patient is about 72 years of age or older. In some embodiments, the patient is about 74 years of age or older. In some embodiments, the patient is about 76 years of age or older. In some embodiments, the patient is about 78 years of age or older. In some embodiments, the patient is about 80 years of age or older. In some embodiments, the patient is about 85 years of age or older. In some embodiments, the patient is about 90 years of age or older.In some embodiments, the patient's age is about 95 years or older. In some embodiments, the patient's ethnicity can be African American, American Indian or Alaska Native, Asian American, Hispanic or Latino, or Native Hawaiian, or Pacific Islander.

[0404] (General synthesis method) The compounds of the present disclosure can be prepared, for example, from readily available starting materials using the following general methods and procedures. Where specific process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it is understood that other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0405] Also, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting specific functional groups are well known in the art. For example, numerous protecting groups are described in TW Greene and GM Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and the references cited therein.

[0406] Additionally, compounds of the present disclosure may contain one or more chiral centers. Thus, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of the present disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, chiral resolving agents, and the like.

[0407] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, CA USA), EMKA-Chemie Gmbh & Co. KG (Eching Germany) or Millipore Sigma (Burlington, MA USA). Others may be prepared by procedures described in standard references, such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or obvious modifications thereof.

[0408] Scheme I illustrates a general method that can be used to synthesize the compounds described herein, where 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 QBare each independently as defined herein, and LG is a leaving group, for example, halo (e.g., hydroxy, alkoxy, halo, etc.). [ka]

[0409] A compound of formula I can be obtained by coupling compound I-1 with compound I-2 under suitable coupling reaction conditions, such as amide bond formation reaction conditions or nucleophilic substitution reaction conditions. The resulting product can be further derivatized to obtain another compound of formula I by methods and chemical transformations known to those skilled in the art. For example, when the leaving group is an electrophile such as an aldehyde, the coupling reaction conditions can include reductive amination reaction conditions. Thus, the transformation can involve two or more reactions or sets of reactants.

[0410] Upon completion of the reaction, the compound of Formula I may be recovered by conventional techniques, such as neutralization, extraction, precipitation, chromatography, filtration, etc. In certain embodiments, where control of stereochem...

Claims

1. Formula I: 【Chemistry 1】 I [In the formula, X is C and Z is N, or X is N and Z is C; Q 1 and Q 5 are each independently N or CR QA and Q 2 , Q 3 and Q 4 are each independently N, CR QA or CR QB where Q 2 , Q 3 and Q 4 At least one of the following is CR QB or Q 1 is a bond; Q 2 , Q 3 , Q 4 and Q 5 are each independently O, S, N, NH, or NR c , C.R. QA or CR QB where Q 2 , Q 3 , Q 4 and Q 5 At least one of the following is CR QB and However, Q 1 -Q 5 the ring containing is aromatic; 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 and R 1a are each independently C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and halo 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; R a are hydrogen, cyano, each independently halo, oxo, C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and heteroaryl 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; R b are each independently C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and halo 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; Or, R a and R b are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, which heterocyclyl is selected from 1 to 3 independently selected C 1-6 optionally substituted with alkyl; n is 1, 2, 3, 4, 5 or 6; Each R i are independently hydrogen, halo, or C 1-6 is alkyl; Or, R a and R i , or R b and R i are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, which heterocyclyl is selected from 1 to 3 independently selected C 1-6 optionally substituted with alkyl; Each R j are independently hydrogen, halo, or C 1-6 is alkyl; Or, one R i and one R j together with the atoms to which they are bonded, form C 3-6 Form a cycloalkyl, wherein the cycloalkyl is selected from 1 to 3 independently selected C 1-6 optionally substituted with alkyl; Or, one R on an adjacent carbon atom i and one R j each taken together with the atom to which it is attached forms an alkene, the alkene being selected from 1 to 3 independently selected C 1-6 optionally substituted with alkyl; Each R QA are independently hydrogen, halo, cyano, hydroxy, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e , 1 to 6 independently selected R f C optionally substituted with 1-6 alkyl, each independently hydroxy, halo and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 Alkoxy, each independently C 1-6 Alkyl and -C(O)(C 1-6 3- to 12-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of alkyl, 1 to 3 independently selected -C(O)(C 1-6 C optionally substituted with alkyl 6-10 aryl, and 1 to 6 independently selected R g is a 5-10 membered heteroaryl optionally substituted with Or, two R on adjacent carbon atoms QA are taken together with the atom to which each is attached to form a 5- to 8-membered heterocyclyl, the ring being joined by 1 to 2 independently selected R h optionally substituted with; Or, R a or R b and adjacent R QA are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, which heterocyclyl is selected from 1 to 2 independently selected R h optionally substituted with; L 2 is one to two independently selected R h C optionally substituted with 6-10 aryl, 1 to 2 independently selected R h 5- to 10-membered heteroaryl optionally substituted with 【Chemistry 2】 where aa is Q 1 -Q 5 represents a point of attachment to a ring containing n1 is 1, 2 or 3; L 2A is a bond or C 1-10 alkylene; R La is hydrogen, C 1-6 Alkyl or -C(O)(C 1-6 alkyl); R Lb and R Lc each independently represents hydrogen or C 1-6 is alkyl; Ring A is C 6-10 Aryl, C 5-7 cycloalkyl, 5- to 7-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is selected from 1 to 5 independently selected R A optionally substituted with; Each R A independently, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 is cycloalkyl; R 1 , R 2 and R 3 are each independently hydrogen, or independently halo, hydroxy, and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 is alkyl; L 1 is -C(O)-, -CH 2 -, -CH(C 1-6 alkyl)- or -S(O) 2 - and; Ring B is a 5,6-fused heteroaryl having 5 to 8 carbon atoms and 1 to 3 heteroatoms independently selected from O, S, and N, and said ring B is R 8 and independently substituted with halo, oxo, and C 1-6 optionally substituted with 1 to 4 substituents selected from alkyl; R 8 is phenyl, 5- to 6-membered heteroaryl, or 【Transformation 3】 and the phenyl or 5- to 6-membered heteroaryl is R 8c and substituted with 1 to 3 independently selected R h optionally substituted with; L 3 is a bond or C 1-3 alkylene; L 4 is a bond or C 1-5 alkylene; R 8a and R 8b are each independently hydrogen, or independently halo and C 3-15 C optionally substituted with one or more substituents selected from the group consisting of cycloalkyl 1-6 is alkyl; or R 8a and R 8b Each of these, together with the carbon atom to which it is attached, is one to three independently selected C 1-6 C optionally substituted with alkyl 3-15 Forms a cycloalkyl ring, 1-6 Alkyl is one to six independently selected R f optionally substituted with; Each R 8c are independently -C(O)OH, -S(O) 2 OH, -S(O) 2 NH 2 , -L 5 -C 1-6 Alkyl, -L 5 -C 3-6 Cycloalkyl, -L 5 -C 6-10 Aryl, -L 5 -5- to 6-membered heterocyclyl, -L 5 -(5- to 6-membered heteroaryl), each of which is independently hydroxy, halo, and C 1-6 optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy; Each L 5 are independently -C(O)-, -C(O)O-, -OC(O)-, -S(O) 1-2 -, -S(O) 2 O-, -S(O) 2 NH- or -NHS(O) 2 - and; R 9 is -C(O)OR 9a , -C(O)NR 9a R 9b , 1 to 3 independently selected R 9c 5-6 membered heteroaryl optionally substituted with 1 to 3 independently selected R 9c 4- to 6-membered heterocyclyl optionally substituted by 【Chemistry 4】 and X 1 is O or S; R 9a is hydrogen or C 1-6 is alkyl; R 9b is hydrogen, C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -S(O) 0-2 (C 1-6 alkyl) or cyano; Each R 9c are independently selected from hydrogen, oxo, 1 to 6 independently selected halo, and C 1-6 C optionally substituted with alkoxy 1-6 Alkyl, or -C(O)(C 1-6 alkyl); Ring C is a 3- to 12-membered heterocyclyl, C 3-15 cycloalkyl or 5- to 10-membered heteroaryl, each of which is selected from 1 to 3 R Ca optionally substituted with; Each R Ca are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c R d and or a pair of R on the same or different ring atoms Ca are taken together with the ring atoms to which they are each attached to form a carbocyclic ring containing from 3 to 8 ring atoms; Each R c and R d are each 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), -S(O) 1-2 (C 1-6 alkyl) or -S(O) 1-2 (C 3-6 cycloalkyl), and the C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)O(C 1-6 alkyl), -S(O) 1-2 (C 1-6 alkyl) and -S(O) 1-2 (C 3-6 cycloalkyl) are each independently selected from hydroxy, halo, and C 1-6 optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy; R e is hydrogen, C 1-6 Alkyl or C 1-6 haloalkyl; Each R f are independently halo, hydroxy, -NR c R d , C 1-6 Alkoxy, C 1-6 haloalkoxy, or each independently hydroxy, C 1-6 is a 3- to 12-membered heterocyclyl optionally substituted by 1 to 4 substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; Each R g independently, C 1-6 Alkyl, C 1-6 Alkoxy, -NR c R d , or each independently C 1-6 Alkyl and -C(O)C 1-6 alkyl; and Each R h are independently halo, cyano, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, -NH 2 , -NH(C 1-3 alkyl), -N(C 1-3 alkyl) 2 , C 1-3 Alkoxy or C 1-3 haloalkoxy] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof.

2. The compound has the formula II: 【Transformation 5】 II 2. The compound of claim 1, represented by:

3. The compound has formula III: 【Transformation 6】 III 2. The compound of claim 1, represented by:

4. Q 1 and Q 5 are each independently N or CR QA and Q 2 , Q 3 and Q 4 are each independently N, CR QA or CR QB where Q 2 , Q 3 and Q 4 At least one of the QB The compound according to any one of claims 1 to 3, wherein

5. Each R QA are independently hydrogen, halo, C 1-6 Alkyl, C 1-6 Alkoxy or -NR c R d The compound according to any one of claims 1 to 4, wherein

6. Q 1 and Q 5 Each independently CR QA and each R QA The compound of any one of claims 1 to 5, wherein is independently hydrogen or halo.

7. Q 2 , Q 3 and Q 4 The compound according to any one of claims 1 to 6, wherein one of is N.

8. R QB But -S(O)(=NR a )R b or -CH 2 -S(O)(=NR a )R b The compound according to any one of claims 1 to 7, wherein

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

10. R a are hydrogen, cyano, each independently halo, oxo, C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and heteroaryl 1-6 The compound of any one of claims 1 to 9, which is alkyl.

11. R b However, each independently C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and halo 1-6 Alkyl, or C 3-6 The compound of any one of claims 1 to 10, which is cycloalkyl.

12. R a and R b and R 1 and R 2 together with the atom to which they are each attached form a 5- to 8-membered heterocyclyl.

13. R a or R b and adjacent R QA are taken together with the atom to which each is attached to form a 5- to 8-membered heterocyclyl, and the heterocyclyl is selected from 1 to 2 independently selected R h The compound of any one of claims 1 to 9, optionally substituted with

14. L 2 is one to two independently selected R h C optionally substituted with 6-10 aryl, 【Transformation 7】 wherein aa is Q 1 -Q 5 14. The compound of any one of claims 1 to 13, wherein the compound represents a point of attachment to a ring comprising:

15. L 2A The compound of any one of claims 1 to 14, wherein is a bond.

16. R 1 and R 2 The compound of any one of claims 1 to 15, wherein each is hydrogen.

17. R 3 But C 1-6 17. The compound of any one of claims 1 to 16, which is alkyl.

18. L 1 The compound of any one of claims 1 to 17, wherein is -C(O)-.

19. Ring A is independently halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-6 C optionally substituted with 1 to 5 substituents selected from the group consisting of cycloalkyl 6-10 The compound of any one of claims 1 to 18, which is aryl.

20. Ring A is independently halo, C 1-6 Alkyl and C 3-6 20. The compound of any one of claims 1 to 19, which is phenyl substituted with 2 to 3 substituents selected from the group consisting of cycloalkyl.

21. Ring B is 【Transformation 8】 wherein bb is L 1 21. The compound of any one of claims 1 to 20, wherein the compound represents a point of attachment to

22. R 8 But R 8c 22. The compound of any one of claims 1 to 21, which is a substituted phenyl.

23. R 8 But R 8c The compound of any one of claims 1 to 22, which is a substituted 5- to 6-membered heteroaryl.

24. Ring B is 【Chemistry 9】 wherein bb is L 1 24. The compound of any one of claims 1 to 23, wherein the compound represents a point of attachment to

25. Ring B is 【Chemistry 10】 wherein bb is L 1 25. The compound of any one of claims 1 to 24, wherein the compound represents a point of attachment to

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

27. L 4 26. The compound of any one of claims 1-21 or 24-25, wherein is a bond.

28. Formula IIA: 【Chemistry 11】 IIA wherein q is 0, 1, 2, 3, 4, or 5, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

29. Ring B is 【Chemistry 12】 wherein bb is L 1 29. The compound of any one of claims 1 to 28, wherein the compound represents a point of attachment to

30. R 4 30. The compound of any one of claims 1 to 29, wherein is hydrogen or halo.

31. R 5 , R 6 and R 7 31. The compound of any one of claims 1 to 30, wherein each is hydrogen.

32. R 8a and R 8b 32. The compound of any one of claims 1 to 31, wherein each is independently hydrogen.

33. R 8a and R 8b together with the carbon atoms to which they are attached, form C 1-6 Optionally alkyl-substituted C 3-15 The compound of any one of claims 1 to 32, which forms a cycloalkyl ring.

34. R 9 is one to three independently selected R 9c 5- to 6-membered heteroaryl optionally substituted with 【Chemistry 13】 34. The compound of any one of claims 1 to 33, wherein

35. R 9 is a 6-membered heteroaryl.

36. R 9 but, 【Chemistry 14】 36. The compound of any one of claims 1 to 35, wherein

37. Ring C is one to three R Ca 37. The compound of any one of claims 1 to 36, wherein the heterocyclyl is 3 to 12 membered, optionally substituted with:

38. Each R Ca But C 1-6 38. The compound of any one of claims 1 to 37, which is alkyl.

39. Ring C is 【Chemistry 15】 39. The compound of any one of claims 1 to 38, wherein

40. 3. The compound of formula IIIA: 【Chemistry 16】 IIIA [In the formula, Q 2 is N or CR QA and R a are hydrogen, cyano, each independently halo, oxo, C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and heteroaryl 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; R b are each independently C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and halo 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; Or, R a and R b are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, which heterocyclyl is selected from 1 to 3 independently selected C 1-6 optionally substituted with alkyl; Each R QA are independently hydrogen, halo, cyano, hydroxy, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e , 1 to 6 independently selected R f C optionally substituted with 1-6 alkyl, each independently hydroxy, halo and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 Alkoxy, each independently C 1-6 Alkyl and -C(O)(C 1-6 3- to 12-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of alkyl, 1 to 3 independently selected -C(O)(C 1-6 C optionally substituted with alkyl 6-10 aryl, and 1 to 6 independently selected R g is a 5-10 membered heteroaryl optionally substituted with Or, R a or R b and adjacent R QA are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, which heterocyclyl is selected from 1 to 2 independently selected R h optionally substituted with; Each R Ca independently, C 1-6 is alkyl; q is 0, 1, 2, 3, 4 or 5; Each R A independently, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 is cycloalkyl; R 3 are hydrogen, or independently halo, hydroxy and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 is alkyl; R 9 is -C(O)OR 9a , -C(O)NR 9a R 9b , 1 to 3 independently selected R 9c 5-6 membered heteroaryl optionally substituted with 1 to 3 independently selected R 9c 4- to 6-membered heterocyclyl optionally substituted by 【Chemistry 17】 and X 1 is O or S; R 9a is hydrogen or C 1-6 is alkyl; R 9b is hydrogen, C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -S(O) 0-2 (C 1-6 alkyl) or cyano; Each R 9c are independently selected from hydrogen, oxo, 1 to 6 independently selected halo, and C 1-6 C optionally substituted with alkoxy 1-6 Alkyl, or -C(O)(C 1-6 alkyl); Each R c and R d are each 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), -S(O) 1-2 (C 1-6 alkyl) or -S(O) 1-2 (C 3-6 cycloalkyl), and the C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)O(C 1-6 alkyl), -S(O) 1-2 (C 1-6 alkyl) and -S(O) 1-2 (C 3-6 cycloalkyl) are each independently selected from hydroxy, halo, and C 1-6 optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy; Each R e are independently hydrogen, C 1-6 Alkyl or C 1-6 haloalkyl; w is 0, 1, 2 or 3; Each R 1f independently, C 1-6 alkyl, and each C 1-6 Alkyl is independently selected from 1 to 6 independently selected R f optionally substituted with; Each R f are independently halo, hydroxy, -NR c R d , C 1-6 Alkoxy, C 1-6 haloalkoxy, or each independently hydroxy, C 1-6 is a 3- to 12-membered heterocyclyl optionally substituted by 1 to 4 substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; Each R g independently, C 1-6 Alkyl, C 1-6 Alkoxy, -NR c R d , or each independently C 1-6 Alkyl and -C(O)C 1-6 alkyl; and Each R h are independently halo, cyano, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, -NH 2 , -NH(C 1-3 alkyl), -N(C 1-3 alkyl) 2 , C 1-3 Alkoxy or C 1-3 haloalkoxy] 2. The compound of claim 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, which is a compound of the formula:

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

42. the below described: 【Chemistry 18-1】 【Chemistry 18-2】 【Chemistry 18-3】 【Chemistry 18-4】 【Chemistry 18-5】 【Chemistry 18-6】 A compound selected from: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or prodrug thereof.

43. the below described: 【Chemistry 19-1】 【Chemistry 19-2】 A compound selected from: or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or prodrug thereof.

44. 44. A pharmaceutical composition comprising a compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or prodrug thereof, and a pharmaceutically acceptable excipient.

45. 46. ​​A method of treating a disease, disorder or condition associated with GLP-1, comprising administering to a patient in need thereof an effective amount of a compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or prodrug thereof, or a pharmaceutical composition of claim 44.

46. The disease, disorder or condition is type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), young-onset atypical diabetes (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of adults (LADA), obesity, weight gain due to use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, or sleep apnea. , visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, vascular restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial lipemia, metabolic acidosis, ketosis , hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, treatment of addiction, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulceration, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof.

47. 46. ​​A method of treating type 2 diabetes in a patient in need thereof, comprising administering to a patient in need thereof an effective amount of a compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or prodrug thereof, or a pharmaceutical composition of claim 44.

48. 44. A method of modulating insulin levels in a patient in need thereof, comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or prodrug thereof, or a pharmaceutical composition according to claim 44.

49. 46. ​​A method of regulating glucose levels in a patient in need thereof, comprising administering to a patient in need thereof an effective amount of a compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or prodrug thereof, or a pharmaceutical composition of claim 44.

50. 50. The method of any one of claims 45 to 49, further comprising administering to the patient an additional treatment or therapeutic agent.

51. 51. The method of claim 50, wherein the additional treatment or therapeutic agent is selected from the group consisting of an antidiabetic agent, an antiobesity agent, a GLP-1 receptor agonist, an antiemetic agent, a nonalcoholic steatohepatitis (NASH) therapeutic agent, gastric electrical stimulation, dietary monitoring, physical activity, or a combination thereof.

52. Formula I: 【Chemistry 20】 I or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, comprising a compound of formula I-1: 【Chemistry 21】 I-1 with a compound of formula I-2: 【Chemistry 22】 I-2 under conditions sufficient to obtain a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof; During the ceremony, 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 are each independently N or CR QA and Q 2 , Q 3 and Q 4 are each independently N, CR QA or CR QB where Q 2 , Q 3 and Q 4 At least one of the following is CR QB or Q 1 is a bond; Q 2 , Q 3 , Q 4 and Q 5 are each independently O, S, N, NH, or NR c , C.R. QA or CR QB where Q 2 , Q 3 , Q 4 and Q 5 At least one of the following is CR QB and However, Q 1 -Q 5 the ring containing is aromatic; 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 and R 1a are each independently C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and halo 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; R a are hydrogen, cyano, each independently halo, oxo, C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and heteroaryl 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; R b are each independently C 1-6 Alkoxy, C 3-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of cycloalkyl and halo 1-6 alkyl, each independently C 1-3 C optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl and halo 3-6 cycloalkyl, or 1 to 3 independently selected C 1-3 C optionally substituted with alkyl 6-10 is aryl; Or, R a and R b are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, which heterocyclyl is selected from 1 to 3 independently selected C 1-6 optionally substituted with alkyl; n is 1, 2, 3, 4, 5 or 6; Each R i are independently hydrogen, halo, or C 1-6 is alkyl; Or, R a and R i , or R b and R i are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, which heterocyclyl is selected from 1 to 3 independently selected C 1-6 optionally substituted with alkyl; Each R j are independently hydrogen, halo, or C 1-6 is alkyl; Or, one R i and one R j together with the atoms to which they are bonded, form C 3-6 Form a cycloalkyl, wherein the cycloalkyl is selected from 1 to 3 independently selected C 1-6 optionally substituted with alkyl; Or, one R on an adjacent carbon atom i and one R j each taken together with the atom to which it is attached forms an alkene, the alkene being selected from 1 to 3 independently selected C 1-6 optionally substituted with alkyl; Each R QA are independently hydrogen, halo, cyano, hydroxy, -NR c R d , -C(O)NR c R d , -S(O) 0-2 R e , 1 to 6 independently selected R f C optionally substituted with 1-6 alkyl, each independently hydroxy, halo and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 Alkoxy, each independently C 1-6 Alkyl and -C(O)(C 1-6 3- to 12-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of alkyl, 1 to 3 independently selected -C(O)(C 1-6 C optionally substituted with alkyl 6-10 aryl, and 1 to 6 independently selected R g is a 5-10 membered heteroaryl optionally substituted with Or, two R on adjacent carbon atoms QA are taken together with the atom to which each is attached to form a 5- to 8-membered heterocyclyl, the ring being joined by 1 to 2 independently selected R h optionally substituted with; Or, R a or R b and adjacent R QA are taken together with the atom to which they are attached to form a 5- to 8-membered heterocyclyl, which heterocyclyl is selected from 1 to 2 independently selected R h optionally substituted with; L 2 is one to two independently selected R h C optionally substituted with 6-10 aryl, 1 to 2 independently selected R h 5- to 10-membered heteroaryl optionally substituted with 【Chemistry 23】 where aa is Q 1 -Q 5 represents a point of attachment to a ring containing n1 is 1, 2 or 3; L 2A is a bond or C 1-10 alkylene; R La is hydrogen, C 1-6 Alkyl or -C(O)(C 1-6 alkyl); R Lb and R Lc each independently represents hydrogen or C 1-6 is alkyl; Ring A is C 6-10 Aryl, C 5-7 cycloalkyl, 5- to 7-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is selected from 1 to 5 independently selected R A optionally substituted with; Each R A independently, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-6 is cycloalkyl; R 1 , R 2 and R 3 are each independently hydrogen, or independently halo, hydroxy, and C 1-6 C optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy 1-6 is alkyl; L 1 is -C(O)-, -CH 2 -, -CH(C 1-6 alkyl)- or -S(O) 2 - and; Ring B is a 5,6-fused heteroaryl having 5 to 8 carbon atoms and 1 to 3 heteroatoms independently selected from O, S, and N, and said ring B is R 8 and independently substituted with halo, oxo, and C 1-6 optionally substituted with 1 to 4 substituents selected from alkyl; R 8 is phenyl, 5- to 6-membered heteroaryl, or 【Chemistry 24】 and the phenyl or 5- to 6-membered heteroaryl is R 8c and substituted with 1 to 3 independently selected R h optionally substituted with; L 3 is a bond or C 1-3 alkylene; L 4 is a bond or C 1-5 alkylene; R 8a and R 8b are each independently hydrogen, or independently halo and C 3-15 C optionally substituted with one or more substituents selected from the group consisting of cycloalkyl 1-6 is alkyl; or R 8a and R 8b Each of these, together with the carbon atom to which it is attached, is one to three independently selected C 1-6 C optionally substituted with alkyl 3-15 Forms a cycloalkyl ring, 1-6 Alkyl is one to six independently selected R f optionally substituted with; Each R 8c are independently -C(O)OH, -S(O) 2 OH, -S(O) 2 NH 2 , -L 5 -C 1-6 Alkyl, -L 5 -C 3-6 Cycloalkyl, -L 5 -C 6-10 Aryl, -L 5 -5- to 6-membered heterocyclyl, -L 5 -(5- to 6-membered heteroaryl), each of which is independently hydroxy, halo, and C 1-6 optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy; Each L 5 are independently -C(O)-, -C(O)O-, -OC(O)-, -S(O) 1-2 -, -S(O) 2 O-, -S(O) 2 NH- or -NHS(O) 2 - and; R 9 is -C(O)OR 9a , -C(O)NR 9a R 9b , 1 to 3 independently selected R 9c 5-6 membered heteroaryl optionally substituted with 1 to 3 independently selected R 9c 4- to 6-membered heterocyclyl optionally substituted by 【Chemistry 25】 and X 1 is O or S; R 9a is hydrogen or C 1-6 is alkyl; R 9b is hydrogen, C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -S(O) 0-2 (C 1-6 alkyl) or cyano; Each R 9c are independently selected from hydrogen, oxo, 1 to 6 independently selected halo, and C 1-6 C optionally substituted with alkoxy 1-6 Alkyl, or -C(O)(C 1-6 alkyl); Ring C is a 3- to 12-membered heterocyclyl, C 3-15 cycloalkyl or 5- to 10-membered heteroaryl, each of which is selected from 1 to 3 R Ca optionally substituted with; Each R Ca are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or NR c R d and or a pair of R on the same or different ring atoms Ca are taken together with the ring atoms to which they are each attached to form a carbocyclic ring containing from 3 to 8 ring atoms; Each R c and R d are each 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), -S(O) 1-2 (C 1-6 alkyl) or -S(O) 1-2 (C 3-6 cycloalkyl), and the C 1-6 Alkyl, -C(O)(C 1-6 alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)O(C 1-6 alkyl), -S(O) 1-2 (C 1-6 alkyl) and -S(O) 1-2 (C 3-6 cycloalkyl) are each independently selected from hydroxy, halo, and C 1-6 optionally substituted with 1 to 6 substituents selected from the group consisting of alkoxy; R e is hydrogen, C 1-6 Alkyl or C 1-6 haloalkyl; Each R f are independently halo, hydroxy, -NR c R d , C 1-6 Alkoxy, C 1-6 haloalkoxy, or each independently hydroxy, C 1-6 is a 3- to 12-membered heterocyclyl optionally substituted by 1 to 4 substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; Each R g independently, C 1-6 Alkyl, C 1-6 Alkoxy, -NR c R d , or each independently C 1-6 Alkyl and -C(O)C 1-6 alkyl; and Each R h are independently halo, cyano, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, -NH 2 , -NH(C 1-3 alkyl), -N(C 1-3 alkyl) 2 , C 1-3 Alkoxy or C 1-3 haloalkoxy.

53. 53. The method of claim 52, further comprising a hydrolysis or transesterification step before or after the contacting.

54. 54. A method according to claim 52 or 53, comprising a base, and optionally an elevated temperature.

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