Heterocyclic GLP-1 agonists

Abstract

The present invention relates generally to GLP-1 agonists and pharmaceutical compositions containing same, as well as methods for treating GLP-1-associated diseases, disorders or conditions.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of International Patent Application PCT / CN2022 / 141073, filed December 22, 2022, the contents of which are incorporated herein by reference in their entirety.

[0002] Field This application relates to GLP-1 agonists, pharmaceutical compositions and methods of use thereof. [Background technology]

[0003] background Incretin metabolic hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are important in controlling glucose homeostasis. Drugs 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 mellitus is a group of metabolic disorders characterized by persistent hyperglycemia. The most common form, type 2 diabetes mellitus (T2DM), is an acquired condition that accounts for over 90% of diabetes cases. It typically develops in obese or otherwise sedentary adults and begins with insulin resistance. While lifestyle changes can be useful in managing this disorder, patients with T2DM may require the ingestion of 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 insulin secretion in response to glucose ingestion. Although this incretin effect is significantly reduced (if present) in T2DM, GLP-1 maintains its insulinotropic properties even when the endocrine pancreatic response to GIP is virtually abolished. Thus, incretin mimetics and other GLP-1-based therapies can help stimulate insulin production in T2DM patients. Summary of the Invention [Problem to be solved by the invention]

[0006] overview This application relates to 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 some embodiments, a compound of Formula I: [ka] [In the formula, ring A, ring B, Z 1 , Z 2 , R 1 , R 2 , R 4 , R 5 , R 6 , R 7 and p are each independently as defined herein. or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof is provided.

[0008] The present invention 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 herein are pharmaceutical compositions 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 herein is a method of treating type 2 diabetes in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture, or prodrug thereof, or a pharmaceutical composition thereof.

[0011] Also provided herein 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, stereoisomeric mixture, or prodrug thereof, or a pharmaceutical composition thereof.

[0012] Also provided herein 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 analog, stereoisomer, stereoisomeric mixture, 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 HbA1c level is about 6.5% or higher. In some embodiments, the fasting plasma glucose level is about 126 mg / dL or higher. In some embodiments, the non-fasting plasma glucose level 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 body fluid sample. In some embodiments, the patient is about 40 to about 70 years old and overweight or obese. In some embodiments, the patient is about 22 kg / m 2 In one embodiment, the patient has a body mass index (BMI) of about 30 kg / m 2 Have a BMI of 100 or above.

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

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

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

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

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

[0019] In certain 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 mellitus comprises further administering to patients additional treatments or therapeutic agents.In some embodiments, the additional treatments or therapeutic agents are selected from the group consisting of antidiabetic agents, antiobesity agents, GLP-1 receptor agonists, non-alcoholic steatohepatitis (NASH) treatment agents, antiemetic agents, gastric electrical stimulation, dietary monitoring, physical activity, or any combination thereof.In some embodiments, the antidiabetic agent is selected from the group consisting of biguanides, sulfonylureas, glitazars, thiazolidinediones, dipeptidyl peptidase 4 (DPP-4) inhibitors, meglitinides, sodium-glucose cotransporter 2 (SGLT2) inhibitors, glitazones, GRP40 agonists, glucose-dependent insulinotropic peptide (GIP), insulin or insulin analogs, alpha-glucosidase inhibitors, sodium-glucose cotransporter 1 (SGLT1) inhibitors, or any combination thereof.In some embodiments, the biguanide is metformin. In certain embodiments, the anti-obesity agent is selected from the group consisting of a neuropeptide Y receptor type 2 (NPYR2) agonist, an NPYR1 or NPYR5 antagonist, human islet precursor peptide (HIP), a cannabinoid receptor type 1 (CB1R) antagonist, a lipase inhibitor, a melanocortin receptor 4 agonist, a farnesoid X receptor (FXR) agonist, phentermine, zonisamide, a norepinephrine / dopamine reuptake inhibitor, a GDF-15 analog, an opioid receptor antagonist, a cholecystokinin agonist, a serotonergic agent, a methionine aminopeptidase 2 (MetAP2) inhibitor, diethylpropion, phendimetrazine, benzphetamine, a fibroblast growth factor receptor (FGFR) modulator, an AMP-activated protein kinase (AMPK) activator, or any combination thereof. In certain embodiments, the GLP-1 receptor agonist is selected from the group consisting of liraglutide, exenatide, dulaglutide, albiglutide, taspoglutide, lixisenatide, semaglutide, or any combination thereof.In some embodiments, the NASH treatment agent is selected from the group consisting of FXR agonist, PF-05221304, synthetic fatty acid-bile acid conjugate, anti-lysyl oxidase homolog 2 (LOXL2) monoclonal antibody, caspase inhibitor, MAPK5 inhibitor, galectin 3 inhibitor, fibroblast growth factor 21 (FGF21) agonist, niacin analog, leukotriene D4 (LTD4) receptor antagonist, acetyl-CoA carboxylase (ACC) inhibitor, ketohexokinase (KHK) inhibitor, ileal bile acid transporter (IBAT) inhibitor, apoptosis signal-regulating kinase 1 (ASK1) inhibitor, or any combination thereof.In some embodiments, the compound of Formula I, or its pharmaceutically acceptable salt, isotope-enriched analog, stereoisomer, stereoisomer mixture or prodrug, or pharmaceutical composition thereof, and additional therapeutic agent are administered sequentially as separate doses in any order.

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

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

[0023] Also provided herein is a method for treating a GLP-1-associated disease, disorder, or condition, comprising administering to a patient in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the disease, disorder, or condition is selected from the group consisting of type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of adults (LADA), obesity, weight gain due to the use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, lipid Adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, vascular restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial lipemia, The disease is selected from the group consisting of metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot 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, Alzheimer's disease, cognitive impairment, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof.In certain embodiments, the disease, disorder, or condition is selected from the group consisting of type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar 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, atherosclerotic cardiovascular disease, hyperglycemia, postprandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorder, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulceration, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS), or any combination thereof. In certain embodiments, the disease, disorder, or condition includes, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar 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. In the event that the publications and patents or patent applications incorporated by reference conflict with the disclosure contained herein, it is intended that the present specification supersede and / or take precedence over any such conflicting material. DETAILED DESCRIPTION OF THE INVENTION

[0025] description 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.

[0026] Before the present compounds and methods are described, it is to be understood that this invention is not limited to the methodology, protocols, 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 invention, and is not intended in any way to limit the scope of the invention, which is set forth in the appended claims.

[0027] definition The following description sets forth 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 invention, but rather is provided as a description of exemplary embodiments.

[0028] As used herein, the following words, phrases and symbols are generally intended to have the meanings indicated below, unless otherwise indicated by the context in which they are used.

[0029] A dash ("-") that is not between two letters or symbols is used to indicate the 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; a chemical group may be written with or without one or more dashes without losing its ordinary meaning. A wavy or dashed line drawn through a line in a structure indicates a particular point of attachment of a group. Unless chemically or structurally required, no orientation or stereochemistry is indicated or implied by the order in which chemical groups are written or named.

[0030] Prefix “C” u-v " indicates that the following group has u to v carbon atoms. For example, "C1-6 "Alkyl" indicates that the alkyl group has from 1 to 6 carbon atoms.

[0031] Reference herein to "about" a value or parameter includes (and describes) embodiments relating to the value or parameter itself. In certain embodiments, the term "about" includes the indicated amount ±10%. In other embodiments, the term "about" includes the indicated amount ±5%. In certain other embodiments, the term "about" includes the indicated amount ±1%. Also, the term "about x" includes reference to "x". Also, references to singular entities include references to plural entities unless the context clearly dictates otherwise. Thus, for example, reference to a "compound" includes reference to a plurality of such compounds, and reference to an "assay" includes reference to one or more assays, and equivalents thereof, known to those of skill in the art.

[0032] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to a group having 1 to 20 carbon atoms (i.e., C 1-20 alkyl), 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 identified 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).

[0033] "Alkenyl" refers to an alkyl group containing at least one (e.g., 1 to 3, or 1) carbon-carbon double bond and having 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 Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0034] "Alkynyl" refers to an alkyl group containing at least one (e.g., 1 to 3, or 1) carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2-20 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" refers to an alkyl group having one triple bond and one double bond.

[0035] 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.

[0036] "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.

[0037] "Thioalkoxy" refers to the group "alkyl-S-".

[0038] "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, when a residue is substituted with more than one halogen, it can be described using a prefix corresponding to the number of halogens attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two ("di") or three ("tri") halo groups, which may, but are not necessarily, 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.

[0039] "Haloalkoxy" refers to an alkoxy group, as defined above, in which one or more (eg, 1 to 6, or 1 to 3) hydrogen atoms have been replaced with halogen.

[0040] "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 a hydroxy group.

[0041] "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.

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

[0043] "Acyl" refers to the group -C(O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which is optionally substituted as defined herein. Examples of acyl include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0044] An "amide" is the group -C(O)NR y R z The group -NR refers to a "C-amido" group and the group -NR refers to an "N-amido" group. y C(O)R z (where R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which is optionally substituted as defined herein, or R y and R z together form a cycloalkyl or heterocyclyl, each of which is optionally substituted as defined herein.

[0045] "Amino" is the group -NR y R z (where R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which is optionally substituted as defined herein.

[0046] "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 is optionally substituted as defined herein.

[0047] "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 a group having 6 to 20 ring carbon atoms (i.e., C 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12aryl), or 6 to 10 carbon ring atoms (i.e., C 6-10 aryl). Examples of aryl groups include, for example, phenyl, naphthyl, fluorenyl, and anthryl. However, aryl in no way encompasses or overlaps with heteroaryl, as defined below. If one or more aryl groups are fused to a heteroaryl, the resulting ring system is a heteroaryl, regardless of the point of attachment. If one or more aryl groups are fused to a heterocyclyl, the resulting relationship is a heterocyclyl, regardless of the point of attachment. If one or more aryl groups are fused to a cycloalkyl, the resulting relationship is a cycloalkyl, regardless of the point of attachment.

[0048] "Carbamoyl" is the group -OC(O)NR y R z refers to the "O-carbamoyl" group and the group -NR y C(O)OR z "N-carbamoyl" group (where R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which is optionally substituted as defined herein.

[0049] "Carboxyl ester" or "ester" is -OC(O)R x and -C(O)OR x (where R x is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which is optionally substituted as defined herein.

[0050] "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., cyclic 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. Furthermore, the term cycloalkyl is intended to encompass any non-aromatic ring that may be fused to an aryl ring, regardless of the point of attachment to the rest of the molecule. Still further, cycloalkyl also includes "spirocycloalkyl" when there are two substitutions on the same carbon atom, such as spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.

[0051] "Imino" is the group -C(NR y )R z (where R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which is optionally substituted as defined herein.

[0052] "Halogen" or "halo" refers to atoms occupying Group VIIA of the periodic table, such as fluoro, chloro, bromo, or iodo.

[0053] "Heteroalkyl" refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatomic 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 heteroatomic groups. Heteroatomic 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.

[0054] "Heteroalkylene" refers to a divalent heteroalkyl group. A "heteroalkylene" group must have at least one carbon and at least one heteroatomic group in 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 heteroatomic groups. A heteroatomic group can be -NR y -, -O-, -S-, -S(O)-, -S(O)2-, etc. (where R yis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may 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-, -CH2NR y CH2-, -CH(CH3)NR y CH2-, -CH2CH2NR y CH2-, -CH2CH2NR y CH2CH2NR y CH2- etc. (where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which is 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 with oxo present at one or more carbon atoms.

[0055] "Heteroaryl" refers to an aromatic group having a single ring or multiple condensed rings and having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to a group having from 1 to 20 ring carbon atoms (i.e., C 1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3-12heteroaryl), or 3 to 8 carbon ring atoms (i.e., C 3-8 Heteroaryl) and 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 some cases, heteroaryl includes 5- to 10-membered, 5- to 7-membered, or 5- to 6-membered ring systems, each 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, isoquinolyl, Includes 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. Examples of 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, where the heteroaryl may be attached via any ring of the fused system. Any aromatic ring having a single ring or multiple fused rings containing at least one heteroatom is considered heteroaryl, regardless of the point of attachment to the rest of the molecule (i.e., via any of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.

[0056] "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 spiro-heterocyclyl groups. A heterocyclyl can be a single ring or multiple rings, where the rings can be fused, bridged, or spiro, and can 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 the point 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., can be attached via a carbon atom or a heteroatom) regardless of the attachment point 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 the point of attachment to the rest of the molecule. As used herein, heterocyclyl refers to a ring of 2 to 20 ring carbon atoms (i.e., C) 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. 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) has 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom. 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, octahydroindolinyl, and the like.

[0033] The term "heterocyclyl" includes "spiroheterocyclyl" when there are two substitutions at the same carbon atom. Examples of spiro-heterocyclyl rings include bicyclic and tricyclic ring systems such as, for example, 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. Examples of 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, where the heterocyclyl may be attached via either ring of the fused system.

[0057] "Sulfonyl" refers to the group -S(O)R y (where R yis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which is optionally substituted as defined herein. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0058] "Alkylsulfonyl" refers to the group -S(O)R where R is alkyl.

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

[0060] The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occurs and instances 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 of a specified atom or group that may or may not be replaced with a non-hydrogen moiety.

[0061] 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 depicted structures. Compounds identified by name or structure herein as a particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0062] 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, an amide-containing compound is understood to include its imidic acid tautomer. Similarly, an imidic acid-containing compound is understood to include its amide tautomer.

[0063] Any compound or structure depicted herein is intended to represent unlabeled and isotopically labeled forms of the compound. These forms of the compound may also be referred to as "isotopically enriched analogs." Isotopically labeled compounds have the structures depicted herein except that one or more atoms are replaced with an atom having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, e.g., 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 invention, such as 3 H and 14 Those incorporating a radioactive isotope such as C. Such isotopically labeled compounds may be useful in metabolism 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 radioactive treatment of patients.

[0064] The term "isotopically enriched analog" includes "deuterated analogs" of the compounds described herein in which one or more hydrogens, such as hydrogens on carbon atoms, have been replaced with deuterium. Such compounds exhibit increased resistance to metabolism and are therefore useful for extending the half-life of a compound when administered to mammals, particularly humans. See, e.g., 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, using starting materials in which one or more hydrogens have been replaced with deuterium.

[0065] Deuterium-labeled or substituted therapeutic compounds disclosed herein may have improved DMPK (drug metabolism and pharmacokinetic) properties, which relate to distribution, metabolism, and excretion (ADME). Substitution with heavy isotopes such as deuterium may provide 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 C-labeled compounds may be useful for PET or SPECT or other imaging studies. Isotopically labeled compounds of the present invention and their prodrugs can generally be prepared by carrying out the procedures disclosed in the schemes or examples, substituting readily available isotopically labeled reagents for non-isotopically labeled reagents. It is understood that deuterium in this context is considered a substituent of the compounds described herein.

[0066] The concentration of such heavy isotopes, particularly deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present invention, 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", it is understood that the position has hydrogen of its natural abundance isotopic composition. Thus, in the compounds of the present invention, any atom specifically designated as deuterium (D) is intended to represent deuterium.

[0067] In many cases, the compounds of the present invention are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0068] 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 substances that are useful in the manufacture of pharmaceutical compositions suitable for veterinary or human medical use.

[0069] The term "pharmaceutically acceptable salt" of a compound refers to a salt that retains the biological effectiveness and properties of the compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. Furthermore, if a compound described herein is obtained as an acid addition salt, the free base can be obtained by dissolving the acid salt and basifying it. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid, following conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, for example, acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic 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 those derived from N-containing heterocycles, N-containing heteroaryls, or compounds of the formula N(R N )3 (e.g., HN + (R N )3 or (alkyl)N + (R N ) 3) amine-derived salts (wherein each R Nare independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally substituted with one or more (e.g., 1-5 or 1-3) substituents (e.g., halo, cyano, hydroxy, amino, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, or haloalkoxy), etc. 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.

[0070] The term "substituted" means that any one or more hydrogen atoms on the specified atom or group have been replaced with one or more non-hydrogen substituents, provided that the normal valence of the specified atom is not exceeded. 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 certain 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, sulfonate, sulfonyl, thiocyanate, thiol, thione, or a combination thereof.

[0071] Polymers or similar indefinite structures arrived at by the definition of substituent with an infinite number of additional substituents (e.g., a substituted aryl with a substituted alkyl, which is itself substituted with a substituted aryl group, which is further substituted with a substituted heteroalkyl group, etc.) are not intended to be encompassed 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 of skill in the art. When used to modify a chemical group, the term "substituted" may describe other chemical groups described herein. Unless otherwise specified, when a group is described as optionally substituted, any substituents of the group are themselves unsubstituted. For example, in some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents, including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, one or more substituents can be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituent can be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

[0072] As used herein, "pharmaceutically acceptable carriers" or "pharmaceutically acceptable additives" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in the oil compositions is contemplated. Supplementary active ingredients may also be incorporated into the compositions.

[0073] A "solvate" is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0074] As used herein, when a ring is described as "aromatic," it means that the ring has a contiguous, delocalized π-electron system. Typically, the number of out-of-plane π-electrons obeys 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 are aromatic.

[0075] 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 unsaturation due to the ring itself, e.g., one or more double bonds between constituent ring atoms), but 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 degrees of partial unsaturation, but none of the constituent rings of the ring system is aromatic.

[0076] As used herein, the term "compound" is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structure. Compounds identified herein by name or structure as a particular tautomeric form are intended to include other tautomeric forms unless otherwise indicated.

[0077] As used herein, the term "tautomer" refers to a compound whose structure differs significantly in the arrangement of atoms but which exists in ready and rapid equilibrium; the compounds provided herein may be described as different tautomers; it should be understood that when a compound has tautomeric forms, all tautomeric forms are described as being within the scope of the invention, and the naming of a compound does not exclude any tautomers.

[0078] 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, homologs, and / or orthologous GLP-1R molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, various species, and active fragments thereof.

[0079] As used herein, the term "GLP-1 associated disease" is meant to include, but is not limited to, all such diseases 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.

[0080] 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 inappropriate increases in glucagon levels in both fasting and postprandial states; and slow gastric emptying. Karla et al., Glucagon-like peptide-1 receptor agonists in the treatment of type 2 diabetes: Past, present, and future, Indian J Endocrinol Metab. 2016 Mar-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.

[0081] As used herein, the term "pharmaceutically acceptable" indicates that a compound, or a salt thereof, or a composition thereof is chemically and / or toxicologically compatible with other ingredients contained in the formulation and / or the subject being treated therewith.

[0082] The terms "administration" or "administering" refer to a method of giving 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.

[0083] As used herein, the term "effective amount" or "effective dosage" or "pharmaceutically effective amount" or "therapeutically effective amount" refers to a sufficient quantity of an administered chemical entity (e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt or solvate thereof) to relieve to some extent one or more symptoms of the disease or condition being treated, and may include curing the disease. "Cure" means that the symptoms of active disease are eliminated. Results include reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein that is required to provide a clinically significant reduction in disease symptoms. An appropriate "effective" amount for a given individual case can be determined using any suitable technique, such as a dose escalation study. In certain embodiments, a "therapeutically effective amount" of a compound provided herein refers to an amount of the compound that is effective as a monotherapy or combination therapy.

[0084] The term "excipient" or "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In certain embodiments, each component is "pharmaceutically acceptable" in that it is compatible with the other organisms of the pharmaceutical formulation, is 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 is 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.

[0085] 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 such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or thickening agents (collectively referred to herein as "excipients"). A pharmaceutical composition facilitates administration of a compound to an organism. Multiple techniques for administering a compound exist in the art, including rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0086] The terms "treatment" and "treating" in the context of treating a disease, disorder, or condition are meant to include the alleviation or elimination of a disorder, disease, or condition or one or more symptoms associated with a disorder, disease, or condition; or the slowing of the progression, spread, or worsening of a disease, disorder, or condition, or one or more of its symptoms.

[0087] As used herein, the term "prevention" refers to the prevention, in whole or in part, of the onset, recurrence or spread of a disease or condition described herein or of the condition.

[0088] 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 necessary. 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.

[0089] The terms "treatment regimen" and "dosing regimen" are used interchangeably to refer to the dosage and timing of administration of each therapeutic agent in a combination.

[0090] As used herein, the term "pharmaceutical combination" refers to a pharmaceutical treatment resulting from the mixing or combining of more than one active ingredient, and includes fixed and non-fixed combinations of the active ingredients.

[0091] The term "combination therapy" herein refers to a dosing regimen of two different therapeutically active agents (i.e., components of a combination or combination partners), where the therapeutically active agents are administered together or separately as prescribed by a healthcare professional or in accordance with regulatory authorities as defined herein.

[0092] As used herein, the term "modulation" or "modulate" refers to regulation or modulation (e.g., increase or decrease) and can include, for example, agonism, partial agonism, or antagonism.

[0093] compound Formula I: [ka] [During the ceremony, Ring A is [ka] where: [ka] The bond represents a single or double bond; where X is N or CH and Y is O, CH, CHR 3 , or C(R 3 )2; Z 1 is N or CR 4 and; Z 2 is N or CR 4 and; Ring B is absent; or Ring B is present and, together with the carbon atom of the phenyl ring to which it is fused, is C 5-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein ring B independently optionally contains 1 to 5 R 1 is replaced by; p is 0, 1, 2, or 3; n is 0, 1, 2, or 3; m is 0, 1, 2, or 3; Each R 1 are independently halo, cyano, nitro, oxo, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)OR 10 , -OC(O)R 10 , -OC(O)OR 10 , -C(O)N(R10 )2, -NR 10 C(O)R 10 , -OC(O)N(R 10 )2, -NR 10 C(O)OR 10 , -NR 10 C(O)N(R 10 )2, -S(O)R 10 , -S(O)2R 10 , -S(O)N(R 10 )2, -S(O)2N(R 10 )2, -NR 10 S(O)R 10 , -NR 10 S(O)2R 10 , -NR 10 S(O)N(R 10 )2, -NR 10 S(O)2N(R 10 )2, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 1-9 Haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 the cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with 1 to 5 Z; R 2 is hydrogen, heterocyclyl, C 1-6 Alkyl, or C 1-6 Alkoxy, C 1-6 Thioalkoxy, C 1-6 Haloalkoxy, S(O)2(C 1-6 alkyl), C 3-6 C substituted with cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl 1-6 alkyl; 3-6 Each of the cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl optionally has 1 to 4 R 12 is replaced by; R3 Cyano, halo, hydroxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 1-9 Alkoxy, C 1-9 Haloalkyl, C 1-9 Haloalkoxy, or C 3-10 is cycloalkyl; or 2 R's 3 together with the carbon atoms to which they are attached, C 3-10 Form a cycloalkyl or heterocyclyl; 3-10 cycloalkyl or heterocyclyl independently optionally substituted with 1 or 2 halo; Each R 4 are independently hydrogen, cyano, halo, hydroxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-9 Alkoxy, C 1-9 Haloalkyl, C 1-9 Haloalkoxy, or C 3-10 is cycloalkyl; R 5 is hydrogen, cyano, halo, hydroxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-9 Alkoxy, C 1-9 Haloalkyl, C 1-9 Haloalkoxy, or C 3-10 is cycloalkyl; R 6 is hydrogen, cyano, halo, hydroxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-9 Alkoxy, C 1-9Haloalkyl, C 1-9 Haloalkoxy, or C 3-10 is cycloalkyl; R 7 is hydrogen, cyano, halo, hydroxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-9 Alkoxy, C 1-9 Haloalkyl, C 1-9 Haloalkoxy, or C 3-10 is cycloalkyl; Each R 10 are independently hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 )2, -S(O)R 20 , -S(O)2R 20 , -S(O)N(R 20 )2, or -S(O)2N(R 20 )2; where each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a is replaced by; Each R 12 are independently cyano, halo, hydroxy, SH, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, Amino, C1-6 Alkylamino, and di-C 1-6 alkylamino; Each Z is independently halo, cyano, nitro, oxo, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -L 1 -C 1-9 Alkyl, -L 1 -C 2-9 Alkenyl, -L 1 -C 2-9 Alkynyl, -L 1 -C 3-10 Cycloalkyl, -L 1 -heterocyclyl, -L 1 -aryl, or -L 1 -heteroaryl; wherein each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a is replaced by; Each L 1 are independently -O-, -S-, and -NR 20 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR 20 -, -NR 20 C(O)-, -OC(O)NR 20 -, -NR 20 C(O)O-, -NR 20 C(O)NR 20 -, -S(O)-, -S(O)2-, -S(O)NR 20 -, -S(O)NR 20 -, -NR 20 S(O)-, -NR 20 S(O)2-, -NR 20 S(O)NR 20 -, or -NR 20 S(O)NR 20 - and; Each R 20are independently hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 20 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a is substituted with; and each Z 1a are independently halo, hydroxy, cyano, nitro, oxo, -SH, -NH2, -NH-C 1-9 Alkyl, -N(C 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-6 cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1a Each of -NH-C 1-9 Alkyl, -N(C 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-6 Cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally represent C 1-9 and substituted with 1 to 5 substituents selected from alkyl, oxo, halo, hydroxy, and cyano. or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0094] Formula I': [ka] [During the ceremony, Ring A is [ka] where: [ka] The bond represents a single or double bond; where X is N or CH and Y is O, CH, CHR 3 , or C(R 3 )2; Z 1 is N or CR 4 and; Z 2 is N or CR 4 and; Ring B is absent; or Ring B is present and, together with the carbon atom of the phenyl ring to which it is fused, is C 5-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein ring B independently optionally contains 1 to 5 R 1 is replaced by; p is 0, 1, 2, or 3; n is 0, 1, 2, or 3; m is 0, 1, 2, or 3; Each R 1 are independently halo, cyano, nitro, oxo, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)OR 10 , -OC(O)R 10 , -OC(O)OR 10 , -C(O)N(R 10 )2, -NR 10 C(O)R 10 , -OC(O)N(R 10 )2, -NR 10 C(O)OR 10 , -NR 10 C(O)N(R 10 )2, -S(O)R 10 , -S(O)2R 10, -S(O)N(R 10 )2, -S(O)2N(R 10 )2, -NR 10 S(O)R 10 , -NR 10 S(O)2R 10 , -NR 10 S(O)N(R 10 )2, -NR 10 S(O)2N(R 10 )2, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 1-9 Haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 the cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with 1 to 5 Z; R 2 is hydrogen, heterocyclyl, C 1-6 Alkyl, or C 1-6 Alkoxy, C 1-6 Thioalkoxy, C 1-6 Haloalkoxy, S(O)2(C 1-6 alkyl), C 3-6 C substituted with cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl 1-6 alkyl; 3-6 Each of the cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl optionally has 1 to 4 R 12 is replaced by; R 3 Cyano, halo, hydroxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 1-9 Alkoxy, C 1-9 Haloalkyl, C 1-9 Haloalkoxy, or C 3-10 is cycloalkyl; or 2 R's 3 together with the carbon atoms to which they are attached, C 3-10 Form a cycloalkyl or heterocyclyl; 3-10 cycloalkyl or heterocyclyl independently optionally substituted with 1 or 2 halo; Each R 4 are independently hydrogen, cyano, halo, hydroxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-9 Alkoxy, C 1-9 Haloalkyl, C 1-9 Haloalkoxy, or C 3-10 is cycloalkyl; R 5 is hydrogen, cyano, halo, hydroxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-9 Alkoxy, C 1-9 Haloalkyl, C 1-9 Haloalkoxy, or C 3-10 is cycloalkyl; R 6 is hydrogen, cyano, halo, hydroxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-9 Alkoxy, C 1-9 Haloalkyl, C 1-9 Haloalkoxy, or C 3-10 is cycloalkyl; R 7 is hydrogen, cyano, halo, hydroxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 1-6 Cyanoalkyl, C1-6 Hydroxyalkyl, C 1-9 Alkoxy, C 1-9 Haloalkyl, C 1-9 Haloalkoxy, or C 3-10 is cycloalkyl; Each R 10 are independently hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 )2, -S(O)R 20 , -S(O)2R 20 , -S(O)N(R 20 )2, or -S(O)2N(R 20 )2; where each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a is replaced by; Each R 12 are independently cyano, halo, hydroxy, SH, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, Amino, C 1-6 Alkylamino, and di-C 1-6 alkylamino; Each Z is independently halo, cyano, nitro, oxo, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10Cycloalkyl, heterocyclyl, aryl, heteroaryl, -L 1 -C 1-9 Alkyl, -L 1 -C 2-9 Alkenyl, -L 1 -C 2-9 Alkynyl, -L 1 -C 3-10 Cycloalkyl, -L 1 -heterocyclyl, -L 1 -aryl, or -L 1 -heteroaryl; wherein each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a is replaced by; Each L 1 are independently -O-, -S-, and -NR 20 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR 20 -, -NR 20 C(O)-, -OC(O)NR 20 -, -NR 20 C(O)O-, -NR 20 C(O)NR 20 -, -S(O)-, -S(O)2-, -S(O)NR 20 -, -S(O)NR 20 -, -NR 20 S(O)-, -NR 20 S(O)2-, -NR 20 S(O)NR 20 -, or -NR 20 S(O)NR 20 - and; Each R 20 are independently hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 20 Each C 1-9 Alkyl, C 2-9Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a is substituted with; and each Z 1a are independently halo, hydroxy, cyano, nitro, oxo, -SH, -NH2, -NH-C 1-9 Alkyl, -N(C 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-6 cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1a Each of -NH-C 1-9 Alkyl, -N(C 1-9 Alkyl)2, -SC 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-6 Cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally represent C 1-9 and substituted with 1 to 5 substituents selected from alkyl, oxo, halo, hydroxy, and cyano. or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0095] In certain embodiments, one or more of the following may occur: A) Ring A is [ka] and; B)R 5 and R 6 one of which is other than hydrogen; C) Ring B is present; D) at least one R4 is other than hydrogen; E)R 2 optionally, 1 to 4 R 12 or a heterocyclyl substituted with F) At least one R 12 is -C(O)-C 1-6 It is alkyl.

[0096] In certain embodiments, one or more of the following may occur: A) Ring A is [ka] and; B)R 5 and R 6 one of which is other than hydrogen; C)R 2 optionally, 1 to 4 R 12 or a heterocyclyl substituted with D) at least one R 12 is -C(O)-C 1-6 It is alkyl.

[0097] In some embodiments, ring A is: [ka] is.

[0098] In certain embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] is.

[0099] In certain embodiments, ring A is [ka] is.

[0100] In some embodiments, R 5 and R 6 One of the atoms is other than hydrogen.

[0101] In some embodiments, ring B is present.

[0102] In certain embodiments, at least one R 4 is other than hydrogen.

[0103] In some embodiments, Z 1 is CR 4 and R 4 is other than hydrogen. In some embodiments, Z 1 is CR 4 and R 4 is other than hydrogen. In some embodiments, Z 2 is CR 4 and R 4 is other than hydrogen.

[0104] In some embodiments, R 2 optionally, 1 to 4 R 12 is a heterocyclyl substituted with

[0105] In certain embodiments, at least one R 12 is -C(O)-C 1-6 It is alkyl.

[0106] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0107] In some embodiments, m is 0.

[0108] In certain embodiments, each R 3 is independently C 1-9 It is alkyl.

[0109] In some embodiments, n is 1; and R 3 is methyl.

[0110] In some embodiments, two R 3 together with the carbon atoms to which they are attached, C 3-10 Form a cycloalkyl or heterocyclyl; 3-10 The cycloalkyl or heterocyclyl is independently optionally substituted with 1 or 2 halo. In certain embodiments, two R 3together with the carbon atoms to which they are attached, optionally substituted with one or two halo groups. 3-10 In some embodiments, two R 3 together with the carbon atoms to which they are attached, C 3-10 Forms a cycloalkyl.

[0111] In some embodiments, provided herein is a compound of formula IA: [ka] [Wherein, the dashed line, ring B, Z 1 , Z 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n, and p are each independently as defined herein. or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof.

[0112] In some embodiments, provided herein is a compound of formula IB: [ka] [In the formula, rings B, Z 1 , Z 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n, and p are each independently as defined herein. or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof.

[0113] In some embodiments, provided herein is a compound of formula IC: [ka] [In the formula, rings B, Z 1 , Z 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n, and p are each independently as defined herein. or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof.

[0114] In some embodiments, provided herein is a compound of formula ID: [ka] [In the formula, rings B, Z 1 , Z 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and p are each independently as defined herein. or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof.

[0115] In some embodiments, provided herein is a compound of formula IE: [ka] [In the formula, rings B, Z 1 , Z 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n, and p are each independently as defined herein. or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof.

[0116] In some embodiments, provided herein is a compound of formula IF: [ka] [In the formula, rings B, Z 1 , Z 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n, and p are each independently as defined herein. or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof.

[0117] In some embodiments, provided herein is a compound of formula I'A: [ka] [Wherein, the dashed line, ring B, Z 1 , Z 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n, and p are each independently as defined herein. or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof.

[0118] In some embodiments, provided herein is a compound of formula I'B: [ka] [In the formula, rings B, Z 1 , Z 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n, and p are each independently as defined herein. or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof.

[0119] In some embodiments, provided herein is a compound of formula I'C: [ka] [In the formula, rings B, Z 1 , Z 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n, and p are each independently as defined herein. or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof.

[0120] In some embodiments, provided herein is a compound of formula I'D: [ka] [In the formula, rings B, Z 1 , Z 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and p are each independently as defined herein. or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof.

[0121] In some embodiments, provided herein is a compound of formula I'E: [ka] [In the formula, rings B, Z 1 , Z 2 , R 1 , R 2 , R 3 , R4 , R 5 , R 6 , n, and p are each independently as defined herein. or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof.

[0122] In some embodiments, provided herein is a compound of formula I'F: [ka] [In the formula, rings B, Z 1 , Z 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n, and p are each independently as defined herein. or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof.

[0123] In some embodiments, R 5 Cyano, halo, hydroxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 1-9 Alkoxy, C 1-9 Haloalkyl, C 1-9 Haloalkoxy, or C 3-10 It is cycloalkyl.

[0124] In some embodiments, R 6 Cyano, halo, hydroxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 1-9 Alkoxy, C 1-9 Haloalkyl, C 1-9 Haloalkoxy, or C 3-10 It is cycloalkyl.

[0125] In some embodiments, R 5 is hydrogen, halo, or C 1-9 In some embodiments, R 5 is hydrogen or halo. In certain embodiments, R 5 is hydrogen. In some embodiments, R 5 is a halo.

[0126] In some embodiments, R 6 is hydrogen, halo, or C 1-9 In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is halo. In certain embodiments, R 6 is C 1-9 It is an alkoxy.

[0127] In some embodiments, R 5 and R 6 At least one of the following is halo or C 1-9 It is an alkoxy.

[0128] In some embodiments, R 5 is hydrogen or halo; and R 6 is halo or C 1-9 In some embodiments, R 5 is hydrogen; and R 6 is halo or C 1-9 In some embodiments, R 5 is hydrogen; and R 6 is fluoro or methoxy.

[0129] In some embodiments, R 5 is the halo; and R 6 is hydrogen, halo, or C 1-9 In some embodiments, R 5 is the halo; and R 6 is hydrogen.

[0130] In some embodiments, ring B is absent. In some embodiments, ring B is present.

[0131] In some embodiments, ring B is present and, together with the carbon atom of the phenyl ring to which it is fused, is C 5-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein ring B independently optionally contains 1 to 5 R 1 has been replaced by .

[0132] In certain embodiments, ring B is present and, together with the carbon atoms of the phenyl ring to which it is fused, optionally comprises 1 to 5 R 1 C is replaced by 5-10 Forms a cycloalkyl.

[0133] In certain embodiments, ring B is present and, together with the carbon atoms of the phenyl ring to which it is fused, optionally comprises 1 to 5 R 1 to form a heterocyclyl substituted with

[0134] In certain embodiments, ring B is present and, together with the carbon atoms of the phenyl ring to which it is fused, optionally comprises 1 to 5 R 1 to form an aryl substituted with

[0135] In certain embodiments, ring B is present and, together with the carbon atoms of the phenyl ring to which it is fused, optionally comprises 1 to 5 R 1 Form a heteroaryl substituted with

[0136] In one embodiment, the moiety [ka] teeth [ka] is.

[0137] In one embodiment, the moiety [ka] teeth [ka] is.

[0138] In one embodiment, the moiety [ka] teeth [ka] is.

[0139] In one embodiment, the moiety [ka] teeth [ka] is.

[0140] In one embodiment, the moiety [ka] teeth [ka] is.

[0141] In one embodiment, the moiety [ka] teeth [ka] is.

[0142] In one embodiment, the moiety [ka] teeth [ka] is.

[0143] In one embodiment, the moiety [ka] teeth [ka] is.

[0144] In certain embodiments, each R 1 are independently halo, cyano, or C 1-9 It is haloalkyl.

[0145] In some embodiments, p is 1. In some embodiments, p is 1; and R 1 is halo, cyano, or C 1-9 It is haloalkyl.

[0146] In one embodiment, the moiety [ka] teeth [ka] is.

[0147] In one embodiment, the moiety [ka] teeth [ka] is.

[0148] In one embodiment, the moiety [ka] teeth [ka] is.

[0149] In one embodiment, the moiety [ka] teeth [ka] is.

[0150] In some embodiments, R 1 is halo, cyano, or C 1-9 In some embodiments, R 1 is halo or cyano. In certain embodiments, R 1 is chloro or cyano.

[0151] In certain embodiments, at least one R 4 is other than hydrogen.

[0152] In certain embodiments, at least one R 4 is a halo.

[0153] In some embodiments, Z 2 is CR 4 and Z 4 R 4 Cyano, halo, hydroxy, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-9 Alkoxy, C 1-9 Haloalkyl, C 1-9 Haloalkoxy, or C 3-10 It is cycloalkyl.

[0154] In some embodiments, R 2 is heterocyclyl or C 1-6 Alkoxy, C 1-6 Thioalkoxy, C 1-6 Haloalkoxy, S(O)2(C 1-6 alkyl), C 3-6 C substituted with cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl 1-6 alkyl; where heterocyclyl, C 3-6 Each of the cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl optionally has 1 to 4, 1 to 3, 1 to 2, or 1 R 12 is replaced by .

[0155] In some embodiments, R 2 is heterocyclyl or C 3-6 C substituted with cycloalkyl, 3- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl 1-6 alkyl; where heterocyclyl, C 3-6 Each of the cycloalkyl, 3- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl optionally has 1 to 4, 1 to 3, 1 to 2, or 1 R 12 is replaced by .

[0156] In some embodiments, R 2 is heterocyclyl or C 3-6 C substituted with cycloalkyl, 3- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl 1-6 alkyl; where heterocyclyl, C 3-6 Each of the cycloalkyl, 3- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl optionally has 1 to 4, 1 to 3, 1 to 2, or 1 R 12 is replaced by .

[0157] In some embodiments, R 2 is heterocyclyl or C 3-6C substituted with cycloalkyl, 3- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl 1-6 alkyl; where heterocyclyl, C 3-6 Each of the cycloalkyl, 3- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl optionally has 1 to 4, 1 to 3, 1 to 2, or 1, cyano, halo, C 1-6 Alkyl, C 1-6 Cyanoalkyl, or -C(O)-C 1-6 It is substituted with alkyl.

[0158] In some embodiments, R 2 optionally, 1 to 4 R 12 is a heterocyclyl substituted with

[0159] In some embodiments, R 2 is C 1-6 It is a 3- to 6-membered heterocyclyl substituted with alkoxy.

[0160] R 2 is hydrogen, heterocyclyl, C 1-6 Alkyl, or C 1-6 Alkoxy, C 1-6 Thioalkoxy, C 1-6 Haloalkoxy, S(O)2(C 1-6 alkyl), C 3-6 C substituted with cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl 1-6 alkyl; 3-6 Each of the cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl optionally has 1 to 4 R 12 is replaced by;

[0161] Each R 12 are independently cyano, halo, hydroxy, SH, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C(O)-C 1-6 Alkyl, C 3-6 Cycloalkyl, Amino, C 1-6 Alkylamino, and di-C 1-6 alkylamino;

[0162] In certain embodiments, each R 4 are independently hydrogen or halo.

[0163] In some embodiments, R 7 is hydrogen.

[0164] In some embodiments, Z 1 is N.

[0165] In some embodiments, Z 2 is N.

[0166] In one embodiment, the moiety [ka] teeth [ka] is.

[0167] In certain embodiments, provided is a compound selected from Table 1 or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof: [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6]

[0168] In certain embodiments, provided is a compound selected from compounds 103, 104, 108, 109, 110, 111, 112, 113, 114, 115, 116, 118, 119, 120, 121, 122, 123, 124, and 127, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0169] The compounds of formula I include pharmaceutically acceptable salts thereof. In addition, the compounds of formula I also include other salts of such compounds, which are not necessarily pharmaceutically acceptable but which may be useful as intermediates for the preparation and / or purification of the compounds of formula I and / or for the resolution of the enantiomers of the compounds of formula I.

[0170] It is further recognized that the compounds of Formula I or their salts may be isolated in the form of a solvate, and therefore, any such solvates are included within the scope of the present invention. For example, the compounds of Formula I and their salts can exist in unsolvated and solvated forms formed with pharmaceutically acceptable solvents such as water, ethanol, and the like.

[0171] Pharmaceutical Compositions and Administration When used as pharmaceuticals, the compounds described herein (e.g., a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture, or prodrug thereof) can be administered in the form of a pharmaceutical composition. These compositions can be prepared by methods well known in the pharmaceutical arts and can be administered by 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 intracerebroventricular, administration. Parenteral administration can be in the form of a single bolus dose, or can be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder, or oily bases, thickeners, etc. may be necessary or desirable.

[0172] Also provided herein are pharmaceutical compositions comprising, as an active ingredient, a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture, or prodrug thereof, in combination with one or more pharmaceutically acceptable excipients (carriers). For example, pharmaceutical compositions prepared using a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture, or prodrug thereof. In some embodiments, the compositions are suitable for topical administration. When preparing the compositions provided herein, the active ingredient is typically mixed with the excipient, diluted with the excipient, or enclosed within such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid substance that acts as a vehicle, carrier, or medium for the active ingredient. Therefore, composition c can be in the form of tablets, pills, powder, 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.

[0173] Further provided herein are pharmaceutical compositions comprising a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture, or prodrug thereof, together with a pharmaceutically acceptable excipient. Pharmaceutical compositions comprising a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture, or prodrug thereof as an active ingredient can be prepared by intimately admixing a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture, or prodrug thereof, with a pharmaceutical carrier 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 certain embodiments, the composition is a solid oral composition.

[0174] 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.

[0175] Methods for preparing pharmaceutical compositions are described in numerous publications, such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al.; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al.; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al.; published by Marcel Dekker, Inc.

[0176] 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, electrolytes such as salt or protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylic acid, wax, polyethylene-polyoxypropylene block polymer and wool fat. Cyclodextrins, such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives, such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilizing derivatives, can also be used to enhance delivery of the compounds described herein. Dosage forms or compositions can 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%, in some embodiments, 0.1% to 95%, in other embodiments, 75% to 85%, and in further embodiments, 20% to 80% of the chemicals provided herein. Actual methods for preparing such dosage forms will be known or apparent to those skilled in the art; see, for example, Remington: The Science and Practice of Pharmacy, 22nd Edition (Pharmaceutical Press, London, UK. 2012).

[0177] In certain 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 administration routes include, but are not limited to, buccal, skin, intracervical, intrasinus, intratracheal, enteral, epidural, interstitial, intraabdominal, intraarterial, intrabronchial, intravesical, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intraspinal, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinus, intrathecal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, intranasal (e.g., intranasal), nasogastric, oral, parenteral, transdermal, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and vaginal. In some embodiments, the administration route is parenteral (e.g., intratumoral).

[0178] In some embodiments, the compound of Formula I described herein, or its subformula, or its pharmaceutically acceptable salt, isotope-enriched analog, stereoisomer, stereoisomeric mixture, or prodrug, or its pharmaceutical composition, can be formulated for parenteral administration, for example, for injection via intraarterial, intrasternal, intracranial, intravenous, intramuscular, subcutaneous, or intraperitoneal route.For example, such compositions can be prepared as injections, such as liquid solutions or suspensions; can also be prepared as solid forms suitable for preparing solutions or suspensions by adding liquid before injection; and the preparations can also be emulsified.The preparation of such formulations 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 devices can include needle-type injectors, needleless injectors, and infusion technology.

[0179] In some embodiments, pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions; formulations containing sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the immediate preparation of sterile injectable solutions or dispersions.In some embodiments, this form must be sterile and fluid enough to be easily injected.In some embodiments, this form must be stable under the conditions of manufacture and storage, and must be protected against the contaminating activity of microorganisms such as bacteria and fungi.

[0180] 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 dispersion, and by the use of surfactants. In some embodiments, the prevention of microbial activity can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In some embodiments, isotonic agents, for example, sugars or sodium chloride, are included. In some embodiments, prolonged absorption of injectable compositions can be achieved by using agents that delay absorption in the composition, for example, aluminum monostearate and gelatin.

[0181] In some embodiments, sterile injectable solution is prepared by incorporating the required amount of the compound of formula I, or its subformula, or its pharmaceutically acceptable salt, isotope-enriched analog, stereoisomer, stereoisomeric mixture or prodrug in a suitable solvent, and optionally with various other components as listed above, followed by filtration sterilization.In some embodiments, dispersion is prepared by incorporating various sterilized active ingredients into a sterile medium that contains a basic dispersion medium and other necessary components 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 produces powder of active ingredient and any other desired component from the solution that has been previously sterile filtered.

[0182] In some embodiments, pharmaceutically acceptable additives 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. Ingredients include, but are not limited to, any one or more of: SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-hydroxybenzoate, sodium propyl p-hydroxybenzoate, diethylamine, carbomer, carbopol, methyl hydroxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins such as vitamins A and E, and potassium acetate.

[0183] In some embodiments, suppositories can be prepared by mixing a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture, or prodrug thereof, or pharmaceutical composition described herein, with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository wax, which is solid at ambient temperature but liquid at body temperature and thus melts in the rectum to release the active compound. In some embodiments, the composition for rectal administration is in the form of an enema.

[0184] In certain embodiments, a compound of Formula I described herein, or a subformula thereof, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture, or prodrug thereof, or a pharmaceutical composition thereof, is formulated for local delivery to the digestive or GI tract via oral administration (e.g., solid or liquid dosage form).

[0185] In some embodiments, solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In some embodiments, the compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture, or prodrug thereof, is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as, for example, carboxymethylcellulose, alginic acid, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants, such as glycerol; d) chilling agents, such as hydroxybenzoates, ... Disintegrating agents such as starch, calcium carbonate, potato or tapioca starch, alginic acid, some silicic acid and sodium carbonate, e) dissolution retarders 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) absorbents such as kaolin and bentonite clay are mixed with lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof.For example, in the case of capsules, tablets and pills, dosage forms can also contain buffering agents.In some embodiments, similar solid compositions can also be used as fillers for soft and hard-filled gelatin capsules, using lactose or papillae and high molecular weight polyethylene glycol, etc.

[0186] In some embodiments, the pharmaceutical composition is in the form of a unit dosage form such as a pill or tablet, and thus the composition may contain a compound of Formula I provided herein, or a subformula thereof, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture, or prodrug thereof, together with diluents such as lactose, sucrose, dicalcium phosphate, etc.; lubricants such as magnesium stearate, etc.; and binders such as starch, acacia gum, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, etc. In some embodiments, other solid dosage forms, such as powders, quince, solutions, or suspensions (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) are encapsulated in capsules (gelatin or cellulose-based capsules). In some embodiments, unit dosage forms in which one or more compounds provided herein and a pharmaceutical composition or additional active agent are physically separated are also contemplated; for example, capsules (or tablets in capsules) of granules of each drug; bilayer tablets; bicompartment gelcaps, etc. In certain embodiments, enteric coated or delayed release oral dosage forms are also contemplated.

[0187] In certain embodiments, other physiologically acceptable compounds may include wetting agents, emulsifying agents, dispersing agents, or preservatives, which are particularly useful in preventing the growth or action of microorganisms. For example, various preservatives are well known and include, for example, phenol and ascorbic acid.

[0188] In some embodiments, the additives are sterile and generally free of undesirable substances. For example, these compositions can be sterilized by conventional, well-known sterilization techniques. In some embodiments, sterility is not required for various oral dosage form additives, such as tablets and capsules. For example, the United States Pharmacopeia / National Formulary (USP / NF) standard may be sufficient.

[0189] In some embodiments, the compound of Formula I described herein, or a subformula thereof, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture, or prodrug thereof, or a pharmaceutical composition thereof, is formulated for ocular administration. In some embodiments, the ocular composition may contain one or more of the following, but is not limited to: viscogen (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, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

[0190] In certain embodiments, a compound of Formula I described herein, or a subformula thereof, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture, or prodrug thereof, or a pharmaceutical composition thereof, is formulated for topical administration to the skin or mucosa (e.g., dermal or transdermal). In certain embodiments, topical compositions can include ointments and creams. In certain embodiments, ointments are semi-solid formulations typically based on petrolatum or other petroleum derivatives. In certain embodiments, creams containing a selected active agent are viscous liquids or semi-solid emulsions, often oil-in-water or water-in-oil, in droplets. For example, cream bases are typically water-washable and contain an oil phase, an emulsifier, and an aqueous phase. For example, the oil phase, sometimes referred to as the "internal" phase, is generally composed of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume and generally contains a humectant. In certain embodiments, the emulsifier in a cream formulation is generally a nonionic, anionic, cationic, or amphoteric surfactant. In certain embodiments, the ointment base, like other carriers or vehicles, must be inert, stable, non-irritating, and non-sensitizing.

[0191] In any of the above embodiments, the pharmaceutical compositions described herein may comprise one or more of the following: lipids, interlayer 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.

[0192] 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 invention based on the total formulation, with the remainder being one or more suitable pharmaceutical excipients. In some embodiments, the compound is present at a level of about 1 to 80 wt%. Representative pharmaceutical formulations are described below.

[0193] Formulation Example 1 - Tablet Formulation The following ingredients are intimately mixed and compressed into single scored tablets: [Table 7]

[0194] Formulation Example 2 - Capsule Formulation The following ingredients are intimately mixed and loaded into a hard shell gelatin capsule: [Table 8]

[0195] Formulation Example 3 - Suspension Formulation The following ingredients are mixed to form a suspension for oral administration: [Table 9]

[0196] Formulation Example 4 - Injectable formulation The following ingredients are mixed to form an injectable formulation: [Table 10]

[0197] Formulation Example 5 - Suppository Formulation Suppositories weighing 2.5 g total are prepared by mixing a compound of the invention with Witepsol® H-15 (triglyceride of saturated vegetable fatty acids; Riches-Nelson, Inc., New York) and have the following composition: [Table 11]

[0198] In some embodiments, the dosage of the compound of Formula I, or its subformula, or its pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture, or prodrug is determined based on multiple factors, including but not limited to, the patient's type, age, weight, sex, medical condition, the severity of the patient's medical condition, the route of administration, and the activity of the compound or its pharmaceutically acceptable salt or solvate.In some embodiments, the appropriate dosage for a particular situation can be determined by 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 a means that provides continuous delivery.

[0199] In certain embodiments, a compound of Formula I, or a subformula thereof, 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 certain embodiments, the dose is a therapeutically effective amount.

[0200] In certain embodiments, a compound of Formula I described herein, or a subformula thereof, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture, or prodrug thereof, is administered in 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 100 mg / Kg). ~About 10mg / Kg; Approx. 0.0002mg / Kg ~ Approx. 5mg / Kg; Approx. 0.0002mg / Kg ~ Approx. 1mg / Kg; Approx. 0.0002mg / Kg ~ Approx. 0.5mg / Kg; Approx. 0.0002mg / Kg ~ approx. 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 ~ approx. 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. 1m In certain embodiments, the compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture, or prodrug thereof, described herein, is administered at a dosage of about 100 mg / Kg.

[0201] In certain embodiments, the dosage of the compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof may be administered on a daily basis (e.g., in a single dose or two or more divided doses) or on a non-daily basis (e.g., every other day, every two days, every three days, once a week, twice a week, once every two weeks, once a month).

[0202] In certain embodiments, the administration period of a compound of Formula I described herein, or a subformula thereof, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture, 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 certain 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 certain embodiments, a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture, 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 subformula thereof, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture, or prodrug thereof is suspended. In certain embodiments, a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture, or prodrug thereof is administered for a first period of time, followed by a second period during which administration is stopped, followed by a third period during which administration of the compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture, or prodrug thereof is initiated, followed by a fourth period during which administration is stopped after the third period of time. For example, the period of administration of the compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture, or prodrug thereof, followed by a period during which administration is stopped, is repeated for a set or an indeterminate period of time.In some embodiments, the administration period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or 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.

[0203] In certain embodiments, a compound of Formula I, or a subformula thereof, 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).

[0204] In certain embodiments, a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof is administered to a patient by parenteral administration one or more times daily (e.g., 1 to 4 times, once daily, twice daily, three times daily, four times daily, or in a single daily dose).

[0205] In certain embodiments, a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof is administered to a patient weekly by parenteral administration.

[0206] Treatment method In certain embodiments, the present invention relates to methods for treating a patient (e.g., a human) having a disease, disorder, or condition in which modulation of GLP-1R (e.g., suppressed or impaired and / or elevated or unwanted GLP-1R) is beneficial in treating the underlying pathology and / or symptoms and / or progression of the disease, disorder, or condition. In certain embodiments, the methods described herein can include, or further include, treatment of one or more conditions associated with, concurrent with, or secondary to any one or more of the conditions described herein.

[0207] Provided herein are methods for treating a GLP-1-related disease, disorder, or condition, comprising administering to a patient in need thereof an effective amount of a compound of Formula I, or a subformula thereof, as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture, or prodrug thereof, or pharmaceutical composition.

[0208] In certain embodiments, the disease, disorder, or condition is type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of adults (LADA), obesity, weight gain due to use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, 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, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, vascular restenosis, thrombosis, hypertension, pulmonary hypertension, post-angioplasty restenosis, intermittent claudication, hyperglycemia, postprandial These conditions include, but are not limited to, hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot 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, Alzheimer's disease, cognitive impairment, schizophrenia, and polycystic ovary syndrome (PCOS).

[0209] In certain embodiments, the disease, disorder, or condition is 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, 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, atherosclerotic cardiovascular disease, hyperglycemia, postprandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders. The present invention relates to a method for treating or preventing atopic dermatitis, including, but not limited to, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis (RACE), rheumatoid arthritis (RHEA), rheumatoid arthritis (RIA), rheumatoid arthritis (ROI ...

[0210] In certain embodiments, the disease, disorder, or condition includes, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar 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.

[0211] In certain embodiments, the compounds and pharmaceutical compositions and methods of treating a patient described herein induce one or more of blood glucose reduction (e.g., reduction in blood glucose levels), reduction in blood hemoglobin A1c (HbA1c) levels, promotion of insulin synthesis, stimulation of insulin secretion, increase in beta-cell mass, regulation of gastric acid secretion, regulation of gastric emptying, reduction in body mass index (BMI), and / or reduction in glucagon production (e.g., levels). In certain embodiments, the compounds and pharmaceutical compositions and methods of treating a patient described herein stabilize serum glucose and serum insulin levels (e.g., serum glucose and serum insulin concentrations). Also provided herein are methods for regulating glucose or insulin levels in a patient in need thereof, comprising administering to the patient an effective amount of a compound of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture, or prodrug thereof, or pharmaceutical composition disclosed herein.

[0212] In certain embodiments, provided herein are methods of reducing the risk of major adverse cardiovascular events (MACE) in a patient in need thereof (e.g., by approximately at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80%), comprising administering to the patient an effective amount of a compound of Formula I disclosed herein, or a subformula thereof, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture, or prodrug thereof, or pharmaceutical composition. 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.

[0213] Indications obesity In some embodiments, the condition, disease, or disorder is obesity and conditions, diseases, or disorders associated with or related to obesity. Non-limiting examples of obesity and obesity-related conditions include symptomatic obesity, simple obesity, childhood obesity, morbid obesity, and abdominal obesity (central obesity characterized by abdominal 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).

[0214] In some embodiments, the condition, disease or disorder is associated with obesity.Examples of such condition, disease or disorder include, but are not limited to, impaired glucose tolerance, diabetes (e.g., type 2 diabetes, obese diabetes), dyslipidemia, hyperlipidemia, hypertension, heart failure, hyperuricemia, gout, fatty liver (including non-alcoholic steatohepatitis (NASH)), coronary heart disease (e.g., myocardial infarction, angina pectoris), cerebral infarction (e.g., cerebral thrombosis, transient ischemic attack), bone or joint disease (e.g., knee osteoarthritis, hip osteoarthritis, spondylitis osteoarthritis, lower back pain), sleep apnea syndrome, obesity hypoventilation syndrome (Pickwickian syndrome), menstrual disorders (e.g., menstrual cycle abnormalities, menstrual bleeding and cycle abnormalities, amenorrhea, abnormal menstrual symptoms), visceral obesity syndrome, and metabolic syndrome.In some embodiments, the chemical compounds and pharmaceutical compositions described herein can be used to treat patients who show symptoms of both obesity and insulin deficiency.

[0215] 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, advanced type 2 diabetes, long-term insulin-treated type 2 diabetes), diabetes (e.g., non-insulin-dependent diabetes, insulin-dependent diabetes), gestational diabetes, obesity-induced 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, advanced type 2 diabetes, long-term insulin-treated type 2 diabetes).

[0216] Provided herein are methods for treating diabetes in a patient, the methods comprising: (a) determining that the patient has type 2 diabetes; and (b) administering to the patient a therapeutically effective amount of a compound of Formula I, or a subformula thereof, as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture or prodrug thereof, or pharmaceutical composition.

[0217] Provided herein is a method for treating type 2 diabetes in a patient, the method comprising administering to the patient identified or diagnosed as having type 2 diabetes a therapeutically effective amount of a compound of Formula I, or a subformula thereof, as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture or prodrug thereof, or pharmaceutical composition.

[0218] Also provided herein is a method of treating type 2 diabetes in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a subformula thereof, as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture or prodrug thereof, or pharmaceutical composition.

[0219] In certain embodiments, the compounds and pharmaceutical compositions described herein and methods of treating patients with a condition, disease, or disorder (e.g., type 2 diabetes) reduce fasting plasma glucose levels. In certain embodiments, the compounds and pharmaceutical compositions described herein and methods of treating patients with a condition, disease, or disorder (e.g., type 2 diabetes) reduce non-fasting plasma glucose levels. In certain embodiments, the compounds and pharmaceutical compositions described herein and methods of treating patients with a condition, disease, or disorder (e.g., type 2 diabetes) reduce HbA1c levels. In certain embodiments, the compounds and pharmaceutical compositions described herein and methods of treating patients with a condition, disease, or disorder (e.g., type 2 diabetes) reduce glucagon levels. In certain embodiments, the compounds and pharmaceutical compositions described herein and methods of treating patients with a condition, disease, or disorder (e.g., type 2 diabetes) increase insulin levels. In certain embodiments, the compounds and pharmaceutical compositions described herein and methods of treating patients with a condition, disease, or disorder (e.g., type 2 diabetes) reduce BMI.

[0220] In certain embodiments, about a 5% to about 95% reduction in fasting plasma glucose levels indicates treatment of type 2 diabetes. In certain embodiments, about a 15% to about 80% reduction in fasting plasma glucose levels indicates treatment of type 2 diabetes. In certain embodiments, about a 25% to about 60% reduction in fasting plasma glucose levels indicates treatment of type 2 diabetes. In certain 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.

[0221] In certain embodiments, about a 5% to about 95% decrease in non-fasting plasma glucose levels indicates treatment of type 2 diabetes. In certain embodiments, about a 15% to about 80% decrease in non-fasting plasma glucose levels indicates treatment of type 2 diabetes. In certain embodiments, about a 25% to about 60% decrease in non-fasting plasma glucose levels indicates treatment of type 2 diabetes. In certain embodiments, a decrease 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.

[0222] In certain embodiments, a reduction of about 5% to about 95% in HbA1c levels indicates treatment of type 2 diabetes. In certain embodiments, a reduction of about 15% to about 80% in HbA1c levels indicates treatment of type 2 diabetes. In certain embodiments, a reduction of about 25% to about 60% in HbA1c levels indicates treatment of type 2 diabetes. In certain embodiments, a reduction of 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.

[0223] In certain embodiments, about a 5% to about 95% decrease in glucagon levels indicates treatment of type 2 diabetes. In certain embodiments, about a 15% to about 80% decrease in glucagon levels indicates treatment of type 2 diabetes. In certain embodiments, about a 25% to about 60% decrease in glucagon levels indicates treatment of type 2 diabetes. In certain embodiments, about a 5% to about 95% increase in insulin levels indicates treatment of type 2 diabetes. In certain embodiments, about a 15% to about 80% increase in insulin levels indicates treatment of type 2 diabetes. In certain embodiments, about a 25% to about 60% increase in insulin levels indicates treatment of type 2 diabetes.

[0224] In certain embodiments, a reduction in BMI of about 5% to about 95% indicates treatment of type 2 diabetes. In certain embodiments, a reduction in BMI of about 15% to about 80% indicates treatment of type 2 diabetes. In certain embodiments, a reduction in BMI of about 25% to about 60% indicates treatment of type 2 diabetes. In certain embodiments, a reduction in BMI of about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% indicates treatment of type 2 diabetes. In certain 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.

[0225] In some embodiments, the condition, disease or disorder is associated with diabetes (e.g., diabetic complications).Non-limiting examples of disorders associated with diabetes include obesity, obesity-related disorders, metabolic syndrome, neuropathy, nephropathy (e.g., diabetic nephropathy), retinopathy, diabetic cardiomyopathy, cataract, macroangiopathy, osteopenia, hyperosmolar diabetic coma, infectious diseases (e.g., respiratory infection, urinary tract infection, digestive infection, skin and soft tissue infection, lower limb infection), diabetic gangrene, dry mouth, hyperacusis, cerebrovascular disease, diabetic cachexia, delayed wound healing, diabetic dyslipidemia, peripheral blood circulation disorder, cardiovascular risk factors (e.g., coronary artery disease, peripheral artery disease, cerebrovascular disease, hypertension, and risk factors associated with uncontrolled cholesterol and / or lipid levels, and / or inflammation), NASH, fractures, and cognitive impairment.

[0226] Non-limiting examples of other disorders associated with 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.

[0227] In certain embodiments, the condition, disease, or disorder is diabetes and obesity (diabetic obesity). In certain embodiments, the compounds described herein are also useful for improving the therapeutic effectiveness of metformin.

[0228] Disorders of metabolically important tissues In certain embodiments, the condition, disease, or disorder is a disorder of a metabolically significant tissue. Non-limiting examples of metabolically significant tissue include liver, adipose, pancreas, kidney, and intestine.

[0229] In some embodiments, the condition, disease or disorder is fatty liver disease.Fatty liver disease includes but is not limited to non-alcoholic fatty liver disease (NAFLD), steatohepatitis, non-alcoholic steatohepatitis (NASH), fatty liver disease 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.

[0230] Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of diseases occurring without alcohol abuse and is typically characterized by the presence of steatosis (fat in the liver). NAFLD is thought to be associated with a variety of conditions, such as metabolic syndrome (including obesity, diabetes, and hypertriglyceridemia) and insulin resistance. It can cause liver disease in adults and children, ultimately leading to cirrhosis (Skelly et al., J Hepatol 2001; 35: 195-9; Chitturi et al., Hepatology 2002; 35(2):373-9). The severity of NAFLD ranges from relatively benign isolated macrovesicular steatosis (i.e., nonalcoholic fatty liver or NAFL) to nonalcoholic steatohepatitis (NASH) (Angulo et al., J Gastroenterol Hepatol 2002; 17 Suppl:s186-90). In certain embodiments, the patient is a pediatric patient. As used herein, the term "pediatric patient" refers to a patient under the age of 21 at the time of diagnosis or treatment. The term "pediatric" can be further divided into various subgroups, including: neonates (birth to 1 month); infants (1 month to 2 years); children (2 to 12 years); and adolescents (12 to 21 years, up to but not including the 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 certain embodiments, the pediatric patient is between birth and 28 days of age, between 29 days and less than 2 years of age, between 2 years and less than 12 years of age, or between 12 years and 21 years of age (up to but not including the 22nd birthday).In certain embodiments, the pediatric patient is between birth and 28 days old, between 29 days old and less than 1 year old, between 1 month and less than 4 months old, between 3 months and less than 7 months old, between 6 months and less than 1 year old, between 1 year and less than 2 years old, between 2 years and less than 3 years old, between 2 years and less than 7 years old, between 3 years and less than 5 years old, between 5 years and less than 10 years old, between 6 years and less than 13 years old, between 10 years and less than 15 years old, or between 15 years and less than 22 years old. In certain embodiments, the patient is an adult patient.

[0231] Other non-limiting examples of disorders of metabolically important tissues include joint disorders (e.g., osteoarthritis, secondary osteoarthritis), steatosis (e.g., in the liver); gallstones; gallbladder disorders; gastroesophageal reflux; sleep apnea; hepatitis; fatty liver; bone disorders characterized by altered bone metabolism, including menopausal osteoporosis, low bone strength, osteopenia, Paget's disease, osteolytic metastases in cancer patients, osteodystrophy in liver disease, and altered bone metabolism due to renal failure or dialysis, fractures, bone surgery, aging, pregnancy, protection against fractures, and nutritional disorders, polycystic ovary syndrome; renal 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 certain embodiments, the compounds and pharmaceutical compositions described herein can be used to treat surgical trauma by improving post-operative recovery and / or preventing the catabolic response caused by surgical trauma.

[0232] Cardiovascular and vascular diseases In some embodiments, the condition, disease, or disorder is a cardiovascular disease. Non-limiting examples of cardiovascular disease include congestive heart failure, atherosclerosis, arteriosclerosis, coronary heart disease, coronary artery disease, congestive heart failure, coronary heart disease, hypertension, heart failure, cerebrovascular disease (e.g., cerebral infarction), vascular insufficiency, myocardial infarction, hypertension (e.g., 130 / 85 mmHg or higher), and thrombotic conditions (e.g., high blood fibrinogen or plasminogen activator inhibitor levels).

[0233] In some embodiments, the condition, disease, or disorder is associated with vascular disease. Non-limiting examples of vascular disease include peripheral vascular disease, macrovascular complications (e.g., stroke), vascular insufficiency, peripheral arterial disease, abdominal aortic aneurysm, carotid artery disease, cerebrovascular disease (e.g., cerebral infarction), pulmonary embolism, chronic venous insufficiency, critical limb ischemia, retinopathy, nephropathy, and neuropathy.

[0234] Neurological disorders In some embodiments, the condition, disease, or disorder is a neurological disorder (e.g., a neurodegenerative disorder) or a psychiatric disorder. Non-limiting examples of neurological disorders include 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 chorea, tardive dyskinesia, hyperactivity, mania, Parkinson's disease, Steele-Richard syndrome, Down's syndrome, myasthenia gravis, neurotrauma, brain trauma, vascular amyloidosis, cerebral hemorrhage with amyloidosis I, brain inflammation, Friedreich's 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.

[0235] Non-limiting examples of psychiatric disorders include drug dependence / addiction (narcotics and amphetamines) and attention deficit / hyperactivity disorder (ADHD).The compounds and pharmaceutical compositions described herein can be useful for improving behavioral responses to addictive drugs, reducing drug dependence, preventing drug abuse relapse, and alleviating anxiety caused by the absence of certain addictive substances.See, for example, US2012 / 0021979A1.

[0236] In certain embodiments, the compounds and pharmaceutical compositions described herein are useful for improving learning and memory by enhancing neuroplasticity and promoting cell differentiation, and for protecting dopamine neurons and motor function in Parkinson's disease.

[0237] Insulin-Related Conditions and Disorders In certain embodiments, the condition, disease or disorder is poor 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, dysesthesias caused by hyperinsulinemia, hyperlipidemia, hypercholesterolemia, impaired wound healing, leptin resistance, glucose intolerance, elevated fasting glucose, dyslipidemia (e.g., atherogenic dyslipidemia characterized by hyperlipidemia, high triglycerides and low HDL cholesterol), glucagonoma, hyperprolactinemia, hypoglycemia (e.g., nocturnal hypoglycemia), and insulin-associated coma endpoints.

[0238] In certain embodiments, the compounds and pharmaceutical compositions described herein can reduce or slow the progression of borderline, poor fasting glucose, or impaired fasting glucose to diabetes.

[0239] autoimmune disorders In some embodiments, condition, disease or disorder is autoimmune disorder.Non-limiting examples of autoimmune disorder include multiple sclerosis, experimental autoimmune encephalomyelitis, autoimmune disorder 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.

[0240] Stomach and bowel related disorders In some embodiments, the condition, disease, or disorder is a stomach or intestinal-related disorder. Non-limiting examples of these disorders include ulcers of any etiology (e.g., peptic ulcers, Zollinger-Ellison syndrome, drug-induced ulcers, and ulcers associated with infections or other pathogens), digestive disorders, malabsorption, short bowel syndrome, Cul-de-Sac syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), celiac sprue, hypogammaglobulinemic sprue, chemotherapy- and / or radiation therapy-induced mucositis and diarrhea, gastrointestinal inflammation, short bowel syndrome, ulcerative colitis, gastric mucosal injury (e.g., gastric mucosal injury caused by aspirin), small intestinal mucosal injury, and cachexia (e.g., cancer cachexia, tuberculous cachexia, cachexia associated with blood disorders, cachexia associated with endocrine disorders, cachexia associated with infectious diseases, and cachexia caused by acquired immune deficiency syndrome).

[0241] body weight In some embodiments, the compounds and pharmaceutical compositions described herein can be used to reduce weight (e.g., excess weight), prevent weight gain, induce weight loss, reduce body fat, or reduce food intake in a patient (e.g., a patient in need thereof). In some embodiments, the patient's weight gain can be due to excessive food intake or an unbalanced diet, or the weight gain can be due to a concomitant medication (e.g., an insulin sensitizer with PPARγ agonist-like activity, such as troglitazone, rosiglitazone, englitazone, ciglitazone, or pioglitazone). In some embodiments, the weight gain can be weight gain before obesity is reached or can be weight gain in an obese patient. In some embodiments, the weight gain can also be medication-induced weight gain or weight gain after smoking cessation.

[0242] In certain embodiments, the condition, disease or disorder is an eating disorder such as binge eating, binge eating, bulimia nervosa, or compulsive eating.

[0243] inflammatory diseases In some embodiments, the condition, disease or disorder is inflammatory disorder.Non-limiting examples of inflammatory disorder include rheumatoid arthritis, spondylitis deformans, osteoarthritis, lower back pain, gout, post-operative or post-traumatic inflammation, bloating, neuralgia, pharyngitis, cystitis, pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory bowel disease), inflammation in metabolically important tissues including liver, fat, pancreas, kidney and intestine, and pro-inflammatory condition (for example, the level of the marker of pro-inflammatory cytokine inflammatory-like C-reactive protein in blood is increased).

[0244] cancer In some embodiments, the condition, disease, or disorder is cancer. Suitable examples of cancer include breast cancer (e.g., invasive ductal carcinoma, ductal carcinoma in situ, inflammatory breast cancer), prostate cancer (e.g., hormone-dependent prostate cancer, hormone-independent prostate cancer), pancreatic cancer (e.g., pancreatic ductal carcinoma), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), lung cancer (e.g., non-small cell lung cancer, small cell lung carcinoma, malignant mesothelioma), colon cancer (e.g., gastrointestinal stromal tumor), rectal cancer (e.g., gastrointestinal stromal tumor), and rectal cancer (e.g., gastrointestinal stromal tumor). tumors), colorectal cancer (e.g., familial colorectal cancer, hereditary non-polyposis 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., For example, primary liver cancer, extrahepatic bile duct cancer), kidney cancer (for example, renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter), bile duct cancer, endometrial cancer, cervical cancer, ovarian cancer (for example, epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, low-grade ovarian tumor), bladder cancer, urethral cancer, skin cancer (for example, intraocular (eye) melanoma, Merkel cell carcinoma), hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer (for example, medullary thyroid carcinoma) ), parathyroid cancer, 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, childhood solid tumors (e.g., Wilms' tumor, childhood kidney tumor), Kaposi's sarcoma, Kaposi's sarcoma caused by AIDS, maxillary sinus tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia).

[0245] Hypothalamic-pituitary disorders In some embodiments, the condition, disease, or disorder is associated with the hypothalamic-pituitary-gonadal axis. For example, the condition, disease, or disorder is associated with the hypothalamic-pituitary-ovarian axis. In other examples, the condition, disease, or disorder is associated with the hypothalamic-pituitary-testicular axis. Hypothalamic-pituitary-gonadal axis disorders include, but are not limited to, hypogonadism, polycystic ovary syndrome, hypothyroidism, hypopituitarism, hypogonadism, and Cushing's disease.

[0246] In certain embodiments, the condition, disease or disorder associated with diabetes is related to the hypothalamic-pituitary-gonadal axis.

[0247] Pulmonary disease In certain embodiments, the condition, disease, or disorder is associated with a pulmonary disease, including, but not limited to, asthma, idiopathic pulmonary fibrosis, pulmonary hypertension, obstructive sleep apnea-hypopnea syndrome, and chronic obstructive pulmonary disease (COPD) (e.g., emphysema, chronic bronchitis, and refractory (irreversible) asthma).

[0248] In certain embodiments, the condition, disease or disorder associated with diabetes is a pulmonary disease.

[0249] Combination therapy In certain embodiments, the present invention contemplates both monotherapy and combination therapy regimens.

[0250] In certain embodiments, the methods described herein may further include the administration of 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.

[0251] In some embodiments, the methods described herein include administration of a compound described herein in combination with one or more of dietary therapy (e.g., dietary monitoring, diabetic dietary therapy), exercise therapy (e.g., physical activity), blood glucose monitoring, gastric electrical stimulation (e.g., TANTALUS®), and dietary modification.

[0252] In certain embodiments, a compound of Formula I described herein, or a subformula thereof, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture, or prodrug thereof, may be administered in combination with one or more additional therapeutic agents.

[0253] Representative additional therapeutic agents include, but are not limited to, anti-obesity agents, antidiabetic agents, antidiabetic complication agents, antihyperlipidemic agents, antihypertensive agents, diuretics, chemotherapy, immunotherapy, anti-inflammatory drugs, antithrombotic agents, antioxidants, osteoporosis therapeutic agents, vitamins, anti-dementia drugs, erectile dysfunction drugs, drugs for treating frequent urination or urinary incontinence, NAFLD therapeutic agents, NASH therapeutic agents, dysuria therapeutic agents, and antiemetic agents.

[0254] 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), including GABA receptor agonists (e.g., gabapentin, pregabalin), neuropeptide Y antagonists (e.g., velneperit), cannabinoid receptor antagonists ( (e.g., rimonabant, taranabant), ghrelin antagonists, ghrelin receptor antagonists, ghrelin acylation enzyme inhibitors, opioid receptor antagonists (e.g., GSK-1521498), orexin receptor antagonists, melanocortin 4 receptor agonists, 11β-hydroxysteroid dehydrogenase inhibitors (e.g., AZD-4017, BVT-3498, INCB-13739), pancreatic lipase inhibitors (e.g., orlistat, cetilistat), β3 agonists (e.g., N-5984), diabetics, Dysglycerol acyltransferase 1 (DGAT1) inhibitors, acetyl-CoA carboxylase (ACC) inhibitors, stearoyl-CoA desaturase inhibitors, microsomal triglyceride transfer protein inhibitors (e.g., R-256918), sodium-glucose cotransporter 2 (SGLT-2) inhibitors (e.g., JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, remogliflozin), NFK inhibitors (e.g., HE-3286), PPAR agonists (e.g., GFT-505, DRF-11605, gemfibrozil, and fenofibrate), phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate, trodosquemine), GPR119 agonists (e.g., PSN-821, MBX-2982, APD597), glucokinase activators (e.g., pyragliatin, AZD-1656, AZD6370, TTP-355, W0006 / 112549, W0007 / 028135, W0008 / 047821, W0008 / 050821,compounds described in WO008 / 136428 and WO008 / 156757), leptin, leptin derivatives (e.g., metreleptin), leptin resistance improving drugs, 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 FGF extracted from bovine or porcine pancreas), FGF21 preparations; human FGF21 preparations genetically synthesized using E. coli or yeast; fragments or derivatives of FGF21), anorexigens (e.g., P-57), human islet precursor peptide (HIP), farnesoid X receptor (FXR) agonists, phentermine, zonisamide, norepinephrine / dopamine reuptake inhibitors, GDF-15 analogs, methionine aminopeptidase 2 (MetAP2) inhibitors, diethylpropion, phendimetrazine, benzphetamine, fibroblast growth factor receptor (FGFR) modulators, and AMP-activated protein kinase (AMPK) activators.

[0255] In certain 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; insulin fragments or derivatives (e.g., INS-1), oral insulin preparations, synthetic human insulin), insulin sensitizers (e.g., pioglitazone or a salt thereof), biguanides (e.g., metformin, buformin or a salt thereof (e.g., hydrochloride, fumarate, succinate)), glucagon analogs. (e.g., any of the glucagon analogues described in WO2010 / 011439), agents that antagonize the action of glucagon or reduce its secretion, sulfonylureas (e.g., chlorpropamide, toluazamide, gliclazide, glimepiride, tolbutamide, glibenclamide, gliclazide, acetohexamide, glycopyramide, glybuzole, glyburide), thiazolidinediones (e.g., rosiglitazone or pioglitazone), α-glucosidase inhibitors (e.g., voglibose, acarbose, miglitol, emiglitate). , insulin secretagogues, such as prandial glucose control agents (sometimes referred to as "short-acting secretagogues"), e.g., meglitinides (e.g., repaglinide and nateglinide), cholinesterase inhibitors (e.g., donepezil, galantamine, rivastigmine, tacrine), NMDA receptor antagonists, dual GLP-1 / GIP receptor agonists (e.g., LBT-2000, ZPD1-70), GLP-1R agonists (e.g., exenatide, liraglutide, albiglutide, dulaglutide, albiglutide, tacrine), and dipeptidyl peptidase IV (DPP-4) inhibitors (e.g., vildagliptin, dutogliptin, gemigliptin, alogliptin, saxagliptin, sitagliptin, linagliptin, berberine, adgliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, SK-0403, ALS2-0426, TA-6666, TS-021, KRP-104, trelagliptin).

[0256] 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-lysyl 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-alpha-tocopherol, ascorbic acid, glutathione, vitamin B complex, glitazones / thiazolidinediones (e.g., troglitazone, rosiglitazone, pioglitazone), metformin, cysteamine, sulfonylureas, alpha-glucosidase inhibitors, meglitinides, vitamins, tetrahydrolipstatin, milk thistle protein, antivirals, and antioxidants.

[0257] 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 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., propyl mesylate), voxistaurin), 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.

[0258] In certain 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, e.g., N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetate), and the like. [ethyl]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., soy sterol, gamma oryzanol (γ-oryzanol)), cholesterol absorption inhibitors (e.g., zetia), CETP inhibitors (e.g., dalcetrapib, anacetrapib), and omega-3 fatty acid preparations (e.g., omega-3 fatty acid ethyl esters 90).

[0259] 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 β-blockers (e.g., metoprolol, atenolol, propranolol, carvedilol, pindolol).

[0260] 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., sodium theobromine salicylate, calcium theobromine 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) and chlorobenzenesulfonamides (e.g., chlorthalidone, mefruside, indapamide).

[0261] 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, sizofiran, krestin), cytokines obtained by genetic engineering approaches (e.g., interferons, interleukins (IL), such as IL-1, IL-2, IL-12), and colony-stimulating factors (e.g., granulocyte colony-stimulating factor, erythropoietin).

[0262] In some embodiments, the one or more additional therapeutic agents include, for example, those useful as antithrombotic agents. Non-limiting examples include heparin (e.g., heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarin (e.g., warfarin potassium), antithrombin drugs (e.g., argatroban, dabigatran), FXa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, betrixaban, YM150, compounds described in WO02 / 06234, WO2004 / 048363, WO2005 / 030740, WO2005 / 058823, and WO2005 / 113504). Thrombolytic agents (e.g., urokinase, tisokinase, alteplase, nateplase, monteplase, pamiteplase), and platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cilostazol, ethyl icosapentate, beraprost sodium, and sarpogrelate hydrochloride).

[0263] In some embodiments, the one or more additional therapeutic agents include, for example, those useful for treating osteoporosis. Non-limiting examples include alfacalcidol, calcitriol, elcitonin, salmon calcitonin, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium, and risedronate disodium. Suitable examples of vitamins include vitamin B1 and vitamin B12. Suitable examples of erectile dysfunction medications 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.

[0264] Other examples of 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 intended 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 agents such as HMG-CoA reductase inhibitors (statins, e.g., rosuvastatin), cholesterol-lowering drugs such as erythritol phosphate dehydrogenase (ERD) inhibitors (e.g., erythritol phosphate dehydrogenase), ... Adrenergic receptor antagonists such as sterol-lowering agents, bile acid sequestrants (e.g., cholestyramine), cholesterol absorption inhibitors (e.g., plant sterols such as phytosterols), cholesteryl ester transfer protein (CETP) inhibitors, ileal bile acid transport system inhibitors (IBAT inhibitors), bile acid-binding resins, nicotinic acid (niacin) and its analogs, antioxidants (e.g., probucol), omega-3 fatty acids, beta-blockers (e.g., atenolol), alpha-blockers (e.g., doxazosin), and combined alpha / beta-blockers (e.g., labetalol). antihypertensives, including receptor antagonists; adrenergic receptor agonists, including alpha-2 agonists (e.g., clonidine); calcium channel blockers, such as angiotensin-converting enzyme (ACE) inhibitors (e.g., lisinopril), dihydropyridines (e.g., nifedipine), phenylalkylamines (e.g., verapamil), and benzothiazepines (e.g., diltiazem); angiotensin II receptor antagonists (e.g., candesartan); aldosterone receptor antagonists (e.g., eplerenone); central alpha agonists (e.g., clonidine); centrally acting adrenergic drugs such as thrombin antagonists, factor VIIa inhibitors, anticoagulants (e.g., vitamin K antagonists such as warfarin), hemostatic modulators including heparin and its low molecular weight analogs, factor Xa inhibitors, and direct thrombin inhibitors (e.g., argatroban), antiplatelet agents (e.g., cyclooxygenase inhibitors (e.g., aspirin)), adenosine diphosphate (ADP) receptor inhibitors (e.g., clopidogrel),Phosphodiesterase inhibitors (e.g., cilostazol), glycoprotein IIB / IIA inhibitors (e.g., tirofiban), adenosine reuptake inhibitors (e.g., dipyridamole), noradrenergic agents (e.g., phentermine), serotonergic agents (e.g., sibutramine), diacylglycerol acyltransferase (DGAT) inhibitors, feeding behavior modifiers, pyruvate dehydrogenase kinase (PDK) modulators, serotonin receptor modulators, selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine) monoamine transport modifiers such as noradrenaline reuptake inhibitors (NARIs), noradrenaline-serotonin reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs) (e.g., toloxatone and amiflamine), compounds described in WO007 / 013694, WO2007 / 018314, WO2008 / 093639 and WO2008 / 099794, GPR40 agonists (e.g., fasiglifam or its hydrate, WO2004 / 041266, WO2004 / 106276, WO2005 / 0 63729, compounds described in WO2005 / 063725, WO2005 / 087710, WO2005 / 095338, WO2007 / 013689 and WO2008 / 001931), cachexia improving agents such as SGLT1 inhibitors, adiponectin or its agonists, IKK inhibitors (e.g., AS-2868), somatostatin receptor agonists, ACC2 inhibitors, cyclooxygenase inhibitors (e.g., indomethacin), progesterone derivatives (e.g., megestrol acetate), glucocorticoids (e.g., dexamethasone), methasone), metoclopramide agents, tetrahydrocannabinol agents, fat metabolism improvers (e.g., eicosapentaenoic acid), growth hormone, IGF-1, cachexia-inducing factors TNF-α, LIF, IL-6, and antibodies against oncostatin M, metabolic modifying proteins or peptides such as glucokinase (GK), glucokinase regulatory protein (GKRP), uncoupling proteins 2 and 3 (UCP2 and UCP3), peroxisome proliferator-activated receptor α (PPARα), MC4r agonists, insulin receptor agonists, PDE 5 inhibitors, glycation inhibitors (e.g., ALT-711),Neuroregeneration promoting drugs (e.g., Y-128, VX853, prosaptide), antidepressants (e.g., desipramine, amitriptyline, imipramine), antiepileptic drugs (e.g., lamotrigine, trileptal, Keppra, Zonegran, pregabalin, halcoceride, carbamazepine), antiarrhythmic drugs (e.g., mexiletine), acetylcholine receptor ligands (e.g., ABT-594), endothelin receptor antagonists (e.g., ABT-627), narcotic analgesics These include: anti-inflammatory drugs (e.g., morphine), α2 receptor agonists (e.g., clonidine), topical analgesics (e.g., capsaicin), anti-anxiety drugs (e.g., benzothiazepines), phosphodiesterase inhibitors (e.g., sildenafil), dopamine receptor agonists (e.g., apomorphine), cytotoxic antibodies (e.g., T cell receptor- and IL-2 receptor-specific antibodies), B cell-depleting treatments (e.g., anti-CD20 antibodies (e.g., Rituxan), i-BLyS antibodies), and drugs that affect T cell migration. Drugs (e.g., anti-integrin alpha 4 / beta 1 antibodies (e.g., Tysabri), drugs acting on immunophilins (e.g., cyclosporine, tacrolimus, sirolimus, rapamycin), interferons (e.g., IFN-β), immunomodulators (e.g., glatiramer), TNF-binding proteins (e.g., circulating receptors), immunosuppressants (e.g., mycophenolic acid), and other drugs, such as metaglidasen, AMG-131, balaglitazone, MBX-2044, rivoglitazone, These include fluticasone, aleglitazar, 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).

[0265] In some embodiments, the one or more additional therapeutic agents include, for example, those useful as antiemetics. As used herein, an "antiemetic" agent refers to any agent that counters (e.g., reduces or eliminates) nausea or emesis (vomiting). When referring to a therapeutically effective amount of an antiemetic, it should be understood that the amount administered refers to the amount necessary to counter (e.g., reduces or eliminates) nausea or emesis (vomiting). Without wishing to be bound by theory, it is believed that administering one or more antiemetics in combination with a compound of formula (I) described herein may, for example, allow a patient to consume a normal amount of food, thereby allowing for the administration of a higher dose of the compound of formula (I), thereby resulting in a faster response to treatment.

[0266] 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, cannabinoids.

[0267] For example, the antiemetic agent may be selected from the group consisting of neuroleptics, antihistamines, anticholinergics, steroids, 5HT-3 receptor antagonists, NK1 receptor antagonists, antidopaminergics / dopamine receptor antagonists, benzodiazepines and non-psychoactive cannabinoids.

[0268] In certain 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 mitrazepine. Other non-limiting examples of 5HT3 receptor antagonists (serotonin receptor antagonists) include cilansetron, clozapine, cyproheptadine, dazopride, hydroxyzine, lerisetron, metoclopramide, mianserin, olanzapine, palonosetron (plus netupitant), quetiapine, camosetron, ramosetron, licasetron, risperidone, ziprasidone, and zatosterone.

[0269] 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 mitrazepine.

[0270] In certain embodiments, the 5HT-3 receptor antagonist is granisetron, dolasetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemesetron, and zatisetron.

[0271] In certain embodiments, the 5HT-3 receptor antagonist is granisetron, dolasetron, and ondansetron.

[0272] In certain embodiments, the 5HT-3 receptor antagonist is granisetron.

[0273] In certain embodiments, the 5HT-3 receptor antagonist is ondansetron.

[0274] In some embodiments, the antiemetic agent is an antihistamine. Non-limiting examples of antihistamines include piperazine derivatives (e.g., cyclizine, meclizine, and cinnarizine); promethazine; dimenhydrinate (dramamine, gravol); diphenhydramine; hydroxyzine; buclizine; and meclizine hydrochloride (bonine, antivert), doxylamine, and mitrazapine.

[0275] In some embodiments, the antiemetic agent is an anticholinergic (acetylcholine receptor inhibitor). Non-limiting examples of anticholinergic agents include atropine, scopolamine, glycopyrone, hyoscine, Artane (trihexy-5 trihexyphenidyl hydrochloride), Cogentin (benztropine mesylate), Akineton (biperiden hydrochloride), Disipal (Norflex orphenadrine citrate), diphenhydramine, hydroxyzine, hyoscyamine, and Chemadrin (procyclidine hydrochloride).

[0276] 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).

[0277] In certain embodiments, the antiemetic agent is an NK1 receptor antagonist (e.g., a neurokinin 1 substance P receptor antagonist). Non-limiting examples of NK1 receptor antagonists include aprepitant, casopitant, ezlopitant, fosaprepitant, maropitant, netupitant, rolapitant, and vestipitant.

[0278] 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)-alpha-MeTrp-(S)-NHCH(CH)Ph), FK888, and (D-Pro, D-Trp, Phe)SP.

[0279] In some embodiments, the antiemetic agent is an antidopaminergic / dopamine receptor antagonist (e.g., a dopamine receptor antagonist, e.g., a D2 or D3 antagonist). Non-limiting examples include phenothiazines (e.g., promethazine, chlorpromazine, prochlorperazine, perphenazine, hydroxyzine, thiethylperazine, metopimazine); benzamides (e.g., metoclopramide, domperidone), butyrophenones (e.g., haloperidol, droperidol); alizapride, bromopride, clebopride, domperidone, itopride, metoclopramide, trimethobenzamide, and amisulpride.

[0280] In some embodiments, the antiemetic agent is a non-psychoactive cannabinoid (e.g., cannabidiol (CBD), cannabidiol dimethylheptyl (CBD-DMH), tetra-hydro-cannabinol (THC), cannabinoid agonists such as WIN 55-212 (a CB1 and CB2 receptor agonist), dronabinol (Marinol®), and nabilone (Cesamet)).

[0281] Other exemplary antiemetic agents include C-9280 (Merck); benzodiazepines (diazepam, midazolam, lorazepam); neuroleptic / antipsychotic agents (e.g., dixyrazine, haloperidol, and prochlorperazine (Compazine®)); cerium oxalate; propofol; sodium citrate; dextrose; fructose (Nauzene); orthophosphate; fructose; glucose (Emetrol); bismuth subsalicylate (Pepto-Bismol); ephedrine; vitamin B6; peppermint, lavender, and lemon essential oils; and ginger.

[0282] Still other exemplary antiemetic agents include those disclosed 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).

[0283] In certain embodiments, the additional therapeutic agent or regimen is administered to the patient before contacting or administering the compounds and pharmaceutical compositions (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).

[0284] In some embodiments, the additional therapeutic agent or regimen is administered to patient at the same time as contacting or administering with the compound and pharmaceutical composition.For example, the additional therapeutic agent or regimen and the compound and pharmaceutical composition are simultaneously provided to patient in the same dosage form.In other examples, the additional therapeutic agent or regimen and the compound and pharmaceutical composition are simultaneously provided to patient in separate dosage forms.

[0285] Patient Selection In certain embodiments, the methods described herein further include identifying a patient (e.g., subject) in need of such treatment (e.g., by blood assay, body mass index, or other conventional method known in the art).

[0286] In certain embodiments, the methods described herein further include a step of identifying a patient (e.g., a subject) having a disease, disorder, or condition (e.g., a GLP-1-associated disease, disorder, or condition) provided herein.

[0287] In certain embodiments, the methods described herein further comprise identifying a patient (e.g., a patient) with type 2 diabetes. In certain 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 certain embodiments, the HbA1c level is about 6.5% to about 24.0%. In certain embodiments, the HbA1c level is about 6.5% or higher. In certain embodiments, the HbA1c level is about 8.0% or higher. In certain embodiments, the HbA1c level is about 10.0% or higher. In certain embodiments, the HbA1c level is about 12.0% or higher. In certain embodiments, the HbA1c level is about 14.0% or higher. In certain embodiments, the HbA1c level is about 16.0% or higher. In certain embodiments, the HbA1c level is about 18.0% or higher. In some embodiments, the HbA1c level is about 20.0% or greater. In some embodiments, the HbA1c level is about 22.0% or greater. In some embodiments, the HbA1c level is about 24.0% or greater.

[0288] In some embodiments, the fasting plasma glucose level is about 120 mg / dL or more to about 750 mg / dL or more. In some embodiments, the fasting plasma glucose level is about 200 mg / dL or more to about 500 mg / dL or more. In some embodiments, the fasting plasma glucose level is about 300 mg / dL or more to about 700 mg / dL or more.

[0289] In some embodiments, the non-fasting plasma glucose level is about 190 mg / dL or more to about 750 mg / dL or more. In some embodiments, the non-fasting plasma glucose level is about 250 mg / dL or more to about 450 mg / dL or more. In some embodiments, the non-fasting plasma glucose level is about 400 mg / dL or more to about 700 mg / dL or more.

[0290] In certain embodiments, determining whether a patient has type 2 diabetes includes determining the patient's BMI. In certain embodiments, the patient's BMI is about 22 kg / m 2 More than ~ about 100kg / m 2 In one embodiment, the patient's BMI is about 30 kg / m 2 More than ~90kg / m 2 In one embodiment, the patient's BMI is about 40 kg / m 2 More than ~about 80kg / m 2 In one embodiment, the patient's BMI is about 50 kg / m 2 More than ~ about 70kg / m 2 is.

[0291] In certain embodiments, additional factors (e.g., risk factors) used in determining whether a patient has type 2 diabetes include the patient's age and ethnicity. In certain embodiments, the patient is about 10 years of age or older. In certain embodiments, the patient is about 15 years of age or older. In certain embodiments, the patient is about 20 years of age or older. In certain embodiments, the patient is about 25 years of age or older. In certain embodiments, the patient is about 30 years of age or older. In certain embodiments, the patient is about 35 years of age or older. In certain embodiments, the patient is about 40 years of age or older. In certain embodiments, the patient is about 42 years of age or older. In certain embodiments, the patient is about 44 years of age or older. In certain embodiments, the patient is about 46 years of age or older. In certain embodiments, the patient is about 48 years of age or older. In certain embodiments, the patient is about 50 years of age or older. In certain embodiments, the patient is about 52 years of age or older. In certain embodiments, the patient is about 54 years of age or older. In certain embodiments, the patient is about 56 years of age or older. In certain embodiments, the patient is about 58 years of age 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 is about 95 years of age or older. In some embodiments, the patient's ethnicity may be African American, American Indian or Alaska Native, Asian American, Hispanic or Latino, or Native Hawaiian or Pacific Islander.

[0292] General synthesis method The compounds of the present invention can be prepared from readily available starting materials, for example, using the following general methods and procedures. Where certain process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it is recognized that other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the reactants or solvents used, although such conditions can be determined by one skilled in the art by routine optimization of the procedures.

[0293] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary for certain functional groups to prevent undesired reactions from occurring. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting certain 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.

[0294] Additionally, compounds of the present invention may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., individual enantiomers or diastereomers, or stereoisomer-enriched mixtures. Unless otherwise specified, all such stereoisomers (and enriched mixtures) are included within the scope of the present invention. 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.

[0295] 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 sources 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 are described in Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 5 th Organic synthesis compounds can be prepared by methods described in standard reference texts such as "The Organic Synthesis of Organic Compounds" (VCH Publishers Inc., 1989), "The Organic Synthesis of Organic Compounds" (VCH Publishers Inc., 1989), or obvious modifications thereof.

[0296] Scheme I illustrates a general method that may be used to synthesize the compounds described herein, where Ring A, Ring B, Ring Z 1 , Z 2 , R 1 , R 2 , R 4 , R 5 , R 6 , R 7 and p are each independently as defined herein; LG is a leaving group such as halo (e.g., Cl, Br, or I); and R is hydrogen or a suitable carboxyl protecting group such as alkyl or benzyl. Scheme I [ka]

[0297] Compounds of formula I and I' can be provided by coupling compound I-1 or I'-1 with compound I-2 under suitable coupling reaction conditions, such as SN2 reaction conditions, where ring A contains a complementary functional group, such as, but not limited to, a nucleophilic moiety. Examples of suitable reaction conditions include, but are not limited to, a polar aprotic solvent (e.g., acetonitrile) optionally in the presence of a base (e.g., DIEA, or an amine base such as potassium carbonate). For methods where R is a carboxyl protecting group such as alkyl or benzyl, the method can further include a deprotection step, e.g., a hydrolysis step. Suitable reagents for the deprotection step can include the presence of water under basic conditions, such as aqueous LiOH or a suitable aqueous solvent mixture (e.g., water in methanol, THF, or a combination thereof).

[0298] It should be appreciated that the resulting product can be further derivatized via methods and chemical transformations known to those skilled in the art to provide compounds of other formulas I, I', or other subformulas thereof. 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 more than one reaction or set of reactants.

[0299] It should be understood that for any compound shown in Scheme I, various derivatives can be provided by functional group interconversion at any step. For example, with R as alkyl, various compounds of Formula I, I', or other subformulas thereof can be provided via transesterification or hydrolysis using methods known to those skilled in the art. Similarly, various compounds of Formula I can be prepared by modifying one or more substituents (e.g., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7) is or contains a leaving group (e.g., a halo, such as Cl, Br, or I, or a pseudohalide, such as a triflate, sulfonate, or phosphate) with a reagent containing a complementary functional group, such as, but not limited to, a boronic acid or a derivative thereof, such as a boronic acid ester, a zinc or magnesium halide, an organotin compound, such as tributylstannane or trimethylstannane, a fluorosulfonyl ester, tin, sodium, hydrogen, etc., under appropriate coupling reaction conditions. Such reactions are commonly utilized for aromatic functionalization and are typically carried out using a suitable solvent / solvent mixture in the presence of a suitable catalyst, such as, but not limited to, a palladium catalyst including [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, Pd(OAc)2, Pd(PPh3)4, PdCl2(PPh3)2, or tris(dibenzylideneacetone)dipalladium(0), or a copper catalyst, such as CuCl or CuI, and, if necessary, a suitable mediator, cocatalyst, and / or base known to those skilled in the art. After completion of the reaction, the compound of Formula I can be recovered by conventional techniques, such as neutralization, extraction, precipitation, chromatography, filtration, and the like. In certain embodiments, when control of stereochemistry is desired, the formation of various stereoisomers can be defined or preserved, at least in part, by appropriate control of reaction conditions and selection of reagent substituents.

[0300] In certain embodiments, the various substituents of Formula I-1, I'-1, or I-2 are defined herein. However, derivatization prior to the reaction at any step and / or further derivatization of the resulting reaction product will provide various compounds of Formula I or I'. Suitable starting materials and reagents can be purchased or prepared by methods known to those skilled in the art. After each reaction step, each intermediate or final compound can be recovered and, if desired, purified by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, and the like. Other modifications to arrive at compounds of the present invention are within the skill of the art.

[0301] In certain embodiments, a method for producing a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture, or prodrug thereof, comprises reacting a compound of Formula I-1: [ka] and a compound of formula I-2: [ka] Compounds of [In the above compound, ring A, ring B, Z 1 , Z 2 , R 1 , R 2 , R 4 , R 5 , R 6 , R 7 and p are each independently as defined herein; LG is a leaving group; and R is hydrogen or C optionally substituted with phenyl. 1-6 It is alkyl.

[0023] A method is provided, comprising contacting

[0302] In certain embodiments, a method for preparing a compound of formula I', or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture, or prodrug thereof, comprises reacting a compound of formula I'-1: [ka] and a compound of formula I-2: [ka] Compounds of [In the above compound, ring A, ring B, Z 1 , Z 2 , R 1 , R2 , R 4 , R 5 , R 6 , R 7 and p are each independently as defined herein; LG is a leaving group; and R is hydrogen or C optionally substituted with phenyl. 1-6 It is alkyl.

[0023] A method is provided, comprising contacting

[0303] In some embodiments, the method further comprises a hydrolysis or transesterification step before or after the contacting step. In some embodiments, the method comprises a base. In some embodiments, the method comprises elevated temperature. [Example]

[0304] The present invention will be further understood with reference to the following examples, which are intended to be purely exemplary of the invention. The present invention is not limited in scope by the exemplary embodiments, which are intended only to illustrate one aspect of the invention. Any methods that are functionally equivalent are within the scope of the present invention. Various modifications of the present invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications fall within the scope of the appended claims.

[0305] Abbreviations (as used here): [Table 12]

[0306] General information: Total evaporation or concentration was performed under reduced pressure on a rotary evaporator. Analytical samples were dried under reduced pressure (1-5 mmHg) at room temperature. Thin-layer chromatography (TLC) was performed on silica gel plates, and spots were visualized with UV light (214 nm and 254 nm). Purification by column and flash chromatography was performed using silica gel (100-200 mesh). Solvent systems are listed as mixtures by volume. NMR spectra were recorded on a Bruker 400 or Varian (400 MHz) spectrometer. 1 H and 19 F chemical shifts are reported in δ values ​​(ppm) using deuterated solvents as internal standards. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constant (Hz), and integration. LCMS spectra were obtained on a SHIMADZU LC20-MS2020 or Agilent 1260 Series 6125B mass spectrometer or an Agilent 1200 Series, 6110, or 6120 mass spectrometer using electrospray ionization unless otherwise indicated.

[0307] General synthetic scheme Scheme 1. Synthesis scheme of Int-A [ka]

[0308] Key intermediate Int-A is synthesized via the method described in Scheme 1. A-1 proceeds via an SNAr reaction with an appropriate amine A-2 to give A-3. In certain embodiments, the reaction involves DIEA. A-3 then undergoes a palladium-catalyzed carbonylative Suzuki coupling to give intermediate A-4. In certain embodiments, the reaction involves Pd(dppf)Cl. The nitro group of A-4 is then reduced by catalytic hydrogenation, and the resulting phenyldiamine is reacted with 2-chloroacetic anhydride A-6, for example, in dioxane, to give Int-A.

[0309] Scheme 2. Synthesis scheme of Int-B [ka]

[0310] The synthesis of Int-B begins with the bromination of acetophenone B-1, for example, using pyridinium tribromide to give B-2, which is then reacted with B-3 to give B-4. In some embodiments, the reaction includes a base such as K2CO3. B-4 is then enantioselectively reduced with RuCl[(S,S)-Tsdpen](p-cymene) and subjected to an intramolecular coupling reaction to give B-6. In some embodiments, the reaction from B-4 to B-5 includes TEA and formic acid. In some embodiments, the reaction from B-5 to B-6 includes toluene and heating. B-6 is then coupled with benzylboronic acid pinacol ester B-7 to give Int-B. In some embodiments, the reaction includes Pd(dppf)Cl2.

[0311] Scheme 3. Synthesis scheme of C [ka]

[0312] Reaction of Int-A with Int-B gives intermediate C-1. In some embodiments, the reaction includes DIEA. Hydrolysis of C-1 gives final product C. In some embodiments, the reaction includes LiOH.

[0313] Scheme 2'. Synthesis scheme of Int-B' [ka]

[0314] The synthesis of Int-B' begins with the bromination of acetophenone B'-1, for example, using pyridinium tribromide, followed by reaction with B'-2 and then B'-3 to give B'-4. In some embodiments, the reaction includes a base such as K2CO3. B'-4 is then enantioselectively reduced with RuCl[(S,S)-Tsdpen](p-cymene) and undergoes an intramolecular coupling reaction to give B'-6. In some embodiments, the reaction of B'-4 to B'-5 includes TEA and formic acid. In some embodiments, the reaction of B'-5 to B'-6 includes toluene and heating. B'-6 is then coupled with benzylboronic acid pinacol ester B'-7 to give Int-B'. In some embodiments, the reaction includes Pd(dppf)Cl2.

[0315] Scheme 3'. Synthesis scheme of C' [ka]

[0316] Reaction of Int-A' with Int-B' provides intermediate C'-1. In some embodiments, the reaction includes DIEA. Hydrolysis of C'-1 provides final product C'. In some embodiments, the reaction includes LiOH.

[0317] Example A1 2-({4-[(2R)-2-(4-cyanophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperidin-1-yl}methyl)-1-[(oxolan-3-yl)methyl]-1H-1,3-benzodiazole-6-carboxylic acid (Compound 106) [ka] [ka]

[0318] Step A Methyl 4-nitro-3-(((tetrahydrofuran-3-yl)methyl)amino)benzoate [ka]

[0319] To a solution of methyl 3-fluoro-4-nitrobenzoate (1.514 g, 76 mmol), (tetrahydrofuran-3-yl)methanamine (1 g, 9.88 mmol) in CH3CN (15 mL) was added DIEA (2.944 g, 22.8 mmol) and tetrahydro-3-furylmethanamine (2.306 g, 22.8 mmol). The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was diluted with EtOAc (50 mL) and washed with water (50 mL × 4). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, eluent: 0-5% EtOAc / PE gradient at 50 mL / min) to give methyl 4-nitro-3-(((tetrahydrofuran-3-yl)methyl)amino)benzoate (2.062 g, 96.8% yield). LC-MS: m / z 281.1 (M+H) + .

[0320] Step B Methyl 4-amino-3-(((tetrahydrofuran-3-yl)methyl)amino)benzoate [ka]

[0321] To a solution of methyl 4-nitro-3-(((tetrahydrofuran-3-yl)methyl)amino)benzoate (500 mg, 1.784 mmol) in MeOH (12 mL) and THF (10 mL) was added 10% Pd / C (100 mg). The resulting mixture was stirred at room temperature for 16 hours under a H2 balloon. The mixture was filtered and the filtrate was concentrated to give methyl 4-amino-3-(((tetrahydrofuran-3-yl)methyl)amino)benzoate (490 mg, crude). LC-MS: m / z 251.2 (M+H) + .

[0322] Step A Methyl 2-(chloromethyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate [ka]

[0323] A solution of a mixture of methyl 4-amino-3-(((tetrahydrofuran-3-yl)methyl)amino)benzoate (590 mg, 2.357 mmol) and 2-chloroacetic anhydride (403.01 mg, 2.357 mmol) in dioxane (2 mL) was stirred at 60° C. for 2 hours. Then, HOAc (0.2 mL) was added. The resulting reaction mixture was stirred at 70° C. for 2 hours. After completion of the reaction, the mixture was diluted with DCM (50 mL) and washed with saturated aqueous NaHCO. The organic phase was dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, eluent: 0-25% EtOAc / PE gradient at 50 mL / min) to give methyl 2-(chloromethyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (644 mg, 88.5% yield). LC-MS: m / z 309.1 (M+H). + .

[0324] Step D (R)-4-(5-(piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)benzonitrile TFA salt [ka]

[0325] To a solution of tert-butyl (R)-4-(2-(4-cyanophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate (160 mg, 0.38 mmol) in DCM (3 mL) was added TFA (0.6 mL). The reaction mixture was stirred at 25° C. for 1 hour. The solution was then concentrated to give (R)-4-(5-(piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)benzonitrile TFA salt (130 mg, crude). LC-MS: m / z 321.2 (M+H) + .

[0326] Step E Methyl 2-((4-((R)-2-(4-cyanophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate [ka]

[0327] To a solution of (R)-4-(5-(piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)benzonitrile TFA salt (182.89 mg, 0.421 mmol) in DMF (2 mL) was added DIEA (0.5 mL). The reaction mixture was stirred at room temperature for 2 minutes, and then methyl 2-(chloromethyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (130 mg, 0.421 mmol) was added. The reaction was stirred at 50° C. for 1 hour. After cooling, the mixture was diluted with EtOAc (50 mL) and washed with water (50 mL×3). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, eluent: 0-25% EtOAc / PE gradient at 50 mL / min) to give methyl 2-((4-((R)-2-(4-cyanophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (148 mg, 61.8% yield). LC-MS: m / z 593.4 (M+H) + .

[0328] Step F 2-({4-[(2R)-2-(4-cyanophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperidin-1-yl}methyl)-1-[(oxolan-3-yl)methyl]-1H-1,3-benzodiazole-6-carboxylic acid (Compound 106) [ka]

[0329] A mixture of methyl 2-((4-((R)-2-(4-cyanophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 0.169 mmol) and LiOH.HO (20.25 mg, 0.844 mmol) in THF / HO (1 mL / 0.2 mL) was stirred at 40 °C for 16 hours. After cooling, the mixture was directly purified by preparative HPLC (column: Sunfire C18, 19*250 mm*10 μm; mobile phase A: water (0.1% formic acid), B: CH3CN; flow rate: 20 mL / min; gradient: 36% B to 38% B; retention time: 8.9 to 13.2 min) to give compound 106 (85.61 mg, 87.6% yield). LC-MS: m / z 579.4 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ 12.99 (br s, 1 H), 8.35 (s, 1 H), 7.96 - 7.89 (m, 3 H), 7.80 (d, J = 8.4 Hz, 1 H), 7.69 (d, J = 8.0 Hz, 2 H), 6.96 - 6.90 (m, 2 H), 6.90 - 6.76 (m, 1 H), 5.44 - 5.37 (m, 1 H), 4.87 - 4.77 (m, 2 H), 4.59 - 4.52 (m, 1 H), 4.43 (d, J = 8.0 Hz, 2 H), 4.20 - 4.11 (m, 1 H), 3.95 - 3.87 (m, 1 H), 3.81 - 3.78 (m, 2 H), 3.71 - 3.61 (m, 3 H), 3.48 - 3.42 (m, 2 H), 3.21 -3.14 (m, 1 H), 2.84 - 2.73 (m, 1 H), 2.10 - 1.86 (m, 5 H), 1.72 - 1.61 (m, 1 H).

[0330] Example compounds 105 and 107 were synthesized using procedures analogous to Example A1 above, using the appropriate materials.

[0331] Example A2 2-({4-[(2R)-2-(4-cyanophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperidin-1-yl}methyl)-4-fluoro-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (Compound 104) [ka] [ka] [ka]

[0332] (S)-2-(Chloromethyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate was synthesized according to the procedure described for the preparation of intermediate 1-4 (Steps AB and C), using (S)-oxetan-2-ylmethanamine and methyl 3,5-difluoro-4-nitrobenzoate in Step A. LC-MS: m / z 313.2 (M+H) + .

[0333] Step A Methyl 2-((4-((R)-2-(4-cyanophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate [ka]

[0334] To a mixture of (R)-4-(5-(piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)benzonitrile TFA salt (130 mg, crude) in CH3CN (3.0 mL) was added DIEA (248 mg, 1.91 mmol) and methyl (S)-2-(chloromethyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 0.34 mmol). The reaction mixture was stirred at 60 °C for 1 h. After cooling and concentration, the residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, eluting with a 0-5% MeOH / DCM gradient at 50 mL / min) to give methyl 2-((4-((R)-2-(4-cyanophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (205 mg, 90.5% yield over two steps). LC-MS: m / z 597.3 (M+H) + .

[0335] Step B 2-({4-[(2R)-2-(4-cyanophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperidin-1-yl}methyl)-4-fluoro-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (Compound 104) [ka]

[0336] To a solution of methyl 2-((4-((R)-2-(4-cyanophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (205 mg, 0.34 mmol) in THF / HO (V / V = 4:1, 2.5 mL) was added LiOH HO (58 mg, 1.38 mmol). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (column: Sunfire C18, 19*250 mm*10 μm; mobile phase A: water (0.1% formic acid), B: CH3CN; flow rate: 20 mL / min; gradient: 32% B to 33% B; retention time: 8.4 to 11.1 min in 16 min) to give 2-({4-[(2R)-2-(4-cyanophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperidin-1-yl}methyl)-4-fluoro-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (80.2 mg, 40.1% yield). LC-MS: m / z 583.2 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ 8.16 (s, 1 H), 7.91 (d, J = 8.4 Hz, 2 H), 7.68 (d, J = 8.4 Hz, 2 H), 7.50 (d, J = 11.2 Hz, 1 H), 6.87 - 6.78 (m, 3 H), 5.42 - 5.35 (m, 1 H), 5.16 - 5.06 (m, 1 H), 4.80 (dd, J1= 13.2 Hz, J2= 2.4 Hz, 1 H), 4.73 (d, J = 9.6 Hz, 1 H), 4.58 - 4.46 (m, 2 H), 4.42 - 4.33 (m, 1 H), 4.13 - 4.05 (m, 1 H), 3.95 (d, J = 13.6 Hz, 1 H), 3.82 (d, J = 13.6 Hz, 1 H), 3.05 - 2.96 (m, 1 H), 2.91 - 2.81 (m, 2 H), 2.77 - 2.65 (m, 1 H), 2.48 - 2.38 (m, 1 H), 2.32 - 2.13 (m, 2 H), 1.81 - 1.71 (m, 1 H), 1.69 - 1.55 (m, 3 H). 19 F NMR (377MHz, DMSO-d6) δ -129.16.

[0337] Example A3 2-({4-[(2R)-2-(4-cyanophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperidin-1-yl}methyl)-4-methoxy-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (Compound 118) [ka] [ka]

[0338] Step A 5-Bromo-1-fluoro-3-methoxy-2-nitrobenzene [ka]

[0339] A mixture of 5-bromo-1,3-difluoro-2-nitrobenzene (10.0 g, 42.02 mmol) and KOH (2.47 g, 44.12 mmol) in MeOH (100 mL) was stirred at 90 °C for 1.5 h. After cooling, the reaction mixture was diluted with EtOAc (400 mL) and washed with water (300 mL × 2) and brine (100 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (120 g SepaFlash® Silica Flash Column, eluent: 0–10% EtOAc / PE gradient at 100 mL / min) to give 5-bromo-1-fluoro-3-methoxy-2-nitrobenzene (5.6 g, 53.3% yield).

[0340] Step B (S)-5-Bromo-3-methoxy-2-nitro-N-(oxetan-2-ylmethyl)aniline [ka]

[0341] To a solution of 5-bromo-1-fluoro-3-methoxy-2-nitrobenzene (10.8 g, 43.37 mmol) in CH3CN (130 mL) was added DIEA (16.81 g, 130.12 mmol) and (S)-oxetan-2-ylmethanamine (3.77 g, 43.37 mmol). The resulting mixture was stirred at 40 °C for 2 h. After cooling, the reaction mixture was diluted with EtOAc (300 mL) and washed with water (300 mL × 2) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (120 g SepaFlash® Silica Flash Column, eluent: 0-25% EtOAc / PE gradient at 100 mL / min) to give (S)-5-bromo-3-methoxy-2-nitro-N-(oxetan-2-ylmethyl)aniline (10.4 g, 75.9% yield). LC-MS: m / z 317.2 (M+H). + .

[0342] Step C Ethyl (S)-3-methoxy-4-nitro-5-((oxetan-2-ylmethyl)amino)benzoate [ka]

[0343] To a mixture of (S)-5-bromo-3-methoxy-2-nitro-N-(oxetan-2-ylmethyl)aniline (10.4 g, 32.91 mmol) in EtOH (120 mL) was added AcOK (6.46 g, 65.8 mmol) and Pd(dppf)Cl (2.41 g, 3.29 mmol). The reaction mixture was stirred at 75 °C for 16 h under a CO atmosphere. After completion of the reaction, the mixture was concentrated. The residue was purified by flash silica gel chromatography (120 g SepaFlash® Silica Flash Column, eluent: 10-25% EtOAc / PE gradient at 100 mL / min) to give ethyl (S)-3-methoxy-4-nitro-5-((oxetan-2-ylmethyl)amino)benzoate (6.1 g, 59.8% yield). LC-MS: m / z 310.9 (M+H).+ .

[0344] Step D Ethyl (S)-4-amino-3-methoxy-5-((oxetan-2-ylmethyl)amino)benzoate [ka]

[0345] To a solution of ethyl (S)-3-methoxy-4-nitro-5-((oxetan-2-ylmethyl)amino)benzoate (6.1 g, 19.68 mmol) in THF (60 mL) was added 10% Pd / C (915 mg). The reaction mixture was degassed and filled with H three times, then stirred at 25 °C for 2 h under a H balloon. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by flash silica gel chromatography (120 g SepaFlash® Silica Flash Column, eluent: 0-5% MeOH / DCM gradient at 100 mL / min) to give ethyl (S)-4-amino-3-methoxy-5-((oxetan-2-ylmethyl)amino)benzoate (5.05 g, 91.7% yield). LC-MS: m / z 281.0 (M+H) + .

[0346] Step E Ethyl (S)-4-(2-chloroacetamido)-3-methoxy-5-((oxetan-2-ylmethyl)amino)benzoate [ka]

[0347] To a solution of ethyl (S)-4-amino-3-methoxy-5-((oxetan-2-ylmethyl)amino)benzoate (166 mg, 0.59 mmol) in dioxane (3 mL) was added 2-chloroacetic anhydride (101 mg, 0.59 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 3 h. Then, AcOH (0.5 ml) was added, and the reaction mixture was heated to 100° C. and stirred for an additional 2 h. After cooling, the mixture was diluted with EtOAc (40 mL) and washed with water (50 mL × 2) and brine (40 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, eluting with a 0-5% MeOH / DCM gradient at 50 mL / min) to give ethyl (S)-2-(chloromethyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (120 mg, 60% yield). LC-MS: m / z 338.8 (M+H). + .

[0348] Step F Ethyl 2-((4-((R)-2-(4-cyanophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate [ka]

[0349] To a solution of ethyl (S)-2-(chloromethyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (120 mg, 0.36 mmol) in CHCN, DIEA (465 mg, 3.6 mmol) and (R)-4-(5-(piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)benzonitrile TFA salt (156 mg, 0.36 mmol) were added. The reaction mixture was stirred at 60 °C for 1 hour. The reaction mixture was diluted with EtOAc (40 mL) and washed with brine (30 mL × 3). The organic layer was dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, elution with a 0-5% MeOH / DCM gradient at 50 mL / min) to give ethyl 2-((4-((R)-2-(4-cyanophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (133 mg, 60.4% yield). LC-MS: m / z 622.8 (M+H) + .

[0350] Step G 2-({4-[(2R)-2-(4-cyanophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperidin-1-yl}methyl)-4-methoxy-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (Compound 118) [ka]

[0351] To a solution of ethyl 2-((4-((R)-2-(4-cyanophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (133 mg, 0.21 mmol) in THF / MeOH / HO (V / V / V = 4:1:1, 1 mL) was added LiOH HO (36 mg, 0.85 mmol). The resulting mixture was stirred at 25 °C for 1 h. The solution was filtered, and the filtrate was purified by preparative HPLC (column: Pursuit XRs C18, 19*250 mm*10 μm; mobile phase A: water (0.1% formic acid), B: CH3CN; flow rate: 20 mL / min; gradient: 35% B to 35% B; retention time: 6.38 to 8.5 min) to give 2-({4-[(2R)-2-(4-cyanophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperidin-1-yl}methyl)-4-methoxy-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (24.0 mg, 18.9% yield). LC-MS: m / z 595.1 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ 12.80 (br s, 1 H), 7.95 - 7.86 (m, 3 H), 7.68 (d, J = 8.4 Hz, 2 H), 7.26 (s, 1 H), 6.88 - 6.79 (m, 3 H), 5.41- 5.35 (m, 1 H), 5.13 - 5.04 (m, 1 H), 4.80 - 4.72 (m, 1 H), 4.68 - 4.60 (m, 1 H), 4.58 - 4.46 (m, 2 H), 4.39 - 4.30 (m, 1 H), 4.14 - 4.05 (m, 1H), 3.95 (s, 3H), 3.90 (d, J = 13.2 Hz, 1 H), 3.78 (d, J = 13.6 Hz, 1 H), 3.03 - 2.92 (m, 1 H), 2.80 - 2.70 (m, 2 H), 2.72 - 2.64 (m, 1 H), 2.45 - 2.32 (m, 1 H), 2.26 - 2.10 (m, 2 H), 1.80 - 1.53 (m, 4 H).

[0352] Example A4 2-({4-[(2R)-2-(4-chlorophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperidin-1-yl}methyl)-4-fluoro-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (Compound 111) [ka] [ka]

[0353] Step A tert-Butyl (R)-4-(2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate [ka]

[0354] To a mixture of tert-butyl (R)-4-(2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (50 mg, 0.117 mmol) in MeOH (1 mL) was added 5% Pd / C (10 mg). The reaction mixture was degassed and filled with H three times, then stirred at 25 °C for 16 h. After completion of the reaction, the mixture was filtered and concentrated to give tert-butyl (R)-4-(2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate (50 mg, 99.5% yield). LC-MS: m / z 374.2 (M+Ht-Bu). + .

[0355] Step B (R)-4-(2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine HCl salt [ka]

[0356] A mixture of tert-butyl (R)-4-(2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate (50 mg, 0.116 mmol) in 4 M HCl (gas) / dioxane (2 mL) was stirred at 25° C. for 1 hour. After completion of the reaction, the mixture was concentrated to give (R)-4-(2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine HCl salt (50 mg crude). LC-MS: m / z 330.2 (M+H) + .

[0357] Step C Methyl 2-((4-((R)-2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate [ka]

[0358] To a solution of (R)-4-(2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine HCl salt (50 mg, crude) in DMF (1 mL) was added TEA (92 mg, 0.91 mmol). After stirring for 2 minutes, methyl (S)-2-(chloromethyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (28 mg, 0.091 mmol) was added. The reaction mixture was stirred at 60° C. for 6 hours. The reaction mixture was concentrated. The residue was purified by preparative TLC purification (PE / EtOAc=2 / 1) to give methyl 2-((4-((R)-2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (44 mg, 62.9% yield). LC-MS: m / z 606.3 (M+H) + .

[0359] Step D 2-({4-[(2R)-2-(4-chlorophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperidin-1-yl}methyl)-4-fluoro-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (Compound 111) [ka]

[0360] To a mixture of methyl 2-((4-((R)-2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (44 mg, 0.073 mmol) in THF (1 mL) and HO (0.2 mL) was added LiOH (15 mg, 0.363 mmol). The reaction mixture was stirred at 25 °C for 16 hours, then concentrated, and the residue was purified by preparative HPLC (column: Sunfire C18, 19*250 mm*10 μm; mobile phase A: water (0.1% formic acid), B: CH3CN; flow rate: 20 mL / min; gradient: 33% B to 43% B; retention time: 9.0 to 11.1 min) to give 2-({4-[(2R)-2-(4-chlorophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperidin-1-yl}methyl)-4-fluoro-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (17.88 mg, 41.6% yield). LC-MS: m / z 592.2 (M+H) + . 1 H NMR(400MHz, DMSO-d6) δ 12.96 (br s, 1 H), 8.16 (s, 1 H), 7.58 -7.45 (m, 5 H), 6.89 - 6.78 (m, 3 H), 5.25 (dd, J1= 8.4 Hz, J2= 2.4 Hz, 1 H), 5.16 - 5.06 (m, 1 H), 4.89 - 4.78 (m, 1 H), 4.74 - 4.65 (m, 1 H), 4.56 - 4.45 (m, 2 H), 4.42 - 4.33 (m, 1 H), 4.12 - 4.01 (m, 1 H), 3.95 (d, J = 14.0 Hz, 1 H), 3.82 (d, J = 13.6 Hz, 1 H), 3.06 - 2.99 (m, 1 H), 2.96 - 2.80 (m, 2 H), 2.78 - 2.64 (m, 1 H), 2.47 - 2.37 (m, 1 H), 2.31 - 2.12 (m, 2 H), 1.81 - 1.53 (m, 4 H).19 F NMR (377MHz, DMSO-d6) δ -129.14.

[0361] Example A5 2-({4-[(2R)-2-(4-chlorophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperidin-1-yl}methyl)-4-methoxy-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (Compound 119) [ka] [ka]

[0362] Step A Ethyl 2-((4-((R)-2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate [ka]

[0363] To a mixture of (R)-4-(2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine HCl salt (55 mg, 0.15 mmol) and ethyl (S)-2-(chloromethyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (60 mg, 0.18 mmol) in CH3CN (6 mL) was added TEA (172 mg, 0.75 mmol). The reaction mixture was stirred at 60 °C for 2 hours. After completion of the reaction, the mixture was concentrated. The residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, eluent: 0-50% EtOAc / PE gradient at 50 mL / min) to give ethyl 2-((4-((R)-2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (77 mg, 95.9% yield). LC-MS: m / z 632.1 (M+H) + .

[0364] Step B 2-({4-[(2R)-2-(4-chlorophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperidin-1-yl}methyl)-4-methoxy-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (Compound 119) [ka]

[0365] To a mixture of ethyl 2-((4-((R)-2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (77 mg, 0.12 mmol) in HO (4 mL) and THF (12 mL) was added LiOH.HO (26 mg, 0.61 mmol). The reaction mixture was stirred at 25 °C for 16 h. After completion of the reaction, the reaction mixture was diluted with HO (10 mL), acidified to pH = 5-6 with 1 M aqueous HCl, and extracted with EtOAc (10 mL × 2). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by preparative HPLC (column: Atlantis™ T3 Prep OBD™ C18, 19*250 mm*10 μm; mobile phase A: water (0.1% formic acid), B: CH3CN; flow rate: 20 mL / min; gradient: 39% B to 49% B; retention time: 6.5 to 8.2 min) to give 2-({4-[(2R)-2-(4-chlorophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperidin-1-yl}methyl)-4-methoxy-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (19.81 mg, 27.5% yield). LC-MS: m / z 604.1 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ 12.74 (s, 1H), 7.90 (s, 1H), 7.50 (s, 4H), 7.26 (s, 1H), 6.82 - 6.81 (m, 3H), 5.26 - 5.24 (m, 1H), 5.11 - 5.07 (m, 1H), 4.79 - 4.73 (m, 1H), 4.65 - 4.62 (m, 1H), 4.51 - 4.48 (m, 2H), 4.35 - 4.33 (m, 1H), 4.08 - 4.05 (m, 1H), 3.95 (s, 3H), 3.80 - 3.75 (m, 1H), 3.03 - 2.96 (m, 1H), 2.89 - 2.83 (m, 2H), 2.73 - 2.67 (m, 2H), 2.25 - 2.05 (s, 3H), 1.79 - 1.51 (m, 4H).

[0366] Example A6 2-({4-[(2R)-2-(4-chloro-1-benzofuran-7-yl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperidin-1-yl}methyl)-4-methoxy-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (Compound 120) [ka] [ka]

[0367] Step A 1-Bromo-4-chloro-2-(2,2-diethoxyethoxy)benzene [ka]

[0368] To a mixture of 2-bromo-5-chlorophenol (5.00 g, 24.3 mmol) and 1-bromo-4-chloro-2-(2,2-diethoxyethoxy)benzene (7.14 g, 36.24 mmol) in DMSO (30 mL) was added KOH (2.03 g, 36.25 mmol). The reaction mixture was stirred at 160 °C for 10 min. After cooling to 25 °C, the mixture was poured into water (300 mL) and extracted with ethyl acetate (300 mL × 5). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (120 g SepaFlash® Silica Flash Column, eluent: 0-10% EtOAc / PE gradient at 100 mL / min) to give 1-bromo-4-chloro-2-(2,2-diethoxyethoxy)benzene (7.1 g, 91.3% yield).

[0369] Step B 7-Bromo-4-chlorobenzofuran [ka]

[0370] To a mixture of 1-bromo-4-chloro-2-(2,2-diethoxyethoxy)benzene (7.1 g, 22.05 mmol) in DCE (50 mL) was added PPA (10.8 g, 31.95 mmol). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with saturated aqueous NaHCO (200 mL) and extracted with ethyl acetate (200 mL × 3). The organic layers were combined, washed with brine, dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (120 g SepaFlash® Silica Flash Column, eluent: 0–10% EtOAc / PE gradient at 100 mL / min) to give 7-bromo-4-chlorobenzofuran (2.1 g, 41.4% yield).

[0371] Step C 1-(4-chlorobenzofuran-7-yl)ethan-1-one [ka]

[0372] To a mixture of 7-bromo-4-chlorobenzofuran (1.9 g, 8.26 mmol) and tributyl(1-ethoxyvinyl)stannane (3.6 g, 9.97 mmol) in dioxane (20 mL) was added Pd(dppf)Cl2 (604 mg, 0.83 mmol). The reaction mixture was stirred at 100 °C for 16 h. After cooling, the mixture was quenched with 1 M aqueous HCl (20 mL) and stirred at 25 °C for 1 h. The reaction mixture was then filtered and concentrated. The residue was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, eluent: 0-5% EtOAc / PE gradient at 50 mL / min) to give 1-(4-chlorobenzofuran-7-yl)ethan-1-one (1.37 g, 85.6% yield). LC-MS: m / z 195.1 (M+H) + .

[0373] Step D 2-Bromo-1-(4-chlorobenzofuran-7-yl)ethan-1-one [ka]

[0374] To a mixture of 1-(4-chlorobenzofuran-7-yl)ethan-1-one (1.17 g, 6.03 mmol) in THF (12.0 mL) was added pyridinium tribromide (1.83 g, 5.72 mmol). The reaction mixture was stirred at 40 °C for 2 h. After completion of the reaction, the mixture was quenched with saturated aqueous NaHCO (40 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, eluent: 10–20% EtOAc / PE gradient at 50 mL / min) to give 2-bromo-1-(4-chlorobenzofuran-7-yl)ethan-1-one (790 mg, 48.1% yield). LC-MS: m / z 273.0 (M+H) + .

[0375] Step E 1-(4-chlorobenzofuran-7-yl)-2-(2,6-dibromophenoxy)ethan-1-one [ka]

[0376] A mixture of 2-bromo-1-(4-chlorobenzofuran-7-yl)ethan-1-one (790 mg, 2.90 mmol), 2,6-dibromophenol (1.1 g, 4.37 mmol), and K2CO3 (1.2 g, 8.69 mmol) in acetone (10 mL) was stirred at 50 °C for 2 h. After completion of the reaction, the mixture was concentrated. The residue was purified by flash silica gel chromatography (24 g SepaFlash® Silica Flash Column, eluent: 10-20% EtOAc / PE gradient at 50 mL / min) to give 1-(4-chlorobenzofuran-7-yl)-2-(2,6-dibromophenoxy)ethan-1-one (580 mg, 45.3% yield). LC-MS: m / z 442.7 (M+H). + .

[0377] Step F (R)-1-(4-chlorobenzofuran-7-yl)-2-(2,6-dibromophenoxy)ethan-1-ol [ka]

[0378] A mixture of RuCl[(S,S)-Tsdpen](p-cymene) (53 mg, 0.083 mmol) in TEA (18.5 mL) and formic acid (3.7 mL) was stirred at 0 °C for 1 h. Then, 1-(4-chlorobenzofuran-7-yl)-2-(2,6-dibromophenoxy)ethan-1-one (370 mg, 0.84 mmol) was added. The resulting reaction mixture was stirred at 0 °C for 4 h. The solution was quenched with HO (40 mL) and extracted with ethyl acetate (30 mL × 3). The organic layers were combined, washed with brine, dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, eluent: 0-25% EtOAc / PE gradient at 50 mL / min) to give (R)-1-(4-chlorobenzofuran-7-yl)-2-(2,6-dibromophenoxy)ethan-1-ol (270 mg, 72.6% yield). LC-MS: m / z 447.2 (M+H) + .

[0379] Step G (R)-5-Bromo-2-(4-chlorobenzofuran-7-yl)-2,3-dihydrobenzo[b][1,4]dioxine [ka]

[0380] A mixture of (R)-1-(4-chlorobenzofuran-7-yl)-2-(2,6-dibromophenoxy)ethan-1-ol (320 mg, 0.72 mmol), 1,10-phenanthroline (39 mg, 0.22 mmol), CuI (14 mg, 0.074 mmol), and CsCO (705 mg, 2.16 mmol) in toluene (5.0 mL) was stirred at 120 °C for 16 h. After completion of the reaction, the reaction mixture was concentrated. The residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, eluent: 0-15% EtOAc / PE gradient at 50 mL / min) to give (R)-5-bromo-2-(4-chlorobenzofuran-7-yl)-2,3-dihydrobenzo[b][1,4]dioxine (220 mg, 83.6% yield). LC-MS: m / z 365.0 (M+H) + .

[0381] Step H tert-Butyl (R)-4-(2-(4-chlorobenzofuran-7-yl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate [ka]

[0382] To a solution of (R)-5-bromo-2-(4-chlorobenzofuran-7-yl)-2,3-dihydrobenzo[b][1,4]dioxine (220 mg, 0.60 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (280 mg, 0.91 mmol), and KCO (250 mg, 1.81 mmol) in dioxane (5 mL) and HO (0.5 mL) was added Pd(dppf)Cl (49 mg, 0.006 mmol). The reaction mixture was stirred at 90 °C for 16 h. After cooling, the mixture was diluted with HO (30 mL) and extracted with EA (30 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, eluent: 0-5% EtOAc / PE gradient at 50 mL / min) to give tert-butyl (R)-4-(2-(4-chlorobenzofuran-7-yl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (210 mg, 74.5% yield). LC-MS: m / z 490.2 (M+Na). + .

[0383] Step I tert-Butyl (R)-4-(2-(4-chlorobenzofuran-7-yl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate [ka]

[0384] To a mixture of tert-butyl (R)-4-(2-(4-chlorobenzofuran-7-yl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (175 mg, 0.37 mmol) in THF (3.0 mL) was added PtO (8 mg, 0.037 mmol). The reaction mixture was degassed three times and filled with H, then stirred at 25 °C for 1.5 h under a H balloon. After filtration, the filtrate was concentrated to give tert-butyl (R)-4-(2-(4-chlorobenzofuran-7-yl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate (160 mg, crude). LC-MS: m / z 492.2 (M+Na). + .

[0385] Step J (R)-4-(2-(4-chlorobenzofuran-7-yl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine HCl salt [ka]

[0386] To a solution of tert-butyl (R)-4-(2-(4-chlorobenzofuran-7-yl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate (80 mg, crude) in dioxane (2 mL) was added 4 M HCl (gas) in dioxane (1 mL). The reaction mixture was stirred at 25° C. for 1.5 hours and then concentrated to give (R)-4-(2-(4-chlorobenzofuran-7-yl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine HCl salt (80 mg, crude). LC-MS: m / z 370.1 (M+H) + .

[0387] Step K 2-({4-[(2R)-2-(4-chloro-1-benzofuran-7-yl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperidin-1-yl}methyl)-4-methoxy-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (Compound 120) [ka]

[0388] 2-({4-[(2R)-2-(4-chloro-1-benzofuran-7-yl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperidin-1-yl}methyl)-4-methoxy-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (compound 120) was synthesized according to the procedure described for the preparation of Example A5 (Steps A-B), using (R)-4-(2-(4-chlorobenzofuran-7-yl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine HCl salt and ethyl (S)-2-(chloromethyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate in Step A. LC-MS: m / z 644.3 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ 8.19 (d, J = 2.0 Hz, 1 H), 7.90 (s, 1 H), 7.42 (s, 2 H), 7.26 (s, 1 H), 7.09 (d, J = 2.0 Hz, 1 H), 6.90 - 6.77 (m, 3 H), 5.67 (dd, J1= 8.0 Hz, J2= 2.0 Hz, 1 H), 5.15 - 5.02 (m, 1 H), 4.82 - 4.72 (m, 1 H), 4.68 - 4.57 (m , 2 H), 4.53 - 4.45 (m, 1 H), 4.40 - 4.29 (m, 2 H), 3.95 (s, 3 H), 3.91 (d, J = 13.2 Hz, 1 H), 3.77 (d, J = 13.6 Hz, 1 H), 3.05 - 2.95 (m, 1 H), 2.93 - 2.82 (m, 2 H), 2.76 - 2.65 (m, 1 H), 2.47 - 2.36 (m, 1 H), 2.30 - 2.09 (m, 2 H), 1.82 - 1.74 (m, 1 H), 1.72 - 1.55 (m, 3 H).

[0389] Example A7 2-({4-[(2R)-2-(4-chloro-1-benzofuran-7-yl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperidin-1-yl}methyl)-4-fluoro-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (Compound 122) [ka]

[0390] 2-({4-[(2R)-2-(4-chloro-1-benzofuran-7-yl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperidin-1-yl}methyl)-4-fluoro-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (compound 122) was synthesized according to the procedure described for the preparation of Example A5 (Steps A-B), using (R)-4-(2-(4-chlorobenzofuran-7-yl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine HCl salt and methyl (S)-2-(chloromethyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate in Step A. LC-MS: m / z 632.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ 8.25 - 8.14 (m, 2 H), 7.53 (d, J = 11.6 Hz, 1 H), 7.43 (s, 2 H), 7.09 (d, J = 2.0 Hz, 1 H), 6.91 - 6.79 (m, 3 H), 5.68 (dd, J1= 7.6 Hz, J2= 2.0 Hz, 1 H), 5.17 - 5.05 (m, 1 H), 4.91 - 4.80 (m, 1 H), 4.72 - 4.68 (m, 1 H), 4.64 - 4.60 (m, 1 H), 4.56 - 4.46 (m, 1 H), 4.43 - 4.30 (m, 2 H), 4.10 - 3.72 (m, 2 H), 3.10 - 2.82 (m, 3 H), 2.79 - 2.66 (m, 1 H), 2.43 - 2.36 (m, 1 H), 2.36 - 2.08 (m, 2 H), 1.88 - 1.58 (m, 4 H). 19 F NMR (377MHz, DMSO-d6) δ -129.06.

[0391] Example compounds 115 and 116 were synthesized using procedures analogous to Example A7 above, using the appropriate materials.

[0392] Example A8 2-({4-[(2R)-2-(4-cyanophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperidin-1-yl}methyl)-4,7-difluoro-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (Compound 108) [ka] [ka]

[0393] Step A 4-Bromo-2,3,6-trifluoroaniline [ka]

[0394] A solution of 2,3,6-trifluoroaniline (5.0 g, 34.00 mmol) and NBS (7.2 g, 40.80 mmol) in DMF (50 mL) was stirred at 25 °C for 2 h. The reaction mixture was then diluted with EtOAc (200 mL) and washed with 10% aqueous NaSO solution (100 mL × 2), HO (100 mL), and brine (100 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (120 g SepaFlash® Silica Flash Column, eluent: 0–10% EtOAc / PE gradient at 100 mL / min) to give 4-bromo-2,3,6-trifluoroaniline (6.0 g, 80% yield). 1 H NMR (400MHz, DMSO-d6) δ 7.33 (ddd, J1= 10.4 Hz, J2= 6.0 Hz, J3= 2.4 Hz, 1H), 5.71 (s,2H).

[0395] Step B 1-Bromo-2,3,5-trifluoro-4-nitrobenzene [ka]

[0396] A mixture of 4-bromo-2,3,6-trifluoroaniline (2.86 g, 12.71 mmol) and NaBO (7.83 g, 50.84 mmol) in AcOH (50 mL) was stirred at 52 °C for 16 h. After cooling, the reaction mixture was concentrated. The residue was diluted with water and extracted with diethyl ether (100 mL × 2). The combined organic extracts were washed with brine, dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (120 g SepaFlash® Silica Flash Column, eluent: 0–10% EtOAc / PE gradient at 100 mL / min) to give 1-bromo-2,3,5-trifluoro-4-nitrobenzene (3.0 g, 93% yield).

[0397] Step C (S)-3-Bromo-2,5-difluoro-6-nitro-N-(oxetan-2-ylmethyl)aniline [ka]

[0398] A mixture of 1-bromo-2,3,5-trifluoro-4-nitrobenzene (800 mg, 3.14 mmol), (S)-oxetan-2-ylmethanamine TsOH salt (894 mg, 3.45 mmol), and DIEA (2.02 g, 15.70 mmol) in MeCN (15 mL) was stirred at 55 °C for 2 h. After cooling and concentration, the residue was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, eluent: 10-20% EtOAc / PE gradient at 50 mL / min) to give (S)-3-bromo-2,5-difluoro-6-nitro-N-(oxetan-2-ylmethyl)aniline (340 mg, 34% yield). LC-MS: m / z 323.1 (M+H). + . 1H NMR (400MHz, DMSO-d6) δ 7.23 (dd, J1= 10.4 Hz, J2= 5.2 Hz, 1H), 6.91 - 6.87 (m, 1H), 4.87 - 4.81 (m, 1H), 4.51 - 4.46 (m, 1H), 4.33 - 4.27 (m, 1H), 3.54 - 3.46 (m, 2H), 2.64 - 2.55 (m, 1H), 2.46 - 2.37 (m, 1H).

[0399] Step D (S)-5-Bromo-3,6-difluoro-N1-(oxetan-2-ylmethyl)benzene-1,2-diamine [ka]

[0400] To a mixture of (S)-3-bromo-2,5-difluoro-6-nitro-N-(oxetan-2-ylmethyl)aniline (340 mg, 1.06 mmol) and NHCl (285 mg, 5.28 mmol) in EtOH / HO (20 mL / 4 mL) was added Fe powder (296 mg, 5.28 mmol). The resulting mixture was stirred at 45 °C for 3 h. After cooling, the mixture was diluted with EtOAc (50 mL) and filtered. The filtrate was washed with brine (30 mL × 2), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (24 g SepaFlash® Silica Flash Column, eluent: 10-20% EtOAc / PE gradient at 50 mL / min) to give (S)-5-bromo-3,6-difluoro-N1-(oxetan-2-ylmethyl)benzene-1,2-diamine (140 mg, 46% yield). LC-MS: m / z 295.1 (M+H). + .

[0401] Step E (S)—N-(4-bromo-3,6-difluoro-2-((oxetan-2-ylmethyl)amino)phenyl)-2-chloroacetamide [ka]

[0402] To a mixture of (S)-5-bromo-3,6-difluoro-N1-(oxetan-2-ylmethyl)benzene-1,2-diamine (140 mg, 0.49 mmol) in THF (10 mL) was added 2-chloroacetic anhydride (91 mg, 0.54 mmol). The resulting mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO (50 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated to give (S)-N-(4-bromo-3,6-difluoro-2-((oxetan-2-ylmethyl)amino)phenyl)-2-chloroacetamide (190 mg, crude). LC-MS: m / z 369.1 (M+H) + .

[0403] Step F (S)-6-Bromo-2-(chloromethyl)-4,7-difluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole [ka]

[0404] A mixture of (S)-N-(4-bromo-3,6-difluoro-2-((oxetan-2-ylmethyl)amino)phenyl)-2-chloroacetamide (190 mg crude) in dioxane (10 mL) / AcOH (1 mL) was stirred at 100 °C for 16 h. After cooling, the reaction mixture was poured into saturated aqueous Na2CO3 (20 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, eluent: 0-50% EtOAc / PE gradient at 50 mL / min) to give (S)-6-bromo-2-(chloromethyl)-4,7-difluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole (170 mg, 93% yield). LC-MS: m / z 353.0 (M+H) + .1 H NMR (400MHz, DMSO-d6) δ 7.49 (dd, J1= 9.6 Hz, J2= 4.8 Hz, 1H), 5.15 - 5.03 (m, 3H), 4.77 - 4.71 (m, 1H), 4.63 - 4.59 (m, 1H), 4.51 - 4.46 (m, 1H), 4.38 - 4.32 (m, 1H), 2.77 - 2.69 (m, 1H), 2.43 - 2.36 (m, 1H). 19 F NMR (377MHz, DMSO-d6) δ -130.20, -131.30.

[0405] Step G 4-((R)-5-(1-((6-bromo-4,7-difluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)methyl)piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)benzonitrile [ka]

[0406] A solution of (S)-6-bromo-2-(chloromethyl)-4,7-difluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole (200 mg, 0.57 mmol), (R)-4-(5-(piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)benzonitrile TFA salt (295 mg, 0.68 mmol) and DIEA (221 mg, 1.71 mmol) in MeCN (2 mL) was stirred at 55° C. for 3 hours. After cooling and concentration, the residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, eluent: 0-5% MeOH / DCM gradient at 50 mL / min) to give 4-((R)-5-(1-((6-bromo-4,7-difluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)methyl)piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)benzonitrile (230 mg, 63.6% yield). LC-MS: m / z 635.2 (M+H) + .

[0407] Step H Ethyl 2-((4-((R)-2-(4-cyanophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-4,7-difluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate [ka]

[0408] To a solution of 4-((R)-5-(1-((6-bromo-4,7-difluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)methyl)piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)benzonitrile (120 mg, 0.19 mmol) in EtOH (5 mL) was added Pd(dppf)Cl.CHCl (15 mg, 0.019 mmol) and KOAc (56 mg, 0.57 mmol). The reaction mixture was stirred at 80 °C for 16 h under a CO atmosphere. After completion of the reaction, the mixture was diluted with EtOAc (50 mL), filtered, and the filtrate was concentrated. The residue was purified by preparative TLC (DCM:MeOH=20:1) to give ethyl 2-((4-((R)-2-(4-cyanophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-4,7-difluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (90 mg, 75.7% yield). LC-MS: m / z 629.3 (M+H) + .

[0409] Step I 2-({4-[(2R)-2-(4-cyanophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperidin-1-yl}methyl)-4,7-difluoro-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (Compound 108) [ka]

[0410] To a mixture of ethyl 2-((4-((R)-2-(4-cyanophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-4,7-difluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (90 mg, 0.14 mmol) in THF (2 mL) / HO (2 mL) was added LiOH (17 mg, 0.72 mmol). The resulting mixture was stirred at 25 °C for 5 h. After concentration, the residue was purified by preparative HPLC (column: Phenomenex C18, 19*250 mm*10 μm; mobile phase A: water (0.1% formic acid), B: CH3CN; flow rate: 40 mL / min; gradient: 20% B to 60% B; retention time: 10 min) to give 2-({4-[(2R)-2-(4-cyanophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperidin-1-yl}methyl)-4,7-difluoro-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (10.74 mg, 12.5% ​​yield). LC-MS: m / z 601.3 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ 7.91 (d, J = 7.6 Hz, 2H), 7.69 (d, J = 7.2 Hz, 2H), 7.38 (d, J = 6.8 Hz, 1H), 6.85 - 6.80 (m, 3H), 5.38 (d, J = 6.8 Hz, 1H), 5.11 (s, 1H), 4.94 - 4.89 (m, 1H), 4.76 - 4.72 (m, 1H), 4.56 - 4.50 (m, 2H), 4.38 (d, J = 6.4 Hz, 1H), 4.12 - 4.07 (m, 1H), 3.97 - 3.83 (m, 2H), 3.02 - 2.99 (m, 1H), 2.92 - 2.89 (m, 2H), 2.76 - 2.74 (m, 1H), 2.46 - 2.44 (m, 1H), 2.29 - 2.23 (m, 2H), 1.75 - 1.66 (m, 4H). 19F NMR (377MHz, DMSO-d6) δ -133.04, -133.52.

[0411] Example A9 2-({4-[(2R)-2-(4-cyanophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperidin-1-yl}methyl)-1-[(3S,4S)-4-methoxyoxolan-3-yl]-1H-1,3-benzodiazole-6-carboxylic acid (Compound 114) [ka] [ka]

[0412] Step A Methyl 3-(((3S,4S)-4-hydroxytetrahydrofuran-3-yl)amino)-4-nitrobenzoate [ka]

[0413] A mixture of methyl 3-fluoro-4-nitrobenzoate (117 mg, 0.59 mmol), (3S,4S)-4-aminotetrahydrofuran-3-ol (200 mg, 0.71 mmol), and DIEA (228 mg, 1.77 mmol) in CHCN (20 mL) was stirred at 45 °C for 4 h. The resulting mixture was concentrated and then purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, eluent: 0-20% EtOAc / PE gradient at 50 mL / min) to give methyl 3-(((3S,4S)-4-hydroxytetrahydrofuran-3-yl)amino)-4-nitrobenzoate (140 mg, 83.3% yield). LC-MS: m / z 283.2 (M+H). + .

[0414] Step B Methyl 4-amino-3-(((3S,4S)-4-hydroxytetrahydrofuran-3-yl)amino)benzoate [ka]

[0415] A mixture of methyl 3-(((3S,4S)-4-hydroxytetrahydrofuran-3-yl)amino)-4-nitrobenzoate (140 mg, 0.50 mmol), Fe powder (84 mg, 1.5 mmol), and NHCl (80 mg, 1.5 mmol) in EtOH / HO (10 mL / 2 mL) was stirred at 45 °C for 3 h. The mixture was diluted with EtOAc (50 mL), filtered, and the filtrate was washed with brine (50 mL × 3). The organic layer was separated, dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, eluent: 0–50% EtOAc / PE gradient at 50 mL / min) to give methyl 4-amino-3-(((3S,4S)-4-hydroxytetrahydrofuran-3-yl)amino)benzoate (100 mg, 80% yield). LC-MS: m / z 253.2 (M+H) + .

[0416] Step C Methyl 4-(2-chloroacetamido)-3-(((3S,4S)-4-hydroxytetrahydrofuran-3-yl)amino)benzoate [ka]

[0417] A solution of methyl 4-amino-3-(((3S,4S)-4-hydroxytetrahydrofuran-3-yl)amino)benzoate (100 mg, 0.40 mmol) and 2-chloroacetic anhydride (74 mg, 0.44 mmol) in THF (5 mL) was stirred at room temperature for 2 hours. The mixture was poured into saturated aqueous Na2CO3 and extracted with EtOAc (100 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, eluent: 0–50% EtOAc / PE gradient at 50 mL / min) to give methyl 4-(2-chloroacetamido)-3-(((3S,4S)-4-hydroxytetrahydrofuran-3-yl)amino)benzoate (120 mg, 92.3% yield). LC-MS: m / z 329.2 (M+H) + .

[0418] Step D Methyl 2-(chloromethyl)-1-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-1H-benzo[d]imidazole-6-carboxylate [ka]

[0419] A mixture of methyl 4-(2-chloroacetamido)-3-(((3S,4S)-4-hydroxytetrahydrofuran-3-yl)amino)benzoate (120 mg, 0.37 mmol) in AcOH / dioxane (1 mL / 10 mL) was stirred at 100 °C for 3 h. After cooling, the mixture was poured into saturated aqueous Na2CO3 and extracted with EtOAc (100 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated, and the residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, eluent: 0-50% EtOAc / PE gradient at 50 mL / min) to give methyl 2-(chloromethyl)-1-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-1H-benzo[d]imidazole-6-carboxylate (60 mg, 53.1% yield). LC-MS: m / z 311.1 (M+H) + .

[0420] Step E Methyl 2-((4-((R)-2-(4-cyanophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-1H-benzo[d]imidazole-6-carboxylate [ka]

[0421] A solution of a mixture of methyl 2-(chloromethyl)-1-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-1H-benzo[d]imidazole-6-carboxylate (60 mg, 0.20 mmol), (R)-4-(5-(piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)benzonitrile TFA salt (100 mg, 0.23 mmol) and DIEA (129 mg, 1.00 mmol) in CHCN (10 mL) was stirred at 55° C. for 3 hours. The mixture was concentrated, and the residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, eluent: 0-50% EtOAc / PE gradient at 50 mL / min) to give methyl 2-((4-((R)-2-(4-cyanophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-1H-benzo[d]imidazole-6-carboxylate (110 mg, 95.7% yield). LC-MS: m / z 595.3 (M+H) + .

[0422] Step F Methyl 2-((4-((R)-2-(4-cyanophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-((3S,4S)-4-methoxytetrahydrofuran-3-yl)-1H-benzo[d]imidazole-6-carboxylate [ka]

[0423] A solution of methyl 2-((4-((R)-2-(4-cyanophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-1H-benzo[d]imidazole-6-carboxylate (110 mg, 0.19 mmol), NaH (18 mg, 0.74 mmol), and CHCl (105 mg, 0.74 mmol) in THF (10 mL) was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was diluted with EtOAc (50 mL), washed with brine (50 mL x 2), dried, filtered and concentrated to give methyl 2-((4-((R)-2-(4-cyanophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-((3S,4S)-4-methoxytetrahydrofuran-3-yl)-1H-benzo[d]imidazole-6-carboxylate (150 mg, crude). LC-MS: m / z 609.4 (M+H) + .

[0424] Step G 2-({4-[(2R)-2-(4-cyanophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperidin-1-yl}methyl)-1-[(3S,4S)-4-methoxyoxolan-3-yl]-1H-1,3-benzodiazole-6-carboxylic acid (Compound 114) [ka]

[0425] A mixture of methyl 2-((4-((R)-2-(4-cyanophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-((3S,4S)-4-methoxytetrahydrofuran-3-yl)-1H-benzo[d]imidazole-6-carboxylate (75 mg, 0.12 mmol) and LiOH (26 mg, 0.61 mmol) in HO (4 mL) / THF (12 mL) was stirred at rt for 16 h. After completion of the reaction, the reaction was diluted with HO (20 mL) and adjusted to pH = 5-6 with HCl (1 M), followed by extraction with EtOAc (20 mL × 2). The organic layer was washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under vacuum. The crude material was purified by preparative HPLC (column: Sunfire C18, 19*250 mm*10 μm; mobile phase A: water (0.1% formic acid), B: CH3CN; flow rate: 20 mL / min; gradient: 28% B to 30% B; retention time: 8.8 to 10.1 min in 15 min) to give 2-({4-[(2R)-2-(4-cyanophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperidin-1-yl}methyl)-1-[(3S,4S)-4-methoxyoxolan-3-yl]-1H-1,3-benzodiazole-6-carboxylic acid (7.03 mg, 9.6% yield). LC-MS: m / z 595.4 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ 12.68 (s, 1H), 8.37 (s, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.77 (d, J = 8.4 Hz,, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.4 Hz, 1H), 6.85 - 6.81 (m, 3H), 5.63 - 5.56 (m, 1H), 5.38 - 5.36 (m, 1H), 4.56 - 4.53 (m, 1H), 4.37 - 4.30 (m, 2H), 4.16 - 4.05 (m, 3H), 4.01 (t, J = 8.8 Hz, 1H), 3.87 (dd, J1= 10.4 Hz, J2= 4.0 Hz,, 1H), 3.67 (d, J = 13.2 Hz, 1H), 3.08 - 3.05 (m, 1H), 2.89 (s, 3H), 2.86 - 2.82 (m, 2H), 2.33 - 2.21 (m, 2H), 2.15 - 2.09 (m, 1H), 1.71 - 1.69 (m, 3H).

[0426] Example A10 2-({6-[(2R)-2-(4-cyanophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]-3-azabicyclo[4.1.0]heptan-3-yl}methyl)-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (Compound 110) [ka] [ka] [ka]

[0427] (R)-5-Bromo-2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxine was synthesized according to the procedure described for the preparation of intermediate 6-8 (Steps E, F, and G), using 2,6-dibromophenol and 2-bromo-1-(4-chlorophenyl)ethan-1-one in Step E. 1 H NMR (400MHz, DMSO-d6) δ 7.41 (dd, J1= 8.0 Hz, J2= 2.0 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), (dd, J = 8.0 Hz, 1.2 Hz, 1H), 6.95 - 6.93 (m, 1H), 6.78 (t, J = 8.0 Hz, 1H), 5.11 (dd, J1= 8.8 Hz, J2= 2.4 Hz, 1H), 4.48 (dd, J1= 10.6 Hz, J2= 2.4 Hz, 1H), 4.05 (dd, J1= 11.6 Hz, J2= 8.8 Hz, 1H). [ka]

[0428] Methyl (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate was synthesized according to the procedure described for the preparation of intermediate 1-4 (Steps A, B, and C), using methyl 3-fluoro-4-nitrobenzoate and (2S)-oxetan-2-ylmethanamine in Step A. LC-MS: m / z 295.1 (M+H) + .

[0429] Step A Benzyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate [ka]

[0430] To a solution of ZnEt (1 M in THF, 69.93 mL, 69.93 mmol) in DCM (45 mL), CHClI (24.7 g, 139.94 mmol) was slowly added at −40° C., and the mixture was stirred at −40° C. for 1 h. TFA (7.98 g, 69.93 mmol) was added at −40° C., and the mixture was stirred at −15° C. for an additional 1 h. Then, a solution of benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (3 g, 8.73 mmol) in DCM (15 mL) was slowly added to the reaction mixture at −15° C., and the reaction mixture was stirred at 25° C. for 16 h. After completion of the reaction, the mixture was concentrated and purified by flash silica gel chromatography (120 g SepaFlash® Silica Flash Column, eluent: 0-20% EtOAc / PE gradient at 100 mL / min) to give benzyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (1.8 g, 57.6% yield). LC-MS: m / z 358.2 (M+H). + . 1 H NMR (400MHz, DMSO-d6) δ 7.38 -7.29 (m, 5H), 5.09 - 5.05 (m, 2H), 3.76 - 3.73 (m, 1H), 3.52 (s, 1H), 3.43 - 3.37 (m,1H), 2.89 - 2.86 (m, 1H), 2.02 - 1.96 (m, 1H), 1.50 - 1.42 (m, 1H), 1.23 - 1.18 (m, 13H), 0.78 - 0.75 (m, 1H), 0.37 - 0.35 (m, 1H).

[0431] Step B Benzyl 6-((R)-2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate [ka]

[0432] A solution of (R)-5-bromo-2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxine (400 mg, 1.23 mmol), benzyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (527 mg, 1.47 mmol), CsCO (1.2 g, 3.69 mmol), and Pd(dppf)Cl.DCM (98 mg, 0.12 mmol) in dioxane (10 mL) was stirred at 100 °C for 16 h. After completion of the reaction, the mixture was concentrated and purified by reverse ISCO (CHCN / water (0.1% formic acid) = 0-85.2%) to give benzyl 6-((R)-2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (250 mg, 42.8% yield). LC-MS: m / z 476.2 (M+H). + .

[0433] Step C Benzyl 6-((R)-2-(4-cyanophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate [ka]

[0434] A solution of benzyl 6-((R)-2-(4-chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (250 mg, 0.53 mmol), K4[Fe(CN)6] (967 mg, 2.63 mmol), Na2CO3 (167 mg, 1.58 mmol), and Xphos Pd G3 (43 mg, 0.05 mmol) in DMF (10 mL) was stirred at 120 °C for 16 h. After completion of the reaction, the mixture was concentrated and purified by reverse ISCO (CHCN / water (0.1% formic acid) = 0-82%) to give benzyl 6-((R)-2-(4-cyanophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (150 mg, 61.2% yield). LC-MS: m / z 467.2 (M+H). + .

[0435] Step D 4-((2R)-5-(3-azabicyclo[4.1.0]heptan-6-yl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)benzonitrile [ka]

[0436] A solution of benzyl 6-((R)-2-(4-cyanophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (150 mg, 0.32 mmol) and 5% Pd / C (15 mg) in THF (10 mL) was stirred at 40 °C for 4 hours under a H balloon. After filtration, the filtrate was concentrated to give 4-((2R)-5-(3-azabicyclo[4.1.0]heptan-6-yl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)benzonitrile (60 mg, 56.14% yield). LC-MS: m / z 333.2 (M+H) + .

[0437] Step E 2-({6-[(2R)-2-(4-cyanophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]-3-azabicyclo[4.1.0]heptan-3-yl}methyl)-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (Compound 110) [ka]

[0438] 2-({6-[(2R)-2-(4-cyanophenyl)-2,3-dihydro-1,4-benzodioxin-5-yl]-3-azabicyclo[4.1.0]heptan-3-yl}methyl)-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (compound 110) was synthesized according to the procedure described for the preparation of Al (Steps E and F), using 4-((2R)-5-(3-azabicyclo[4.1.0]heptan-6-yl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)benzonitrile and methyl (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate in Step E. LC-MS: m / z 358.2 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ 8.25 (s, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.79 - 7.81 (m, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.63 - 7.60 (m, 1H), 6.85 - 6.83 (m, 1H), 6.78 - 6.76 (m, 2H), 5.40 - 5.38 (m, 1H), 5.09 - 5.08 (m, 1H), 4.84 - 4.81 (m, 1H), 4.71 - 4.66 (m, 1H), 4.59 - 4.57 (m, 1H), 4.49 - 4.46 (m, 1H), 4.42 - 4.34 (m, 1H), 4.15 - 4.10 (m, 1H), 3.96 - 3.81 (m, 2H), 3.65 (d, J = 13.2 Hz, 1H), 2.92 - 2.82 (m, 1H), 2.77 - 2.68 (m, 2H), 2.46 - 2.33 (m, 2H), 2.26 - 2.20 (m, 1H),2.00 - 1.90 (m, 1H), 1.23 - 1.21 (m, 1H), 0.91 - 0.78 (m, 2H).

[0439] Example compounds 125, 126 and 127 were synthesized using procedures analogous to Example A10 above, using the appropriate materials.

[0440] Example A11 2-((4-((R)-3-(4-chlorophenyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 130) [ka] [ka]

[0441] Step A 2-((2-bromopyridin-3-yl)oxy)-1-(4-chlorophenyl)ethan-1-one [ka]

[0442] To a solution of 2-bromopyridin-3-ol (10 g, 57.5 mmol) and 2-bromo-1-(4-chlorophenyl)ethan-1-one (13.4 g, 57.5 mmol) in MeCN (300 mL) was added K2CO3 (15.9 g, 115 mmol). The mixture was stirred at 25 °C for 3 h. The mixture was diluted with HO (100 mL), and the precipitate was collected by filtration. The solid was purified by flash silica gel chromatography (Silica Flash Column, 50-60% EtOAc / PE gradient at 50 mL / min) to give 2-((2-bromopyridin-3-yl)oxy)-1-(4-chlorophenyl)ethan-1-one (17.5 g, 93.2% yield). 1 H NMR (400MHz, CDCl3) δ 8.04 (d, J = 4.0 Hz, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.19 (dd, J1= 8.0 Hz, J2= 4.7 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 5.33 (s, 2H)

[0443] Step B (S)-2-((2-bromopyridin-3-yl)oxy)-1-(4-chlorophenyl)ethan-1-ol [ka]

[0444] To a mixture of formic acid (35 mL) and TEA (175 mL) was added RuCl[(S,S)-Tsdpen](p-cymene) (1.71 g, 2.68 mmol). The mixture was stirred at 25 °C for 1 hour, and then 2-[(2-bromo-3-pyridyl)oxy]-1-(4-chlorophenyl)ethanone (17.5 g, 53.6 mmol) was added, and the resulting mixture was stirred at 25 °C for 4 hours. The reaction mixture was diluted with HO (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic phase was dried over NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (Silica Flash Column, eluent: 30-50% EtOAc / PE gradient) to give (S)-2-((2-bromopyridin-3-yl)oxy)-1-(4-chlorophenyl)ethan-1-ol (15 g, 85.7% yield). 1 H NMR (400MHz, CDCl3) δ 7.96 (d, J = 4.2 Hz, 1H), 7. 44 - 7.38 (m, 2H), 7.37 - 7.30 (m, 2H), 7.20 - 7.08 (m, 2H), 5.17 (d, J = 4.6 Hz, 1H), 4.17 - 4.06 (m, 2H), 3.54 (s, 1H)

[0445] Step C (R)-3-(4-chlorophenyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine [ka]

[0446] To a solution of (S)-2-((2-bromopyridin-3-yl)oxy)-1-(4-chlorophenyl)ethan-1-ol (8.5 g, 25.9 mmol) in DMF (20 mL) was added CuI (4.93 g, 25.9 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (7.36 g, 51.7 mmol), and Cs2CO3 (16.9 g, 51.7 mmol). The mixture was stirred at 110 °C for 16 h. After cooling, the reaction mixture was diluted with brine and extracted with EtOAc (100 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (Silica Flash Column, eluent: 10-60% EtOAc / PE gradient) to give (R)-3-(4-chlorophenyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (1.2 g, 18.7% yield). 1 H NMR (400MHz, CDCl3) δ 7.89 (d, J = 4.2 Hz, 1H), 7.46 - 7.36 (m, 4H), 7.28 - 7.23 (m, 1H), 6.93 (dd, J1= 7.8, J2= 4.8 Hz, 1H), 5.31 (dd, J = 8.8, 2.4 Hz, 1H), 4.36 (dd, J = 11.6, 2.4 Hz, 1H), 3.98 (dd, J = 11.6, 8.8 Hz, 1H)

[0447] Step D (R)-3-(4-chlorophenyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine 5-oxide [ka]

[0448] To a solution of (3R)-3-(4-chlorophenyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (150 mg, 605.63 μmol) in DCM (5 mL) was added 85% m-CPBA (620 mg, 727 μmol). The mixture was stirred at 25° C. for 1 hour. The reaction mixture was diluted with saturated aqueous NaHCO (20 mL) and extracted with DCM (20 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated to give (3R)-3-(4-chlorophenyl)-5-oxide-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-5-ium (145 mg, 90.7% yield), which was used in the next step without further purification. LC-MS: m / z 264.2 (M+H) + .

[0449] Step E (R)-8-chloro-3-(4-chlorophenyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine [ka]

[0450] A mixture of (3R)-3-(4-chlorophenyl)-5-oxide-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-5-ium (145 mg, 550 μmol) in POCl (422 mg, 2.75 mmol) was stirred at 90° C. for 1 hour. The reaction mixture was concentrated. The residue was diluted with saturated aqueous NaHCO (20 mL) and extracted with EtOAc (20 mL×2). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give the crude product (3R)-8-chloro-3-(4-chlorophenyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (80 mg, 51.6% yield). LC-MS: m / z 282.0 (M+H) + .

[0451] Step F tert-butyl (R)-4-(3-(4-chlorophenyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate [ka]

[0452] To a solution of (3R)-8-chloro-3-(4-chlorophenyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (230 mg, 815 μmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (252 mg, 815 μmol) in THF (5 mL) and HO (3 mL) was added XPhos Pd G (69.0 mg, 81.5 μmol) and CsCO (531 mg, 1.63 mmol). The reaction mixture was stirred at 80 °C for 16 h. After cooling, the reaction mixture was diluted with brine and extracted with EtOAc (50 mL × 2). The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (Silica Flash Column, eluting with a gradient of 10-20% EtOAc / PE) to give tert-butyl (R)-4-(3-(4-chlorophenyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate (200 mg, 57.2% yield). LC-MS: m / z 429.2 (M+H). + .

[0453] Step G tert-butyl (R)-4-(3-(4-chlorophenyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)piperidine-1-carboxylate [ka]

[0454] To a solution of tert-butyl 4-[(3R)-3-(4-chlorophenyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (200 mg, 466 μmol) in 5 mL of EtOAc was added PtO (318 mg, 1.40 mmol) under a N atmosphere. The suspension was degassed three times and purged with H. The mixture was stirred under H (35 Psi) at 25 °C for 16 h. After filtration, the filtrate was concentrated to give tert-butyl (R)-4-(3-(4-chlorophenyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)piperidine-1-carboxylate (200 mg, 99% yield). LC-MS: m / z 431.2 (M+H) + .

[0455] Step H (R)-3-(4-chlorophenyl)-8-(piperidin-4-yl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine TFA salt [ka]

[0456] To a solution of tert-butyl (R)-4-(3-(4-chlorophenyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)piperidine-1-carboxylate (200 mg, 464 μmol) in DCM (2 mL) was added TFA (2 mL). The mixture was stirred at 25° C. for 2 hours. The solvent was removed to give (3R)-3-(4-chlorophenyl)-8-(4-piperidyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine TFA salt (150 mg, crude). LC-MS: m / z 331.2 (M+H) + .

[0457] Step I 2-((4-((R)-3-(4-chlorophenyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka]

[0458] 2-((4-((R)-3-(4-chlorophenyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 130) was synthesized according to the procedure described for the preparation of Example A5 (Steps A-B), using (R)-3-(4-chlorophenyl)-8-(piperidin-4-yl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine TFA salt and methyl (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate in Step A. LC-MS: m / z 575.3 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ 8.28 (s, 1H), 8.20 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 5.0 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.52 (s, 3H), 6.94 (d, J = 5.2 Hz, 1H), 5.46 (d, J = 7.8 Hz, 1H), 5.10 (d, J = 6.8 Hz, 1H), 4.80 (dd, J1= 15.2 Hz, J2= 7.2 Hz, 1H), 4.66 (d, J = 14.4 Hz, 1H), 4.52 (d, J = 9.4 Hz, 2H), 4.42 - 4.36 (m, 1H), 4.09 (d, J = 10.8 Hz, 1H), 3.95 (d, J = 13.4 Hz, 2H), 3.80 (d, J = 13.6 Hz, 1H), 3.03 (s, 1H), 2.89 (d, J = 8.6 Hz, 2H), 2.77 - 2.71 (m, 1H), 2.47 - 2.42 (m, 1H), 2.29 - 2.16 (m, 2H), 1.80 - 1.61 (m, 4H).

[0459] Example compound 128 was synthesized using procedures analogous to those described above for Example A11, using the appropriate materials.

[0460] Example A12 2-[[4-[(2R)-2-(4-chlorophenyl)-6-fluoro-2,3-dihydro-1,4-benzodioxin-5-yl]-1-piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid (Compound 129) [ka] [ka]

[0461] Step A 2-Bromo-3-fluoro-6-iodophenol [ka]

[0462] To a solution of 2-bromo-3-fluorophenol (9.42 g, 50 mmol) in CHCl (30 mL) was added NIS (10 g, 44.4 mmol) and DMSO (771 mg, 9.86 mmol). The resulting mixture was stirred at 25 °C for 3 h. The mixture was diluted with brine and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with saturated aqueous NaSO (50 mL), dried over NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (Silica Flash Column, eluent: 10–30% EtOAc / PE gradient) to give 2-bromo-3-fluoro-6-iodophenol (3.8 g, 24% yield).

[0463] Step B 2-(2-bromo-3-fluoro-6-iodophenoxy)-1-(4-chlorophenyl)ethan-1-one [ka]

[0464] To a solution of 2-bromo-3-fluoro-6-iodophenol (3.8 g, 12 mmol) and 2-bromo-1-(4-chlorophenyl)ethanone (2.80 g, 12 mmol) in MeCN (20 mL) was added K2CO3 (3.31 g, 24.0 mmol). The mixture was stirred at 25 °C for 4 h. The reaction mixture was diluted with HO (50 mL) and extracted with EtOAc (50 mL × 2). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (Silica Flash Column, eluent: 10-20% EtOAc / PE gradient) to give 2-(2-bromo-3-fluoro-6-iodo-phenoxy)-1-(4-chlorophenyl)ethanone (3 g, 53.3% yield).

[0465] Step C (S)-2-(2-bromo-3-fluoro-6-iodophenoxy)-1-(4-chlorophenyl)ethan-1-ol [ka]

[0466] To a solution of formic acid (15 mL) and TEA (75 mL) was added RuCl[(S,S)-Tsdpen](p-cymene) (407 mg, 639 μmol). The mixture was stirred at 25 °C for 1 h, and then 2-(2-bromo-3-fluoro-6-iodo-phenoxy)-1-(4-chlorophenyl)ethanone (6 g, 12.8 mmol) was added. The resulting mixture was stirred at 25 °C for 4 h. The reaction mixture was diluted with water and extracted with EtOAc (50 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (Silica Flash Column, eluent: 10–40% EtOAc / PE gradient) to give (S)-2-(2-bromo-3-fluoro-6-iodophenoxy)-1-(4-chlorophenyl)ethan-1-ol (2.5 g, 5.30 mmol). 1 H NMR (400MHz, CDCl3) δ 7.72 (dd, J1= 8.8 Hz, J2= 6.0 Hz, 1H), 7.40-7.47 (m, 2H), 7.38 - 7.33 (m, 2H), 6.77 (t, J = 8.4 Hz, 1H), 5.28 (d, J = 8.8 Hz, 1H), 4.21 - 4.12 (m, 1H), 4.12 - 4.02 (m, 1H), 3.14 (d, J = 2.0 Hz, 1H).

[0467] Step D (R)-5-Bromo-2-(4-chlorophenyl)-6-fluoro-2,3-dihydrobenzo[b][1,4]dioxine [ka]

[0468] To a solution of (1S)-2-(2-bromo-3-fluoro-6-iodo-phenoxy)-1-(4-chlorophenyl)ethanol (500 mg, 1.06 mmol) in toluene (5 mL) was added CuI (20.20 mg, 106.00 μmol), 1,10-phenanthroline (38.2 mg, 212 μmol), and CsCO (691 mg, 2.12 mmol). The reaction mixture was stirred at 120 °C for 16 hours. After cooling, the reaction mixture was diluted with water and extracted with EtOAc (50 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (Silica Flash Column, eluting with a gradient of 10-20% EtOAc / PE) to give (2R)-5-bromo-2-(4-chlorophenyl)-6-fluoro-2,3-dihydro-1,4-benzodioxine (250 mg, 68.7% yield). LC-MS: m / z 343.2 (M+H). + . 1 H NMR (400MHz, CDCl3) δ 7.45 - 7.39 (m, 2H), 7.38 - 7.33 (m, 2H), 6.94 - 6.87 (m, 1H), 6.76 - 6.64 (m, 1H), 5.06 (d, J = 8.8 Hz, 1H), 4.49 (dd, J1= 11.6 Hz, J2= 1.6 Hz, 1H), 4.04 (dd, J1= 11.2, J2= 9.4 Hz, 1H)

[0469] Step E tert-butyl (R)-4-(2-(4-chlorophenyl)-6-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate [ka]

[0470] To a solution of (2R)-5-bromo-2-(4-chlorophenyl)-6-fluoro-2,3-dihydro-1,4-benzodioxin (250 mg, 728 μmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (270 mg, 873 μmol) in dioxane (2 mL) and HO (0.2 mL) was added Pd(dppf)Cl (53.2 mg, 72.8 μmol) and KCO (201 mg, 1.46 mmol). The reaction mixture was stirred at 80 °C for 16 h. After cooling, the reaction mixture was diluted with water and extracted with EtOAc (50 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (Silica Flash Column, eluent: 0-20% EtOAc / PE gradient) to give tert-butyl (R)-4-(2-(4-chlorophenyl)-6-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (200 mg, 61.7% yield).

[0471] 1 H NMR (400MHz, CDCl3) δ 7.38 - 7.30 (m, 2H), 7.30 - 7.23 (m, 2H), 6.82 (dd, J1= 9.0 Hz, J2= 5.3 Hz, 1H), 6.62 (t, J = 8.4 Hz, 1H), 4.97 (d, J = 8.8 Hz, 1H), 4.40 (dd, J1= 11.6 Hz, J2= 1.2 Hz, 1H), 3.96 (dd, J1= 11.0, J2= 9.6 Hz, 1H)

[0472] Step F tert-Butyl (R)-4-(2-(4-chlorophenyl)-6-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-1-carboxylate [ka]

[0473] To a solution of tert-butyl 4-[(2R)-2-(4-chlorophenyl)-6-fluoro-2,3-dihydro-1,4-benzodioxin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (200 mg, 449 μmol) in EtOAc (3 mL) was added PtO (102 mg, 449 μmol) under a N atmosphere. The suspension was degassed three times and purged with H. The mixture was stirred under H (35 Psi) at 25 °C for 16 h. After filtration, the filtrate was concentrated to give tert-butyl 4-[(2R)-2-(4-chlorophenyl)-6-fluoro-2,3-dihydro-1,4-benzodioxin-5-yl]piperidine-1-carboxylate (100 mg, 50% yield). LC-MS: m / z 348.1 (M+H-Boc) + .

[0474] Step G (R)-4-(2-(4-chlorophenyl)-6-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine TFA salt [ka]

[0475] To a solution of tert-butyl 4-[(2R)-2-(4-chlorophenyl)-6-fluoro-2,3-dihydro-1,4-benzodioxin-5-yl]piperidine-1-carboxylate (100 mg, 223 μmol) in DCM (2 mL) was added TFA (2 mL). The reaction mixture was stirred at 25 °C for 3 hours. The mixture was concentrated to give 4-[(2R)-2-(4-chlorophenyl)-6-fluoro-2,3-dihydro-1,4-benzodioxin-5-yl]piperidine TFA salt (50 mg, crude), which was used in the next step without further purification. LC-MS: m / z 348.1 (M+H) + .

[0476] Step H 2-((4-((R)-2-(4-chlorophenyl)-6-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka]

[0477] 2-[[4-[(2R)-2-(4-chlorophenyl)-6-fluoro-2,3-dihydro-1,4-benzodioxin-5-yl]-1-piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid (compound 129) was synthesized according to the procedure described for the preparation of Example A5 (Steps A-B), using (R)-4-(2-(4-chlorophenyl)-6-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine TFA salt and methyl (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate in Step A. LC-MS: m / z 592.2 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ 8.27 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.51 (s, 4H), 6.91 - 6.80 (m, 1H), 6.75 - 6.61 (m, 1H), 5.23 (d, J = 8.4 Hz, 1H), 5.12 (d, J = 6.2 Hz, 1H), 4.78 (dd, J1= 14.8 Hz, J2= 7.2 Hz, 1H), 4.68 - 4.62 (m, 1H), 4.55 - 4.48 (m, 2H), 4.40 (d, J = 7.6 Hz, 1H), 4.12 - 4.03 (m, 1H), 3.94 (d, J = 12.8 Hz, 1H), 3.76 (d, J = 13.6 Hz, 1H), 3.02 (d, J = 10.3 Hz, 2H), 2.85 (d, J = 9.7 Hz, 2H), 2.70 (d, J = 9.4 Hz, 2H), 2.26 - 2.17 (m, 1H), 2.12 - 2.05 (m, 2H), 1.65 - 1.53 (m, 2H).

[0478] Example A13 2-({4-[(2R)-2-[1-(2,2-difluoroethyl)-1H-indazol-6-yl]-2,3-dihydro-1,4-benzodioxin-5-yl]piperidin-1-yl}methyl)-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (Compound 102) [ka] [ka]

[0479] Step A 6-Bromo-1-(2,2-difluoroethyl)-1H-indazole [ka]

[0480] To a solution of 6-bromo-1H-indazole (5.0 g, 25.38 mmol) in DMF (50 mL) was added 1,1-difluoro-2-iodoethane (4.9 g, 25.38 mmol) and CsCO (16.5 g, 50.75 mmol). The reaction was stirred at 25 °C for 16 h. After completion, the reaction was diluted with HO (300 mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (Silica Flash Column, eluent: 0-10% EtOAc / PE gradient) to give 6-bromo-1-(2,2-difluoroethyl)-1H-indazole (3 g, 57.6% yield). 1 H NMR (400MHz, DMSO-d6) δ 8.20 (d, J = 1.2 Hz, 1 H), 8.12 (s, 1 H), 7.76 (d, J = 8.4 Hz, 1 H), 7.33 (dd, J1= 8.4 Hz, J2= 1.2 Hz, 1 H), 6.59 - 6.31 (m, 1 H), 5.02 - 4.94 (m, 2 H).

[0481] Step B 1-(1-(2,2-difluoroethyl)-1H-indazol-6-yl)ethan-1-one [ka]

[0482] To a solution of 6-bromo-1-(2,2-difluoroethyl)-1H-indazole (2.0 g, 7.66 mmol) in DMF / HO (16 mL / 2 mL) was added 1-(vinyloxy)butane (2.3 g, 22.98 mmol), KCO (4.2 g, 30.64 mmol), Pd(OAc) (172 mg, 0.77 mmol), and 1,3-bis(diphenylphosphino)propane (632 mg, 1.53 mmol). The reaction mixture was stirred at 80 °C for 24 h in a sealed tube under N. After completion of the reaction, the reaction was filtered and concentrated, and the residue was purified by flash silica gel chromatography (Silica Flash Column, eluent: 0-15% EtOAc / PE gradient) to give 1-(1-(2,2-difluoroethyl)-1H-indazol-6-yl)ethan-1-one (660 mg, 38.4% yield). LC-MS: m / z 225.1 (M+H). + .

[0483] Step C 2-Bromo-1-(1-(2,2-difluoroethyl)-1H-indazol-6-yl)ethan-1-one [ka]

[0484] To a solution of 1-(1-(2,2-difluoroethyl)-1H-indazol-6-yl)ethan-1-one (660 mg, 2.94 mmol) in THF (8 mL) was added pyridinium tribromide (942 mg, 2.94 mmol). The reaction was stirred at 40 °C for 2 h. After cooling, the reaction was quenched with HO (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse ISCO (0-80% CHCN in water (0.1% NHHCO)) to give 2-bromo-1-(1-(2,2-difluoroethyl)-1H-indazol-6-yl)ethan-1-one (470 mg, 52.7% yield). LC-MS: m / z 302.9 (M+H) + .

[0485] Step D 2-({4-[(2R)-2-[1-(2,2-difluoroethyl)-1H-indazol-6-yl]-2,3-dihydro-1,4-benzodioxin-5-yl]piperidin-1-yl}methyl)-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid [ka]

[0486] 2-({4-[(2R)-2-[1-(2,2-difluoroethyl)-1H-indazol-6-yl]-2,3-dihydro-1,4-benzodioxin-5-yl]piperidin-1-yl}methyl)-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (compound 102) was synthesized according to the procedure described for the preparation of Example A12 (Steps B-H), using 2-bromo-1-(1-(2,2-difluoroethyl)-1H-indazol-6-yl)ethan-1-one and 2,6-dibromophenol in Step B. LC-MS: m / z 644.4 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ 8.27 (s, 1 H), 8.19 (s, 1 H), 7.88 (s, 1 H), 7.85 - 7.78 (m, 2 H), 7.64 (d, J = 8.4 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 1 H), 6.89 - 6.78 (m, 3 H), 6.43 (m, 1 H), 5.38 (dd, J1= 8.4 Hz, J2= 2.0 Hz, 1 H), 5.17 - 5.06 (m, 1 H), 4.97 - 4.89 (m, 2 H), 4.83 (dd, J1= 15.6 Hz, J2= 7.2 Hz, 1 H), 4.68 (dd, J1= 14.8 Hz, J2= 2.4 Hz, 1 H), 4.55 - 4.47 (m, 2 H), 4.43 - 4.34 (m, 1 H), 4.12 (dd, J1= 19.2 Hz, J2= 18.0 Hz, 1 H), 3.96 (d, J = 2.4 Hz, 1 H), 3.82 (d, J = 13.6 Hz, 1 H), 3.79 (d, J = 13.2 Hz, 1 H), 3.06 - 2.97 (m, 1 H), 2.94 - 2.81 (m, 2 H), 2.75 -2.65 (m, 1 H), 2.47- 2.40 (m, 1H), 2.35 - 2.18 (m, 2 H), 1.85 - 1.55 (m, 4 H). 19 F NMR (377MHz, DMSO-d6) δ -121.77.

[0487] The following molecules were synthesized using procedures analogous to the above examples using the appropriate starting materials: [Table 13]

[0488] Biological Examples Biological Example 1: cAMP Assay Activation of the GLP-1 receptor is known to stimulate cyclic AMP (cAMP) production in cells, which is primarily coupled to the Gα subunit of the G protein heterotrimeric complex. Evidence suggests that Gα signaling-induced cAMP stimulation elicits the desired pharmacological response of insulin release from pancreatic β cells.

[0489] To optimize Gα-directed functional activity, we used the HEK293 / CRE-Luc cell line developed by HDB, which stably expresses the GLP-1 receptor. Compound working solutions at 200x concentration were prepared by half-log serial dilution in 384-well Echo LDV plates (Labcyte, Cat# LP-0200) (Agilent Technologies Bravo). 50 nL / well of 200x compound working solution was transferred to a 384-well white low-volume plate (Greiner, Cat#784075) using a Labcyte ECHO55. A 0.1 x 10 cells / mL HEK293 / GLP1R / CRE-LUC (HD Biosciences) cell suspension was prepared in assay buffer [DPBS containing 0.5 mM IBMX (Sigma, Cat#I5879) and 0.1% BSA (GENVIEW, Cat#FA016-100g)]. 10 μL of the cell suspension was added to each well of the pre-prepared assay plate (already containing 50 nL of compound at 200x concentration) using a ThermoFisher Multidrop Combi (1000 cells / well). The plate was sealed and incubated at 37°C with 5% CO for 30 minutes.

[0490] After incubation, cAMP assay signals were generated using the cAMP dynamic 2 Kit (Cisbio). 5 μL of cAMP-d2 working solution was added to each well, followed by 5 μL of anti-cAMP antibody-cryptate working solution, using a ThermoFisher Multidrop Combi. The wells were incubated for 1 hour at room temperature, protected from light. Fluorescence was read at 665 nm and 615 nm on a PerkinElmer EnVision reader. % Activity = 100% x (Test Sample Mean RLU - Vehicle Control Mean RLU) / (MAX Control Mean RLU - Vehicle Control Mean RLU)

[0491] Table 2 shows the biological activity of compounds in the GLP-1R agonist cAMP stimulation assay (EC 50 ). [Table 14]

Claims

1. Formula I: 【Chemistry 1】 [During the ceremony, Ring A is 【Chemistry 2】 where: 【Transformation 3】 The bond represents a single or double bond; where X is N or CH and Y is O, CH ２ , CHR ３ , or C(R ３ ) ２ and Z １ is N or CR ４ and Z ２ is N or CR ４ and Ring B is absent; or Ring B is present and, together with the carbon atom of the phenyl ring to which it is fused, is C ５－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl; where Ring B independently optionally contains 1 to 5 R １ is substituted with; p is 0, 1, 2, or 3; n is 0, 1, 2, or 3; m is 0, 1, 2, or 3; Each R １ are independently halo, cyano, nitro, oxo, -OR １０ , -SR １０ , -N(R １０ ) ２ , -C(O)R １０ , -C(O)OR １０ , -OC(O)R １０ , -OC(O)OR １０ , -C(O)N(R １０ ) ２ , -NR １０ C(O)R １０ , -OC(O)N(R １０ ) ２ , -NR １０ C(O)OR １０ , -NR １０ C(O)N(R １０ ) ２ , -S(O)R １０ , -S(O) ２ R １０ , -S(O)N(R １０ ) ２ , -S(O) ２ N(R １０ ) ２ , -NR １０ S(O)R １０ , -NR １０ S(O) ２ R １０ , -NR １０ S(O)N(R １０ ) ２ , -NR １０ S(O) ２ N(R １０ ) ２ , C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C １－９ Haloalkyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl; １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C ３－１０ the cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with 1 to 5 Z; R ２ is hydrogen, heterocyclyl, C １－６ Alkyl, or C １－６ Alkoxy, C １－６ Thioalkoxy, C １－６ Haloalkoxy, S(O) ２ (C １－６ alkyl), C ３－６ C substituted with cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl １－６ alkyl; ３－６ Each of the cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl optionally has 1 to 4 R １２ is substituted with; R ３ Cyano, halo, hydroxy, C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C １－９ Alkoxy, C １－９ Haloalkyl, C １－９ haloalkoxy, or C ３－１０ is cycloalkyl; or Two R's ３ together with the carbon atoms to which they are attached, ３－１０ form a cycloalkyl or heterocyclyl; ３－１０ cycloalkyl or heterocyclyl independently optionally substituted with 1 or 2 halo; Each R ４ are independently hydrogen, cyano, halo, hydroxy, C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C １－６ Cyanoalkyl, C １－６ Hydroxyalkyl, C １－９ Alkoxy, C １－９ Haloalkyl, C １－９ haloalkoxy, or C ３－１０ is cycloalkyl; R ５ is hydrogen, cyano, halo, hydroxy, C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C １－６ Cyanoalkyl, C １－６ Hydroxyalkyl, C １－９ Alkoxy, C １－９ Haloalkyl, C １－９ haloalkoxy, or C ３－１０ is cycloalkyl; R ６ is hydrogen, cyano, halo, hydroxy, C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C １－６ Cyanoalkyl, C １－６ Hydroxyalkyl, C １－９ Alkoxy, C １－９ Haloalkyl, C １－９ haloalkoxy, or C ３－１０ is cycloalkyl; R ７ is hydrogen, cyano, halo, hydroxy, C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C １－６ Cyanoalkyl, C １－６ Hydroxyalkyl, C １－９ Alkoxy, C １－９ Haloalkyl, C １－９ haloalkoxy, or C ３－１０ is cycloalkyl; Each R １０ are independently hydrogen, C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R ２０ , -C(O)OR ２０ , -C(O)N(R ２０ ) ２ , -S(O)R ２０ , -S(O) ２ R ２０ , -S(O)N(R ２０ ) ２ , or -S(O) ２ N(R ２０ ) ２ where each C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z １ａ is substituted with; Each R １２ are independently cyano, halo, hydroxy, SH, nitro, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C １－６ Cyanoalkyl, C １－６ Hydroxyalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C ３－６ Cycloalkyl, amino, C １－６ Alkylamino, and di-C １－６ alkylamino; Each Z is independently halo, cyano, nitro, oxo, C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, heteroaryl, -L １ -C １－９ Alkyl, -L １ -C ２－９ Alkenyl, -L １ -C ２－９ Alkynyl, -L １ -C ３－１０ cycloalkyl, -L １ -heterocyclyl, -L １ -aryl, or -L １ -heteroaryl; where each C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z １ａ is substituted with; Each L １ are independently —O—, —S—, or —NR ２０ -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR ２０ -, -NR ２０ C(O)-, -OC(O)NR ２０ -, -NR ２０ C(O)O-, -NR ２０ C(O)NR ２０ -, -S(O)-, -S(O) ２ -, -S(O)NR ２０ -, -S(O) ２ NR ２０ -, -NR ２０ S(O)-, -NR ２０ S(O) ２ -, -NR ２０ S(O)NR ２０ - or -NR ２０ S(O) ２ NR ２０ - and; Each R ２０ are independently hydrogen, C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R ２０ Each C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z １ａ is substituted with; Each Z １ａ are independently halo, hydroxy, cyano, nitro, oxo, —SH, —NH ２ , —NH—C １－９ Alkyl, -N(C １－９ alkyl) ２ , -S-C １－９ Alkyl, C １－９ Alkoxy, C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C ３－６ cycloalkyl, heterocyclyl, aryl, or heteroaryl; １ａ Each of -NH-C １－９ Alkyl, -N(C １－９ alkyl) ２ , -S-C １－９ Alkyl, C １－９ Alkoxy, C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C ３－６ Cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally represent C １－９ substituted with 1 to 5 substituents selected from alkyl, oxo, halo, hydroxy, and cyano; However, any one or more of the following may occur: A) Ring A is 【Chemistry 4】 and B)R ５ and R ６ is other than hydrogen; C)R ２ optionally 1 to 4 R １２ or a heterocyclyl substituted with D) at least one R １２ Ha -C(O)-C １－６ It is alkyl. or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof.

2. Ring A is 【Transformation 5】 2. The compound of claim 1, wherein:

3. 1. The compound of formula IA: 【Transformation 6】 10. The compound of claim 1, which is represented by: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

4. 1. The compound of formula IB: 【Transformation 7】 10. The compound of claim 1, which is represented by: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

5. 1. The compound of formula IC: 【Transformation 8】 10. The compound of claim 1, which is represented by: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

6. 1. The compound of formula ID: 【Chemistry 9】 10. The compound of claim 1, which is represented by: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

7. 1. The compound of formula IE: 【Chemistry 10】 10. The compound of claim 1, which is represented by: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

8. R ５ Cyano, halo, hydroxy, C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C １－９ Alkoxy, C １－９ Haloalkyl, C １－９ haloalkoxy, or C ３－１０ The compound of any one of claims 1 to 7, which is cycloalkyl.

9. R ６ Cyano, halo, hydroxy, C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C １－９ Alkoxy, C １－９ Haloalkyl, C １－９ haloalkoxy, or C ３－１０ The compound of any one of claims 1 to 8, which is cycloalkyl.

10. portion 【Chemistry 11】 but 【Chemistry 12】 The compound of any one of claims 1 to 9,

11. The compound of any one of claims 1 to 10, wherein Ring B is present.

12. portion 【Chemistry 13】 but 【Chemistry 14】 The compound of any one of claims 1 to 11,

13. Each R １ are independently halo, cyano, or C １－９ The compound of any one of claims 1 to 12, which is haloalkyl.

14. 14. The compound of any one of claims 1 to 13, wherein p is 1.

15. At least one R ４ 15. The compound of any of claims 1 to 14, wherein is other than hydrogen.

16. Z ２ is CR ４ and Z ４ R ４ Cyano, halo, hydroxy, C １－９ Alkyl, C ２－９ Alkenyl, C ２－９ Alkynyl, C １－６ Cyanoalkyl, C １－６ Hydroxyalkyl, C １－９ Alkoxy, C １－９ Haloalkyl, C １－９ haloalkoxy, or C ３－１０ 16. The compound of any one of claims 1 to 15, which is cycloalkyl.

17. R ２ is heterocyclyl or C ３－６ C substituted with cycloalkyl, 3- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl １－６ alkyl; where heterocyclyl, C ３－６ Each of the cycloalkyl, 3- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl optionally has 1 to 4, 1 to 3, 1 to 2, or 1 R １２ 17. The compound of any one of claims 1 to 16, substituted with:

18. R ２ is heterocyclyl or C ３－６ C substituted with cycloalkyl, 3- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl １－６ alkyl; where heterocyclyl, C ３－６ Each of the cycloalkyl, 3- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl optionally has 1 to 4, 1 to 3, 1 to 2, or 1, cyano, halo, C １－６ Alkyl, C １－６ cyanoalkyl, or —C(O)—C １－６ 18. The compound of any one of claims 1 to 17, which is substituted with alkyl.

19. R ２ optionally halo, cyano, hydroxy, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Cyanoalkyl, C １－６ Hydroxyalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, and C ３－６ 19. The compound of any of claims 1 to 18, which is heterocyclyl substituted with 1 to 5 substituents independently selected from cycloalkyl.

20. R ２ is C １－６ The compound of any one of claims 1 to 19, which is a 3- to 6-membered heterocyclyl substituted with alkoxy.

21. Each R ４ 21. The compound of any of claims 1 to 20, wherein is independently hydrogen or halo.

22. R ５ 22. The compound of any of claims 1-21, wherein is hydrogen or halo.

23. R ６ is hydrogen, halo, or C １－９ 23. The compound of any one of claims 1 to 22, which is alkoxy.

24. R ５ is hydrogen or halo; and R ６ Halo or C １－９ 24. The compound of any one of claims 1 to 23, which is alkoxy.

25. R ５ is halo; and R ６ is hydrogen, halo, or C １－９ 24. The compound of any one of claims 1 to 23, which is alkoxy.

26. R ７ 26. The compound of any one of claims 1 to 25, wherein is hydrogen.

27. Z １ The compound of any one of claims 1 to 26, wherein is N.

28. Z ２ The compound of any one of claims 1 to 15 and 17 to 27, wherein is N.

29. portion 【Chemistry 15】 but 【Chemistry 16】 29. The compound of any one of claims 1 to 28,

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

31. A pharmaceutical composition comprising a compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or prodrug thereof, and a pharmaceutically acceptable excipient.

32. 32. A method for treating a GLP-1 related disease, disorder or condition, comprising administering to a patient in need thereof an effective amount of a compound of any of claims 1-30, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or prodrug thereof, or the pharmaceutical composition of claim 31.

33. The disease, disorder, or condition is type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of adults (LADA), obesity, weight gain due to use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep-related 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, post-angioplasty restenosis, intermittent claudication, hyperglycemia, postprandial lipemia, metabolic acidosis, 33. The method of claim 32, wherein the condition is selected from the group consisting of ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot 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, Alzheimer's disease, cognitive impairment, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof.

34. 32. A method of treating type 2 diabetes in a patient in need thereof, comprising administering to the patient in need thereof an effective amount of a compound of any of claims 1-30, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, or the pharmaceutical composition of claim 31.

35. 32. A method for regulating insulin levels in a patient in need thereof, comprising administering to a patient in need thereof an effective amount of a compound of any of claims 1-30, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or prodrug thereof, or a pharmaceutical composition of claim 31.

36. 32. 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 of claims 1-30, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or prodrug thereof, or the pharmaceutical composition of claim 31.

37. 37. The method of any of claims 32-36, further comprising administering to the patient an additional treatment or therapeutic agent.

38. 38. The method of claim 37, wherein the additional therapy 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) treatment, gastric electrical stimulation, meal monitoring, physical activity, or a combination thereof.

39. 10. A method for preparing a compound of formula I of claim 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomeric mixture, or prodrug thereof, comprising reacting a compound of formula I-1: 【Chemistry 17】 and a compound of formula I-2: [Chemistry 18] Compounds of wherein LG is a leaving group; and R is hydrogen or a C １－６ It is alkyl. The method of claim 1, wherein the first and second nucleotide sequences are methyl 2-methyl-2-propanol.

40. 40. The method of claim 39, wherein the method further comprises a hydrolysis or transesterification step before or after the contacting.

Images