GLP-1R agonists and uses thereof

Abstract

The present disclosure provides compounds of formula (I) and pharmaceutical compositions thereof for use in the treatment of, for example, type 2 diabetes, pre-diabetes, obesity, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and cardiovascular disease. TIFF2022527607000201.tif38122

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of priority to International Patent Application No. PCT / CN2019 / 082381, filed April 12, 2019. The entire contents of the aforementioned application are incorporated herein by reference. [Background technology]

[0002] Diabetes mellitus (Diabetes mellitus) is a major public health concern due to its increasing prevalence and associated health risks. The disease is characterized by high blood glucose levels resulting from defects in insulin production, insulin action, or both. The two main forms of diabetes are known as type 1 and type 2. Type 1 diabetes (T1D) develops when the body's immune system destroys beta cells in the pancreas, which are the only cells that produce insulin, the hormone that regulates blood sugar. People with type 1 diabetes require insulin injections or pumps to survive. Type 2 diabetes (commonly referred to as T2DM) typically begins with insulin resistance or when insulin production is insufficient to maintain acceptable glucose levels.

[0003] Currently, a variety of pharmacological approaches are available to treat hyperglycemia and subsequently T2DM (Hampp et al., Use of Antidiabetic Drugs in the US, 2003–2012, Diabetes Care 37:1367–1374, 2014). These can be grouped into six main classes, each of which acts via a different primary mechanism:

[0004] Insulin secretagogues, including sulfonylureas (e.g., glipizide, glimpiride, glyburide), meglitinides (e.g., nateglizine, repaglinide), dipeptidyl peptidase IV (DPP-IV) inhibitors (e.g., sitagliptin, vildagliptin, alogliptin, dugliptin), and glucagon-like peptide-1 receptor (GLP-1R) agonists (e.g., liraglutide, albiglutide, exenatide, linagliptin, dulaglutide, semaglutide), enhance insulin secretion by acting on pancreatic beta cells. Sulfonylureas and meglitinides have limited efficacy and tolerability, cause weight gain, and often induce hypoglycemia. DPP-IV inhibitors have limited efficacy. Commercially available GLP-1R agonists are peptides administered by subcutaneous injection. Liraglutide is further approved for the treatment of obesity.

[0005] Biguanides (e.g., metformin) are thought to act primarily by decreasing hepatic glucose production. Biguanides often cause gastrointestinal upset and lactic acidosis, further limiting their use.

[0006] Alpha-glucosidase inhibitors (e.g., acarbose) decrease intestinal glucose absorption, and these drugs often cause gastrointestinal upset.

[0007] Thiazolidinediones (e.g., pioglitazone, rosiglitazone) act on specific receptors (peroxisome proliferator-activated receptor-gamma) in the liver, muscle, and adipose tissue. They regulate lipid metabolism and subsequently enhance the response of these tissues to insulin action. Frequent use of these medications can lead to weight gain, edema, and anemia.

[0008] Insulin, used alone or in combination with the above drugs, is used in more severe cases and, if used frequently, can lead to weight gain and carries the risk of hypoglycemia.

[0009] Sodium-glucose cotransporter type 2 (SGLT2) inhibitors (e.g., dapagliflozin, empagliflozin, canagliflozin, and ertugliflozin) inhibit glucose reabsorption in the kidney, thereby reducing blood glucose levels. This new class of medications may be associated with ketoacidosis and urinary tract infections.

[0010] However, with the exception of GLP-1R agonists and SGLT2 inhibitors, these drugs have limited efficacy and do not address the most important problem: declining beta-cell function and associated obesity.

[0011] Obesity is a highly prevalent chronic disease in modern society and is associated with many medical problems, including hypertension, hypercholesterolemia, and coronary heart disease. Obesity is also highly correlated with T2DM and insulin resistance, the latter of which is generally accompanied by hyperinsulinemia, hyperglycemia, or both. Furthermore, T2DM is associated with a two- to four-fold increased risk of coronary artery disease. Currently, the only effective treatment for obesity is weight loss surgery, but this treatment is expensive and risky. Pharmacological interventions are generally ineffective and associated with side effects.

[0012] Therefore, there is a need for more effective pharmacological interventions with fewer side effects and easier administration.

[0013] Although T2DM is most commonly associated with hyperglycemia and insulin resistance, other diseases associated with T2DM include hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, obesity, dyslipidemia, hypertension, hyperinsulinemia, and non-alcoholic fatty liver disease (NAFLD).

[0014] NAFLD is the hepatic manifestation of metabolic syndrome and is a constellation of liver diseases that includes steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and ultimately hepatocellular carcinoma. NAFLD and NASH are considered the major fatty liver diseases because they account for the largest proportion of individuals with elevated hepatic lipids. The severity of NAFLD / NASH is based on the presence of lipids, inflammatory cell infiltration, hepatocyte ballooning, and the degree of fibrosis. While not all individuals with steatosis progress to NASH, a significant proportion do.

[0015] GLP-1 is a 30-amino acid incretin hormone secreted by intestinal L-cells in response to food ingestion. GLP-1 has been shown to stimulate insulin secretion physiologically and glucose-dependently, reduce glucagon secretion, inhibit gastric emptying, reduce appetite, and stimulate beta cell proliferation. In preclinical studies, GLP-1 stimulates the transcription of genes important for glucose-dependent insulin secretion and promotes beta cell neogenesis, thereby promoting continued beta cell capacity (Meier et al., Biodrugs, 17(2):93-102, 2013).

[0016] In healthy individuals, GLP-1 plays an important role in regulating postprandial glucose levels by stimulating glucose-dependent insulin secretion by the pancreas and increasing peripheral glucose absorption. GLP-1 also suppresses glucagon secretion and reduces hepatic glucose output. Furthermore, GLP-1 slows gastric emptying and small intestinal motility, slowing food absorption. In individuals with T2DM, the normal postprandial rise in GLP-1 is absent or reduced (Vilsboll et al., Diabetes, 50:609-613, 2001).

[0017] Hoist (Physiol. Rev. 87:1409, 2007) and Meier (Nat. Rev. Endocrinol. 8:728, 2012) have described that GLP-1 receptor agonists, such as liraglutide and exendin-4, have three major pharmacological activities that improve glycemic control in patients with T2DM by lowering fasting and postprandial glucose (FPG and PPG): (i) increasing glucose-dependent insulin secretion (improving phase 1 and phase 2), (ii) glucagon suppression activity under hyperglycemic conditions, and (iii) slowing gastric emptying, which delays the absorption of glucose from meals.

[0018] There remains a need for easily administered prevention and / or treatment for cardiometabolic and related diseases. Summary of the Invention [Problem to be solved by the invention]

[0019] In one aspect, the disclosure provides a compound of a formula described herein (e.g., structural formula (I), (I-1), (I-2), (II), (III), (IA), (IB), (IC), (ID), (II-A), (II-B), (II-B'), (II-C), or (II-D)), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof.

[0020] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of any one of the formulae described herein (e.g., Structural Formulas (I), (I-1), (I-2), (II), (III), (IA), (IB), (IC), (ID), (II-A), (II-B), (II-B'), (II-C), or (II-D)), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, as defined in any one of the embodiments described herein, in admixture with at least one pharmaceutically acceptable excipient.

[0021] In another aspect, the present disclosure provides a compound of any one of the formulas described herein (e.g., structural formulas (I), (I-1), (I-2), (II), (III), (IA), (IB), (IC), (ID), (II-A), (II-B), (II-B'), (II-C), or (II-D)), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, as defined in any one of the embodiments described herein, for use as a medicament.

[0022] In another aspect, the present disclosure provides a compound of any one of the formulas described herein (e.g., structural formulas (I), (I-1), (I-2), (II), (III), (IA), (IB), (IC), (ID), (II-A), (II-B), (II-B'), (II-C), or (II-D)), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, as defined in any one of the embodiments described herein, for use in the prevention and / or treatment of cardiometabolic and related diseases described herein, including T2DM, pre-diabetes, NASH, and cardiovascular disease.

[0023] In another aspect, the present disclosure provides a method of treating a disease for which a GLP-1R agonist is indicated in a subject in need of such prevention and / or treatment, comprising administering to the subject a therapeutically effective amount of a compound of any one of the formulae described herein (e.g., structural formulas (I), (I-1), (I-2), (II), (III), (IA), (IB), (IC), (ID), (II-A), (II-B), (II-B'), (II-C), or (II-D)), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, as defined in any one of the embodiments described herein.

[0024] In another aspect, the present disclosure provides use of a compound of any one of the formulas described herein (e.g., structural formulas (I), (I-1), (I-2), (II), (III), (IA), (IB), (IC), (ID), (II-A), (II-B), (II-B'), (II-C), or (II-D)), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, as defined in any one of the embodiments described herein, for the manufacture of a medicament for treating a disease or condition for which an agonist of GLP-1R is indicated.

[0025] In another aspect, the disclosure provides a compound of any one of the formulas described herein (e.g., structural formulas (I), (I-1), (I-2), (II), (III), (IA), (IB), (IC), (ID), (II-A), (II-B), (II-B'), (II-C), or (II-D)), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, as defined in any one of the embodiments described herein, for use in the treatment of a disease or condition for which an agonist of GLP-1R is indicated.

[0026] In another aspect, the present disclosure provides a pharmaceutical composition for the treatment of a disease or condition for which an agonist of GLP-1R is indicated, comprising a compound of any one of the formulae described herein (e.g., structural formulas (I), (I-1), (I-2), (II), (III), (IA), (IB), (IC), (ID), (II-A), (II-B), (II-B'), (II-C), and (II-D)), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, as defined in any one of the embodiments described herein.

[0027] All examples or pharmaceutically acceptable salts thereof may be claimed individually or grouped together in any combination with any number of each and every embodiment described herein.

[0028] The present disclosure also provides a pharmaceutical composition comprising a compound of any one of the formulae described herein (e.g., structural formulas (I), (I-1), (I-2), (II), (III), (IA), (IB), (IC), (ID), (II-A), (II-B), (II-B'), (II-C), or (II-D)), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, as defined in any one of the embodiments described herein, for use in the treatment and / or prevention of cardiometabolic disorders and their associated diseases discussed herein, including T2DM, pre-diabetes, NASH, and cardiovascular disease.

[0029] In another aspect, the present disclosure provides a method for treating diabetes (T1D and / or T2DM, including prediabetes), idiopathic T1D (type 1b), latent autoimmune diabetes of adults (LADA), early-onset T2DM (EOD), atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease (e.g., acute kidney injury, renal tubular dysfunction, inflammation-induced changes to the proximal tubule), diabetic retinopathy, adipocyte dysfunction, visceral adiposity, sleep apnea, obesity (including hypothalamic obesity and monogenic obesity) and related comorbidities (e.g., osteoarthritis and urinary incontinence), eating disorders (including binge eating disorder, bulimia nervosa, and syndromic obesity such as Prader-Willi syndrome and Bardet-Biedl syndrome), weight gain due to the use of other medications (e.g., due to the use of steroids or antipsychotics), excessive sugar cravings, dyslipidemia (including hyperlipidemia, hypertriglyceridemia, elevated total cholesterol, elevated LDL cholesterol, and low HDL cholesterol), high insulin Thyroid disease, NAFLD (including related disorders such as steatosis, NASH, fibrosis, cirrhosis, and hepatocellular carcinoma), cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction (e.g., necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration prevention or treatment of: diabetes, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, disorders of glucose metabolism, conditions with impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcers, ulcerative colitis, hyperapo B lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome, and treatment of poisoning (e.g.,Provided is a compound of any one of the formulas described herein (e.g., structural formulas (I), (I-1), (I-2), (II), (III), (IA), (IB), (IC), (ID), (II-A), (II-B), (II-B'), (II-C), or (II-D)), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, as defined in any one of the embodiments described herein, for use in the treatment and / or management of cardiometabolic disorders and related disorders, including alcohol and / or drug abuse.

[0030] In another aspect, the present disclosure provides a method of enhancing or stimulating GLP-1R-mediated cAMP signaling with decreased β-arrestin / arrestin-2 recruitment, comprising administering a compound of any one of the formulas described herein (e.g., structural formulas (I), (I-1), (I-2), (II), (III), (IA), (IB), (IC), (ID), (II-A), (II-B), (II-B'), (II-C), or (II-D)), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, as defined in any one of the embodiments described herein. This is based in part on the surprising discovery that the compounds of the present disclosure, although full agonists of GLP-1R-mediated cAMP signaling, are partial agonists of β-arrestin recruitment to activated GLP-1R compared to the native GLP-1R ligand GLP-1, in that the maximal β-arrestin recruitment to activated GLP-1R by the compounds of the present disclosure is lower than the maximal β-arrestin recruitment by GLP-1. Such partial and / or biased agonists of GLP-1R for cAMP signaling may provide more sustained cAMP signaling activity for better efficacy and fewer side effects.

[0031] Thus, the methods of the present disclosure can be advantageously used in the treatment of any of the diseases or conditions described herein, such as type 2 diabetes (T2D) and related diseases.

[0032] In certain embodiments, the treatment induces glycemic benefits without a concomitant increase, or at least a reduced increase, in GI side effects such as nausea, vomiting, or diarrhea. In certain embodiments, the treatment is more tolerable than a control treatment with normal or enhanced β-arrestin recruitment (such as β-arrestin recruitment by GLP-1). [Brief explanation of the drawings]

[0033] [Figure 1] Figure 1 shows dose-response curves for a GLP-1R / β-arrestin recruitment assay using certain compounds of the present disclosure and GLP-1(7-37) as a control. The vertical axis represents the relative effect of the test compound normalized to the percentage of the effect of the natural ligand, GLP-1(7-37). Figure 1 compares compounds 74-91, 93-95, 100, and 101 to GLP-1(7-37). [Figure 2] Figure 2 shows dose-response curves for a GLP-1R / β-arrestin internalization assay using certain compounds of the present disclosure and GLP-1(7-37) as a control. The vertical axis represents the relative effect of the test compound normalized to the percentage of the effect of the natural ligand, GLP-1(7-37). The two panels of Figure 2 compare compounds 74-80, 93-95, 100, and 101 (left panel) and compounds 81-91 (right panel) to GLP-1(7-37), respectively. [Figure 3] Figure 3 shows the time course response of the NanoBit assay for both GLP-1(7-37) and compound 94 at different compound concentrations. [Figure 4] Figure 4 shows dose-response curves for the GLP-1R / β-arrestin NanoBit assay using certain compounds of the present disclosure and GLP-1(7–37) as a control. The vertical axis represents the relative effect of the test compound normalized to the percentage of the effect of the natural ligand, GLP-1(7–37). The two panels of Figure 4 compare compounds 74–91, 93–95, 100, and 101 with GLP-1(7–37) at 3 and 5 minute readouts, respectively. [Figure 5-1] FIG. 5 shows the results of a cAMP assay for selected compounds of the present disclosure (i.e., compounds 75, 84, 93, and 94) using monkey GLP-1R and GLP-1(7-37) as a control. [Figure 5-2] FIG. 5 shows the results of a cAMP assay for selected compounds of the present disclosure (i.e., compounds 75, 84, 93, and 94) using monkey GLP-1R and GLP-1(7-37) as a control. DETAILED DESCRIPTION OF THE INVENTION

[0034] 1.Compound In a first embodiment, the present disclosure provides a compound represented by structural formula (I): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein: [ka] represents a single or double bond, X 1 , X 2 , X 3 , X 4 , and X 5 are each independently selected from N and CH; W is O, S, CR 5 R 6 , and NR 5’ is selected from Ring B is a 6-membered heteroaryl, a 6-membered monocyclic heterocyclyl, or a phenyl; Y 1 is selected from N, NH, CH, and CH2; Ring C is cyclohexyl, phenyl, or pyridyl; L is CHR d , O, S, or NR 5’ and Ring D is a bicyclic heteroaryl; EE is —COOH or a carboxylic acid group surrogate, and optionally the carboxylic acid group surrogate is [ka] R a and R b are hydrogen, deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, and NR 5 'R 6 ', 6- to 10-membered aryl, 5- to 8-membered heteroaryl, 3- to 8-membered saturated or partially saturated cycloalkyl, and 3- to 8-membered saturated or partially saturated heterocyclyl, wherein R a / R b The C1-C6 alkyl or C1-C6 alkoxy represented by the formula (I) may be substituted with one or more groups selected from halogen, oxo, CN, OH, and C3-C6 saturated or partially saturated cycloalkyl, wherein R a / R b or R a / R b The aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl in the group represented by the formula (I) may be substituted with halogen, oxo (if necessary), CN, OH, C1-C3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and C1-C3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and NR 5’ R 6’ and optionally substituted with one or more groups selected from R c and R d are hydrogen, deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, and NR 5’ R 6’ , 6- to 10-membered aryl, 5- to 8-membered heteroaryl, 3- to 8-membered saturated or partially saturated cycloalkyl, and 3- to 8-membered saturated or partially saturated heterocyclyl, wherein R c / R dThe C1-C6 alkyl or C1-C6 alkoxy represented by the formula (I) may be substituted with one or more groups selected from halogen, oxo, CN, OH, and C3-C6 saturated or partially saturated cycloalkyl, wherein R c / R d or R c / R d In the group represented by the formula: aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl, halogen, oxo (if necessary), CN, and NR 5’ R 6’ and optionally substituted with one or more groups selected from Each R 1 is H, deuterium, halogen, -CN, OH, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, NR 5’ R 6’ , 6- to 10-membered aryl, 5- to 8-membered heteroaryl, 3- to 8-membered saturated or partially saturated cycloalkyl, and 3- to 8-membered saturated or partially saturated heterocyclyl, wherein R 1 The C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl represented by the formula (I) may be substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl (which may be substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3), wherein R 1 or R 1 The aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl in the group represented by the formula (I) can be substituted with halogen, oxo (optionally), CN, OH, C1-C3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and C1-C3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), as well as NR 5’ R 6’ and optionally substituted with one or more groups selected from Each R 2is H, deuterium, halogen, -CN, OH, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR 5’ R 6’ , 6- to 10-membered aryl, 5- to 8-membered heteroaryl, 3- to 8-membered saturated or partially saturated cycloalkyl, and 3- to 8-membered saturated or partially saturated heterocyclyl, wherein R 2 The C1-C6 alkyl or C1-C6 alkoxy represented by the formula (I) may be substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl (which may be substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3), and R 2 or R 2 The aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl in the group represented by the formula (I) may be substituted with halogen, oxo (if necessary), CN, OH, C1-C3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and C1-C3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and NR 5’ R 6’ and optionally substituted with one or more groups selected from Each R 3 is H, deuterium, halogen, -CN, OH, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR 5’ R 6’ , 6- to 10-membered aryl, 5- to 8-membered heteroaryl, 3- to 8-membered saturated or partially saturated cycloalkyl, and 3- to 8-membered saturated or partially saturated heterocyclyl, wherein R 3 The C1-C6 alkyl or C1-C6 alkoxy represented by the formula (I) may be substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl (which may be substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3), wherein R 3is expressed as R 3 The aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl in the group represented by the formula (I) may be substituted with halogen, oxo (if necessary), CN, OH, C1-C3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and C1-C3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and NR 5’ R 6’ and optionally substituted with one or more groups selected from Each R 4 is H, deuterium, halogen, OH, -CN, C1-C6 alkyl, C1-C6 alkoxy or NR 5’ R 6’ wherein R is independently selected from 4 The C1-C6 alkyl and C1-C6 alkoxy represented by the formula (I) may be substituted with one or more groups selected from halogen, oxo, CN, CF3, and saturated or partially saturated C3-C6 cycloalkyl (which may be substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, and OCH2CH3), R 5 and R 6 are hydrogen, deuterium, halogen, CN, OH, C1-C6 alkyl, C1-C6 alkoxy, and NR 5’ R 6’ , 6- to 10-membered aryl, 5- to 8-membered heteroaryl, 3- to 8-membered saturated or partially saturated cycloalkyl, and 3- to 8-membered saturated or partially saturated heterocyclyl, wherein R 5 or R 6 The C1-C6 alkyl or C1-C6 alkoxy represented by the formula (I) may be substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl (which may be substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3), wherein R 5 or R 6 or R5 or R 6 In the group represented by the formula (I), the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl is substituted with halogen, oxo (if necessary), CN, OH, C1-C3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and C1-C3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and NR 5’ R 6’ and optionally substituted with one or more groups selected from R 5’ and R 6’ are each independently selected from hydrogen and C1-C6 alkyl; Here, two R 1 ;2 R 2 ;2 R 3 ;2 R 4 ;R 1 and R 2 ;R 2 and R 3 ;R a and R 1 ;R a and R 2 ;R 1 and R 5 , R (in the group represented by W) 5’ or R 6 Any of the following;R a and R 5 , R (in the group represented by W) 5’ or R 6 Any of the following;R 2 and R 5 , R (in the group represented by W) 5’ or R 6 Any of the following;R 5 and R 6 ;R c , R d , R e and R f any two groups selected from; or R 4 and R c , R d , R e and R fany one of which, together with each intervening carbon atom or heteroatom, may form phenyl, a 5- to 6-membered heteroaryl, a 4- to 8-membered saturated or partially saturated cycloalkyl, or a 4- to 8-membered saturated or partially saturated heterocyclyl, each of which is optionally substituted with one or more groups selected from halogen, —CN, —OH, CF, C-C alkyl, C-C alkoxy, —NH, —NHC-C alkyl, —N(C-C alkyl) , oxo, and saturated or partially saturated C-C cycloalkyl, where C-C alkyl and C-C alkoxy are optionally substituted with one or more groups selected from halogen, oxo, CN, CF, OH, OCH, OCHCH, and saturated or partially saturated C-C cycloalkyl, where cycloalkyl is optionally substituted with one or more groups selected from halogen, oxo, CN, CF, OH, OCH, OCHCH; m is an integer selected from 0, 1, 2, 3, and 4; n is an integer selected from 0, 1, 2, 3, 4, and 5; o is an integer selected from 0, 1, 2, 3, and 4; p is an integer selected from 0, 1, 2, 3, and 4.

[0035] In a second embodiment, the present disclosure provides a compound according to the first embodiment, the compound having structural formula (II): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein: X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from N and CH, 1 , X 2 , X 3 , X 4 and X 5are N, and ring A does not contain three nitrogen ring atoms in three consecutive positions; Ring B is a 6-membered heteroaryl or phenyl, where Y 1 , Y 3 , Y 4 , and Y 5 are each independently selected from N or CH, wherein Ring B has three or fewer nitrogen ring atoms, and Ring B does not contain three nitrogen ring atoms in three adjacent positions; T 2 is selected from N and C; T 4 is N, NR 4 , O, S, and CR 4 Selected from T 6 , T 7 and T 8 are each independently N and CR 4 is selected from where T 2 , T 4 , T 6 , T 7 , and T 8 No more than four of are selected from N, O, and S.

[0036] In a third embodiment, the present disclosure provides a compound according to the first or second embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein: W is O, NH, or CH; R a is H, CH3, or CF3, R b is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, NR 5’ R 6’ , 6- to 10-membered aryl, selected from 5- to 6-membered heteroaryl, 3- to 6-membered saturated or partially saturated cycloalkyl, and 3- to 7-membered saturated or partially saturated heterocyclyl, wherein R bThe C1-C6 alkyl or C1-C6 alkoxy represented by the formula (I) may be substituted with one or more groups selected from halogen, oxo, CN, OH, and C3-C6 saturated or partially saturated cycloalkyl, wherein R b or R b In the group represented by the formula (I), aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl is not particularly limited, and halogen, oxo (R b is non-aromatic), CN, OH, C1-C3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and C1-C3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and NR 5’ R 6’ and optionally substituted with one or more groups selected from R c is selected from hydrogen, halogen, and C1-C4 alkyl optionally substituted with one or more groups selected from halogen and hydroxy; R d is H, F, CH3, or CF3, Each R 1 is H, deuterium, halogen, -CN, OH, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, NR 5’ R 6’ , 6- to 10-membered aryl, 5- to 8-membered heteroaryl, 3- to 8-membered saturated or partially saturated cycloalkyl, and 3- to 8-membered saturated or partially saturated heterocyclyl, wherein R 1 The C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl represented by the formula (I) may be substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl (which may be substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3), wherein R 1 or R 1In the group represented by the formula (I), aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl is not particularly limited, and halogen, oxo (R 1 is non-aromatic), CN, OH, C1-C3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and C1-C3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and NR 5’ R 6’ and optionally substituted with one or more groups selected from R 2 and R 3 are each H, deuterium, halogen, —CN, OH, oxo, C1-C6 alkyl, C1-C6 alkoxy, or NR 5’ R 6’ are independently selected from, where R 2 and / or R 3 The C1-C6 alkyl and C1-C6 alkoxy represented by the following formula (I) may be substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl (which may be substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3), Each R 4 is H, deuterium, halogen, OH, —CN, C1-C6 alkyl, C1-C6 alkoxy, or NR 5’ R 6’ are independently selected from, where R 4 The C1-C6 alkyl and C1-C6 alkoxy represented by the formula (I) may be substituted with one or more groups selected from halogen, oxo, CN, CF3, and saturated or partially saturated C3-C6 cycloalkyl (which may be substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, and OCH2CH3), o is an integer selected from 0, 1, 2, 3, and 4.

[0037] In a fourth embodiment, the present disclosure provides a compound according to the first, second, or third embodiment, represented by structural formula (III): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein R 4 is H, F, Cl, methyl, or methoxy.

[0038] In a fifth embodiment, the present disclosure provides a compound according to the second, third, or fourth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein [ka] teeth, [ka] and n is an integer optionally selected from 0, 1, 2, 3, and 4.

[0039] In a sixth embodiment, the present disclosure provides a compound according to the first, second, third, fourth, or fifth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein ring A is [ka] and Each R 1 is independently selected from halogen, OH, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 hydroxyalkoxy, C2-C4 alkenyl, C2-C4 alkynyl, -NH2, -NHC1-C4 alkyl, -N(C1-C4 alkyl)2, and m is an integer selected from 0, 1, and 2.

[0040] In a seventh embodiment, the present disclosure provides a compound according to the first, second, third, fourth, fifth, or sixth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein EE is COOH.

[0041] In an eighth embodiment, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, or seventh embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein R b teeth, [ka] and These are halogen, oxo (R b is non-aromatic), CN, NR 5’ R 6’ , C1-C4 alkyl, and C1-C4 alkoxy, wherein R b The C1-C4 alkyl or C1-C4 alkoxy in the group represented by the formula (I) may be substituted with one or two groups selected from F, OH, and OCH3.

[0042] In a ninth embodiment, the present disclosure provides a compound according to the second, third, fourth, fifth, sixth, seventh, or eighth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein: [ka] teeth, [ka] is.

[0043] In a tenth embodiment, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein: R 3 is halogen, CN, OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, or NR 5’ R 6’ and o is an integer selected from 0, 1, 2, 3, and 4.

[0044] In an eleventh embodiment, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein each R 2 is independently selected from deuterium, halogen, —CN, OH, C1-C2 alkyl, C1-C2 haloalkyl, and C1-C2 alkoxy; and n is an integer selected from 0, 1, 2, 3, and 4.

[0045] In a twelfth embodiment, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein ring A is [ka] and Each R 1 is independently selected from halogen, OH, CN, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy, C1-C2 hydroxy, and C2-C4 alkynyl; and m is an integer selected from 0, 1, and 2.

[0046] In a thirteenth embodiment, the present disclosure provides a compound according to the fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein: [ka] teeth, [ka] is.

[0047] In a fourteenth embodiment, the present disclosure provides a compound according to the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof; [ka] teeth, [ka] is.

[0048] In a fifteenth embodiment, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein each R 2 are independently selected from halogen (e.g., F) or deuterium, and n is an integer selected from 0, 1, and 2, with the proviso that R 2 is deuterium, then ring B is fully substituted with deuterium.

[0049] In a sixteenth embodiment, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein each R 3 is F, Cl, or CH3, and o is 0, 1, or 2.

[0050] In a seventeenth embodiment, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein ring A is [ka] is.

[0051] In an eighteenth embodiment, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein ring A is [ka] is.

[0052] In a nineteenth embodiment, the present disclosure provides a compound according to the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, or eighteenth embodiment, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein: [ka] teeth, [ka] is.

[0053] The present disclosure also provides a compound represented by structural formula (I-1) or (I-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein: [ka] represents a single or double bond, X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from N and CH, 1 , X 2 , X 3 , X 4 and X 5 are N, and ring A does not contain three nitrogen ring atoms in three consecutive positions; W is O, S, CR 5 R 6 , and NR 5’ is selected from Ring B is a 5- to 6-membered heteroaryl, a 5- to 6-membered monocyclic heterocyclyl, or phenyl; Z 1 and Z 2 are each independently selected from N, C, and CH; Z 3 and Z 4 are each independently selected from a bond, CH, CH2, CH=CH, CH2CH2, CH2CH, and CHCH2, where: Ring C contains two or less double bonds, L is CHR d , O, S, or NR 5’ and Ring D is a bicyclic heteroaryl; EE is —COOH or a carboxylic acid group surrogate, and optionally the carboxylic acid group surrogate is [ka] R a and R b are hydrogen, deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, and NR 5 'R6 ', 6- to 10-membered aryl, 5- to 8-membered heteroaryl, 3- to 8-membered saturated or partially saturated cycloalkyl, and 3- to 8-membered saturated or partially saturated heterocyclyl, wherein R a / R b The C1-C6 alkyl or C1-C6 alkoxy represented by the formula (I) may be substituted with one or more groups selected from halogen, oxo, CN, OH, and C3-C6 saturated or partially saturated cycloalkyl, wherein R a / R b or R a / R b The aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl in the group represented by the formula (I) may be substituted with halogen, oxo (if necessary), CN, OH, C1-C3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and C1-C3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and NR 5’ R 6’ and optionally substituted with one or more groups selected from R c and R d are hydrogen, deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, and NR 5’ R 6’ , 6- to 10-membered aryl, 5- to 8-membered heteroaryl, 3- to 8-membered saturated or partially saturated cycloalkyl, and 3- to 8-membered saturated or partially saturated heterocyclyl, wherein R c / R d The C1-C6 alkyl or C1-C6 alkoxy represented by the formula (I) may be substituted with one or more groups selected from halogen, oxo, CN, OH, and C3-C6 saturated or partially saturated cycloalkyl, wherein R c / R d or R c / R dIn the group represented by the formula: aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl, halogen, oxo (if necessary), CN, and NR 5’ R 6’ and optionally substituted with one or more groups selected from Each R 1 is H, deuterium, halogen, -CN, OH, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, NR 5’ R 6’ , 6- to 10-membered aryl, 5- to 8-membered heteroaryl, 3- to 8-membered saturated or partially saturated cycloalkyl, and 3- to 8-membered saturated or partially saturated heterocyclyl, wherein R 1 The C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl represented by the formula (I) may be substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl (which may be substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3), wherein R 1 or R 1 The aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl in the group represented by the formula (I) can be substituted with halogen, oxo (optionally), CN, OH, C1-C3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and C1-C3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), as well as NR 5’ R 6’ and optionally substituted with one or more groups selected from Each R 2 is H, deuterium, halogen, -CN, OH, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR 5’ R 6’ , 6- to 10-membered aryl, 5- to 8-membered heteroaryl, 3- to 8-membered saturated or partially saturated cycloalkyl, and 3- to 8-membered saturated or partially saturated heterocyclyl, wherein R2 The C1-C6 alkyl or C1-C6 alkoxy represented by the formula (I) may be substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl (which may be substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3), and R 2 or R 2 The aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl in the group represented by the formula (I) may be substituted with halogen, oxo (if necessary), CN, OH, C1-C3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and C1-C3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and NR 5’ R 6’ and optionally substituted with one or more groups selected from Each R 3 is H, deuterium, halogen, -CN, OH, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR 5’ R 6’ , 6- to 10-membered aryl, 5- to 8-membered heteroaryl, 3- to 8-membered saturated or partially saturated cycloalkyl, and 3- to 8-membered saturated or partially saturated heterocyclyl, wherein R 3 The C1-C6 alkyl or C1-C6 alkoxy represented by the formula (I) may be substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl (which may be substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3), wherein R 3 is expressed as R 3 The aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl in the group represented by the formula (I) may be substituted with halogen, oxo (if necessary), CN, OH, C1-C3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and C1-C3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and NR 5’ R 6’ and optionally substituted with one or more groups selected from Each R 4 is H, deuterium, halogen, OH, -CN, C1-C6 alkyl, C1-C6 alkoxy or NR 5’ R 6’ wherein R is independently selected from 4 The C1-C6 alkyl and C1-C6 alkoxy represented by the formula (I) may be substituted with one or more groups selected from halogen, oxo, CN, CF3, and saturated or partially saturated C3-C6 cycloalkyl (which may be substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, and OCH2CH3), R 5 and R 6 are hydrogen, deuterium, halogen, CN, OH, C1-C6 alkyl, C1-C6 alkoxy, and NR 5’ R 6’ , 6- to 10-membered aryl, 5- to 8-membered heteroaryl, 3- to 8-membered saturated or partially saturated cycloalkyl, and 3- to 8-membered saturated or partially saturated heterocyclyl, wherein R 5 or R 6 The C1-C6 alkyl or C1-C6 alkoxy represented by the formula (I) may be substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl (which may be substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3), wherein R 5 or R 6 or R 5 or R 6In the group represented by the formula (I), the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl is substituted with halogen, oxo (if necessary), CN, OH, C1-C3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and C1-C3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and NR 5’ R 6’ and optionally substituted with one or more groups selected from R 5’ and R 6’ are each independently selected from hydrogen and C1-C6 alkyl; Here, two R 1 ;2 R 2 ;2 R 3 ;2 R 4 ;R 1 and R 2 ;R 2 and R 3 ;R a and R 1 ;R a and R 2 ;R 1 and R 5 , R (in the group represented by W) 5’ or R 6 Any of the following;R a and R 5 , R (in the group represented by W) 5’ or R 6 Any of the following;R 2 and R 5 , R (in the group represented by W) 5’ or R 6 Any of the following;R 5 and R 6 ;R c , R d , R e and R f any two groups selected from; or R 4 and R c , R d , R e and R fany one of -C(R) ... a )-, W, and R 2 is ring B [ka] formed together with two adjacent carbon atoms, each of which is optionally substituted with one or more groups selected from halogen, —CN, —OH, CF3, C1-C6 alkyl, C1-C6 alkoxy, —NH2, —NHC1-C6 alkyl, —N(C1-C6 alkyl)2, oxo, and saturated or partially saturated C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3; m is an integer selected from 0, 1, 2, 3, and 4; n is an integer selected from 0, 1, 2, 3, 4, and 5; o is an integer selected from 0, 1, 2, 3, 4, and 5; p is an integer selected from 0, 1, 2, 3, and 4.

[0054] The present disclosure also provides compounds of the structural formula A compound represented by (IA), (IB), (IC), or (ID), [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein: [ka] represents a single or double bond, X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from N and CH, 1 , X 2 , X 3 , X 4 and X 5 are N, and ring A does not contain three nitrogen ring atoms in three consecutive positions; W is O, S, CR 5 R 6 , and NR 5’ is selected from Y 1 is N or CH, Y 3 and Y 5 are each independently selected from N, CH, O, or S; Y 4 is absent, N or CH, Y 2’ are each independently N or CH; Y 3’ and Y 5’ are each independently selected from N, CH, O, and S; Y 4’ is absent, N or CH, wherein there are three or fewer hetero ring atoms in Ring B, and Ring B does not contain three hetero ring atoms in three adjacent positions; Z 1 and Z 2 are each independently selected from N, C, and CH; Z 1 and Z 2 At least one of is N and Z 3 and Z 4 are each independently selected from a bond, CH, CH2, CH=CH, CH2CH2, CH2CH, and CHCH2, and Ring C contains up to two double bonds; T 2 , T 3 , and T 4are each independently N, NR 4 , O, S, C, and CR 4 is selected from T 6 , T 7 and T 8 are each independently N and CR 4 is selected from where T 2 , T 3 , T 4 , T 6 , T 7 , and T 8 are selected from N, O, and S; The remaining variables are as defined in the previous embodiments for compounds represented by structural formula (I-1) or (I-2).

[0055] In some embodiments, the present disclosure provides a compound according to structural formula (I-1), (I-2), (IA), (IB), (IC), or (ID), which is represented by structural formula (II-A), (II-B), (II-B'), (II-C), or (II-D): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein the variables are as defined in the previous embodiments for a compound represented by Structural Formula (I-1), (I-2), (IA), (IB), (IC), or (ID).

[0056] In some embodiments, the present disclosure provides a compound according to structural formula (I-1), (I-2), (IA), (IB), (IC), (II-A), (II-B), (II-B'), (II-C), or (II-D), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein ring A is [ka] and Each R 1is independently selected from halogen, OH, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 hydroxyalkoxy, C2-C4 alkenyl, C2-C4 alkynyl, —NH2, —NHC1-C4 alkyl, —N(C1-C4 alkyl)2; m is an integer selected from 0, 1, and 2, and the remainder of the variables are as defined in the previous embodiment.

[0057] In some embodiments, the present disclosure provides a compound according to structural formula (I-1), (I-2), (IA), (IB), (IC), (II-A), (II-B), (II-B'), (II-C), or (II-D), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein ring A is [ka] and Each R 1 is independently selected from halogen, OH, CN, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy, C1-C2 hydroxyalkoxy, C2-C4 alkenyl, C2-C4 alkynyl, m is an integer selected from 0, 1, and 2, and the remaining variables are as defined in the previous embodiments. [ka] is.

[0058] In some embodiments, the present disclosure provides a compound according to structural formula (I-1), (I-2), (IA), (IB), (IC), (II-A), (II-B), (II-B'), (II-C), or (II-D), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof; [ka] teeth [ka] and the remaining variables are as defined in the previous embodiment. [ka] teeth, [ka]

[0059] In a more specific embodiment, [ka] teeth, [ka] is.

[0060] In some embodiments, the present disclosure provides a compound according to structural formula (I-1), (I-2), (IA), (IB), (IC), (II-A), (II-B), (II-B'), or (II-C), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein: [ka] teeth, [ka] where R 3 is halogen, CN, OH, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, or NR 5’ R 6’wherein o is an integer selected from 0, 1, 2, and 3, and the remainder of the variables are as defined in the previous embodiments. [ka] teeth, [ka] where R 3 is independently halogen, C1-C4 alkyl, or C1-C4 haloalkyl, and o is 0, 1, or 2. In more specific embodiments, [ka] teeth, [ka] is.

[0061] In some embodiments, the present disclosure provides a compound according to structural formula (II-A) or (II-B'), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein: [ka] teeth, [ka] and the remaining variables are as defined in the previous embodiment. [ka] teeth, [ka] In certain embodiments, [ka] teeth, [ka] is.

[0062] In some embodiments, the present disclosure provides a compound according to structural formula (II-D), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein: [ka] teeth, [ka] is.

[0063] In one embodiment, the compound, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, is selected from the compounds disclosed in the Examples and Table 1.

[0064] 2.Definition As used herein, the term "halogen" refers to fluoride, chloride, bromide, or iodide.

[0065] The term "alkyl," whether used alone or as part of a larger moiety such as "alkoxy" or "haloalkyl," refers to a group of the formula -C n H (2n+1) "(C1-C4) alkyl" refers to a saturated aliphatic straight-chain or branched monovalent hydrocarbon radical of the formula (I). Unless otherwise specified, an alkyl group typically has 1 to 4 carbon atoms, i.e., (C1-C4) alkyl. As used herein, a "(C1-C4) alkyl" group refers to a radical having from 1 to 4 carbon atoms in a linear or branched arrangement. Examples include methyl, ethyl, n-propyl, isopropyl, and the like.

[0066] As used herein, the term "alkylene" refers to a group of the formula -C n H 2n- " refers to a straight or branched chain divalent hydrocarbon radical of the formula: Non-limiting examples include ethylene and propylene.

[0067] The term "alkenyl" refers to an alkyl group in which one or more carbon / carbon single bonds are replaced with a double bond.

[0068] The term "alkynyl" refers to an alkyl group in which one or more carbon / carbon single bonds are replaced with a triple bond.

[0069] The term "alkoxy" refers to an alkyl radical attached through an oxygen linking atom, represented by -O-alkyl. For example, "(C1-C4)alkoxy" includes methoxy, ethoxy, propoxy, and butoxy.

[0070] The terms "haloalkyl" and "haloalkoxy" mean alkyl or alkoxy, as the case may be, substituted with one or more halogen atoms.

[0071] The terms "hydroxyalkyl" and "hydroxyalkoxy" mean alkyl or alkoxy, as the case may be, substituted with one or more hydroxy groups.

[0072] As used herein, the term "cycloalkyl" refers to a cyclic hydrocarbon group containing at least three carbon atoms (e.g., C3, C4, C5, C6, C7, C8, or C 3~8 or C 3~6 Cycloalkyl may be (fully) saturated or partially saturated (i.e., not aromatic) and may contain one or more carbon-carbon double bonds.

[0073] Fully saturated cycloalkyls have the formula C n H (2n-1) Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0074] The term "heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone (a "3- to 12-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 3- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur (a "3- to 8-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be to a carbon atom or a nitrogen atom, valence permitting. Heterocyclyl groups can be either monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., bicyclic systems ("bicyclic heterocyclyl") or tricyclic systems ("tricyclic heterocyclyl"), where polycyclic systems include fused rings, bridged rings, spirocyclic rings, etc.). Exemplary monocyclic heterocyclyl groups include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxepanyl, thiepanyl, tetrahydropyridinyl, and the like. Heterocyclyl polycyclic ring systems can contain heteroatoms in one or more rings of the polycyclic ring system. Substituents can be present on one or more rings of the polycyclic ring system.

[0075] In general, a cycloalkyl or heterocyclyl may be unsubstituted or, valence permitting, substituted with one or more substituents, which may be independently selected from several groups such as oxo, -CN, halogen, alkyl, and alkoxyl, and optionally, alkyl substituents may be further substituted.

[0076] As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic aromatic hydrocarbon in which at least one of the ring carbon atoms is replaced with a heteroatom independently selected from oxygen, nitrogen, and sulfur. Preferably, heteroaryl refers to a C 1 -C 2 -C 3 -C 4 -C 5 -C 6 -C 7 -C 8 -C 9 -C 10 -C 11 -C 12 -C 13 -C 14 -C 15 -C 16 -C 17 -C 18 -C 19 -C 20 -C 21 -C 22 -C 23 -C 24 -C 25 -C 26 -C 27 -C 28 -C 29 -C 30 -C 31 -C 32 -C 33 -C 40 -C 41 -C 42 -C 43 -C 54 -C 55 -C 56 -C 57 -C 5~8 Based on aryl. Heteroaryl groups may be attached via a ring carbon atom or, if valence allows, via a ring nitrogen atom. In general, heteroaryls may be unsubstituted or, if valence allows, substituted with one or more substituents independently selected from halogen, OH, alkyl, alkoxyl, and amino (e.g., NH, NH alkyl, N(alkyl)), and optionally, alkyl may be further substituted.

[0077] Specific abbreviations used herein include room temperature: RT, methanol: MeOH, ethanol: EtOH, isopropanol: iPrOH, ethyl acetate: EtOAc, tetrahydrofuran: THF, toluene: PhCH, cesium carbonate: CsCO, lithium bis(trimethylsilyl)amide: LiHMDS, sodium t-butoxide: NaOtBu, potassium t-butoxide: KotBu, lithium diisopropylamide: LDA, triethylamine: EtN, N,N-diisopropylethylamine: DIPEA, potassium carbonate: KCO, dimethylformamide: DMF, dimethylacetamide: DMAc, dimethyl sulfoxide: DMSO, N-methyl-2-pyrrolidinone: NMP, sodium hydride: NaH, trifluoroacetic acid: TFA, trifluoroacetic anhydride: TFAA, acetic anhydride: AcO, dichloromethane: DCM, 1,2-dichloroethane: DCE, hydrochloric acid: HCl, 1,8-diazabicyclo[5.4.0]Undec-7-ene: DBU, borane-dimethyl sulfide complex: BH3-DMS, borane-tetrahydrofuran complex: BH3-THF, lithium aluminum hydride: LAH, acetic acid: AcOH, acetonitrile: MeCN, p-toluenesulfonic acid: pTSA, dibenzylideneacetone: DBA, 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene: BINAP, 1,1'-ferrocenediyl-bis(diphenylphosphine): dppf, 1,3-bis(diphenylphosphino)propane: DPPP, 3-chloroperbenzoic acid: m-CPBA, tert-butyl methyl ether: MTBE, methanesulfonyl: Ms, N-methylpyrrolidino Examples of analytical methods include NMP, thin layer chromatography (TLC), supercritical fluid chromatography (SFC), 4-(dimethylamino)pyridine (DMAP), tert-butyloxycarbonyl (Boc), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), petroleum ether (PE), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), and 2-amino-2-(hydroxymethyl)propane-1,3-diol (tris), tris(dibenzylideneacetone)dipalladium (Pd2(dba)3).

[0078] 1 H nuclear magnetic resonance (NMR) spectra were consistent with the proposed structures in all cases. Characteristic chemical shifts (δ) are given in parts per million relative to residual proton signals in deuterated solvents (CHCl3 at 7.27 ppm, CD2HOD at 3.31 ppm, MeCN at 1.94 ppm, DMSO at 2.50 ppm) and are reported using conventional abbreviations for major peak designations, e.g., s for singlet, d for doublet, t for triplet, q for quartet, m for multiplet, and br for broad. Unless otherwise stated, measurements were performed at a field strength of 400 or 600 MHz. 1 1 H NMR spectra were obtained.

[0079] As used herein, a wavy line indicates a point of attachment of a substituent to another group.

[0080] pharmaceutically acceptable salts Pharmaceutically acceptable salts of the compounds of any of the above formulas include acid addition and base salts.

[0081] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, hydrogensulfate / sulfate, borate, camsylate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methyl sulfate, naphthylate, 2-naphthylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / hydrogenphosphate, pyroglutamate, saccharate, stearate, stearate, trifluoroacetate, 1,5-naphthalenedisulfonate and xinafoate salts.

[0082] Suitable base salts are formed from bases which form non-toxic salts, examples of which include aluminum, arginine, benzathine, calcium, choline, diethylamine, bis(2-hydroxyethyl)amine (diolamine), glycine, lysine, magnesium, meglumine, 2-aminoethanol (olamine), potassium, sodium, 2-amino-2-(hydroxymethyl)propane-1,3-diol (tris or tromethamine), and zinc salts.

[0083] Hemisalts of acids and bases, such as hemisulfates and hemicalcium salts, can also be formed. For a review of suitable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, 2002), incorporated herein by reference.

[0084] Pharmaceutically acceptable salts of compounds of any one of the above formulas may be prepared by one or more of three methods. (i) by reacting a compound of any one of the above formulas with a desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of a compound of any one of the above formulae, or by ring-opening a suitable cyclic precursor, such as a lactone or lactam, using the desired acid or base; or (iii) By converting one salt of a compound of any one of the above formulas to another salt by reaction with a suitable acid or base followed by a suitable ion exchange column.

[0085] All three reactions are typically carried out in solution. The resulting salts can either precipitate and be recovered by filtration or by evaporation of the solvent. The degree of ionization of the resulting salts can vary from completely ionized to almost non-ionized.

[0086] Compounds of any one of the above formulas, and pharmaceutically acceptable salts thereof, can exist in unsolvated and solvated forms.

[0087] Solvates and Hydrates The term 'solvate' is used herein to describe a molecular complex comprising a compound of any one of the above formulas, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.

[0088] The term "hydrate" is used when the solvent is water.

[0089] A currently accepted classification system for organic hydrates defines isolated site, channel, or metal-ion coordinated hydrates; see KR Morris, Polymorphism in Pharmaceutical Solids (Ed. HG Brittain, Marcel Dekker, 1995). Isolated site hydrates are those in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bound to the metal ion.

[0090] If the solvent or water is tightly bound, the complex may have a well-defined stoichiometry independent of humidity. However, if the solvent or water is weakly bound, such as in channel solvates or hygroscopic compounds, the water / solvent content may depend on humidity and drying conditions. In such cases, non-stoichiometry becomes the norm.

[0091] Stereoisomers and other variations Compounds of any one of the above formulas can exhibit one or more types of isomerism (e.g., optical isomerism, geometric isomerism, or tautomerism). Compounds of any one of the above formulas may also be isotopically labeled. Such variations are implicit in compounds of any one of the above formulas defined by reference to their structural features and, therefore, are within the scope of the present disclosure.

[0092] Compounds of any one of the above formulas containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. When compounds of any of the above formulas contain an alkenyl or alkenylene group, geometric (or Z / E) isomers are possible. When structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ("tautomerism") can occur. This can take the form of, for example, proton tautomerism in compounds of any one of the above formulas containing an imino, keto, or oxime group, or so-called valence tautomerism in compounds containing an aromatic moiety. Thus, a single compound can exhibit more than one type of isomerism.

[0093] Compounds with one or more chiral centers can exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in spatial configuration. Stereoisomers include all diastereomeric, enantiomeric, and epimeric forms, as well as racemates and mixtures thereof. The term "geometric isomer" refers to a compound having at least one double bond, which double bond can exist in cis (also called syn or entgegen (E)) or trans (also called anti or zusammen (Z)) form, as well as mixtures thereof. When a disclosed compound is named or depicted by structure without indicating stereochemistry, it is understood that the name or structure encompasses one or more possible stereoisomers, or geometric isomers, or mixtures of the encompassed stereoisomers or geometric isomers.

[0094] When a geometric isomer is depicted by name or structure, it is to be understood that the named or depicted isomer is present to a greater extent than another isomer, i.e., the geometric isomeric purity of the named or depicted geometric isomer is greater than 50%, e.g., at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. Geometric isomeric purity is determined by dividing the weight of the named or depicted geometric isomer in the mixture by the total weight of all geometric isomers in the mixture.

[0095] A racemic mixture means 50% of one enantiomer and 50% of the corresponding enantiomer. When a compound with one chiral center is named or depicted without indicating the stereochemistry of the chiral center, the name or structure is understood to encompass both possible enantiomeric forms of the compound (e.g., both enantiomerically pure, enantiomerically enriched, or racemic). When a compound with two or more chiral centers is named or depicted without indicating the stereochemistry of the chiral centers, the name or structure is understood to encompass all possible diastereomeric forms of the compound (e.g., diastereomerically pure, diastereomerically enriched, and equimolar mixtures of one or more diastereomers (e.g., racemic mixtures)).

[0096] Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well-known methods such as chiral-phase gas chromatography, chiral-phase high-performance liquid chromatography, crystallizing the compounds as chiral salt complexes, or crystallizing the compounds in chiral solvents. Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0097] When a compound is designated by a name or structure that denotes a single enantiomer, unless otherwise specified, the compound is at least 60%, 70%, 80%, 90%, 99%, or 99.9% optically pure (also referred to as "enantiomerically pure"). Optical purity is the weight of the mixture of the named or depicted enantiomer divided by the total weight of the mixture of both enantiomers.

[0098] When the stereochemistry of a disclosed compound is named or indicated by a structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in the case of a diastereomeric pair), it is understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. It is further understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight. Stereoisomeric purity in this case is determined by dividing the total weight of the mixture of stereoisomers encompassed by the name or structure by the total weight of the mixture of all stereoisomers.

[0099] Pharmaceutically acceptable salts of compounds of any one of the above formulas can also include counterions that are optically active (e.g., d-lactate or l-lysine) or racemic (e.g., dl-tartrate or dl-arginine).

[0100] Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

[0101] Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors, or separation of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). Alternatively, the racemate (or racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, if a compound of any one of the above formulas contains an acidic or basic moiety, with a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization, and one or both of the diastereoisomers can be converted to the corresponding pure enantiomer by means well known to those skilled in the art. Chiral compounds of any one of the above formulas (and their chiral precursors) can be obtained in enantiomerically enriched form by chromatography, typically using HPLC, on an asymmetric resin using a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing 0 to 50% by volume, typically 2% to 20% isopropanol, and 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. The eluate is concentrated to provide the enriched mixture. Chiral chromatography using subcritical and supercritical fluids can be used. Chiral chromatography methods useful in some embodiments of the present disclosure are known in the art (see, for example, Smith, Roger M., Loughborough University, Loughborough, UK, Chromatographic Science Series (1998), 75 (Supercritical Fluid Chromatography with Packed Columns), pp. 223-249 and references cited therein). Columns are available from Chiral Technologies, Inc., West Chester, PA, USA, a subsidiary of Daicel® Chemical Industries, Inc., Tokyo, Japan.

[0102] It must be emphasized that, as used herein, the compounds of any one of the above formulas are depicted in a single tautomeric form, and all possible tautomeric forms are included within the scope of the present disclosure.

[0103] The present disclosure also includes all pharmaceutically acceptable isotopically labeled compounds of any one of the above formulas in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature.

[0104] Examples of isotopes suitable for inclusion in compounds of the present disclosure include: 2 H and 3 Hydrogen such as H 11 C. 13 C and 14 carbon isotopes such as C, 36 chlorine isotopes such as Cl, 18 fluorine isotopes such as F, 123 I and 125 isotopes of iodine, such as I, 13 N and 15 nitrogen isotopes such as N, 15 O. 17 O and 18 isotopes of oxygen, such as O 32 Isotopes of phosphorus such as P, as well as 35 Examples include sulfur isotopes such as S.

[0105] Certain isotopically labeled compounds of any one of the above formulas, for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e., 3 H, and carbon-14, i.e., 14 C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[0106] Deuterium, i.e., 2 Substitution with heavier isotopes such as H may offer certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0107] 11 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes, such as N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0108] Isotopically labeled compounds of any one of the above formulas can generally be prepared by conventional techniques known to those skilled in the art, or by methods similar to those described in the accompanying examples and preparations, substituting an appropriate isotopically labeled reagent for the previously used non-labeled reagent.

[0109] Pharmaceutically acceptable solvates in accordance with the present disclosure include those wherein the solvent of crystallization may be isotopically substituted, eg, D2O, d6-acetone, d6-DMSO.

[0110] Prodrug One way to implement the present disclosure is to administer a compound of any one of the above formulas in the form of a prodrug. Thus, certain derivatives of a compound of any one of the above formulas, which may have little or no pharmacological activity, can be converted into a compound of any one of the above formulas having the desired activity when administered to or on the body, for example, by hydrolytic cleavage, particularly hydrolytic cleavage promoted by esterase or peptidase enzymes. Such derivatives are called "prodrugs." Further information on the use of prodrugs can be found in "Prodrugs as Novel Delivery Systems," Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (E.B. Roche, ed., American Pharmaceutical Association). Reference may also be made to Nature Reviews / Drug Discovery, 7:355, 2008, and Current Opinion in Drug Discovery and Development, 10:550, 2007.

[0111] Prodrugs according to the present disclosure can be prepared by replacing appropriate functional groups present in compounds of any one of the above formulas with certain moieties known to those skilled in the art as "promoieties," as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985) and in Designing Prodrugs and Bioprecursors by YM Choi-Sledeski and C.G. Wermuth in Practice of Medicinal Chemistry (4th ed.), Chapter 28, pp. 657-696 (Elsevier, 2015).

[0112] Thus, a prodrug according to the present disclosure is (a) an ester or amide derivative of a carboxylic acid in a compound of any one of the above formulas; (b) an ester, carbonate, carbamate, phosphate or ether derivative of a hydroxyl group in a compound of any one of the above formulas; (c) an amide, imine, carbonate or amine derivative of an amino group in a compound forming any one of the above formulas; (d) an oxime or imine derivative of a carbonyl group in a compound of any one of the above formulas; or (e) a methyl, primary alcohol or aldehyde group that can be metabolically oxidized to a carboxylic acid in a compound of any one of the above formulas.

[0113] Some specific examples of prodrugs according to the present disclosure include: (i) When a compound of any one of the above formulas contains a carboxylic acid functional group (—COOH), an ester thereof, the hydrogen of the carboxylic acid functional group of a compound of any one of the above formulas is replaced with a C1-C8 alkyl (e.g., ethyl) or (C1-C8 alkyl)C(═O)OCH2— (e.g., t BuC(=O)OCH2-), (ii) When the compound of any one of the above formulas contains an alcohol functional group (-OH), an ester thereof, a compound in which the hydrogen of the alcohol functional group of the compound of any one of the above formulas is replaced with -CO(C1-C8 alkyl) (e.g., methylcarbonyl), or the alcohol is esterified with an amino acid; (iii) When any one of the compounds of the above formulas contains an alcohol functional group (-OH) or an ether thereof, a compound in which the hydrogen of the alcohol functional group of any one of the compounds of the above formulas is replaced with (C1-C8 alkyl)C(=O)OCH2- or -CH2OP(=O)(OH)2; (iv) When a compound of any one of the above formulas contains an alcohol functional group (-OH), the hydrogen of the alcohol functional group of the compound of any one of the above formulas is replaced by -P(=O)(OH)2 or -P(=O)(ONa)2 or -P(=O)(O - )2Ca 2+ Compounds replaced by (v) When a compound of any one of the above formulae contains a primary or secondary amino functional group (—NH or —NHR, where R≠H), its amide, for example, in some cases, one or both of the hydrogens of the amino functional group of a compound of any one of the above formulae may be replaced by a (C1-C 10 ) compounds in which the alkanoyl group is replaced by -COCH2NH2 or the amino group is derivatized with an amino acid; (vi) When a compound of any one of the above formulae contains a primary or secondary amino functional group (-NH or -NHR where R≠H), the amine, for example, optionally, a compound in which one or both hydrogens of the amino functional group of a compound of any one of the above formulae are replaced with -CHOP(=O)(OH); (vii) Compounds in which the carboxylic acid group in any one of the above formulas is replaced with a methyl group, a —CH 2 OH group, or an aldehyde group.

[0114] Any particular compound of any one of the above formulas can itself act as a prodrug of any other compound of any one of the above formulas.Two compounds of any one of the above formulas can also be linked together in the form of a prodrug.In certain circumstances, the prodrug of any one of the above formulas compounds can be made by internally linking two functional groups in any one of the above formulas compounds, for example, by forming lactone.

[0115] A reference to a compound of any one of the above formulas is intended to include the compound itself and prodrugs thereof. The present disclosure includes such compounds of any one of the above formulas, as well as pharmaceutically acceptable salts of such compounds, and pharmaceutically acceptable solvates of such compounds and salts.

[0116] 3. Administration and Dosage Typically, the compounds of the present disclosure are administered in an amount effective to treat the conditions described herein. The compounds of the present disclosure can be administered as the compound itself or as a pharmaceutically acceptable salt. In administration and dosage, the compound itself or its pharmaceutically acceptable salt is simply referred to as the compound of the present disclosure.

[0117] The compounds of the present disclosure are administered by any suitable route in the form of a pharmaceutical composition adapted for such route, in a dose effective for the intended treatment. The compounds of the present disclosure can be administered orally, rectally, vaginally, parenterally, or topically.

[0118] The compounds of the present disclosure can be administered orally, which may involve swallowing, so that the compound enters the gastrointestinal tract, or may employ buccal or sublingual administration by which the compound enters the blood stream directly from the mouth.

[0119] In another embodiment, the compounds of the present disclosure can also be administered directly into the bloodstream, muscle, or internal organs. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques.

[0120] In another embodiment, the compounds of the present disclosure can also be administered topically to the skin or mucosa, i.e., dermally or transdermally. In another embodiment, the compounds of the present disclosure can also be administered intranasally or by inhalation. In another embodiment, the compounds of the present disclosure can also be administered rectally or vaginally. In another embodiment, the compounds of the present disclosure can also be administered directly to the eye or ear.

[0121] The dosing regimen for the compounds of the present disclosure and / or compositions containing such compounds is based on various factors, including the type, age, weight, sex, and condition of the patient, the severity of the condition, the route of administration, and the activity of the specific compound used. Thus, the dosing regimen can vary widely. In one embodiment, the total daily dose of the compounds of the present disclosure is typically about 0.001 to about 100 mg / kg (i.e., mg of the compound of the present disclosure per kg of body weight) for the treatment of the conditions discussed herein. In another embodiment, the total daily dose of the compounds of the present disclosure is about 0.01 to about 30 mg / kg, in another embodiment, about 0.03 to about 10 mg / kg, and in yet another embodiment, about 0.1 to about 3 mg / kg. It is not uncommon for the administration of the compounds of the present disclosure to be repeated multiple times (typically up to four times) per day. If necessary, multiple daily doses can typically be used to increase the total daily dose.

[0122] For oral administration, the compositions can be provided in the form of tablets containing 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 30.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250, and 500 milligrams of active ingredient for symptomatic adjustment of dosage to the patient. The medicament typically contains about 0.01 mg to 500 mg of active ingredient, or, in another embodiment, about 1 mg to about 100 mg of active ingredient. Intravenously, doses may range from about 0.01 to about 10 mg / kg / minute during a constant rate infusion.

[0123] Suitable subjects according to the present disclosure include mammalian subjects, including non-human mammals such as primates, rodents (mice, rats, hamsters, rabbits, etc.). In one embodiment, a human is a suitable subject. Human subjects may be of any gender and at any stage of development.

[0124] 4. Pharmaceutical Compositions In another embodiment, the present disclosure includes pharmaceutical compositions. Such pharmaceutical compositions include a compound of the present disclosure presented together with a pharmaceutically acceptable carrier. Other pharmacologically active substances may also be present.

[0125] As used herein, "pharmaceutically acceptable carrier" includes all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, and combinations thereof; isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol or sorbitol, may be included in the composition. Pharmaceutically acceptable substances, such as wetting agents, which enhance the shelf life or effectiveness of the antibody or antibody portion, or minor amounts of auxiliary substances, such as wetting or emulsifying agents, preservatives, or buffers.

[0126] The compositions of the present disclosure may be in a variety of forms, including, for example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. The form depends on the intended mode of administration and therapeutic application.

[0127] Typical compositions are in the form of injectable or infusible solutions, such as compositions similar to those generally used for passive immunization of humans with antibodies. One mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In another embodiment, the antibody is administered by intravenous infusion or injection. In yet another embodiment, the antibody is administered by intramuscular or subcutaneous injection.

[0128] Oral solid dosage forms can be presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present disclosure. In another embodiment, oral dosage forms can be in the form of powder or granules. In another embodiment, oral dosage forms are sublingual, such as troches. In such solid dosage forms, the compound of any one of the above formulas is usually combined with one or more adjuvants. Such capsules or tablets can also contain sustained-release formulations. In the case of capsules, tablets, and pills, dosage forms can also contain buffering agents or can be prepared with enteric coatings.

[0129] In another embodiment, oral administration may be in a liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions may also contain auxiliary agents such as wetting agents, emulsifying agents, suspending agents, flavoring agents (e.g., sweeteners), and / or aromatic agents.

[0130] In another embodiment, the present disclosure comprises a parenteral dosage form.

[0131] "Parenteral administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection, and infusion. Injectable preparations (i.e., sterile injectable aqueous or oily suspensions) can be formulated according to known techniques using suitable dispersing agents, wetting agents, and / or suspending agents.

[0132] In another embodiment, the present disclosure comprises a topical dosage form.

[0133] "Topical administration" includes, for example, transdermal administration, such as via a transdermal patch or iontophoresis device, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. Topical formulations may contain compounds that enhance absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of the present disclosure are administered via a transdermal device, administration is achieved using a patch, either of the reservoir and porous membrane type or of the solid matrix variety. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers can be incorporated; see, eg, Finnin and Morgan, J. Pharm. Sci., 88:955-958, 1999.

[0134] Formulations suitable for topical administration to the eye include, for example, eye drops in which the compounds of the present disclosure are dissolved or suspended in a suitable carrier. Typical formulations suitable for ocular or aural administration may be in the form of droplets of a micronized suspension or solution in isotonic, pH-adjusted sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (i.e., absorbent gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses, and particle or vesicular systems such as niosomes or liposomes. Polymers such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose-based polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or heteropolysaccharide polymers such as gellan gum may be incorporated, along with preservatives such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

[0135] For intranasal administration or inhalation administration, the compounds of the present disclosure are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient using a suitable propellant, or as an aerosol spray from a pressurized container or nebulizer.Formulations suitable for intranasal administration are typically administered in the form of dry powder from a dry powder inhaler (either alone, as a mixture, for example, with lactose, or as mixed-component particles, for example, mixed with phospholipids such as phosphatidylcholine), with or without a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer that uses electrohydrodynamics to generate a fine mist), or nebulizer.For intranasal use, the powder may contain a bioadhesive agent, for example, chitosan or cyclodextrin.

[0136] In another embodiment, the present disclosure includes a rectal dosage form. Such a rectal dosage form may be, for example, in the form of a suppository. Cocoa butter is a traditional suppository base, although various alternatives can be used as needed.

[0137] Other carrier materials and modes of administration known in the pharmaceutical art may also be used. The pharmaceutical compositions of the present disclosure may be prepared by any of the known techniques of pharmacy, including effective formulation and administration procedures.

[0138] The above considerations regarding effective formulations and administration procedures are known in the art and are described in standard texts. Drug formulations are discussed, for example, in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing, Easton, PA, 1975, Liberman et al. (eds.), Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980, and Kibbe et al. (eds.), Handbook of Pharmaceutical Excipients (3rd ed.), American Pharmaceutical Association, Washington, 1999.

[0139] 5. Simultaneous administration The compounds of the present disclosure can be used alone or in combination with other therapeutic agents. The present disclosure provides any of the uses, methods, or compositions defined herein, wherein a compound of any embodiment of any one of the formulas herein above, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, is used in combination with one or more other therapeutic agents discussed herein.

[0140] Administration of two or more compounds "in combination" means that all compounds are administered close enough in time to produce a biological effect within the same time frame. The presence of one compound may alter the biological effect of the other compound. Two or more compounds can be administered simultaneously, concurrently, or sequentially. Furthermore, simultaneous administration can be achieved by mixing the compounds prior to administration, or by administering the compounds as separate dosage forms at the same time but at the same or different administration sites.

[0141] The phrases "concurrent administration," "co-administration," "simultaneous administration," and "administered simultaneously" mean that compounds are administered in combination.

[0142] In another embodiment, the present disclosure provides a method of treatment comprising administering a compound of the present disclosure in combination with one or more other agents, wherein the one or more other agents may be selected from those discussed herein.

[0143] In one embodiment, the compounds of the present disclosure are administered in combination with a biguanide (e.g., metformin), a sulfonylurea (e.g., tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, or glipizide), a thiazolidinedione (e.g., pioglitazoline), or a thiazolidinedione (e.g., thiazolidinedione), including pharmaceutically acceptable salts of the specifically named agents and pharmaceutically acceptable solvates of the agents and salts. rosiglitazone or lobeglitazone), glitazars (e.g., saroglitazar, aleglitazar, muraglitazar or tesaglitazar), meglitinides (e.g., nateglinide, repaglinide), dipeptidyl peptidase 4 (DPP-4) inhibitors (e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, or omarigliptin, dutogliptin, or omarigliptin), glitazones (e.g., pioglitazone, rosiglitazone, balaglitazone, rivoglitazone, or lobeglitazone), sodium-glucose-coupled transporter 2 (SGLT2) inhibitors (e.g., empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, or ertugliflozin), SGLTL1 inhibitors, GPR40 agonists (FFAR1 / FFA1 agonists, e.g., fasudimifum), glucose-dependent insulinotropic peptide (GIP) and its analogs, α-glucosidase inhibitors (e.g., voglibose, acarbose, or miglitol), or insulin or insulin analogs.

[0144] In another embodiment, the compounds of the present disclosure include, but are not limited to, peptide YY or an analog thereof, neuropeptide Y receptor type 2 (NPYR2) agonists, NPYR1 or NPYR5 antagonists, cannabinoid receptor type 1 (CB1R) antagonists, lipase inhibitors (e.g., orlistat), human islet peptide (HIP), melanocortin receptor 4 agonists (e.g., setomelanotide), melanin-concentrating hormone receptor 1 antagonists, farnesoid X receptor (FXR) agonists (e.g., obeticholic acid), zonisone, and the like. thiaminamides, phentermine (alone or in combination with topiramate), norepinephrine / dopamine reuptake inhibitors (e.g., bupropion), opioid receptor antagonists (e.g., naltrexone), combinations of norepinephrine / dopamine reuptake inhibitors and opioid receptor antagonists (e.g., bupropion and naltrexone), GDF-15 analogs, sibutramine, cholecystokinin agonists, amylin and its analogs (e.g., pramlintide), leptin and its analogs (e.g., metroleptin), serotonergic agents (e.g., lorcaserin), methionine aminopeptidase 2 (MetAP2) inhibitors (e.g., beloranib or ZGN-1061), phendimetrazine, diethylpropion, benzphetamine, SGLT2 inhibitors (e.g., empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, or ertugliflozin), SGLTL1 inhibitors, dual SGLT2 / Administered in conjunction with anti-obesity agents including SGLT1 inhibitors, fibroblast growth factor receptor (FGFR) modulators, AMP-activated protein kinase (AMPK) activators, biotin, MAS receptor modulators, or glucagon receptor agonists (alone or in combination with another GLP-1R agonist, e.g., liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, or semaglutide), including pharmaceutically acceptable salts of the specifically named agents, and pharmaceutically acceptable solvates of such agents and salts.

[0145] In another embodiment, the compounds of the present disclosure are administered in combination with PF-05221304, FXR agonists (e.g., obeticholic acid), PPARα / δ agonists (e.g., elafibranor), synthetic fatty acid-bile acid conjugates (e.g., aramchol), caspase inhibitors (e.g., emricasan), anti-lysyl oxidase homolog 2 (LOXL2), monoclonal antibodies (e.g., cyclosporin), cyclosporin, ... Clonal antibodies (e.g., sintuzumab), galectin 3 inhibitors (e.g., GR-MD-02), MAPK5 inhibitors (e.g., GS-4997), dual antagonists of chemokine receptor 2 (CCR2) and CCR5 (e.g., cenicriviroc), fibroblast growth factor 21 (FGF21) agonists (e.g., BMS-986036), leukotriene D4 (LTD4) receptor antagonists (e.g., tipelukast), niacin analogs (e.g., ARI 3037MO), ASBT inhibitors (e.g., vorixivat), acetyl-CoA carboxylase (ACC) inhibitors (e.g., NDI 010976), ketoexokinase (KHK) inhibitors, diacylglyceryl acyltransferase 2 (DGAT2) inhibitors, CB1 receptor antagonists, anti-CB1R antibodies, or apoptosis signal-regulating kinase 1 (ASK1) inhibitors.

[0146] These agents and compounds of the present disclosure can be combined with pharmaceutically acceptable excipients such as saline, Ringer's solution, dextrose solution, etc. The particular dosing regimen, i.e., dosage, timing, and repetition, will depend on the particular individual and their individual medical history.

[0147] Acceptable carriers, excipients, or stabilizers are non-toxic to recipients at the dosages and concentrations employed and include buffers such as phosphate, citric acid, and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl, or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; serum albumin; The liposomes may contain proteins such as albumin, gelatin, or Ig; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants such as TWEEN®, PLURONICS®, or polyethylene glycol (PEG). Liposomes containing these agents and / or compounds of the present disclosure are prepared by methods known in the art, such as those described in U.S. Pat. Nos. 4,485,045 and 4,544,545. Liposomes with enhanced circulation time are disclosed in U.S. Pat. No. 5,013,556. Particularly useful liposomes can be generated by the reverse-phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter.

[0148] These agents and / or compounds of the present disclosure may also be encapsulated in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively, colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or macroemulsions. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy, 20th Edition, Mack Publishing Co. (2000).

[0149] Sustained-release preparations can be used. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a compound of any one of the above formulas, which matrices are in the form of shaped articles, for example, films or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) or "poly(vinyl alcohol)"), polylactide (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and 7-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as those used in LUPRON DEPOT™ (injectable microspheres consisting of lactic acid-glycolic acid copolymers and leuprolide acetate), sucrose acetoisobutyrate, and poly-D-(-)-3-hydroxybutyric acid.

[0150] The preparations used for intravenous administration must be sterile.This can be easily achieved, for example, by filtration through a sterile filtration membrane.The compound of the present disclosure is generally placed into a container with a sterile access port, for example, an intravenous solution bag or vial with a stopper that can be pierced by a hypodermic injection needle.

[0151] Suitable emulsions can be prepared using commercially available fat emulsions such as Intralipid™, Liposyn™, Infonutrol™, Lipofundin™, and Lipiphysan™. The active ingredient may be dissolved in a premixed emulsion composition, or may be dissolved in an emulsion formed by mixing with oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil, or almond oil) and phospholipids (e.g., egg phospholipids, soybean phospholipids, or soybean lecithin) and water. It is understood that other ingredients, such as glycerol or glucose, can be added to adjust the tonicity of the emulsion. Suitable emulsions typically contain up to 20% oil, for example, 5 to 20%. The fat emulsion may contain lipid droplets of 0.1 μm to 1.0 μm, particularly 0.1 μm to 0.5 μm, and have a pH ranging from 5.5 to 8.0.

[0152] Emulsion compositions may be prepared by mixing a compound of the present disclosure with Intralipid™ or its components (soybean oil, egg phospholipids, glycerol, and water).

[0153] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions, preferably in sterile pharmaceutically acceptable solvents, may be nebulized by the use of gases. Nebulized solutions can be breathed directly from the nebulizing device, or the nebulizing device can be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0154] 6. Kit Another aspect of the present disclosure provides a kit comprising a compound of any one of the above formulas or a pharmaceutical composition comprising a compound of any one of the above formulas of the present disclosure. The kit may include a diagnostic or therapeutic agent of the present disclosure or a pharmaceutical composition thereof in addition to a compound of any one of the above formulas. The kit may also include instructions for use in a diagnostic or therapeutic method. In some embodiments, the kit includes a compound of any one of the above formulas, or a pharmaceutical composition thereof, and a diagnostic agent. In other embodiments, the kit includes a compound of any one of the above formulas, or a pharmaceutical composition thereof.

[0155] In yet another embodiment, the present disclosure includes a kit suitable for use in carrying out the therapeutic methods described herein. In one embodiment, the kit includes a first dosage form containing one or more of the compounds of the present disclosure in an amount sufficient to carry out the method of the present disclosure. In another embodiment, the kit includes one or more of the compounds of the present disclosure in an amount sufficient to carry out the method of the present disclosure, and a dosing container and a dosing container.

[0156] 7. Preparation The compounds of any one of the above formulas can be prepared by the general and specific methods described below using the general general knowledge of those skilled in the art of synthetic organic chemistry. Such common general knowledge can be found in standard reference books such as Comprehensive Organic Chemistry, edited by Barton and Ollis, Elsevier, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, Larock, John Wiley & Sons, and Compendium of Organic Synthetic Methods, Volumes 1-12 (published by Wiley Interscience). The starting materials used herein are commercially available or can be prepared by conventional methods known in the art.

[0157] It should be noted that in preparing compounds of any one of the above formulas, some of the preparative methods described herein may require protection of remote functional groups (e.g., primary amines, secondary amines, carboxyls in precursors of any one of the above formulas). The need for such protection will vary depending on the nature of the remote functional group and the conditions of the preparation method. The need for such protection will be readily determined by one skilled in the art. The use of such protection / deprotection methods is also within the skill of one in the art. For a general description of protecting groups and their use, see Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0158] For example, certain compounds contain primary amine or carboxylic acid functional groups that, if left unprotected, may interfere with reactions at other sites on the molecule. Therefore, such functional groups may be protected by appropriate protecting groups that can be removed in a subsequent step. Suitable protecting groups for amine and carboxylic acid protection include those commonly used in peptide synthesis (e.g., Nt-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9-fluorenylmethylenoxycarbonyl (Fmoc) for amines, and lower alkyl or benzyl esters for carboxylic acids), which generally do not chemically react under the described reaction conditions and can typically be removed without chemically altering any other functional group in any one of the compound formulas.

[0159] The schemes described below are intended to provide a general description of the methodology used to prepare the compounds of this disclosure. Some of the compounds of this disclosure may contain single or multiple chiral centers, with the stereochemical designation (R) or (S). It will be apparent to those skilled in the art that all synthetic transformations can be carried out in a similar manner, regardless of whether the materials are enantiomerically enriched or racemic. Furthermore, resolution to the desired optically active materials can be carried out at any desired point in the sequence using well-known methods, such as those described herein and in the chemical literature.

[0160] The amine compounds prepared by the methods described herein can be alkylated with a protected 2-bromoacetate in the presence of a suitable base, such as K2CO3, Et3N, NaH, or LiHMDS, in a polar aprotic solvent, such as, but not limited to, DMF, DMAc, DMSO, or NMP, to deliver the compound. Standard ester hydrolysis can be performed to afford the acid. Pg 2 When is t-butyl, standard acidic deprotection methods such as TFA / DCM, HCl / 1,4-dioxane, HCl / EtOAc or other appropriate conditions can be used to deliver the acid. [Example]

[0161] Activation of the G protein-coupled receptor (GPCR) GLP-1R by its natural ligand GLP-1 leads to the recruitment of multiple intracellular proteins, each of which can activate a different signaling pathway, most notably downstream G protein activation (which can be measured by cAMP production), β-arrestin recruitment, and / or subsequent internalization of the GPCR (i.e., GLP-1R)-β-arrestin complex. Unlike the natural ligand GLP-1, certain GLP-1R agonists are so-called "biased agonists" in that they preferentially stimulate a subset of the native signaling pathways, such as the G protein activation / cAMP production pathway, relative to β-arrestin recruitment and / or subsequent internalization of the GPCR (i.e., GLP-1R)-β-arrestin complex. The following assays provide a means to measure various downstream signaling pathways upon activation by a compound of interest.

[0162] Biological Example 1: GLP-1R / β-Arrestin Assay and Internalization Assay to Demonstrate Small Molecule Compound-Mediated GLP-1R / β-Arrestin Interaction Activation GLP-1 plays an important physiological role in maintaining blood glucose homeostasis. GLP-1R is known to be expressed in pancreatic beta cells. GLP-1 mediates its effects through a Gαs-coupled pathway. Activated GLP-1R stimulates the adenylate cyclase pathway, increasing the intracellular concentration of cAMP, which in turn increases insulin synthesis and release. Consequently, GLP-1R has been proposed as a potential target for the treatment of diabetes.

[0163] GLP-1R activation after agonist / ligand binding also leads to the recruitment of β-arrestins to the GLP-1 receptor, which blocks GLP-1R signaling by, for example, blocking the binding sites of heterotrimeric G proteins on the GLP-1R to prevent its activation (desensitization) and by linking the GLP-1R to elements of the internalization machinery, such as clathrin and the clathrin adaptor AP2, which promote receptor internalization via coated pits and subsequent transport to endosomes. The receptor is then either directed to a degradative compartment (lysosome) or recycled to the plasma membrane where it can signal again. The strength of the arrestin-receptor interaction is thought to play a role in this selection; denser complexes tend to increase the probability of receptor degradation (Class B), while more transient complexes favor recycling (Class A), although this "rule" is not absolute.

[0164] GLP-1R agonist activity on β-arrestin recruitment can be measured in a cell-based functional assay using the PathHunter eXpress GLP1R CHO-K1 β-arrestin GPCR Assay Kit (DiscoverX Catalog No. 93-0300E2CP0M).

[0165] The PathHunter β-arrestin GPCR assay technology utilizes the β-galactosidase (β-gal) enzyme split into two fragments: a smaller enzyme donor (ED) and a larger enzyme acceptor (EA). These fragments can be fused to two potentially interacting proteins, such as EA-β-arrestin or ED-GLP-1R. Fusions can be stably expressed in test cell lines, such as the PathHunter CHO-K1 GLP1R β-arrestin cells described below.

[0166] Independently, these fragment fusions have no β-gal activity, but in solution or in living cells, interactions between the fused proteins allow them to complement together to form the active β-gal enzyme, which can therefore generate a chemiluminescent signal in the presence of an appropriate β-gal substrate.

[0167] For this experiment, PathHunter CHO-K1 GLP1R β-arrestin cells from the assay kit were seeded into 384-well white / clear-bottom plates (Greiner catalog number 781098) at a density of 1000 or 2000 cells / 20 μl / well. Frozen cells were rapidly thawed, and 10 mL of cell seeding medium (provided by the kit) was added to the thawed cells. Cells were stored in a 37°C incubator under 5% CO2 for approximately 48 hours until ready to run the assay.

[0168] Reference and test compounds were dissolved in 100% DMSO. 5x concentrations of agonists were prepared in serum-free DMEM (Thermo catalog number 11965). 5 μL of this solution was added to 20 μL of cell culture medium in the assay plate for a final maximum concentration of 10 μM. The plate was then incubated at 37°C under 5% CO2 for 90 minutes.

[0169] After a 90-minute incubation, the detection reagent was created by combining 1 part Galacton Star Substrate with 5 parts Emerald II™ Solution and 19 parts PathHunter Cell Assay Buffer. 12.5 μl of detection reagent was added to each well. The plate was then incubated at room temperature in the dark for 60 minutes. The plate was then read on the Envision for 0.1 seconds per well.

[0170] EC 50 Determinations were made from agonist dose-response curves analyzed with a curve-fitting program using a four-parameter logistic dose-response equation.

[0171] The effect of a small molecule compound, such as one of the present disclosure, on GLP-1R / β-arrestin interaction activation or β-arrestin recruitment can be demonstrated and measured using the assays described below and commercially available reagents. preparation Reagents and consumables: [Table 1] device: [Table 2]

[0172] Media and Solutions Prepare the detection working solution by combining 1 part Galacton Star® Substrate with 5 parts Emerald II™ Solution and 19 parts PathHunter Cell Assay Buffer, respectively.

[0173] Once prepared, the working solution is stable at room temperature for at least 24 hours and does not affect assay performance. Sufficient reagents are provided in each kit to perform the indicated number of assays.

[0174] procedure 1. Cell Seeding Cells were seeded at a density of 1000 or 2000 cells / 20 μL / well. Frozen cells were rapidly thawed and added to 10 mL of cell seeding medium. Cells were stored in a 37°C incubator with 5% CO2 for approximately 48 hours before the assay was ready to be performed.

[0175] 2. Compound Preparation 1) Reference agonist compound GLP1(7-37): Dissolved in DMSO to make a 1 mM stock solution, divided into aliquots and stored at -80°C. 2) Test compounds (such as compounds of the present disclosure) were solubilized in 100% DMSO. A 10x concentration of agonist was prepared in serum-free DMEM, and the entire solution was added to the compound plate. 2.5 μL of this solution was added to 20 μL of cell culture medium in the assay plate for a final maximum concentration of 10 μM. The plate was incubated at 37° C., 5% CO2 for 30 minutes. An additional 2.5 μL of buffer was added to the entire plate for agonist mode, and the plate was incubated for an additional 90 minutes at 37° C.

[0176] 3. Detection Reagents After 90 minutes of incubation, the detection reagent was configured as described. 12.5 μL was added to all wells. The plate was then incubated at room temperature in the dark for 60 minutes. The plate was then read on the Envision for 0.1 seconds per well.

[0177] 4. β-Arrestin Assay Data Processing Data analysis: GraphPad Prism 6 was used to establish progress curves. EC 50 Alternatively, IC50 was determined by a four-parameter logistic dose-response equation.

[0178] β-Arrestin recruitment dose-response curves for selected compounds of the present disclosure, compared to GLP-1 (7-37) as a control, are shown in Figure 1. Compounds tested include compounds 74-91, 93-95, 100, 101, 257, 262, 263, 266, 267, 271, 276-278, 281, 284, 285, 289-293, 303, 305, 307, 308, 310-312, 323, and 331-334. Note that the partial maximum relative effect (B) of the compounds tested (at the highest concentration tested in the assay) is max is generally the B of the natural ligand GLP-1 (7-37). max This means that the figure approaches approximately 20 to 40% of the [Table 3]

[0179] For these test compounds of the present disclosure, with a few exceptions, the fractional maximum relative efficacy B of the test compound max (at the highest concentration tested in the assay) generally corresponds to the B of the natural ligand GLP-1(7-37). max Note that the values ​​fall within about 10% to about 40% of B in the table above. max See the values.

[0180] A similar assay can also be used to assess the degree of signal attenuation due to GLP-1R internalization (internalization assay). In this assay, activated GLP1R-internalizing cells were engineered to co-express untagged GLP1R, enzyme-activated receptor (EA)-tagged β-arrestin, and ProLink™ (PK)-tagged GLP1R, which localizes to endosomes. GLP1R activation induces β-arrestin recruitment, which leads to internalization of the receptor / arrestin-EA complex in PK-tagged endosomes. This forces complementation of the two β-galactosidase enzyme fragments (EA and PK) to form a functional enzyme that hydrolyzes the substrate and generates a chemiluminescent signal. These cells were modified to prevent long-term growth and expansion using a proprietary compound that has no apparent effect on assay performance.

[0181] Specifically, U2OS cells engineered by PathHunter from the assay kit (catalog number 93-0724E3CP0L) were seeded into 384-well white / clear-bottom plates (Greiner catalog number 781098) at a density of 2000 cells / 20 μL / well. Frozen cells were rapidly thawed, and 10 mL of cell seeding medium (provided by the kit) was added to the thawed cells. Cells were stored in a 37°C incubator for approximately 48 hours until ready for assay.

[0182] Reference and test compounds were dissolved in 100% DMSO. 5x concentrations of agonists were prepared in serum-free DMEM (Thermo catalog number 11965). 5 μL of this solution was added to 20 μL of cell culture medium in the assay plate for a final maximum concentration of 10 μM. Plates were incubated at 37° C. for 180 minutes.

[0183] After 180 minutes of incubation, the detection reagent was made by combining 1 part Galacton Star Substrate with 5 parts Emerald II™ Solution and 19 parts PathHunter Cell Assay Buffer. 12.5 μL of detection reagent was added to each well. The plate was then incubated at room temperature for 60 minutes. The plate was then read on the Envision for 0.1 seconds per well.

[0184] EC 50 Determinations were made from agonist dose-response curves analyzed with a curve-fitting program using a four-parameter logistic dose-response equation.

[0185] GLP-1R internalization dose-response curves for selected compounds of the present disclosure compared to GLP-1 (7-37) as a control are shown in Figure 2. Compounds tested include compounds 74-80, 93-95, 100, and 101 (left panel), and compounds 81-91 (right panel). Again, the fractional maximum relative efficacy (at the highest concentration tested in the assay) of the test compounds, Bmax is generally the B of the natural ligand GLP-1 (7-37). max approaching about 20-30% of the

[0186] Using this assay system, β-arrestin-mediated GLP1R internalization was also measured for other selected compounds of the disclosure, and the results are summarized in the table below. [Table 4]

[0187] Again, in each case, with few exceptions, the submaximal relative efficacy B of the tested compound max (at the highest concentration tested in the assay) generally corresponds to the B of the natural ligand GLP-1(7-37). max Note that the values ​​fall within about 10% to about 40% of the

[0188] Biological Example 2: NanoBit GLP1R / β-Arrestin Interaction Assay to Demonstrate Small Molecule-Mediated GLP1R and β-Arrestin Interaction Activation GLP-1R-mediated interaction with β-arrestin due to agonist activity is determined in a cell-based functional assay utilizing NanoLuc® Binary Technology (NanoBiT) (Promega N2015), designed to detect the interaction between GLP-1R and β-arrestin in live cells. This method is a two-subunit system based on NanoLuc® luciferase that can be used for intracellular detection of protein:protein interactions (PPIs). The two subunits are known as Large BiT (LgBiT, 17.6 kDa) and Small BiT (SmBiT, 11 amino acids). These two subunits are fused to two proteins of interest, respectively. When both are expressed, PPIs bring the subunits into close proximity to form a functional enzyme that generates a bright luminescent signal.

[0189] More specifically, the human GLP-1R coding sequence (NCBI Reference Sequence NM_002062) and β-Arrestin2 coding sequence (NCBI Reference Sequence NM_004313.3) were subcloned into the transient expression vectors provided in the NanoBiT kit to generate GLP-1R-LgBiT and SmBiT-β-Arrestin2 fusions. 7~37 A total of eight combinations were selected using HEK293T-based transfection with activation by GLP-1R, which showed the widest assay window for testing compounds of the present disclosure (GLP-1R-LgBiT and SmBiT-β-arrestin2).

[0190] The NanoBit assay was performed as briefly described herein: HEK293T cells (7.5k cells / well) were seeded in 96-well culture plates (Corning catalog number 3917) in DMEM (Thermo catalog number 11965) containing heat-inactivated 10% FBS (Biosera catalog number FB-10581) and 25mM glucose. After 48 hours, cells were transfected with GLP-1R-LgBiT and SmBiT-β-Arrestin2 constructs using Lipofectamine 2000 (Thermo catalog number 11668019) according to the manufacturer's assay protocol. Briefly, plasmids encoding GLP-1R-LgBiT and SmBiT-β-Arrestin2 fusions and transfection reagent were diluted in Opti-MEM (Thermo catalog number 31985-070). Approximately 50 ng of GLP-1R-LgBiT and 50 ng of SmBiT-β-Arrestin2 plasmid construct were then mixed, and the resulting plasmid mixture was added to the diluted transfection reagent. The ratio of plasmid (μg):Lipofectamine 2000 (μl) was 1:10. The mixture was then incubated at room temperature for 5 minutes before being added to the cells. Approximately 48 hours after transfection, the medium was replaced with 65 μl / well of fresh Opti-MEM.

[0191] The Nano-Glo® Live Cell Substrate was then diluted 1:24 with Nano-Glo® LCS Dilution Buffer. Approximately 25 μl of Nano-Glo® Live Cell Reagent was added to each well. Various concentrations of each compound to be tested (in DMSO) were diluted with Opti-MEM (Sigma catalog no. A7409) containing 0.1% BSA to create a 10× stock. Approximately 10 μl of compound stock was added to each well using a pipette. Luminescence was immediately measured for 0.25 seconds per well by EnVision for 40, 60, or 120 replicates.

[0192] EC 50 Determinations were made from agonist dose-response curves analyzed with a curve-fitting program using a four-parameter logistic dose-response equation.

[0193] The effect of small molecule compounds, such as one of the present disclosure, on GLP-1R / β-arrestin interaction activation or β-arrestin recruitment can be demonstrated and measured using the assays described herein and commercially available reagents or their equivalents. The reagents and detailed experimental protocols used in this example are further described below. preparation Reagents and consumables: [Table 5] device: [Table 6]

[0194] Preparation of Nano-Glo® Live Cell Reagent: 1. If using for the first time, equilibrate Nano-Glo® LCS Dilution Buffer to ambient temperature.

[0195] 2. Remove Nano-Glo® Live Cell Substrate from storage and mix.

[0196] 3. Prepare the desired amount of reconstituted Nano-Glo® Live Cell Reagent by combining 1 volume of Nano-Glo® Live Cell Substrate with 24 volumes of Nano-Glo® LCS Dilution Buffer (25x dilution) to create a 4x stock and mix with cell culture media.

[0197] procedure Compound preparation: GLP-1(7-36) was dissolved in 100% DMSO, and the stock concentration was 1 mM. HPE: 10 μM GLP-1 (7–36) ZPE: 0.1% DMSO

[0198] For test compounds, dilute 1 mM stock to 100 μM using Opti-MEM containing 1% BSA, for a final top concentration of 10 μM, ¼ log (4-fold) dilutions, 8 dilution points, duplicate samples for each dilution, same layout as for GLP-1 above.

[0199] Assay Procedure: Cell culture and transfection: 293T cells were seeded at 7.5k cells / well in a 96-well culture plate (Corning catalogue no. 3917) in DMEM containing 1.10% FBS (heat inactivated and 25mM glucose). After 2.48 hours, performance transfection was performed according to the Lipofectamine 2000 protocol. 3.50 ng Lg-Bit and 50 ng Sm-Bit / well, with a ratio of plasmid (μg):Lipofectamine 2000 (μl) of 1:10. 4. 48 hours after transfection, the medium was replaced with fresh 65 μL of Opti-MEM / well.

[0200] Activation and luminescence measurement: 5. Prepare Nano-Glo® Live Cell Reagent, diluted Nano-Glo® Live Cell Substrate using Nano-Glo® LCS Dilution Buffer in a 1:24 ratio. Add 6.25 μL of Nano-Glo® Live Cell Reagent to each well. 7. Add 10 μL of 10% DMSO or 10×GLP-1 solution or test compound to each well. 8. Immediately measure luminescence for 0.25 seconds per well for 40, 60 or 120 replicates.

[0201] As shown in Figure 3, the time course response of the NanoBit assay at different compound concentrations is plotted for GLP-1 (7-37) and compound 94 (Figure 3).

[0202] The results clearly show that the time course profiles differ considerably between the natural ligand GLP-1(7-37) and the test compounds of this disclosure.

[0203] NanoBit assay dose-response curves were also generated at 3 min (180 s) and 5 min (300 s) for additional test compounds, including compounds 74-91, 93-95, 100, and 101 (Figure 4). In each of these figures, the tested compounds E max The maximum relative effect of is generally 40% or less (usually about 20-40%) of the maximum relative effect of GLP-1(7-37) for the highest concentrations tested.

[0204] The EC50 values ​​of compounds 74-91, 93-95, 100 and 101 were determined (data not shown).

[0205] Alternatively, if the compound reaches a maximum signal at, say, 450-500 seconds (approximately 8 minutes), the EC 50 Able to perform data analysis / reporting to obtain value.

[0206] Biological Example 3: GLP1R cAMP Assay to Demonstrate Small Molecule-Mediated GLP-1R Activation HEK293 / GLP-1R / CRE / Luc, Clone 4-cAMP assay GLP-1R-mediated agonist activity was determined in a cell-based functional assay utilizing a homogeneous time-resolved fluorescence (HTRF) cAMP detection kit (cAMP Dynamic2 Assay Kit, CisBio catalog number 62AM4PEC) to measure intracellular cAMP levels. This method is a competitive immunoassay between natural cAMP produced by cells and exogenous cAMP labeled with the dye d2. Tracer binding is visualized by a cryptate-labeled mAb anti-cAMP. The specific signal (i.e., energy transfer) is inversely proportional to the concentration of cAMP in either the standard or experimental sample.

[0207] The human GLP-1R coding sequence (NCBI reference sequence NM_002062) was subcloned into the pcDNA3.1+ / Hygro vector (Invitrogen) and transfected into the HEK293 / CRE / Luc parental cell line. Cell lines stably expressing the receptor were isolated. 125 I-GLP-1 7~36 Saturation binding analysis (filtration assay procedure) using PerkinElmer (PerkinElmer) demonstrated that plasma membranes derived from this cell line have a high GLP-1R density (K d :<1nM, B max :>800 fmol / mg protein).

[0208] Various concentrations of each compound to be tested (in DMSO) were diluted with DMSO to first obtain a 200x compound working solution, and then 50 nl of compound was added to a white 384-well assay plate (Greiner 784075) containing ECHO. The final DMSO concentration was 0.5%. The compound concentration range could be adjusted at any time.

[0209] Cells were removed from cryopreservation, resuspended in 5 mL of Dulbecco's phosphate-buffered saline (DPBS - Sigma catalog no. D8537), and centrifuged at 900 × g for 5 minutes at 22 °C. The cell pellet was then resuspended in 1 mL of assay buffer [DPBS containing 500 μM IBMX (Sigma catalog no. I5879) and 0.1% BSA (Sigma catalog no. A1933)]. IBMX and BSA were added fresh on the day of the assay. A 10 μL sample of the cell suspension was counted using an Invitrogen Countess II to determine cell viability and cell number / mL. The remaining cell suspension was then adjusted with assay buffer to deliver 1,000 viable cells per well using a Matrix Combi Multidrop reagent dispenser. 10 μL of the cell suspension was added to each well of the assay plate already containing compound.

[0210] Seal the plate and incubate for 37 o C, incubated at 5% CO for 30 min.

[0211] After a 30-minute incubation, 5 μL of labeled d2 cAMP and 5 μL of anti-cAMP antibody (both diluted 1:20 in cell lysis buffer, as described in the manufacturer's assay protocol) were added to each well of the assay plate. Plates were then incubated at room temperature, and after 60 minutes, the change in HTRF signal was read on an Envision multilabel plate reader using an excitation of 330 nm and emissions of 615 and 665 nm. Raw data were converted to nM cAMP by interpolation from the cAMP standard curve (described in the manufacturer's assay protocol) and the full agonist GLP-1 (GLP-1) contained on each plate. 7~37 Percent efficacy was determined relative to a saturating concentration of (10 nM). EC 50 Determinations were made from agonist dose-response curves analyzed with a curve-fitting program using a four-parameter logistic dose-response equation.

[0212] This assay demonstrates that compounds of the present disclosure activate GLP-1R signaling via the cAMP pathway and therefore behave as GLP-1R agonists. Representative commercially available reagents / kits that can be used for such assays are described below. preparation Reagents and consumables: [Table 7] device: [Table 8]

[0213] Media and solutions: 1) Assay buffer DPBS containing 500 μM IBMX and 0.1% BSA. IBMX and BSA are added fresh on the day of the assay.

[0214] 2) Preparation of cAMP-d2 diluted standard solution a) The lyophilisate was reconstituted with the appropriate amount of distilled water according to the manufacturer's instructions to create a working stock that could be aliquoted and frozen (-20°C). b) Before use, the working stock solution was diluted 1:20 with conjugate and lysis buffer.

[0215] 3) Preparation of anti-cAMP antibody-cryptate diluted standard solution c) The lyophilisate was reconstituted with the appropriate amount of distilled water according to the manufacturer's instructions to create a working stock that could be aliquoted and frozen (-20°C). d) Before use, the working stock solution was diluted 1:20 with conjugate and lysis buffer.

[0216] procedure Cell suspension preparation procedure 1. Frozen cells were thawed very briefly (approximately 1 min) in a 37°C water bath under sterile conditions with continuous agitation until the ice was just about completely melted. Care was taken as longer incubation times may cause cell death. 2. Carefully transfer the thawed cells into a sterile 15 / 50 mL tube, fill the tube with 10-50 mL of complete medium preheated to 37°C, let the cells settle for 5 minutes, and then centrifuge at 900 rpm for 5 minutes to collect the cells, thereby removing DMSO from the medium. 3. Cells were resuspended in assay buffer. 4. For a stable GLP1-R assay, the optimized cell density is 1,000 cells / well. Careful attention was paid to optimizing the cell density, as it was critical and had to be optimized in different laboratories. The level of cAMP produced by the cells must be within the linear range of the standard curve.

[0217] Compound preparation procedure 1) The reference agonist compound GLP1(7-37) was dissolved in DMSO to make a 1 mM stock solution, which was then aliquoted and stored at -80°C. 2) The reference antagonist compound, exendin(9-39), was dissolved in DMSO to make a 2 mM stock solution, which was then aliquoted and stored at -80°C. 3) Test compounds were dissolved in DMSO to make stock solutions, which were then aliquoted and stored at -80°C. Serial dilutions of the compound solutions were performed using DMSO, first obtaining a 200x compound working solution, and then using ECHO to obtain 50nL of the working solution in a 384-well plate. The final DMSO concentration was 0.5%. The compound concentration range could be adjusted at any time. 4) IBMX: 500 mM stock solution in DMSO, aliquoted, and stored at -20°C.

[0218] Agonist assay procedure 1) Compound preparation: A compound addition plate was prepared prior to the assay. 200-fold compound dilution standard solutions were prepared according to the procedure described above. 2) Cell preparation: Before performing the assay, a cell suspension was prepared according to the procedure described above. 3) Compound addition: 50 nL / well of 200x compound working solution was added to a low volume 384 white assay plate equipped with Echo. 4) Cell addition: 10 μL of cell suspension was added to each well of the assay plate that already contained the compound working solution. The plate was sealed and incubated for 37 o C, incubated at 5% CO for 30 min. 5) 5 μL of the cAMP-d2 diluted working solution was added to each well of the assay plate. 6) 5 μL of the anti-cAMP antibody-cryptate working solution was added to each well of the assay plate. The plate was covered with a lid. Incubate at room temperature for 1 hour. 7) Fluorescence was read at 665 nm and 615 nm using an EnVision plate reader equipped with a TRF LASER using the specified settings and data was saved.

[0219] Antagonist blocking assay procedure 1) Compound Preparation: Prepare the compound addition plate prior to the assay. Prepare a 200x compound dilution standard solution according to the procedure above. 2) Cell preparation: Before performing the assay, prepare a cell suspension according to the procedure described above. 3) Compound addition: Add 50 nL / well of 200x working concentration of compound to a low volume 384 white assay plate. 4) Cell addition: Add 5 μL of the 2× cell suspension to each well of the assay plate already containing compound. 5) Exendin(9-39) antagonist addition: Add 5 μL of 2× Exendin(9-39) to each well of the assay plate already containing compound and cells. The final concentration of Exendin(9-39) is IC80. Seal the plate and incubate for 37 min. o C, Incubate at 5% CO2 for 30 min. 6) Add 5 μL of cAMP-d2 working solution to each well of the assay plate. 7) Add 5 μL of the anti-cAMP antibody-cryptate working solution to each well of the assay plate. Cover the plate with the lid. Incubate at room temperature for 1-4 hours. 8) Read the fluorescence at 665 nm and 615 nm on an EnVision plate reader equipped with a TRF laser using the specified settings and save the data.

[0220] Setting up EnVision for HTRF cAMP measurements Necessary filters and mirrors Excitation: TRF laser Emission #1: 665nm (CWL 665nm BW 7.5 nm) Emission #2: 615nm (CWL 615nm BW 8.5nm) Dichroic mirror: DELFIA / LANCE Dual Enh D400 / D630 Required settings: Delay: 50μsec Window time: 300 μs (also called "integration time") Number of sequence windows: 1 Cycle: Default 2000µs (also known as "time between flashes") Flash-to-flash time: 2000µsec Flash count: 20 Number of flashes for the second detector: 10 Measurement height (mm): 6.5 Z-height: Optimize (use the optimization wizard to optimize the well with maximum FRET) Excitation and ejection occur at the top of the well.

[0221] cAMP assay data processing Data analysis: GraphPad Prism 5 or IDBS XLfit software was used to establish progress curves. EC50 or IC50 was determined by a four-parameter logistic dose-response equation.

[0222] Using the assay substantially as described above, dose-response curves were obtained for each compound tested below, and the respective EC 50 The EC values ​​for each compound were calculated and tabulated. 50 Values ​​are defined as the compound concentration that produced 50% of the maximal cAMP level achieved with the same compound.

[0223] Final compound concentrations were 10, 100, or 300 nM in 0.5% DMSO. A total of 11 data points were generated for each compound dilution series.

[0224] The results of the cAMP assay for compounds 75, 84, 93, and 94, and GLP-1(7-37) as a control, are shown in FIG.

[0225] Two different cell types were used in this assay. In one assay, each compound was tested in HEK293T cells. The results are shown in Table 1 below. In another assay, selected compounds were also tested in CHO cells stably transfected to express human GLP-1R. The results are shown in Table 2 below. [Table 9-1] [Table 9-2] [Table 10]

[0226] The data show that, similar to GLP-1 (7–37), many of the test compounds have nanomolar or subnanomolar (<10 nM) EC in the cAMP assay. 50 This indicates that many of the test compounds also have Bmax values ​​that reach substantially the same level as the Bmax value of GLP-1(7-37). max This, combined with the fact that many of the test compounds of the present disclosure have GLP-1R signaling agonists leading to cAMP production, suggests that many of the test compounds of the present disclosure are full agonists of GLP-1R signaling leading to cAMP production.

[0227] In contrast, as shown in the data for Examples 1 and 2 above, specifically the compounds listed in the Tables, the compounds of the present disclosure generally exhibit B activity in the β-arrestin recruitment assay and the GLP-1R internalization assay that is, with some exceptions, approximately 20-40% of that of GLP-1(7-37). max Furthermore, the time course profile of NanoBit differs between the compounds of the present disclosure and GLP-1(7-37).

[0228] Example 4 Compound Synthesis (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 74) [ka] Step 1. Synthesis of methyl 2-(4-bromo-3-fluorophenyl)acetimidate In a Schlenk tube, a mixture of 2-(4-bromo-3-fluorophenyl)acetonitrile (4.24 g, 19.8 mmol), methanol (600 mg, 19.8 mmol), and 1,4-dioxane (20 mL) was bubbled with HCl gas until the reaction was complete. The reaction mixture was filtered to give the title compound, methyl 2-(4-bromo-3-fluorophenyl)acetimidate (2) (4.2 g, 17.1 mmol, 86.2% yield), as a white solid.

[0229] Step 2. Synthesis of 1-bromo-2-fluoro-4-(2,2,2-trimethoxyethyl)benzene A mixture of 2 (2.1 g, 8.53 mmol) in methanol (20 mL) was stirred in a Schlenk tube under a N atmosphere for 18 hours. The reaction was monitored by TLC and LCMS. The reaction mixture was concentrated in vacuo, and then EtOAc was added to the reaction mixture until a large amount of solid precipitated. The solid was filtered off, and the filtrate was concentrated to give the title compound 1-bromo-2-fluoro-4-(2,2,2-trimethoxyethyl)benzene as crude product 3 as a colorless oil (1.8 g, 6.14 mmol, 72% yield).

[0230] Step 3. Synthesis of methyl (S)-2-(4-bromo-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate A mixture of 3 (297.8 mg, 1.02 mmol), p-TSA (100 mg, 0.63 mmol), and methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate 4 (150 mg, 0.63 mmol) in acetonitrile (15 mL) was stirred in a Schlenk tube under N atmosphere for 2 h and then transferred to an oil bath at 85 °C and stirred for 3 h until completion as indicated by TLC. The reaction mixture was concentrated in vacuo and purified by SGC (hexane / EtOAc = 5:1 to 1:1) to afford the title compound, methyl (S)-2-(4-bromo-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (5) (180 mg, 0.42 mmol, 65.4% yield), as a yellow solid.

[0231] Step 4. Synthesis of methyl (S)-2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate A mixture of 5 (220 mg, 0.51 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxan-2-yl)-1,3,2-dioxaborolane (154.7 mg, 0.61 mmol), KOAc (124.6 mg, 1.27 mmol), and Pd(dppf)Cl (37.2 mg, 0.051 mmol) in 1,4-dioxane (5 mL) was prepared in a Schlenk tube under a N atmosphere. The reaction tube was sealed, transferred to a 90 °C oil bath, and stirred for 3 h. The reaction was complete as indicated by TLC and LCMS. The reaction mixture was filtered and the crude product, methyl (S)-2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (6) (280 mg, 0.41 mmol, 80.4% yield, 70% purity), was used in the next step. LCMS: [M+H] + =480.0

[0232] Step 5. Synthesis of methyl (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate A mixture of 7 (30 mg, 0.095 mmol), Pd(dppf)Cl (7.7 mg, 0.0095 mmol), KCO (39.3 mg, 0.28 mmol), and the crude product of 6 (68.3 mg, 0.14 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was stirred in a Schlenk tube under an atmosphere of N for 3 h. The reaction tube was sealed, transferred to a 100 °C oil bath, and stirred for 3 h, at which point the reaction was complete as indicated by TLC and LCMS. The reaction mixture was filtered and the crude product was purified by TLC to give the title compound, methyl (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (8) (9 mg, 0.015 mmol, 17.9% yield). LCMS: [M+H] + =590.1

[0233] Step 6. Synthesis of (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid A mixture of 8 (9 mg, 0.015 mmol) and LiOH (3.7 mg, 0.15 mmol) in methanol (3 mL) was stirred at 25 °C under N atmosphere in a Schlenk tube for 3 h, and the reaction was confirmed by TLC and LCMS. The reaction mixture was adjusted to pH = 7.0 with AcOH. The crude product was then purified by preparative HPLC to give the title compound, (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (3.3 mg, 0.006 mmol, 37.6% yield, 100% purity) as a white solid. LCMS: [M+H] + =576.1

[0234] (S)-2-(4-(6-(4-cyano-2-fluorobenzyloxy)pyridin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 75) [ka] The title compound was prepared as a white solid similar to compound 74. LCMS: [M+H] + =567.3

[0235] (S)-2-((3'-((4-chloro-2-fluorobenzyl)oxy)-2-fluoro-[1,1'-biphenyl]-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 76) [ka] The title compound was prepared as a white solid similar to compound 74. LCMS [M+H] + =575.2

[0236] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 77) [ka] The title compound was prepared as a white solid similar to compound 74. LCMS: [M+H] + =611.8

[0237] (S)-2-((3'-((4-chloro-2-fluorobenzyl)oxy)-2,4'-difluoro-[1,1'-biphenyl]-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 78) [ka] The title compound was prepared as a white solid similar to compound 74. LCMS: [M+H] + =593.1

[0238] (S)-2-((5'-((4-chloro-2-fluorobenzyl)oxy)-2,2'-difluoro-[1,1'-biphenyl]-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 79) [ka] The title compound was prepared as a white solid similar to compound 74. LCMS: [M+H] + =593.0

[0239] (S)-2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 80) [ka] The title compound was prepared as a white solid similar to compound 74. LCMS [M+H] + =576.1

[0240] (S)-2-(4-(4-(4-chloro-2-fluorobenzyloxy)-5-fluoropyrimidin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 81) [ka] The title compound was prepared as a white solid similar to compound 74. LCMS: [M+H] + =594.9

[0241] (S)-2-(4-(2-(4-chloro-2-fluorobenzyloxy)-5-fluoropyrimidin-4-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 82) [ka] The title compound was prepared as a white solid similar to compound 74. LCMS [M+H] + =595.2

[0242] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 83) [ka] The title compound was prepared as a white solid similar to compound 74. LCMS: [M+H] + =594.0

[0243] (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 84) [ka] The title compound was prepared as a white solid similar to compound 74. LCMS: [M+H] + =567.0

[0244] (S)-2-((3'-((4-chloro-2-fluorobenzyl)oxy)-3,4'-difluoro-[1,1'-biphenyl]-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid) (Compound 85) [ka] The title compound was prepared as a white solid similar to compound 74. LCMS: [M+H] + =593.0

[0245] (S)-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 86) [ka] The title compound was prepared as a white solid similar to compound 74. LCMS [M+H] + =576.9

[0246] (S)-2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 87) [ka] The title compound was prepared as a white solid similar to compound 74. LCMS [M+H] + =576.9

[0247] (S)-2-(4-(6-(4-chloro-2-fluorobenzyloxy)-5-fluoropyridin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 88) [ka] The title compound was prepared as a white solid similar to compound 74. LCMS [M+H] + =594.1

[0248] (S)-2-((3'-((4-chloro-2-fluorobenzyl)oxy)-3-fluoro-[1,1'-biphenyl]-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 89) [ka] The title compound was prepared as a white solid similar to compound 74. LCMS: [M+H] + =575.0

[0249] (S)-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 90) [ka] The title compound was prepared as a white solid similar to compound 74. LCMS [M+H] + =594.9

[0250] (S)-2-(4-(2-(4-chloro-2-fluorobenzyloxy)-5-fluoropyrimidin-4-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 91) [ka] The title compound was prepared as a white solid similar to compound 74. LCMS: [M+H] + =595.0

[0251] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)-3-fluoropyridin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 92) [ka] The title compound was prepared as a white solid similar to compound 74. LCMS: [M+H] + =594.8

[0252] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 93) [ka] The title compound was prepared as a white solid similar to compound 74. LCMS: [M+H] + =576.2

[0253] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 94) [ka] The title compound was prepared as a white solid similar to compound 74. LCMS: [M+H] + =558.0

[0254] (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 95) [ka] The title compound was prepared as a white solid similar to compound 74. LCMS: [M+H] + =549.2

[0255] (S)-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 96) [ka] The title compound was prepared as a white solid similar to compound 74. LCMS [M+H] + =577.0

[0256] (S)-2-(4-(6-(4-chloro-2-fluorobenzyloxy)-3-fluoropyridin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 97) [ka] The title compound was prepared as a white solid similar to compound 74. LCMS [M+H] + =594.1

[0257] (S)-2-(4-(6-(4-chloro-2-fluorobenzyloxy)-3,5-difluoropyridin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-benzo[d]imidazole-5-carboxylic acid (Compound 98) [ka] The title compound was prepared as a white solid similar to compound 74. LCMS: [M+H] + =612.0

[0258] (S)-2-(2-chloro-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 99) [ka] The title compound was prepared as a white solid similar to compound 74. LCMS: [M+H] + =593.1

[0259] (S)-2-((6'-(4-chloro-2-fluorobenzyloxy)-2,2'-bipyridin-5-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 100) [ka]

[0260] Step 1. Synthesis of methyl 2-(6-bromo-3-pyridyl)ethaneimidate HCl (g) was bubbled through a mixture of 2-(6-bromo-3-pyridyl)acetonitrile 1 (985 mg, 5.0 mmol), methanol (0.30 mL, 7.5 mmol) in dioxane (20 mL) in a round-bottom flask at room temperature with stirring for 6 hours until the reaction was complete as indicated by LCMS. The reaction mixture was concentrated in vacuo to give the desired product, methyl 2-(6-bromo-3-pyridyl)ethaneimidate (2) (1.4 g, crude) as a white solid. LCMS: (M+H) + =230.0

[0261] Step 2. Synthesis of 2-(6-bromo-3-pyridyl)acetic acid A mixture of the mixture of 2 (1.2 g, 5.24 mmol) and concentrated HCl (10 mL) in water (10 mL) was stirred at 100 °C under N2 in a round-bottom flask for 1 h until the reaction was complete as indicated by LCMS. The reaction mixture was concentrated in vacuo to give the desired product, 2-(6-bromo-3-pyridyl)acetic acid (9) (0.68 g, crude) as a pale yellow solid. LCMS: (M+H) + =217.9

[0262] Step 3. Synthesis of methyl (S)-4-(2-(6-bromopyridin-3-yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate A mixture of 9 (216 mg, 999.9 μmol) and di(imidazol-1-yl)methanone (162.1 mg, 1.0 mol) in THF (20 mL) was stirred at 50° C. for 0.5 h. Then, methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (4) (236.2 mg, 1.0 mmol) was added to the mixture, which was stirred for an additional 2.5 h under N until the reaction was complete as indicated by LCMS. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to give the desired product, methyl (S)-4-(2-(6-bromopyridin-3-yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate (10) (180 mg, 0.42 mol, 41.5% yield), as a white solid. LCMS: (M+H) + =435.9

[0263] Step 4. Synthesis of methyl (S)-2-((6-bromopyridin-3-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate A mixture of 10 (180 mg, 0.41 mmol) in acetic acid (10 mL) was stirred under N2 in a round-bottom flask at 120 °C for 0.5 h until the reaction was complete as indicated by LCMS. The mixture was concentrated in vacuo and dried in vacuo to give the desired product, methyl (S)-2-((6-bromopyridin-3-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (11) (170 mg, crude) as a pale yellow solid. LCMS: (M+H)+ = 416.0

[0264] Step 5. Synthesis of 2-bromo-6-((4-chloro-2-fluorobenzyl)oxy)pyridine A mixture of (4-chloro-2-fluoro-phenyl)methanol 12 (8.0 g, 49.8 mmol), 2-bromo-6-fluoro-pyridine (8.77 g, 49.8 mmol, 5.13 mL), 1,4,7,10,13,16-hexaoxacyclooctadecane (658.4 mg, 2.5 mmol, 0.56 mL), and KOH (4.19 g, 74.7 mmol) in toluene (100 mL) was heated under N 2 O until the reaction was complete as indicated by LCMS. After stirring at room temperature under 2 for 18 hours in a round-bottom flask, the reaction mixture was extracted three times with 50 mL of EtOAc, and the combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo, and purified by silica gel chromatography (hexane / EtOAc = 20:1) to give the desired product, 2-bromo-6-((4-chloro-2-fluorobenzyl)oxy)pyridine (13) (15 g, 47.4 mmol, 95.1% yield) as a white solid. LCMS: (M+H) + =316.0

[0265] Step 6. Synthesis of 2-((4-chloro-2-fluorobenzyl)oxy)-6-(tributylstannyl)pyridine To a mixture of 13 (1.58 g, 4.99 mmol) in THF (20 mL) was added n-butyllithium (383.7 mg, 5.99 mmol, 2.4 mL) and stirred in a round-bottom flask under N at −70 °C for 3 h. BuSnCl (2.44 g, 7.49 mmol, 2.03 mL) was then added to the mixture. After the addition, the mixture was allowed to warm to room temperature for an additional 2 h until the reaction was complete as indicated by LCMS. The reaction mixture was quenched with saturated NH4Cl in an ice bath, dried over Na2SO4, and the organics were concentrated in vacuo to give the desired product, 2-((4-chloro-2-fluorobenzyl)oxy)-6-(tributylstannyl)pyridine (14) (3.5 g, crude) as a pale yellow liquid, which was used directly in the next step.

[0266] Step 7. Synthesis of methyl (S)-2-((6'-((4-chloro-2-fluorobenzyl)oxy)-[2,2'-bipyridin]-5-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate A mixture of 11 (150 mg, 0.35 mmol), 14 (189.8 mg, 0.36 mmol), Pd(PPh)Cl (34 mg, 0.029 mol), and CuI (34 mg, 0.178 mol, 6.05 µL) in DCM (5 mL) was stirred at 90 °C in a RBF under N for 1 h until the reaction was complete as indicated by LCMS. The reaction mixture was filtered and purified by preparative HPLC to give the desired product, methyl (S)-2-((6'-((4-chloro-2-fluorobenzyl)oxy)-[2,2'-bipyridin]-5-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (15) (40.0 mg, 0.070 mmol, 19.4% yield), as a pale yellow solid. LCMS: (M+H) + =573.0

[0267] Step 8. Synthesis of (S)-2-((6'-((4-chloro-2-fluorobenzyl)oxy)-[2,2'-bipyridin]-5-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid A mixture of 15 (40.0 mg, 0.070 mmol) and LiOH (117.2 mg, 2.79 mmol, 77.6 μL) in methanol (1 mL), water (1 mL), and THF (1 mL) was stirred at room temperature under N2 in a RBF for 1 hour until the reaction was complete as indicated by LCMS. The reaction mixture was adjusted to pH = 7 with HOAc, and the mixture was purified by preparative HPLC to give the title compound, (S)-2-((6')-((4-chloro-2-fluorobenzyl)oxy)-[2,2'-bipyridin]-5-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (6.9 mg, 0.012 mmol, 17.7% yield) as a white solid. LCMS: (M+H) + =558.9

[0268] (S)-2-((6-((4-chloro-2-fluorobenzyl)oxy)-[2,3'-bipyridin]-6'-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 101) [ka] The title compound was prepared as a white solid in a similar manner to compound 100. LCMS: (M+H) + =558.9

[0269] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 102) [ka]

[0270] Step 1. Synthesis of 6-chloro-5-nitropicolinic acid To a stirred solution of 2-chloro-6-methyl-3-nitro-pyridine 16 (4.0 g, 23.2 mmol) in 16 mL of furic acid at room temperature was added KCrO (10.2 g, 34.8 mmol). The reaction mixture was stirred at 30 °C for 24 h. Upon completion of the reaction as judged by LCMS, the mixture was diluted with water (200 mL) under ice bath conditions, and the residual precipitate was filtered, washed with water (20 mL), and dried under reduced pressure to give 6-chloro-5-nitropicolinic acid 17 (3.9 g, 19.3 mmol, 83.3% yield, 100% purity) as a light yellow solid. LCMS: [M+H] + =203

[0271] Step 2. Synthesis of methyl 6-chloro-5-nitropicolinate To a suspension of 17 (3.9 g, 19.3 mmol) in dichloromethane (40 mL) was added oxalyl dichloride (4.9 g, 38.5 mmol, 3.35 mL) and N,N-dimethylformamide (0.23 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. Methanol (2.37 g, 74.1 mmol, 3 mL) was added to the reaction mixture at 25 °C. The solution was stirred at 25 °C for an additional 60 min. The mixture was concentrated in vacuo to give a residue, which was purified by flash chromatography (Biotage, 80 g silica gel column, eluting with 0–60% ethyl acetate in petroleum ether at 100 mL / min for 30 min) to give methyl 6-chloro-5-nitropicolinate 18 (2.63 g, 12.1 mmol, 63.1% yield, 100% purity) as a white solid. LCMS[M+H] + =217

[0272] Step 3. Synthesis of methyl (S)-5-nitro-6-((oxetan-2-ylmethyl)amino)picolinate To a stirred solution of [(2S)-oxetan-2-yl]methanamine (663.7 mg, 7.6 mmol) and 18 (1.50 g, 6.9 mmol) in DMF (23 mL) at 25 °C was added N-ethyl-N-isopropyl-propan-2-amine (2.69 g, 20.8 mmol, 3.62 mL). The reaction mixture was stirred at 25 °C for 16 h. Upon completion of the reaction as judged by LCMS, the mixture was diluted with EtOAc (100 mL) and allowed to warm to room temperature. The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 100 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO, petroleum ether / ethyl acetate = 0-40%) to give methyl (S)-5-nitro-6-((oxetan-2-ylmethyl)amino)picolinate 19 (1.80 g, 6.5 mmol, 93.3% yield, 96% purity) as a yellow solid. LCMS: [M+H] + =267

[0273] Step 4. Synthesis of methyl (S)-5-amino-6-((oxetan-2-ylmethyl)amino)picolinate To a stirred solution of 19 (1.8 g, 6.7 mmol) in hexafluoroisopropanol (25 mL) at 25 °C was added 10% Pd / C (304 mg). The reaction mixture was stirred under hydrogen at 25 °C for 4 h. Upon completion of the reaction as judged by LCMS, the mixture was diluted with EtOAc (100 mL), filtered, and the filtrate cake was washed with EtOAc (2 × 100 mL). The combined organic phases were concentrated in vacuo to give methyl (S)-5-amino-6-((oxetan-2-ylmethyl)amino)picolinate 20 (1.6 g, 6.1 mmol, 91.1% yield, 91% purity) as a yellow solid. LCMS: [M+H] + =238

[0274] Step 5. Synthesis of methyl (S)-2-(4-bromo-3-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate To a stirred solution of 20 (260 mg, 1.10 mmol) in CHCN (8 mL) at room temperature was added 4-methylbenzenesulfonic acid (41.9 mg, 0.22 mmol) and 1-bromo-2-fluoro-4-(2,2,2-trimethoxyethyl)benzene (483.7 mg, 1.7 mmol). The reaction mixture was stirred at 90 °C for 2 h, and when the reaction was judged complete by LCMS, the mixture was diluted with EtOAc (100 mL) and cooled to room temperature. The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 150 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO, petroleum ether / ethyl acetate 5:1) to give methyl (S)-2-(4-bromo-3-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 21 (180 mg, 0.41 mmol, 37.7% yield) as a white solid. LCMS: [M+H] + =434

[0275] Step 6. Synthesis of methyl (S)-2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate To a stirred solution of 21 (20.0 mg, 0.046 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaneboron-2-yl)-1,3,2-dioxaborolane (14.0 mg, 55.3 mmol) in 1,4-dioxane (1 mL) at 100 °C was added PdCl(dppf) (5.1 mg) and potassium acetate (13.6 mg). The reaction mixture was stirred at 100° C. for 12 h, and when the reaction was judged complete by LCMS, the mixture was diluted with EtOAc (100 mL), warmed to room temperature, and concentrated in vacuo to afford crude methyl (S)-2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 22 (22 mg, 0.046 mmol, 99.2% yield) as a yellow solid, which was used in the next step without purification.

[0276] Step 7. Synthesis of methyl (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate To a stirred solution of 22 (22.0 mg, 0.046 mmol) and 13 (17.4 mg, 0.055 mmol) in 1,4-dioxane (2 mL) at 25 °C was added PdCl(dppf) (1.7 mg, 0.002 mmol) and potassium carbonate (19.0 mg, 0.14 mmol). The reaction mixture was stirred at 90° C. for 3 h, and when the reaction was judged complete by LCMS, it was diluted with EtOAc (100 mL), warmed to room temperature, concentrated in vacuo, and purified by flash column chromatography (silica gel, petroleum ether / ethyl acetate = 0-40%) to afford methyl (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 23 (20.0 mg, 0.034 mmol, 74.0% yield) as a yellow solid. LCMS: [M+H] + =591

[0277] Step 8. Synthesis of (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid To a stirred solution of 23 (20.0 mg, 0.034 mmol) in water (1 mL), THF (1 mL), and methanol (1 mL) was added lithium hydroxide monohydrate (2.8 mg, 0.068 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 1 h, and when the reaction was judged complete by LCMS, the mixture was acidified with AcOH to approximately pH 6, diluted with DMF (3 mL), and purified by reverse-phase HPLC (instrument: Gilson 281 (PHG012); column: Xtimate C18 10 μm, 21.2 × 250 mm; mobile phase: A: water (10 mM MgCl 2). NH4HCO3, 0.025% NH3·H2O), B: acetonitrile; gradient: 30% B for 1 min, then 45% B for 7 min, stop at 15 min; flow rate: 30 mL / min; detection wavelength: 214 / 254 nm; retention time: 8.0 min; number of injections: 3), the corresponding fractions were combined and concentrated under reduced pressure to remove most of the organic solvent, and the aqueous residue was lyophilized to give the title compound, (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (7.0 mg, 0.012 mmol, 35.9% yield) as a white solid. LCMS: [M+H] + =577

[0278] (S)-2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)thiazol-2-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 246) [ka]

[0279] Step 1 A mixture of 2,4-dibromothiazole (2.0 g, 8.23 ​​mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (2.55 g, 8.23 ​​mmol), Pd(dppf)Cl (602.42 mg, 823.32 μmol), and CsCO (5.37 g, 16.47 mmol) in 1,4-dioxane (40 mL) was stirred at 90 °C in a RBF under N for 10 h until the reaction was complete by LCMS. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography (hexane / EtOAc = 10:1, R f =0.4) to give the desired product, tert-butyl 4-(4-bromothiazol-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (2.2 grams, 6.37 mmol, 77.4% yield, 100% purity) as a pale yellow solid. LCMS: [M+H] + =291.0, retention time (10mM NH4HCO3)=1.79min

[0280] Step 2 A mixture of tert-butyl 4-(4-bromothiazol-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (1.0 g, 2.90 mmol), (4-chloro-2-fluoro-phenyl)methanol (697.6 mg, 4.34 mmol), Sphos-PdG3 (225.92 mg, 289.64 μmol), and t-BuONa (835.1 mg, 8.69 mmol) in toluene (5 mL) was analyzed to determine the reaction was complete by LCMS. The mixture was stirred at 60° C. under N in a RBF for 16 h until the reaction mixture was filtered through a pad of Celite with EtOAc, and the combined organics were concentrated in vacuo and purified by preparative HPLC to give the desired product tert-butyl 4-[4-[(4-chloro-2-fluorophenyl)methoxy]thiazol-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (30 mg, 70.60 μmmol, 2.4% yield) as a yellow oil. LCMS: [M+H] + =425.2, retention time (0.01%TFA)=2.49 minutes

[0281] Step 3 A mixture of tert-butyl-4-[4-[(4-chloro-2-fluorophenyl)methoxy]thiazol-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (26 mg, 61.19 μmol) and 2,2,2-trifluoroacetic acid (1.48 g, 12.98 mmol, 1 mL) in dichloromethane (3 mL) was stirred at 16° C. for 3 hours until the reaction was complete as indicated by LCMS. The reaction mixture was concentrated in vacuo to give the desired product, 4-[(4-chloro-2-fluoro-phenyl)methoxy]-2-(1,2,3,6-tetrahydropyridin-4-yl)thiazole (20 mg, crude) as a yellow solid. LCMS: [M+H] + =325.0, retention time (10mM NH4HCO3)=1.58 min

[0282] Step 4 A mixture of 4-[(4-chloro-2-fluoro-phenyl)methoxy]-2-(1,2,3,6-tetrahydropyridin-4-yl)thiazole (15 mg, 46.18 μmol), tert-butyl 2-(chloromethyl)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (15.55 mg, 46.18 μmol) and N-ethyl-N-isopropyl-propan-2-amine (29.84 mg, 230.91 μmol, 40.22 μL) in N,N-dimethylformamide (3 mL) was analyzed by liquid chromatography (LCC). The mixture was stirred under N2 in a RBF at 50°C for 4 hours until completion by S, and the reaction mixture was concentrated in vacuo to give a residue which was purified by preparative HPLC to give the desired product tert-butyl 2-[[4-[4-[(4-chloro-2-fluoro-phenyl)methoxy]thiazol-2-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (3 mg, 4.80 µmol, 10.39% yield, 100% purity) as a yellow solid. LCMS: [M+H] +=625.3, retention time (10mM NH4HCO3)=1.84min

[0283] Step 5 A mixture of tert-butyl-2-[[4-[4-[(4-chloro-2-fluorophenyl)methoxy]thiazol-2-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (3 mg, 4.80 μmol) and 2,2,2-trifluoroacetic acid (1.48 g, 12.98 mmol, 1 mL) in dichloromethane (4 mL) was purified under N2 in a RBF, and the reaction was found to be complete by LCMS. After stirring at 16° C. for 1 hour until indicated, the reaction mixture was concentrated in vacuo to give a residue which was purified by preparative HPLC to give the desired product 2-[[4-[4-[(4-chloro-2-fluoro-phenyl)methoxy]thiazol-2-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid (0.8 mg, 1.41 μmol, 29.3% yield, 100% purity) as a white solid. LCMS: [M+H] + =569.2, retention time (10mM NH4HCO3) = 1.46 minutes, purity = 100% (254nm) 1 H NMR(400MHz,CD3OD)δ8.20(s,1H),7.97(dd,J=8.5,1.2Hz,1H),7.65-7.52(m,2H),7 .30-7.22(m,2H),6.61-6.60(brs,1H),6.39-6.38(brs,1H),5.24(s,2H),4.71-4.6 3(m,3H),4.43(s,2H),4.15(d,J=13.6Hz,1H),4.05(d,J=13.6Hz,1H),3.25-3.24(m ,2H),2.86-2.80(m,2H),2.80-2.73(m,1H),2.65-2.63(brs,2H),2.52-2.50(m,1H).

[0284] (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)thiazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 247) [ka] Prepared in a similar manner to compound 250. LCMS: [M+H] + =568.9, retention time (10mM NH4HCO3) = 1.41 min 1 H NMR(400MHz,CD3OD)δ8.37(d,J=0.9Hz,1H),8.07(dd,J=8.5,1.5Hz,1H),7.84(d,J=8.5Hz,1H),7 .58(t,J=8.0Hz,1H),7.33-7.23(m,2H),6.93(s,1H),6.60(s,1H),5.54(s,2H),5.28-5.14(m,1H ),5.11-4.90(m,2H),4.79(dd,J=15.8,6.9Hz,1H),4.67(dt,J=13.8,5.4Hz,2H),4.42(dt,J=9.3 ,5.9Hz,1H),4.23(s,2H),3.80(d,J=5.4Hz,2H),3.00-2.72(m,3H),2.51(dq,J=11.3,7.4Hz,1H).

[0285] (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)oxazol-4-yl)-5,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 248) [ka] Prepared in a similar manner to compound 250. LCMS: [M+H] + =553.2, retention time (0.01%TFA)=1.50 minutes 1H NMR(400MHz,CDCl3)δ7.73(brs,3H),7.46(t,J=8.0Hz,1H),7.16(t,J=9.3Hz,3H),6.39(s,1H),5.44(s, 2H),5.15(s,1H),4.59(d,J=5.6Hz,3H),4.34(s,2H),2.70(s,3H),2.41(s,3H),2.06(d,J=14.3Hz,5H).

[0286] (S)-2-((4-(2-((4-(cyclopropylethynyl)-2-fluorobenzyl)oxy)thiazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 249) [ka] Prepared in a similar manner to compound 250. LCMS: [M+H] + =599.0, retention time (10mM NH4HCO3) = 1.68 minutes 1 H NMR(400MHz,DMSO-D6-d6)δ8.23-8.18(brs,1H),7.80(dd,J=8.4,1.4Hz,1H),7.60(d,J=8.4Hz,1H),7.53(t,J=7.9Hz,1H),7.26(dd,J =10.8,1.2Hz,1H),7.22(dd,J=7.9,1.4Hz,1H),6.87-6.82(brs,1H),6.47-6.42(m,1H),5.46(s,2H),5.09-5.02(m,1H),4.78(dd,J=1 5.2,7.2Hz,1H),4.62(dd,J=15.1,2.6Hz,1H),4.47(dd,J=13.7,7.6Hz,1H),4.36(dt,J=9.0,5.9Hz,1H),4.04(d,J=13.4Hz,1H),3.89 (d,J=13.4Hz,1H),3.21-3.11(m,2H),2.73-2.62(m,3H),2.42-3.32(m,3H),1.60-1.50(m,1H),0.94-0.87(m,2H),0.77-0.72(m,2H).

[0287] (S)-2-((4-(2-((5-chloropyridin-2-yl)methoxy)thiazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 250) [ka]

[0288] Step 1 To a suspension of (5-chloro-2-pyridyl)methanol (100 mg, 696.5 μmol) in THF (4 mL) was added sodium hydride (33.4 mg, 1.39 mmol) at 0° C. and stirred for 30 minutes. 2,4-Dibromothiazole (169.2 mg, 696.5 μmol) was then added and stirred at 0° C. for 5 hours. After the reaction was judged complete by LCMS, the reaction mixture was quenched with ice-cold water (20 mL) and extracted with EtOAc (3×20 mL). The organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO, hexane / ethyl acetate 20:1) to give 4-bromo-2-[(5-chloro-2-pyridyl)methoxy]thiazole (78 mg, 232.4 μmol, 33.4% yield) as a colorless oil. LCMS: [M+H] + =304.9, retention time (0.01%TFA)=2.02 minutes

[0289] Step 2 To a suspension of 4-bromo-2-[(5-chloro-2-pyridyl)methoxy]thiazole (78 mg, 255.25 μmol) in 1,4-dioxane (3 mL), methyl 3-[[(2S)-oxetan-2-yl]methyl]-2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneboron-2-yl)-3,6-dihydro-2H-pyridin-1-yl]methyl]benzimidazole-5-carboxylate (119.3 mg, 255.3 μmol), Pd(dppf)Cl (37.35 mg, 51.1 μmol), KCO (105.8 mg, 765.8 μmol, 46.22 μL), and water (0.3 mL) at 100 °C was added and stirred under N for 6 h. After the reaction was judged complete by LCMS, the reaction mixture was quenched with ice-cold water (20 mL) and extracted with EtOAc (3 x 20 mL). The organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC (dichloromethane / methanol 25:1) to afford methyl (S)-2-((4-(2-((5-chloropyridin-2-yl)methoxy)thiazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 139.3 μmol, 54.6% yield, 78.9% purity) as a yellow oil. LCMS: [M+H] + =566.1, retention time (0.01%TFA)=1.48 minutes

[0290] Step 3 To a suspension of methyl (S)-2-((4-(2-((5-chloropyridin-2-yl)methoxy)thiazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 176.7 μmol) in MeOH (3 mL) was added sodium hydroxide (80 mg, 2.00 mmol, 37.6 μL) in water (1 mL) at room temperature and stirred for 12 h. After the reaction was judged complete by LCMS, the reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (3×10 mL). The organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC to give (S)-2-((4-(2-((5-chloropyridin-2-yl)methoxy)thiazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (39.1 mg, 70.8 μmol, 40.1% yield) as a yellow solid. LCMS: [M+H] + =552.0, retention time (0.01%TFA)=1.45 minutes 1 H NMR(400MHz,DMSO-D6)δ8.64(d,J=2.1Hz,1H),8.25(t,J=3.2Hz,1H),7.99(dd,J=8.4,2.5Hz,1H),7.81(dd,J=8.4,1.5Hz, 1H),7.65(d,J=8.4Hz,1H),7.59(t,J=8.4Hz,1H),6.86-6.85(brs,1H),6.39(s,1H),5.51(s,2H),5.05(qd,J=7.4,2.8Hz, 1H),4.79(dd,J=15.2,7.4Hz,1H),4.64(dd,J=15.2,2.6Hz,1H),4.47(dd,J=14.2,7.0Hz,1H),4.36(dt,J=9.0,5.9Hz,1H) ,4.05(d,J=13.5Hz,1H),3.89(d,J=13.5Hz,1H),3.21-3.11(m,2H),2.66(dd,J=16.2,11.1,7.2Hz,3H),2.46-2.31(m,3H).

[0291] (S)-1-(Oxetan-2-ylmethyl)-2-((4-(2-((4-(trifluoromethoxy)benzyl)oxy)thiazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 251) [ka] Prepared in a similar manner to compound 250. LCMS: [M+H] + =601.0, retention time (10mM NH4HCO3)=1.63min 1 H NMR(400MHz,DMSO-D6)δ8.24(s,1H),7.83-7.79(m,1H),7.66-7.61(m,3H),7.43-7 .38(m,2H),6.85(s,1H),6.48-6.44(m,1H),5.48(s,2H),5.10-5.02(m,1H),4.84- 4.75(m,1H),4.68-4.61(m,1H),4.51-4.44(m,1H),4.40-4.33(m,1H),4.09-3.87( dd,J=63.2,13.4Hz,2H),3.22-3.15(m,2H),2.75-2.64(m,3H),2.42-2.35(m,3H).

[0292] (S)-2-((4-(2-((2,4-difluorobenzyl)oxy)thiazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 252) [ka] Prepared in a similar manner to compound 250. LCMS: [M+H] + =553.0, retention time (10mM NH4HCO3) = 1.54 minutes 1H NMR(400MHz,DMSO-D6)δ8.24(s,1H),7.80(dd,J=1.2Hz,J=8.4Hz,1H),7.70-7.62(m,2H),7.35-7. 29(m,1H),7.16-7.11(m,1H),6.84(s,1H),6.46(s,1H),5.45(s,2H),5.06-5.04(m,1H),4.81-4.76 (m,1H),4.66-4.61(dd,J=2.4Hz,J=15.2Hz,1H),4.46(t,J=6Hz,1H),4.39-4.35(m,1H),4.05(d,J =13.6Hz,1H),3.89(d,J=13.6Hz,1H),3.18(d,J=9.6Hz,2H),2.72-2.63(m,3H),2.46-2.32(m,3H).

[0293] (S)-2-((4-(2-((5-bromopyridin-2-yl)methoxy)thiazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 253) [ka] Prepared in a similar manner to compound 250. LCMS: [M+H] + =596.0, retention time (10mM NH4HCO3)=1.47min 1H NMR(400MHz,DMSO-D6)δ8.72(d,J=1.9Hz,1H),8.25(d,J=1.0Hz,1H),8.11(dd,J=8.3,2.4Hz,1H),7.81(dd,J=8.4,1 .5Hz,1H),7.64(d,J=8.4Hz,1H),7.51(d,J=8.3Hz,1H),6.86(s,1H),6.39(s,1H),5.48(s,2H),5.13-4.99(m,1H),4 .79(dd,J=15.2,7.3Hz,1H),4.64(dd,J=15.2,2.6Hz,1H),4.46(dd,J=14.2,7.1Hz,1H),4.36(dt,J=8.9,5.9Hz,1H) ,4.05(d,J=13.5Hz,1H),3.89(d,J=13.5Hz,1H),3.24-3.09(m,2H),2.77-2.59(m,3H),2.40(dd,J=18.2,9.4Hz,3H).

[0294] (S)-2-((4-(2-((2-chloro-4-fluorobenzyl)oxy)thiazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 254) [ka] Prepared in a similar manner to compound 250. LCMS: [M+H] + =569.0, retention time (10mM NH4HCO3) = 1.59 minutes 1H NMR(400MHz,CD3OD)δ8.31(s,1H),8.00-7.97(m,1H),7.69-7.67(m,1H),7.64-7.62(m,1H),7 .31-7.29(m,1H),7.15-7.10(m,1H),6.67(s,1H),6.55-6.52(m,1H),5.54(s,2H),5.28-5.22 (m,1H),4.88-4.86(m,1H),4.74-4.70(m,1H),4.66-4.60(m,1H),4.50-4.45(m,1H),4.12(dd ,J=13.6Hz,2H),3.28-3.22(m,2H),2.84-2.79(m,2H),2.77-2.73(m,1H),2.56-2.48(m,3H).

[0295] (S)-1-(Oxetan-2-ylmethyl)-2-((4-(2-((6-(trifluoromethyl)pyridin-3-yl)methoxy)thiazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 255) [ka] Prepared in a similar manner to compound 250. LCMS: [M+H] + =586.3, retention time (10mM NH4HCO3) = 1.50 minutes, purity 100% (254nm) 1H NMR(400MHz,DMSO-D6)δ8.90(s,1H),8.27-8.18(m,2H),7.96(d,J=8.1Hz,1H),7.80(dd,J=8.4,1.5Hz,1 H),7.63(d,J=8.4Hz,1H),6.87(s,1H),6.45(s,1H),5.61(brs,2H),5.09-5.01(m,1H),4.79(dd,J=15.1, 7.2Hz,1H),4.63(dd,J=15.2,2.6Hz,1H),4.47(dd,J=13.6,7.7Hz,1H),4.36(dt,J=8.9,5.9Hz,1H),4.0 5(d,J=13.5Hz,1H),3.89(d,J=13.5Hz,1H),3.18(d,J=9.3Hz,2H),2.75-2.60(m,3H),2.43-2.32(m,3H).

[0296] (S)-1-(Oxetan-2-ylmethyl)-2-((4-(2-((4-(trifluoromethyl)benzyl)oxy)thiazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 256) [ka] Prepared in a similar manner to compound 250. LCMS: [M+H] + =585.0, retention time (10mM NH4HCO3) = 1.61 min 1 H NMR(400MHz,DMSO-D6)δ8.23(s,1H),7.81-7.76(m,3H),7.70(d,J=8Hz,2H),7.62(d,J=8. 8Hz,1H),6.85(s,1H),6.43(s,1H),5.55(s,2H),5.05(t,J=4.4Hz,1H),4.81-4.75(m,1H), 4.63(dd,J=3.2Hz,J=15.6Hz,1H),4.45(t,J=5.6Hz,1H),4.38-4.33(m,1H),4.05(d,J=13. 6Hz,1H),3.88(d,J=13.6Hz,1H),3.19-3.12(m,2H),2.70-2.63(m,3H),2.43-2.32(m,3H).

[0297] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 257) [ka]

[0298] Step 1 To a mixture of methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (100 mg, 423 μmol) in DCM (20 mL) was slowly added 2-(4-bromo-2,5-difluorophenyl)acetyl chloride (228 mg, 847 μmol) in DCM (20 mL) in an ice bath and stirred at room temperature for 1 h until the reaction was complete as indicated by LCMS. The reaction mixture was concentrated in vacuo and purified by preparative TLC (hexane / EtOAc = 1:2) to give the desired product, methyl 4-[[2-(4-bromo-2,5-difluorophenyl)acetyl]amino]-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (71 mg, 151 μmol, 35.9% yield) as a pale yellow solid. LCMS: [M+H] + =469.0, retention time=1.57 minutes

[0299] Step 2 A mixture of methyl 4-[[2-(4-bromo-2,5-difluorophenyl)acetyl]amino]-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (71 mg, 151 μmol) in AcOH (5 mL) was stirred at 120° C. for 30 min until the reaction was complete as indicated by LCMS. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography (hexane / EtOAc 20:1) to give the desired product, methyl (S)-2-(4-bromo-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (40 mg, 89 μmol, 58.6% yield) as a pale yellow solid. LCMS: [M+H] + =451.1, retention time (0.01%TFA)=1.49 minutes

[0300] Step 3 To the dioxetane (10 mL) was mixed (S)-2-(4-bromo-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (40 mg, 89 μmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (29 mg, 115 μmol), Pd(dppf)Cl (8 mg, 11 μmol), and KOAc (13 mg, 133 μmol). The mixture was stirred under argon at 90° C. for 2 hours until LCMS showed the reaction was complete. The reaction mixture was filtered through a pad of Celite with EtOAc, and the combined organics were concentrated in vacuo to give the desired product, methyl (S)-2-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (42 mg, 33.0% yield), as a pale yellow solid. The crude product was used directly in the next step without further purification. LCMS: [M+H] + =452.9, retention time=1.83 minutes

[0301] Step 4 A mixture of methyl (S)-2-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (42 mg, 84 μmol), 2-bromo-6-[(4-chloro-2-fluoro-phenyl)methoxy]pyridine (32 mg, 101 μmol), Pd(dppf)Cl (6 mg, 8 μmol), and KCO (15 mg, 110 μmol) in dioxane (5 mL) and HO (1 mL) was subjected to LCM under argon. After stirring at 90° C. for 1 h until the reaction was complete as indicated by S, the reaction mixture was filtered through a pad of Celite with EtOAc, and the combined organics were concentrated in vacuo and purified by silica gel chromatography (hexanes / EtOAc=20:1) to give the desired product, methyl (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (12 mg, 20 μmol, 24.0% yield) as a pale yellow solid. LCMS: [M+H] + =608.0, retention time=2.28 minutes

[0302] Step 5 To a mixture of methyl (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (13 mg, 21 μmol) in THF:MeOH:HO (3 mL:3 mL:1 mL) was added LiOH (5 mg, 107 μmol) and the reaction mixture was stirred at room temperature until the reaction was complete as indicated by LCMS. After stirring at room temperature for 1 hour, the reaction mixture was concentrated in vacuo, adjusted to pH=7 with aqueous acetic acid (50%), and purified by preparative HPLC to give the desired product (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (10.1 mg, 17 μmol, 79.5% yield) as a white solid. LCMS: [M+H] + =594.1, retention time=1.44 minutes 1 H NMR(400MHz,DMSO-D6)δ8.24(brs,1H),7.89(t,J=7.6,8Hz,1H),7.83(t,J=6.4,4.4Hz,1H),7.79(t,J=7 .2,1.2Hz,1H),7.62-7.58(m,2H),7.52-7.48(m,2H),7.41(dd,J=6.4,5.2Hz,1H),7.34(dd,J=6.4,1.6Hz ,1H),6.95(d,J=8.4Hz,1H),5.50(s,2H),5.08-5.04(m,1H),4.78(dd,J=7.2,8Hz,1H),4.64(dd,J=2,13. 2Hz,1H),4.54-4.49(m,2H),4.47-4.42(m,1H),4.38-4.33(m,1H),2.74-2.67(m,1H),2.45-2.33(m,1H).

[0303] (S)-2-(2-chloro-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 258) [ka] Prepared in a similar manner to compound 257. LCMS: [M+H] + =593.1, retention time=1.55 minutes 1 H NMR(400MHz,DMSO-D6)δ8.25(s,1H),8.15-8.14(m,1H),8.03-8.00(dd,J=8.1,1.8Hz,1H),7.88-7.8 2(m,1H),7.80-7.77(m,1H),7.68-7.55(m,3H),7.52-7.48(dd,J=10.0,2.0Hz,1H),7.46-7.43(m,1H) ,7.34-7.31(dd,J=8.2,1.9Hz,1H),6.91-6.88(m,1H),5.52(s,2H),5.10-5.04(m,1H),4.75-4.69(m ,1H),4.63-4.56(m,2H),4.52-4.47(m,2H),4.40-4.35(m,1H),2.74-2.67(m,1H),2.43-2.39(m,1H).

[0304] (S)-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 259) [ka] Prepared in a similar manner to compound 257. LCMS: [M+H] + =577.0, retention time=1.54 minutes 1H NMR(400MHz,MeOD)δ8.61(dd,J=23.8,5.1Hz,1H),8.30(s,1H),8.17-7.99(m,2H), 7.70(dd,J=8.5,4.7Hz,1H),7.62-7.57(m,1H),7.34-7.20(m,4H),6.88(d,J=5.9H) z,1H),5.59(s,2H),5.16-5.11(m,1H),4.71-4.62(m,2H),4.60(d,J=5.2Hz,2H),4 .52(d,J=15.6Hz,1H),4.47-4.41(m,1H),2.76(d,J=8.3Hz,1H),2.49-2.44(m,1H).

[0305] (S)-2-(4-(6-(4-chloro-2-fluorobenzyloxy)-3,5-difluoropyridin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 260) [ka] Prepared in a similar manner to compound 257. LCMS: [M+H] + =612.0, retention time=1.65 minutes 1 H NMR(400MHz,DMSO-D6)δ8.22(d,J=0.9Hz,1H),8.14(t,J=9.9Hz,1H),7.78(dd,J =8.4,1.5Hz,1H),7.72(t,J=8.7Hz,2H),7.62(t,J=8.2Hz,1H),7.58-7.44(m,3H ),7.35(dd,J=8.2,1.8Hz,1H),5.57(s,2H),5.10-4.98(m,1H),4.72(dd,J=15.6 ,7.1Hz,1H),4.63-4.29(m,5H),2.75-2.64(m,1H),2.38(dt,J=11.1,7.1Hz,1H).

[0306] (S)-2-(4-(6-(4-chloro-2-fluorobenzyloxy)-3-fluoropyridin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 261) [ka] Prepared in a similar manner to compound 257. LCMS: [M+H] + =594.1, retention time (10mM NH4HCO3) = 1.53 minutes 1 H NMR(400MHz,DMSO-D6)δ8.20(s,1H),7.80-7.86(m,2H),7.55-7.61(m,3H),7.48(dd,J=2.0Hz,10.0Hz,1H),7.32-7.36(m,3H),7.02(dd,J=3.2 Hz,9.2Hz,1H),5.38(s,2H),4.97-5.03(m,1H),4.68-4.72(m,1H),4.44 -4.58(m,4H),4.34-4.39(m,1H),2.66-2.70(m,1H),2.33-2.42(m,1H).

[0307] (S)-2-(4-(6-(4-chloro-2-fluorobenzyloxy)pyridin-2-yl)-2,3-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 262) [ka] Prepared in a similar manner to compound 257. LCMS: [M+H] + =594.0, retention time (0.01%TFA)=1.67 minutes 1H NMR(400MHz,DMSO-D6)δ8.20(s,1H),7.92-7.86(m,1H),7.82-7.73(m,2H),7 .61(t,J=8.2Hz,1H),7.56-7.47(m,3H),7.36-7.26(m,2H),6.95(d,J=8.2Hz ,1H),5.48(s,2H),5.12-5.04(m,1H),4.77-4.68(m,1H),4.64-4.55(m,2H), 4.54-4.46(m,2H),4.40-4.32(m,1H),2.77-2.66(m,1H),2.45-2.32(m,1H).

[0308] (S)-2-(4-(4-(4-cyano-2-fluorobenzyloxy)-5-fluoropyrimidin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 263) [ka] Prepared in a similar manner to compound 257. LCMS: [M+H] + =587.0, retention time=1.50 minutes 1 H NMR(400MHz,DMSO-D6)δ8.79(d,J=2.8Hz,1H),8.12(dd,J=8.0Hz,1.6Hz,1H),8.08-8.0 2(m,2H),7.99-7.93(m,2H),7.84(t,J=7.5Hz,1H),7.82(dd,J=8.0Hz,1.6Hz,1H),7.51 (t,J=7.8Hz,1H),5.81(s,2H),5.18-5.10(m,1H),4.72(dd,J=15.1,6.4Hz,1H),4.68-4 .54(m,3H),4.53-4.49(m,1H),4.38-4.32(m,1H),2.69-2.65(m,1H),2.39-2.31(m,1H).

[0309] (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 264) [ka] Prepared in a similar manner to compound 257. LCMS: [M+H] + =585.1, retention time=1.43 minutes 1 H NMR(400MHz,DMSO-D6)δ8.24(s,1H),7.94(d,J=8.7Hz,1H),7.87-7.79(m,4H),7.76(dd,J=13.3,8.0Hz,3H),7.69(d,J=8.3,2.7Hz,1H),7.58(d,J=8 .4Hz,1H),5.71(s,2H),5.05-4.98(m,1H),4.72(dd,J=15.6,7.2Hz,1H),4 .62-4.47(m,3H),4.44-4.31(m,2H),2.74-2.66(m,1H),2.42-2.36(m,1H).

[0310] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyrazin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 265) [ka] Prepared in a similar manner to compound 257. LCMS: [M+H] + =577.7, retention time (10mM NH4HCO3) = 1.55 minutes 1H NMR(400MHz,DMSO-D6)δ8.92(s,1H),8.36(s,1H),8.25(s,1H),7.98(dd,J=16.0,8.0Hz,2H), 7.78(dd,J=8.0,4.0Hz,1H),7.66(t,J=8.2Hz,1H),7.58(d,J=8.4Hz,1H),7.55-7.46(m,2H),7 .35(dd,J=8.2,1.8Hz,1H),5.57(s,2H),5.11-4.99(m,1H),4.72(d,J=7.0Hz,1H),4.65-4.54 (m,1H),4.54-4.41(m,3H),4.36(dd,J=5.9,3.1Hz,1H),2.77-2.63(m,1H),2.44-2.31(m,1H).

[0311] (S)-2-(4-(4-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyrimidin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 266) [ka] Prepared in a similar manner to compound 257. LCMS: [M+H] + =586.3, retention time=1.51 minutes 1 HNMR (400MHz, DMSO-D6): δ8.78(d,J=3.2Hz,1H),8.24(s,1H),8.11(dd,J=1.6,8.4Hz,1H),8.04( dd,J=1.6,11.6Hz,1H),7.97(dd,J=1.2,10Hz,1H),8.45(t,J=7.6Hz,1H),7.79-7.76(m,2H),7.57 (t,J=8.8Hz,1H),7.48(t,J=7.6Hz,1H),5.80(s,2H),5.05-5.03(m,1H),4.75-4.69(m,1H),4.59( dd,J=2,15.2Hz,1H),4.52-4.43(m,3H),4.37-4.32(m,1H),2.71-2.67(m,1H),2.39-2.32(m,1H).

[0312] (S)-2-(4-(6-(2,4-difluorobenzyloxy)-5-fluoropyridin-2-yl)-3-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 267) [ka] Prepared in a similar manner to compound 257. LCMS: [M+H] + =579.1, retention time (10mM NH4HCO3) = 1.45 minutes 1 H NMR(400MHz,DMSO-D6)δ8.05(d,J=8.4Hz,1H),7.97-7.93(m,2H),7.81(dd, J=8.4Hz,10.4Hz,1H),7.70-7.64(m,1H),7.48-7.46(m,1H),7.36-7.31(m, 3H),7.17-7.12(m,1H),5.55(s,2H),5.15-5.09(m,1H),4.73-4.67(m,1H), 4.60-4.47(m,4H),4.40-4.35(m,1H),2.72-2.68(m,1H),2.47-2.42(m,1H).

[0313] (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)-3-fluoropyridin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 268) [ka] Prepared in a similar manner to compound 257. LCMS: [M+H] + =585.0, retention time=1.55 minutes 1H NMR(400MHz,DMSO-D6)δ8.20(s,1H),7.93(d,J=10.2Hz,1H),7.86(dd,J=10.4,9.0H z,1H),7.74(dt,J=15.8,10.3Hz,5H),7.54(d,J=8.4Hz,1H),7.47(t,J=7.9Hz,1H),7 .02(dd,J=8.9,2.6Hz,1H),5.57(s,2H),5.05(d,J=4.6Hz,1H),4.71(dd,J=15.5,7.0 Hz,1H),4.61-4.55(m,1H),4.54-4.30(m,4H),2.75-2.65(m,1H),2.42-2.34(m,1H).

[0314] (S)-2-(4-(6-((5-chloropyridin-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 269) [ka] Prepared in a similar manner to compound 257. LCMS: [M+H] + =576.9, retention time=1.52 minutes 1 H NMR(400MHz,DMSO-D6)δ8.63-8.62(m1H),8.24(s,1H),7.97-7.87(m,2H),7.79- 7.77(m,1H),7.66-7.62(m,1H),7.59-7.51(m,3H),7.38-7.34(m,1H),7.02(d,J =8.2Hz,1H),5.54(s,2H),5.09-5.06(m,1H),4.77-4.71(m,1H),4.63-4.58(m,1 H),4.53-4.44(m,3H),4.40-4.33(m,1H),2.73-2.67(m,1H),2.42-2.34(m,1H).

[0315] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-methylbenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 270) [ka] Prepared in a similar manner to compound 257. LCMS: [M+H] + =572.0, retention time=1.65 minutes 1 HNMR (400MHz, DMSO-D6): δ8.22(brs,1H),7.83-7.82(m,2H),7.62(d,J=8.4Hz,1H),7.55(t,J= 8.4Hz,1H),7.47(dd,J=2Hz,J=8Hz,1H),7.36(d,J=8.4Hz,1H),7.31(dd,J=8Hz,J=6.4Hz,1H),7 .24-7.20(m,2H),7.14(d,J=8Hz,1H),6.85(d,J=8.4Hz,1H),5.39(s,2H),4.966-4.93(m,1H), 4.96-4.63(m,1H),4.55-4.44(m,2H),4.40-4.33(m,3H),2.67-2.63(m,1H),2.39-2.29(m,4H).

[0316] (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 271) [ka] Prepared in a similar manner to compound 257. LCMS: [M+H] + =585.1, retention time=1.36 minutes 1H NMR(400MHz,DMSO-D6-d6)δ8.24(brs,1H),7.93-7.87(m,2H),7.79-7.71(m,4H),7.59(d,J=8. 4Hz,1H),7.53(dd,J=1.2,6.4Hz,1H),7.40(dd,J=6.4,5.2Hz,1H),7.00(d,J=8.4Hz,1H),5.59( s,2H),5.08(qd,J=2.8,7.8Hz,1H),4.77(dd,J=7.2,8.4Hz,1H),4.63(dd,J=2.4,13.2Hz,1H),4 .54-4.49(m,2H),4.46(d,J=6Hz,1H),4.36-4.33(m,1H),2.70-2.67(m,1H),2.37-2.32(m,1H).

[0317] (S)-2-(4-(4-((5-chloro-3-fluoropyridin-2-yl)methoxy)-5-fluoropyrimidin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 272) [ka] Prepared in a similar manner to compound 257. LCMS: [M+H] + =614.0, retention time=1.48 minutes 1 H NMR(400MHz,DMSO-D6)δ8.83(d,J=2.9Hz,1H),8.54(d,J=1.4Hz,1H),8.27-8.15(m,2H), 7.78(td,J=8.8,3.9Hz,2H),7.59(d,J=8.4Hz,1H),7.37(dd,J=11.1,6.0Hz,1H),5.78(d, J=1.6Hz,2H),5.13-5.02(m,1H),4.74(dd,J=15.5,7.0Hz,1H),4.64-4.58(m,1H),4.56-4 .41(m,3H),4.35(dt,J=9.0,5.9Hz,1H),2.75-2.65(m,1H),2.38(dt,J=11.3,7.1Hz,1H).

[0318] (S)-2-(4-(4-((5-chloro-3-fluoropyridin-2-yl)methoxy)-5-fluoropyrimidin-2-yl)-2,5-difluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 273) [ka] Prepared in a similar manner to compound 257. LCMS: [M+H] + =615.0, retention time=1.37 minutes 1 H NMR(400MHz,DMSO-D6)δ8.83(d,J=2.9Hz,1H),8.54(d,J=1.3Hz,1H),8.20(dd,J=9.7,2.0Hz,1 H),8.04(d,J=8.2Hz,1H),7.94(d,J=8.2Hz,1H),7.78(dd,J=10.2,6.3Hz,1H),7.40(dd,J=11.0 ,6.0Hz,1H),5.77(d,J=1.6Hz,2H),5.18-5.12(m,1H),4.74(dd,J=15.2,6.2Hz,1H),4.63(dd,J =10.3,6.8Hz,2H),4.56-4.48(m,2H),4.37-4.31(m,1H),2.74-2.68(m,1H),2.45-2.40(m,1H).

[0319] (S)-2-(4-(6-((2,4-difluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 274) [ka] Prepared in a similar manner to compound 257. LCMS: [M+H] + =560.0, retention time=1.59 minutes 1H NMR(400MHz,DMSO-D6-d6)δ8.23(brs,1H),7.94(t,J=10,6.4Hz,2H),7.85(t,J=8,8Hz,1H),7.79(dd,J=1.2,7.2H z,1H),7.68(q,J=8.8,8Hz,2H),7.58(d,J=8.4Hz,1H),7.45(t,J=7.6,8.4Hz,1H),7.33(dt,J=2.4,8Hz,1H),7.14( dt,J=2.4,6.4Hz,1H),6.87(d,J=8Hz,1H),5.50(s,2H),5.06-5.02(m,1H),4.75(dd,J=7.2,8.4Hz,1H),4.60(dd,J =2.4,13.6Hz,1H),4.54-4.48(m,2H),4.46-4.40(m,1H),4.38-4.32(m,1H),2.74-2.67(m,1H),2.42-2.33(m,1H).

[0320] (S)-2-(4-(4-((5-cyanopyridin-2-yl)methoxy)-5-fluoropyrimidin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 275) [ka] Prepared in a similar manner to compound 257. LCMS: [M+H] + =587.2, retention time=1.41 minutes 1 H NMR(400MHz,DMSO-D6)δ9.03(d,J=1.4Hz,1H),8.85(d,J=2.8Hz,1H),8.36(dd,J=8.2 ,2.1Hz,1H),8.24(s,1H),7.83-7.65(m,3H),7.58(d,J=8.4Hz,1H),7.36(dd,J=11.1 ,6.1Hz,1H),5.79(s,2H),5.06(d,J=7.0Hz,1H),4.81-4.68(m,1H),4.51(ddd,J=34. 3,30.6,14.9Hz,4H),4.34(dd,J=6.0,3.0Hz,1H),2.69(d,J=8.3Hz,1H),2.38(s,1H).

[0321] (S)-2-(4-(6-((5-chloro-3-fluoropyridin-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 276) [ka]

[0322] Step 1 To a suspension of (5-chloro-3-fluoro-2-pyridyl)methanol (100 mg, 619 μmol) and 2-bromo-6-fluoro-pyridine (114.4 mg, 650 μmol) in THF (5 mL) was slowly added t-BuOK (76.4 mg, 681 μmol) at 0 °C and stirred under N for 2 h. After the reaction was judged complete by LCMS, the reaction mixture was quenched with ice-cold water (20 mL) and extracted with EtOAc (3 × 40 mL). The organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO, hexane / ethyl acetate 10:1) to afford 2-[(6-bromo-2-pyridyl)oxymethyl]-5-chloro-3-fluoro-pyridine (115 mg, 362 μmol) as a white solid. LCMS: [M+H] + =317.0, retention time (0.01%TFA)=2.12 minutes

[0323] Step 2 A mixture of methyl 2-(4-bromo-2,5-difluorophenyl)acetate (400 mg, 1.51 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl)-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (459.9 mg, 1.81 mmol), KOAc (296.22 mg, 3.02 mmol), and Pd(dppf)Cl (110.4 mg, 151 μmol) in dioxane (8 mL) was stirred at 95 °C under N for 2 h until the reaction was complete by LCMS, and the reaction mixture was used in the next analysis without further purification. LCMS: [M+H] + =231.1, retention time (0.01%TFA)=1.53 minutes

[0324] Step 3 In dioxane (8 mL) and water (1.5 mL) were added 2-[(6-bromo-2-pyridyl)oxymethyl]-5-chloro-3-fluoro-pyridine (110 mg, 346 μmol), methyl 2-[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (129.7 mg, 416 μmol), Pd(dppf)Cl (50.7 mg, 69 μmol), and CsCO (225.74 mg, 693 μmol). After stirring at 100° C. under N for 2 h until the reaction was complete as indicated by CMS, the reaction mixture was filtered through a pad of Celite with EtOAc, and the combined organics were concentrated in vacuo and purified by silica gel chromatography (hexane / EtOAc=10:1) to give the desired product, methyl 2-[4-[6-[(5-chloro-3-fluoro-2-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]acetate (110 mg, 260 μmol) as a white solid. LCMS: [M+H] + =423.0, retention time (0.01%TFA)=2.22 minutes

[0325] Step 4 A mixture of methyl 2-[4-[6-[(5-chloro-3-fluoro-2-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]acetate (100 mg, 237 μmol), LiOH (16.99 mg, 710 μmol), and water (0.5 mL) in methanol (3 mL) was stirred at 20° C. under N for 12 hours until complete by LCMS. HOAc was added to quench the reaction, and the combined organics were concentrated in vacuo and purified by HPLC to give the desired product, 2-[4-[6-[(5-chloro-3-fluoro-2-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]acetic acid (90 mg, 220 μmol, 93.1% yield) as a white solid. LCMS: [M+H] + =409.1, retention time (0.01%TFA)=1.99 minutes

[0326] Step 5 A mixture of 2-[4-[6-[(5-chloro-3-fluoro-2-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]acetic acid (90 mg, 220 μmol), methyl 5-amino-6-[[(2S)-oxetan-2-yl]methylamino]pyridine-2-carboxylate (94.03 mg, 396 μmol), HATU (125.6 mg, 330 μmol) and DIEA (85.4 mg, 661 μmol) in DCM (8 mL) was stirred at 20° C. under N2 until the reaction was complete by LCMS. After stirring for 2 hours, the reaction was quenched by the addition of water, and the combined organics were concentrated in vacuo and purified by silica gel chromatography (hexanes / EtOAc=1:1) to give the desired product, methyl 5-[[2-[4-[6-[(5-chloro-3-fluoro-2-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]acetyl]amino]-6-[[(2S)-oxetan-2-yl]methylamino]pyridine-2-carboxylate (120 mg, 191 μmol, 86.8% yield) as a pale yellow solid. LCMS: [M+H] + =628.1, retention time (0.01%TFA)=1.77 minutes

[0327] Step 6 A mixture of methyl 5-[[2-[4-[6-[(5-chloro-3-fluoro-2-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]acetyl]amino]-6-[[(2S)-oxetan-2-yl]methylamino]pyridine-2-carboxylate (90 mg, 143 μmol) and HOAc (20 drops) in toluene (10 mL) was stirred at 60° C. under N for 2 h. Water was added to quench the reaction. The reaction mixture was extracted with EtOAc (3×20 mL). The organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO, dichloromethane / methanol 15:1) to give methyl 2-[[4-[6-[(5-chloro-3-fluoro-2-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylate (74 mg, 121 μmol, 84.7% yield) as a yellow oil. LCMS: [M+H] + =610.2, retention time (0.01%TFA)=2.07 minutes

[0328] Step 7 A mixture of methyl 2-[[4-[6-[(5-chloro-3-fluoro-2-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylate (40 mg, 66 μmol), LiOH (4.7 mg, 197 μmol) and water (0.5 mL) in methanol (3 mL) was analyzed under N2 at 20 °C until the reaction was complete by LCMS. The mixture was stirred for 3 hours until the reaction was quenched by the addition of HOAc, and the combined organics were concentrated in vacuo and purified by HPLC to give the desired product 2-[[4-[6-[(5-chloro-3-fluoro-2-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylic acid (22 mg, 37 μmol, 56.3% yield) as a white solid. LCMS: [M+H] + =596.0, retention time (0.01%TFA)=1.90 minutes 1 H NMR(400MHz,DMSO-D6)δ8.53(d,J=1.2Hz,1H),8.18-8.15(m,1H),8.08(d,J=8.4Hz,1H),7.97(dd,J =8.0Hz,1H),7.90-7.86(m,1H),7.72(dd,J=6.4Hz,10.4Hz,1H),7.52(d,J=6.0Hz,1H),7.41(dd,J= 6.0Hz,11.6Hz,1H),6.96(d,J=8.4Hz,1H),5.59(d,J=1.6Hz,2H),5.17-5.15(m,1H),4.79-4.73(m, 1H),4.65-4.61(m,2H),4.55-4.49(m,2H),4.39-4.33(m,1H),2.76-2.71(m,1H),2.47-2.42(m,1H).

[0329] (S)-2-(4-(6-(2,4-difluorobenzyloxy)-5-fluoropyridin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 277) [ka] Prepared in a similar manner to compound 276. LCMS: [M+H] + =579.1, retention time (10mM NH4HCO3) = 1.46 minutes 1 H NMR(400MHz,DMSO-D6)δ8.02-7.80(m,5H),7.71-7.65(m,2H),7.48-7.44(m,1H),7.36-7.31(m,1H),7.17-7.12(m,1H),5.60(s,2H), 5.17-5.11(m,1H),4.75-4.69(m,1H),4.64-4.59(m,2H),4.53-4.49(m,2H),4.38-4.33(m,1H),2.75-2.67(m,1H),2.48-2.41(m,1H).

[0330] (S)-2-(4-(6-((5-cyano-3-fluoropyridin-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 278) [ka] Prepared in a similar manner to compound 276. LCMS: [M+H] + =587.1, retention time (10mM NH4HCO3) = 1.35 minutes 1H NMR(400MHz,DMSO-D6)δ8.89(s,1H),8.48(dd,J=1.6Hz,9.6Hz,1H),8.07(d,J=8.4Hz,1H),7.96 (d,J=8.4Hz,1H),7.90-7.87(m,1H),7.61-7.57(m,1H),7.51(d,J=6.0Hz,1H),7.39(dd,J=6.4Hz ,11.2Hz,1H),6.99(d,J=8.4Hz,1H),5.69(d,J=1.2Hz,2H),5.19-5.13(m,1H),4.78-4.73(m,1H) ,4.65-4.60(m,2H),4.54-4.48(m,2H),4.38-4.33(m,1H),2.75-2.69(m,1H),2.47-2.40(m,1H).

[0331] (S)-2-(4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 279) [ka]

[0332] Step 1 A mixture of 6-(hydroxymethyl)pyridine-3-carbonitrile (33 mg, 246 μmol), 2-bromo-6-fluoro-pyridine (43.3 mg, 246 μmol), and sodium hydride (5.7 mg, 246 μmol) in THF (3 mL) was stirred under N at 20 °C for 2 h until complete as indicated by LCMS. The reaction mixture was filtered through a pad of Celite with EtOAc, and the combined organics were concentrated in vacuo and purified by silica gel chromatography (hexane: EtOAc = 20:1) to give the desired product, 6-[(6-bromo-2-pyridyl)oxymethyl]pyridine-3-carbonitrile (30 mg, 103 μmol, 42.0% yield) as a pale yellow solid. LCMS: [M+H] + =290, retention time (0.01%TFA)=1.86 minutes

[0333] Step 2 In DMF (20 mL) was added tert-butyl 5-amino-6-[[(2S)-oxetan-2-yl]methylamino]pyridine-2-carboxylic acid (1.39 g, 4.98 mmol), 2-(4-bromo-2,5-difluoro-phenyl)acetic acid (1.25 g, 4.98 mmol), N-ethyl-N-isopropyl-propan-2-amine (643.6 mg, 4.98 mmol), and [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethylammonium hexafluorophosphate (1.89 g, 4.98 mmol). The combined mixture was stirred under N2 at 20 °C for 1 h until LCMS showed the reaction was complete, the reaction mixture was poured into water and extracted with EtOAc, the combined organics were concentrated in vacuo and purified by silica gel chromatography (hexane / EtOAc = 2:1) to give the desired product tert-butyl 5-[[2-(4-bromo-2,5)-difluoro-phenyl)acetyl]amino]-6-[[(2S)-oxetan-2-yl]methylamino]pyridine-2-carboxylate (1.0 g, 1.95 mmol, 39.2% yield) as a pale yellow solid. LCMS: [M+H] + =512, retention time=1.92 minutes

[0334] Step 3 A mixture of tert-butyl 5-[[2-(4-bromo-2,5-difluoro-phenyl)acetyl]amino]-6-[[(2S)-oxetan-2-yl]methylamino]pyridine-2-carboxylate (1.0 g, 1.95 mmol) in toluene (10 mL) was stirred under N at 120 °C for 2 h until complete by LCMS. The reaction mixture was filtered through a pad of Celite with EtOAc, and the combined organics were concentrated in vacuo and purified by silica gel chromatography (hexanes / EtOAc = 2:1) to give the desired product, tert-butyl 2-[(4-bromo-2,5-difluoro-phenyl)methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylate (430 mg, 870 μmol, 44.6% yield) as a pale yellow solid. LCMS: [M+H] + =494, retention time (0.01%TFA)=2.02 minutes

[0335] Step 4 A mixture of tert-butyl 2-[(4-bromo-2,5-difluorophenyl)methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylate (180 mg, 364 μmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-13,2-dioxaborolane (184.93 mg, 728 μmol), and potassium acetate (143.0 mg, 1.46 mmol) in dioxane (20 mL) was stirred at 90° C. under N for 16 hours until the reaction was complete by LCMS. The reaction mixture was filtered through a pad of Celite with EtOAc and used directly in the next step.

[0336] Step 5 A mixture of 6-[(6-bromo-2-pyridyl)oxymethyl]pyridine-3-carbonitrile (60 mg, 207 μmol), tert-butyl 2-[[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylate (112.0 mg, 207 μmol), and sodium bicarbonate (86.87 mg, 1.03 mmol) was analyzed by LCMS at 110 °C under N2. The reaction was stirred for 16 hours until completion was indicated, water was added to the reaction mixture, extracted with EtOAc, and the combined organics were concentrated in vacuo and purified by silica gel chromatography (hexane / EtOAc=5:1) to give the desired product tert-butyl 2-[[4-[6-[(5-cyano-2-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylate (80 mg, 61.9% yield) as a pale yellow oil. LCMS: [M+H] + =625, retention time=1.77 minutes

[0337] Step 6 A mixture of tert-butyl 2-[[4-[6-[(5-cyano-2-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylic acid (80 mg, 128 μmol), 2,2,2-trifluoroacetic acid (23.68 g, 207.68 mmol, 16.00 mL) in CHCl (2 mL) was heated at 30°C under N. The mixture was stirred for 1 hour until LCMS showed the reaction was complete, and the reaction mixture was concentrated in vacuo and further purified by preparative HPLC to give the desired product 2-[[4-[6-[(5-cyano-2-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylic acid (38.3 mg, 51.0% yield) as a pale yellow solid. LCMS: [M+H]+ =569.2, retention time=1.42 minutes 1 H NMR(400MHz,DMSO-D6)δ9.03(d,J=1.4Hz,1H),8.33(dd,J=8.2,2.1Hz,1H),8.08(d,J=8.2Hz,1H),8.02- 7.85(m,2H),7.68(d,J=8.2Hz,1H),7.54(dd,J=10.9,6.7Hz,2H),7.39(dd,J=11.5,6.0Hz,1H),7.06(d, J=8.3Hz,1H),5.64(s,2H),5.15(dd,J=7.1,3.3Hz,1H),4.75(dd,J=15.1,6.4Hz,1H),4.68-4.56(m,2H) ,4.50(dd,J=15.5,5.9Hz,2H),4.35(dd,J=6.0,2.9Hz,1H),2.73(d,J=3.3Hz,1H),2.45(d,J=9.0Hz,1H).

[0338] (S)-2-(4-(4-((5-cyanopyridin-2-yl)methoxy)-5-fluoropyrimidin-2-yl)-2,5-difluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 280) [ka] Prepared in a similar manner to compound 279. LCMS: [M+H] + =588.0, retention time=1.17 minutes 1 H NMR(400MHz,DMSO-D6)δ9.04(d,J=1.4Hz,1H),8.86(d,J=2.8Hz,1H),8.37(dd,J=8.2,2.1Hz,1H),8.03(d,J=8.2Hz,1H),7.94(d,J=8.2Hz,1H), 7.84-7.63(m,2H),7.39(dd,J=11.1,6.1Hz,1H),5.80(s,2H),5.15(s,1 H),4.81-4.41(m,6H),4.41-4.23(m,1H),2.70(dd,J=16.4,8.3Hz,2H).

[0339] 2-[[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 281) [ka] Prepared in a similar manner to compound 279. LCMS: [M+H] + =577.9, retention time (10mM NH4HCO3) = 2.94 minutes 1 H NMR(400MHz,DMSO-D6)δ8.06(d,J=8.2Hz,1H),7.97(d,J=8.2Hz,1H),7.91(dd,J=9.1,5.2Hz,2H),7.84(t,J =7.8Hz,1H),7.66(d,J=7.4Hz,1H),7.62(t,J=8.2Hz,1H),7.54-7.42(m,2H),7.33(d,J=8.2Hz,1H),6.89(d ,J=8.2Hz,1H),5.52(s,2H),5.15(s,1H),4.73(dd,J=15.1,6.2Hz,1H),4.63(dd,J=10.3,6.8Hz,2H),4.51( dd,J=15.3,9.1Hz,2H),4.36(dt,J=12.0,5.9Hz,1H),2.71(dd,J=17.0,9.0Hz,1H),2.42(d,J=18.0Hz,1H).

[0340] (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 282) [ka] Prepared in a similar manner to compound 279. LCMS: [M+H] + =568.2, retention time=1.32 minutes 1H NMR(400MHz,DMSO-D6)δ7.99(d,J=8.4Hz,1H),7.96-7.90(m,4.0Hz,2H),7.90-7.84(m ,J=7.8Hz,3H),7.79-7.71(m,2H),7.67(d,J=7.4Hz,1H),7.44(t,J=8.1Hz,1H),6.93( d,J=8.1Hz,1H),5.62(s,2H),5.14(s,1H),4.71(dd,J=15.3,6.5Hz,1H),4.60(d,J=17 .0Hz,2H),4.54-4.45(m,2H),4.40-4.31(m,1H),2.76-2.68(m,1H),2.43-2.34(m,1H).

[0341] (S)-2-(4-(6-(4-chloro-2-fluorobenzyloxy)-5-fluoropyridin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 283) [ka] Prepared in a similar manner to compound 279. LCMS: [M+H] + =595.2, retention time=1.42 minutes 1 H NMR(400MHz,DMSO-D6)δ8.02(d,J=8.0Hz,1H),7.94(d,J=8.4Hz,1H),7.91-7.79(m,3H),7.69(dd ,J=8.4,2.8Hz,1H),7.64(t,J=8.2Hz,1H),7.52(dd,J=10.0,2.0Hz,1H),7.45(t,J=8.1Hz,1H),7 .36-7.34(m,1H),5.61(s,2H),5.18-5.10(m,1H),4.72(dd,J=15.0,6.4Hz,1H),4.65-4.61(m,1H ),4.60-4.57(m,1H),4.54-4.47(m,2H),4.39-4.32(m,1H),2.69-2.66(m,1H),2.34-2.32(m,1H).

[0342] (S)-2-(4-(6-(4-cyano-2-fluorobenzyloxy)-5-fluoropyridin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 284) [ka] Prepared in a similar manner to compound 279. LCMS: [M+H] + =586.0, retention time=1.51 minutes 1 H NMR(400MHz,DMSO-D6)δ8.04(d,J=8.0Hz,1H),7.97-7.92(m,2H),7.87-7.82(m,3H), 7.80-7.73(m,2H),7.70(dd,J=8.4,2.8Hz,1H),7.45(t,J=8.0Hz,1H),5.71(s,2H),5. 18-5.11(m,1H),4.73(dd,J=15.2,6.4Hz,1H),4.65-4.61(m,1H),4.60-4.57(m,1H), 4.54-4.46(m,2H),4.36(dt,J=9.0,6.0Hz,1H),2.72-2.66(m,1H),2.40-2.30(m,1H).

[0343] (S)-2-(4-(4-((2,4-difluorobenzyl)oxy)-5-fluoropyrimidin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 285) [ka] Prepared in a similar manner to compound 279. LCMS: [M+H] + =580.0, retention time=1.53 minutes 1H NMR(400MHz,DMSO-D6)δ8.82-8.76(m,1H),8.19-8.15(m,1H),8.13-8.03(m,2H),7.99-7.94(m,1H),7.78-7.70(m,1H),7.56-7.50(m,1H),7.4 1-7.32(m,1H),7.22-7.14(m,1H),5.72(s,2H),5.19-5.11(m,1H),4.77 -4.49(m,5H),4.39-4.33(m,1H),2.75-2.67(m,1H),2.47-2.40(m,1H).

[0344] (S)-2-(4-(6-((2,4-difluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 286) [ka] Prepared in a similar manner to compound 279. LCMS: [M+H] + =561.0, retention time=1.57 minutes 1 H NMR(400MHz,DMSO-D6)δ7.96-7.89(m,4H),7.88-7.82(m,1H),7.70-7.62(m,2H),7.48-7.42(m,1H),7.35-7.28(m,1H),7.17-7.08(m,1H),6.9 0-6.85(m,1H),5.51(s,2H),5.18-5.10(m,1H),4.74-4.67(m,1H),4.62 -4.47(m,4H),4.39-4.33(m,1H),2.76-2.65(m,1H),2.45-2.40(m,1H).

[0345] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 287) [ka] Prepared in a similar manner to compound 279. LCMS: [M+H] + =576.3, retention time=2.13 minutes 1 H NMR(400MHz,DMSO-D6)δ7.95-7.89(m,2H),7.65-7.61(m,2H),7.56-7.54(m,2H),7.42-7.31(m,5H),7.06(d,1H),5.2 3(s,2H),5.00(m,1H),4.67-4.66(m,1H),4.57-4.55(m,2H),4.47-4.43(m,2H),4,34(m,1H),2.51(m,1H),2.32(m,1H)

[0346] (S)-2-(4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 288) [ka] Prepared in a similar manner to compound 279. LCMS: [M+H] + =550.7, retention time=1.98 minutes 1 H NMR(400MHz,DMSO-D6)δ9.03(s,1H),8,32(d,1H),7.78(d,1H),7.77(d,1H),7.76(d,1H),7.64-7.63(m,4H),7.39(t ,1H),7.00(d,1H),5.64(s,2H),4.51(m,1H),4.46-4.341(m,4H),4.31(m,1H),2.71-2.67(m,1H),2.45-2.43(m,1H)

[0347] (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)-3-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 289) [ka] Prepared in a similar manner to compound 279. LCMS: [M+H] + =586.2, retention time (0.01%TFA)=1.85 minutes 1 H NMR(400MHz,CDCl3)δ8.25-8.22(m,2H),7.93-7.87(m,1H),7.73-7.67(m,1H),7.50-7.37(m,4H),7.21-7.16(m,1H),7.12-7.08(m, 1H),5.64(s,2H),5.25-5.19(m,1H),4.71-4.60(m,3H),4.57-4.49(m,1H),4.48-4.37(m,2H),2.82-2.75(m,1H),2.46-2.37(m,1H).

[0348] (S)-2-(4-(6-((2,4-difluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 290) [ka] Prepared in a similar manner to compound 279. LCMS: [M+H] + =561.0, retention time=1.57 minutes 1 H NMR(400MHz,DMSO-D6)δ8.15-8.09(d,J=8.2Hz,1H),8.02-7.95(m,2H),7.87-7.81(m ,1H),7.69-7.60(dd,J=15.3,8.5Hz,1H),7.47-7.43(m,1H),7.37-7.27(m,3H),7.15 -7.09(m,1H),6.91-6.87(d,J=8.2Hz,1H),5.46(s,2H),5.17-5.09(m,1H),4.76-4.6 8(m,1H),4.65-4.46(m,4H),4.42-4.35(m,1H),2.76-2.64(m,1H),2.47-2.41(m,1H).

[0349] (S)-2-(4-(2-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyrimidin-4-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 291) [ka] Prepared in a similar manner to compound 279. LCMS: [M+H] + =587.0, retention time=1.43 minutes 1 HNMR (400MHz, DMSO-D6): δ8.84(d,J=3.2Hz,1H),8.04(d,J=4Hz,1H),7.94(d, J=8.4Hz,2H),7.87(t,J=8Hz,2H),7.80-7.74(m,2H),7.58(t,J=8Hz,1H),5.6 0(s,2H),5.16-5.14(m,1H),4.76-4.69(m,1H),4.64(t,J=4Hz,2H,1H),4.60(d,J=6. 4Hz,1H),4.54-4.47(m,1H),4.37-4.32(m,1H),2.74-2.67(m,1H),2.46-2.41(m,2H).

[0350] (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 292) [ka] Prepared in a similar manner to compound 279. LCMS: [M+H] + =586.2, retention time=1.57 minutes 1H NMR(400MHz,CD3OD)δ8.20-8.16(m,1H),8.12-8.08(m,1H),7.90-7.87(m,1H),7 .86-7.77(m,2H),7.70-7.66(m,1H),7.65-7.60(m,2H),7.30-7.24(m,1H),7.00 -6.96(m,1H),5.70(s,2H),5.36-5.34(m,1H),4.90-4.86(m,1H),4.82-4.79(m, 1H),4.73-4.65(m,3H),4.53-4.48(m,1H),2.93-2.93(m,1H),2.61-2.56(m,1H).

[0351] (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 293) [ka] Prepared in a similar manner to compound 279. LCMS: [M+H] + =568.0, retention time=1.50 minutes 1 HNMR (400MHz, DMSO-D6): δ8.76(d,J=8.4Hz,1H),7.95-7.84(m,4H),7.77-7.71(m,2H),7.46(dd,J=1.6Hz,J=7.6Hz,1H),7.30(t,J=11.2Hz,2H),6 .94(d,J=8Hz,1H),5.56(s,2H),5.12-5.09(m,1H),4.70-4.65(m,1H),4. 58-4.46(m,4H),4.38-4.33(m,1H),2.70-2.66(m,1H),2.47-2.40(m,1H).

[0352] (S)-2-(4-(4-((5-chloro-3-fluoropyridin-2-yl)methoxy)-5-fluoropyrimidin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 294) [ka] Prepared in a similar manner to compound 279. LCMS: [M+H] + =597.1, retention time=1.28 minutes 1 H NMR(400MHz,DMSO-D6)δ8.77(d,J=2.8Hz,1H),8.56(d,J=1.4Hz,1H),8.22(dd,J=9.7,1.9Hz,1H),8.10-7.90(m,4H),7.49(t,J=7.9Hz,1H),5. 82(d,J=1.4Hz,2H),5.14(d,J=7.1Hz,1H),4.78-4.45(m,5H),4.35(dt,J=9.0,6.0Hz,1H),2.70(dd,J=17.0,8.8Hz,1H),2.44(d,J=8.8Hz,1H).

[0353] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2-methylbenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 295) [ka] Prepared in a similar manner to compound 279. LCMS: [M+H] + =572.1, retention time=1.52 minutes 1HNMR (400MHz, DMSO-D6): δ8.22(brs,1H),7.90(brs,1H),7.84-7.76(m,3H),7.62-7.56 (m,3H),7.50(dd,J=2Hz,J=10Hz,1H),7.32(dd,J=1.6Hz,J=8.4Hz,1H),7.16(d,J=8Hz, 1H),6.82(d,J=8.4Hz,1H),5.51(s,2H),5.03-5.00(m,1H),4.69-4.63(m,1H),4.56-4. 46(m,2H),4.43-4.38(m,2H),4.37-4.35(m,1H),2.69-2.65(m,1H),2.42-2.34(m,4H).

[0354] (S)-2-(4-(6-((5-chloropyridin-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 296) [ka] Prepared in a similar manner to compound 279. LCMS: [M+H] + =578.2, retention time=1.32 minutes 1 H NMR(400MHz,DMSO-D6)δ8.63(d,J=2.4Hz,1H),8.09(d,J=8.2Hz,1H),7.98-7.94(m, 2H),7.91-7.87(m,1H),7.67-7.62(m,1H),7.55-7.51(m,2H),7.42-7.37(m,1H),7. 02(d,J=8.3Hz,1H),5.54(s,2H),5.18-5.14(m,1H),4.78-4.72(m,1H),4.65-4.60( m,2H),4.53-4.48(m,2H),4.38-4.32(m,1H),2.76-2.70(m,1H),2.46-2.43(m,1H).

[0355] (S)-2-(4-(6-((3,5-difluoropyridin-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 297) [ka] Prepared in a similar manner to compound 279. LCMS: [M+H] + =580.0, retention time=1.48 minutes 1 HNMR (400MHz, DMSO-D6): δ8.52(d,J=2.4Hz,1H),8.08-7.84(m,4H),7.79-7.75(m,1H),7.52-7.49(m,1H),7.42-7.38(m,1 H),6.95-6.92(m,1H),5.58(d,J=1.6Hz,2H),5.18-4.90(m,1H),4.78-4.32(m,5H),2.74-2.66(m,1H),2.46-2.39(m,2H).

[0356] (S)-2-(2,5-difluoro-4-(6-((5-fluoropyridin-2-yl)methoxy)pyridin-2-yl)benzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 298) [ka] Prepared in a similar manner to compound 279. LCMS: [M+H] + =562.0, retention time=1.40 minutes 1H NMR(400MHz,DMSO-D6)δ8.58(d,J=2.9Hz,1H),8.06(d,J=8.2Hz,1H),7.96(d,J=8.2Hz,1H),7.92-7.86(m,1H),7 .76(td,J=8.8,3.0Hz,1H),7.69(dd,J=10.5,6.5Hz,1H),7.59(dd,J=8.7,4.5Hz,1H),7.51(d,J=6.2Hz,1H),7.40 (dd,J=11.5,6.1Hz,1H),7.00(d,J=8.2Hz,1H),5.53(s,2H),5.19-5.11(m,1H),4.75(dd,J=15.1,6.3Hz,1H),4. 66-4.58(m,2H),4.50(dd,J=15.4,6.9Hz,2H),4.35(dt,J=9.0,6.0Hz,1H),2.77-2.67(m,1H),2.47-2.42(m,1H).

[0357] (S)-2-(4-(6-(4-chloro-2-fluorobenzyloxy)-3,5-difluoropyridin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 299) [ka] Prepared in a similar manner to compound 279. LCMS: [M+H] + =612.9, retention time=1.66 minutes 1 H NMR(400MHz,DMSO-D6)δ8.15(t,J=10Hz,1H),8.00(d,J=8Hz,1H),7.93(d,J=8.4Hz, 1H),7.74(t,J=6.8Hz,1H),7.64(t,J=8Hz,1H),7.53-7.48(m,2H),7.36(dd,J=1.6, 6.4Hz,1H),5.57(s,2H),5.15-5.13(m,1H),4.74(dd,J=6.4,8.8Hz,1H),4.65-4.58 (m,2H),4.54-4.47(m,2H),4.37-4.32(m,1H),2.73-2.67(m,1H),2.46-2.39(m,1H).

[0358] (S)-2-(4-(4-((5-chloropyridin-2-yl)methoxy)-5-fluoropyrimidin-2-yl)-2,5-difluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 300) [ka] Prepared in a similar manner to compound 279. LCMS: [M+H] + =597.1, retention time=1.24 minutes 1 H NMR(400MHz,DMSO-D6)δ8.84(d,J=2.9Hz,1H),8.65(d,J=2.1Hz,1H),8.05(d,J=8.2Hz,1H),8.00(dd,J= 8.4,2.5Hz,1H),7.95(d,J=8.2Hz,1H),7.76(dd,J=10.0,6.4Hz,1H),7.61(d,J=8.5Hz,1H),7.41(dd,J= 11.1,6.1Hz,1H),5.70(s,2H),5.18-5.10(m,1H),4.74(dd,J=15.4,6.8Hz,1H),4.63(d,J=16.8Hz,2H), 4.52(dd,J=15.1,6.2Hz,2H),4.37-4.31(dd,J=14.9,5.9Hz,1H),2.75-2.67(m,1H),2.43-2.34(m,1H).

[0359] (S)-2-(4-(4-((5-cyano-3-fluoropyridin-2-yl)methoxy)-5-fluoropyrimidin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 301) [ka] Prepared in a similar manner to compound 279. LCMS: [M+H] + =588.0, retention time=1.41 minutes 1H NMR(400MHz,CDCl3)δ8.70(s,1H),8.45(t,J=11.9Hz,1H),8.18(dt,J=21.0,10.4Hz,2H),8.07-7.94(m,2H),7.75(dd,J=8.7,1.4Hz,1H),7.39(t,J=7 .7Hz,1H),5.84(t,J=7.0Hz,2H),5.21(s,1H),4.60(ddd,J=29.6,16.5,8.5 Hz,4H),4.39(dd,J=34.6,28.6Hz,2H),2.79(d,J=8.4Hz,1H),2.44(s,1H).

[0360] (S)-2-(4-(4-((5-cyano-3-fluoropyridin-2-yl)methoxy)-5-fluoropyrimidin-2-yl)-3-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 302) [ka] Prepared in a similar manner to compound 279. LCMS: [M+H] + =587.9, retention time=1.36 minutes 1 H NMR(400MHz,CD3OD):δ8.61(brs,1H),8.46(d,J=2.8Hz,1H),8.05-8.00(m,2H),7.95(d,J=8.4Hz,1H),7.84(t,J=8Hz,1H),7.12-7.05(m,2H) ),5.75(d,J=1.6Hz,2H),5.16-5.12(m,1H),4.65-4.56(m,2H),4.54-4.46(m,3H),4.34-4.29(m,1H),2.68-2.64(m,1H),2.41-2.38(m,1H).

[0361] (S)-2-(4-(6-(4-(1H-imidazol-1-yl)benzyloxy)pyridin-2-yl)-2,5-difluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 303) [ka] Prepared in a similar manner to compound 279. LCMS: [M+H] + =609.0, retention time=1.69 minutes 1 H NMR(400MHz,DMSO-D6)δ8.28-8.26(brs,1H),8.08(d,J=8.2Hz,1H),7.97(d,J=8.2Hz,1H),7.90-7.86(m,1 H),7.85-7.81(m,1H),7.76-7.74(m,1H),7.69-7.62(m,4H),7.51(d,J=6.0Hz,1H),7.42(dd,J=11.4,6.1Hz ,1H),7.11-7.09(m,1H),6.96(d,J=8.2Hz,1H),5.52(s,2H),5.18-5.13(m,1H),4.76(dd,J=15.1,6.4Hz,1H ),4.67-4.61(m,2H),4.56-4.49(m,2H),4.35(dt,J=9.0,6.1Hz,1H),2.75-2.68(m,1H),2.43-2.40(m,1H).

[0362] (S)-2-(4-(6-((4-(1H-imidazol-1-yl)benzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 304) [ka] Prepared in a similar manner to compound 279. LCMS: [M+H] + =591.1, retention time=1.36 minutes 1H NMR(400MHz,DMSO-D6)δ8.25-8.24(brs,1H),8.06(d,J=8.2Hz,1H),7.99-7.89(m,3H),7.88-7.80( m,1H),7.74(t,J=1.3Hz,1H),7.70-7.61(m,5H),7.46(t,J=8.1Hz,1H),7.10-7.09(brs,1H),6.90( d,J=8.2Hz,1H),5.54(s,2H),5.14(d,J=7.1Hz,1H),4.73(dd,J=15.1,6.4Hz,1H),4.68-4.58(m,2H ),4.51(dd,J=14.9,10.2Hz,2H),4.36(dt,J=8.8,5.9Hz,1H),2.78-2.65(m,1H),2.41-2.35(m,1H).

[0363] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)-3-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 305) [ka] Prepared in a similar manner to compound 279. LCMS: [M+H] + =595.1, retention time=1.93 minutes 1 H NMR(400MHz,DMSO-D6)δ8.07(d,J=8.2Hz,1H),8.02-7.87(m,2H),7.81(dd,J=10. 3,8.3Hz,1H),7.62(t,J=8.2Hz,1H),7.55-7.42(m,2H),7.39-7.26(m,3H),5.55( s,2H),5.11(d,J=6.7Hz,1H),4.69(dd,J=15.0,6.3Hz,1H),4.53(ddd,J=21.4,18 .2,7.7Hz,4H),4.35(dd,J=14.9,6.0Hz,1H),2.67(s,1H),2.44(d,J=8.6Hz,1H).

[0364] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)-3-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 306) [ka] Prepared in a similar manner to compound 279. LCMS: [M+H] + =613.0, retention time=1.93 minutes 1 H NMR(400MHz,DMSO-D6)δ8.20-8.06(m,2H),7.97(d,J=8.2Hz,1H),7.65-7.48(m,3H),7.36(t,J=9.5Hz,3H),5.47(s,2H),5.14(s,1H) ),4.72(dd,J=15.0,6.5Hz,1H),4.55(m,J=21.6,15.3,5.2Hz,4H),4.37(dd,J=14.9,6.0Hz,1H),2.69(d,J=7.7Hz,1H),2.45(s,1H).

[0365] (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 307) [ka]

[0366] Step 1 A solution of 2-(4-bromo-3-fluoro-phenyl)acetic acid (220.7 mg, 947 μmol), ethyl 4-amino-2-fluoro-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (231 mg, 861 μmol), EDCI (494.3 mg, 2.58 mmol), and DIEA (669.90 mg, 5.18 mmol) was stirred for 16 hours at 25° C. The resulting mixture was poured into water and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography (eluted with ethyl acetate / petroleum ether, v / v, 1 / 1) to give ethyl 4-[[2-(4-bromo-3-fluoro-phenyl)acetyl]amino]-2-fluoro-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (82 mg, 15.2% yield) as a yellow solid. LCMS: [M+H] + =483.0, retention time=2.27 minutes

[0367] Step 2 A solution of ethyl 4-[[2-(4-bromo-3-fluorophenyl)acetyl]amino]-2-fluoro-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (82 mg, 170 μmol) in AcOH (1 mL) was stirred at 120 °C for 2 h. The resulting mixture was concentrated to remove most of the solvent, and the pH of the solution was adjusted to 7-8 with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (3 × 10 mL), concentrated, and purified by silica gel chromatography (eluted with ethyl acetate / petroleum ether, v / v, 1 / 1) to give ethyl (S)-2-(4-bromo-3-fluorobenzyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (60 mg, 68.4% yield) as a yellow solid. LCMS: [M+H] + =465.1, retention time (0.01%TFA)=2.07 minutes

[0368] Step 3 A mixture of ethyl (S)-2-(4-bromo-3-fluorobenzyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (105 mg, 226 μmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (63.0 mg, 248 μmol), PdCl(dppf) (36.9 mg, 45 μmol), and KOAc (66.4 mg, 677 μmol) in dioxane (2 mL) was stirred at 100 °C under nitrogen for 16 h. The resulting mixture was filtered, washed with ethyl acetate, and concentrated to give ethyl (S)-7-fluoro-2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (227 mg, 204 μmol, 90.31% yield) as a brown solid, which was used directly in the next stop. LCMS: [M+H] + =513.3, retention time (0.01%TFA)=2.10 minutes

[0369] Step 4 A mixture of ethyl (S)-7-fluoro-2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (110 mg, 215 μmol), 4-[(6-bromo-2-pyridyl)oxymethyl]-3-fluorobenzonitrile (65.9 mg, 215 μmol), KCO (88.9 mg, 644 μmol), and Pd(dppf)Cl (17.5 mg, 21 μmol) in dioxane (2 mL) was stirred at 90 °C under nitrogen for 3 h. The resulting mixture was concentrated and purified by silica gel chromatography (eluted with ethyl acetate / petroleum ether, v / v, 1 / 1) to give ethyl (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (30 mg, 22.8% yield) as a white solid. LCMS: [M+H] + =613.0, retention time=2.33 minutes

[0370] Step 5 A solution of ethyl (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-7-fluoro-1-(oxetan-2)-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (90 mg, 147 μmol) and 0.5 N LiOH (2 mL) in THF (7 mL) was stirred at 25 °C for 16 h. The mixture was neutralized to pH = 5 with acetic acid, and the resulting mixture was extracted with DCM / MeOH (v / v = 10 / 1, 3 × 10 mL). The combined organic layers were concentrated and purified by preparative HPLC (column: Xtimate C18 21.2*250 mm, 10 μm; mobile phase: A: water (10 mM NH4HCO3 & 0.025% NH3·H2O), B: ACN; gradient: 5% B for 3 min, then 50–50% B for 10 min, stop at 18 min; flow rate (ml / min): 30.00; detection wavelength (nm): 214 nm) to give (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (17.3 mg, 20.14% yield) as a white solid. LCMS: [M+H] + =585.1, retention time=1.82 minutes 1 H NMR(400MHz,DMSO-D6)δ7.97-7.82(m,3H),7.80-7.67(m,2H),7.62-7.50(m ,1H),7.46(d,J=5.9Hz,1H),7.30(dd,J=17.4,7.5Hz,3H),6.94(d,J=8.2Hz ,1H),5.57(s,2H),5.04(d,J=4.9Hz,1H),4.71(dd,J=15.6,7.2Hz,1H),4.6 1-4.31(m,5H),2.72(dt,J=16.4,8.3Hz,1H),2.42(dd,J=21.2,12.5Hz,1H).

[0371] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 308) [ka] Prepared in a similar manner to compound 307. LCMS: [M+H] + =594.0, retention time=1.93 minutes 1 H NMR(400MHz,DMSO-D6)δ7.95(t,J=8.4Hz,1H),7.84(t,J=7.9Hz,1H),7.61(dd, J=16.3,8.2Hz,2H),7.46(ddd,J=22.7,13.4,5.1Hz,3H),7.31(dd,J=10.0,5.9 Hz,3H),6.89(d,J=8.2Hz,1H),5.47(s,2H),5.04(d,J=6.6Hz,1H),4.75(dd,J= 15.5,7.4Hz,1H),4.65-4.32(m,5H),2.78-2.67(m,1H),2.43(d,J=8.4Hz,1H).

[0372] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 309) [ka] Prepared in a similar manner to compound 307. LCMS: [M+H] + =594.0, retention time=1.96 minutes 1H NMR(400MHz,MeOD)δ7.74(dd,J=11.5,9.2Hz,2H),7.69-7.57(m,2H),7.48-7.36(m,2H) ),7.35-7.18(m,2H),7.10(dd,J=14.0,4.9Hz,2H),6.70(d,J=8.2Hz,1H),5.43(s,2H) ,5.12(d,J=5.5Hz,1H),4.66(dd,J=15.4,7.2Hz,1H),4.61-4.54(m,1H),4.54-4.44(m ,2H),4.42-4.25(m,2H),3.55(d,J=3.1Hz,2H),2.80-2.64(m,1H),2.49-2.36(m,1H).

[0373] (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 310) [ka] Prepared in a similar manner to compound 307. LCMS: [M+H] + =585.1, retention time=1.85 minutes 1 H NMR(400MHz,DMSO-D6)δ7.89(dd,J=22.8,9.2Hz,4H),7.75(d,J=11.0Hz,2H),7.64(dd,J=16.6,7.0Hz,2H),7.50-7.2 6(m,2H),6.93(d,J=8.2Hz,1H),5.62(s,2H),5.10(s,1H),4.76(s,1H),4.66-4.29(m,5H),2.75(s,1H),2.43(s,1H).

[0374] (S)-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-2-yl)-2-fluorobenzyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 311) [ka] Prepared in a similar manner to compound 307. LCMS: [M+H] + =595.2, retention time (0.01%TFA)=1.64 minutes 1 H NMR(400MHz,DMSO-D6)δ8.73(d,J=5.2Hz,1H),8.09-7.98(m,2H),7.82(d,J=5.2Hz,1H),7.63(dd,J=16.6,8.4Hz,2H),7.56-7.46(m,2H),7.4 3-7.28(m,2H),5.53(s,2H),5.09(d,J=7.0Hz,1H),4.78(dd,J=15.6,7.2Hz,1H),4.67-4.28(m,5H),2.80-2.70(m,1H),2.44(d,J=8.9Hz,1H).

[0375] (S)-2-(4-(4-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyrimidin-2-yl)-2-fluorobenzyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 312) [ka] Prepared in a similar manner to compound 307. LCMS: [M+H] + =603.9, retention time=1.53 minutes 1 H NMR(400MHz,CDCl3)δ8.44-8.43(d,J=2.4Hz,1H),8.11-8.05(m,2H),7.93-7.89(t,J=8.0Hz,1H),7.70-7.66(t,J=7.6Hz,1H),7.63-7.61(d,J=8.0Hz) ,1H),7.51-7.47(t,J=8.0Hz,2H),7.45-7.42(d,J=9.2Hz,1H),5.71(s,2H) ,5.22-5.20(d,J=6.8Hz,1H),4.71-4.47(m,6H),2.82(s,1H),2.47(s,1H).

[0376] (S)-2-(4-(4-((5-cyanopyridin-2-yl)methoxy)-5-fluoropyrimidin-2-yl)-2,5-difluorobenzyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 313) [ka] Prepared in a similar manner to compound 307. LCMS: [M+H] + =605.2, retention time (10mM NH4HCO3)=1.18min

[0377] (S)-2-((1-(6-(4-cyano-2-fluorobenzyloxy)pyridin-2-yl)piperidin-4-ylidene)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 314) [ka]

[0378] Step 1 A mixture of 4-[(6-bromo-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile (10 g, 30.93 mmol), piperidin-4-one (3.99 g, 40.21 mmol), Pd(dba) (1.13 g, 1.55 mmol), BINAP (1.93 g, 3.09 mmol), and CsCO (15.08 g, 46.40 mmol) in toluene (80 mL) was stirred under argon at 110 °C for 18 h until the reaction was complete by LCMS. The reaction mixture was filtered through a pad of Celite with EtOAc, and the combined organics were concentrated in vacuo and purified by silica gel chromatography (hexane / EtOAc = 77:23) to give the desired product, 3-fluoro-4-benzonitrile. [[6-(4-oxo-1-piperidyl)-2-pyridyl]oxymethyl]benzonitrile (5.25 g, 52.2% yield) was obtained as a pale yellow solid. LCMS: [M+H] + =326.2, retention time=1.63 minutes 1 H NMR(400MHz,CDCl3)δ7.62(t,J=7.6Hz,1H),7.50-7.42(m,2H),7.37(dd,J=1.2,8Hz,1H),6.3 2(d,J=8Hz,1H),6.23(d,J=7.6Hz,1H),5.44(s,2H),3.85(t,J=6Hz,4H),2.46(t,J=6Hz,4H).

[0379] Step 2 To a suspension of tert-butyl 2-dimethoxyphosphoryl acetate (7.13 g, 31.81 mmol) in THF (60 mL) was slowly added LDA (3.98 g, 37.12 mmol, 19 mL) at room temperature and stirred for 10 min under Ar. A solution of 3-fluoro-4-[[6-(4-oxo-1-piperidyl)-2-pyridyl]oxymethyl]benzonitrile (3.45 g, 10.60 mmol) in THF (15 mL) was added dropwise at room temperature. After the reaction was judged complete by LCMS, the reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (3 × 20 mL). The organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, hexane / ethyl acetate 10:1) to give 2-[1-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-tert-butylpyridyl]-4-piperidylidene]acetate (2.2 g, 36.1% yield) as a colorless liquid. LCMS: [M+H] + =424.2, retention time=1.98 minutes

[0380] Step 3 To a mixture of tert-butyl 2-[1-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-4-piperidylidene]acetate (2.2 g, 5.20 mmol) in DCM (21 mL) was added TFA (10.36 g, 90.86 mmol, 7 mL) and stirred at room temperature for 1 h until the reaction was complete as indicated by LCMS. The reaction mixture was added DCM (160 mL), washed with saturated aqueous NaHCO3 (2 x 30 mL), dried, evaporated and purified by flash chromatography on silica gel (PE:EA / 0%-66%) to give the desired product 2-[1-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-4-piperidylidene]acetic acid (1.78 g, 4.44 mmol, 85.5% yield) as an off-white solid. LCMS: [M+H] + =368.1, retention time=1.25 minutes

[0381] Step 4 A mixture of 2-[1-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-4-piperidylidene]acetic acid (723 mg, 1.97 mmol) in THF (30 mL) was stirred and cooled on a salt-ice bath. Isobutyl chloroformate (525.00 mg, 3.84 mmol) and N-methylmorpholine (598 mg, 5.91 mmol, 0.65 mL) were then added, and the reaction was stirred on the salt-ice bath for 20 min. tert-Butyl 5-amino-6-[[(2S)-oxetan-2-yl]methylamino]pyridine-2-carboxylate (500 mg, 1.79 mmol) was dissolved in pyridine (6.85 g, 86.55 mmol, 7 mL), and N-methylmorpholine (598 mg, 5.91 mmol, 0.65 mL) was added to the reaction mixture on an ice bath with stirring at 0 °C for 1 h. After completion of the reaction, the solvent was evaporated in vacuo, and the remaining residue was partitioned between DCM (50 mL) and water (20 mL). The DCM layer was washed once with brine, dried over anhydrous NaSO, filtered, and evaporated in vacuo to give the crude product. The crude product was purified by silica gel chromatography (hexane / EtOAc=20:1) to give the desired product tert-butyl 5-[[2-[1-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-4-piperidylidene]acetyl]amino]-6-[[(2S)-oxetan-2-yl]methylamino]pyridine-2-carboxylate (168 mg, 13.35% yield) as a pale yellow solid. LCMS: [M+H] + =629.1, retention time=2.12 minutes

[0382] Step 5 A mixture of tert-butyl 5-[[2-[1-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-4-piperidylidene]acetyl]amino]-6-[[(2S)-oxetan-2-yl]methylamino]pyridine-2-carboxylate (64 mg, 102 μmol) and AcOH (102 μmol) in toluene (4 mL) was heated at 60° C. for 1.5 hours until the reaction was complete as indicated by LCMS. After stirring for 1 h, the reaction mixture was concentrated in vacuo and purified by preparative TLC (PE:EA / 1:1.5) to give the desired product tert-butyl 2-[[1-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-4-piperidylidene]methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylate (5 mg, 8.0% yield) as a pale yellow oil. LCMS: [M+H] + =612.3, retention time (0.01%TFA)=2.04 minutes

[0383] Step 6 To a mixture of tert-butyl 2-[[1-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-4-piperidylidene]methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylate (5 mg, 8 μmol) in DCM (4 mL) was added TFA (1.48 g, 13.0 mmol, 1 mL) until the reaction was complete as indicated by LCMS. After stirring at room temperature for 1 hour, the reaction mixture was concentrated in vacuo, dissolved in THF (1.5 mL), and purified by preparative HPLC to give the desired product, 2-[[1-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-4-piperidylidene]methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylic acid (1.1 mg, 23.3% yield) as a white solid. LCMS: [M+H] + =555.0, retention time=1.51 minutes 1H NMR(400MHz,DMSO-D6-d6)δ8.16-8.09(m,1H),7.68(t,J=8Hz,1H),7.62-7.55(m,2H),7.52(t,J=8Hz,1 H),6.70(s,1H),6.41(d,J=8.4Hz,1H),6.18(d,J=8Hz,1H),5.49(s,2H),5.28(dd,J=2.8,2.4Hz,1H),4. 82-4.80(m,1H),4.74-4.68(m,1H),4.63-4.60(m,1H),4.46-4.41(m,1H),3.74(dd,J=4.4,2Hz,2H),3. 68(t,J=5.6Hz,2H),2.95(t,J=5.6Hz,2H),2.81-2.76(m,1H),2.56-2.54(m,1H),2.50(t,J=5.2Hz,2H).

[0384] (S)-2-((1-(6-(2,4-difluorobenzyloxy)pyridin-2-yl)piperidin-4-ylidene)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 315) [ka] Prepared in a similar manner to compound 314. LCMS: [M+H] + =548.0, retention time (0.01%TFA)=1.97 minutes 1 H NMR(400MHz,MeOD)δ8.15(d,J=16.0Hz,2H),7.48-7.47(brs,2H),6.97(d,J=8.2Hz,2H),6.70- 6.69(brs,1H),6.41-6.40(brs,1H),6.13-6.12(brs,1H),5.38(s,2H),5.33-5.28(m,1H),4.7 7-4.76(brs,1H),4.64-4.63(brs,1H),3.79-3.78(brs,1H),3.73-3.72(brs,1H),3.02-3.01( brs, 2H), 2.78-2.77(brs, 1H), 2.56-2.55(brs, 3H), 2.06-2.05(brs, 2H), 0.92-0.91(brs, 2H).

[0385] (S)-2-((1-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperidin-4-ylidene)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 316) [ka] Prepared in a similar manner to compound 314. LCMS: [M+H] + =538.2, retention time (0.01%TFA)=1.74 minutes 1 H NMR(400MHz,CDCl3)δ8.85-8.83(m,1H),8.26-8.18(m,2H),7.95-7.91(m,1H),7.60- 7.54(m,1H),7.48-7.44(m,1H),6.22-6.20(m,1H),6.17-6.14(m,1H),5.57-5.54(m, 1H),5.52(s,2H),5.20-5.18(m,1H),4.67-4.58(m,3H),4.41-4.35(m,1H),3.95-3.8 3(m,4H),3.69-3.58(m,2H),2.81-2.79(m,1H),2.47-2.42(m,1H),2.21-2.20(m,2H).

[0386] (S)-2-((1-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-4-ylidene)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 317) [ka] Prepared in a similar manner to compound 314. LCMS: [M+H] + =554.0, retention time=1.31 minutes 1H NMRδ8.18(s,1H),7.88(d,J=9.8Hz,1H),7.79(d,J=8.4Hz,1H),7.70-7.66(m,2H),7.58(d,J= 8.4Hz,1H),7.50-7.45(m,1H),6.29(d,J=8.2Hz,1H),6.10(d,J=7.8Hz,1H),5.57-5.53(brs,1 H),5.42(s,2H),5.02-4.96(m,1H),4.62-4.57(m,1H),4.51-4.43(m,2H),4.35-4.30(m,1H),3 .91-3.84(m,2H),3.82-3.71(m,2H),3.65-3.58(m,3H),2.68-2.64(m,1H),2.19-2.12(m,2H).

[0387] (S)-2-((1-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperidin-4-ylidene)methyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 318) [ka]

[0388] Step 1 Tert-butyl 4-(2-ethoxy-2-oxo-ethylidene)piperidine-1-carboxylate (1.0 g, 3.71 mmol) was dissolved in THF (10 mL) and ethanol (8 mL). Lithium hydroxide hydrate (779 mg, 18.56 mmol) in water (7 mL) was added. The mixture was stirred at 50° C. for 16 hours, the mixture was neutralized with acetic acid to pH=5, and the resulting mixture was extracted with EtOAc (2×50 mL). The combined organic layers were concentrated to give 2-(1-tert-butoxycarbonyl-4-piperidylidene)acetic acid (0.9 g, 3.54 mmol, 95.4% yield). LCMS: [M+Na] + =264.1, retention time (0.01%TFA)=1.75 minutes

[0389] Step 2 A solution of ethyl 4-amino-2-fluoro-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (207 mg, 772 μmol), 2-(1-tert-butoxycarbonyl-4-piperidylidene)acetic acid (204.79 mg, 889 μmol), T3P (736.08 mg, 2.31 mmol), and Et3N (311.72 mg, 3.09 mmol) was dissolved in DMF (5 mL), and the mixture was stirred at 30° C. for 16 h. The resulting mixture was poured into water and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography (eluted with ethyl acetate / petroleum ether, v / v, 3 / 2) to give tert-butyl (S)-4-(2-((4-(ethoxycarbonyl)-3-fluoro-2-((oxetan-2-ylmethyl)amino)phenyl)amino)-2-oxoethylidene)piperidine-1-carboxylate (135 mg, 27.4% yield) as a yellow oil. LCMS: [M+H] + =492.3, retention time (0.01%TFA)=2.07 minutes

[0390] Step 3 A solution of tert-butyl 4-[2-[4-ethoxycarbonyl-3-fluoro-2-[[(2S)-oxetan-2-yl]methylamino]anilino]-2-oxo-ethylidene]piperidine-1-carboxylate (64 mg, 130 μmol) in toluene (2 mL) was stirred at 120° C. for 16 hours. The resulting mixture was concentrated and purified by silica gel chromatography (eluted with ethyl acetate / petroleum ether, v / v, 4 / 1) to afford ethyl (S)-2-((1-(tert-butoxycarbonyl)piperidin-4-ylidene)methyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (46 mg, 74.6% yield) as a yellow oil. LCMS: [M+H] + =474.3, retention time (0.01%TFA)=1.97 minutes

[0391] Step 4 To a solution of ethyl (S)-2-((1-(tert-butoxycarbonyl)piperidin-4-ylidene)methyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (20 mg, 41 μmol) in DCM (5 mL) was added TFA (8.5 mg, 75 μmol). The mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated, adjusted to approximately pH 8 with saturated sodium bicarbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give ethyl (S)-7-fluoro-1-(oxetan-2-ylmethyl)-2-(piperidin-4-ylidenemethyl)-1H-benzo[d]imidazole-6-carboxylate (10 mg, 27 μmol, 65.8% yield) as a yellow oil. LCMS: [M+H] + =374.2, retention time (0.1%TFA)=0.89 minutes

[0392] Step 5 In a glove box, a solution of ethyl (S)-7-fluoro-1-(oxetan-2-ylmethyl)-2-(piperidin-4-ylidenemethyl)-1H-benzo[d]imidazole-6-carboxylate (40 mg, 107 μmol), 6-[(6-bromo-2-pyridyl)oxymethyl]pyridine-3-carbonitrile (31.08 mg, 107 μmol), Pd(dba) (9.8 mg, 11 μmol), BINAP (13.3 mg, 21 μmol), and CsCO (104.8 mg, 321 μmol) in toluene (2 mL) was stirred at 110 °C for 16 h. The resulting solution was filtered and purified by silica gel chromatography (eluted with ethyl acetate / petroleum ether, v / v, 4 / 1) to give ethyl (S)-2-((1-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperidin-4-ylidene)methyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (63 mg, 66.6% yield) as a yellow oil. LCMS: [M+H] + =583.3, retention time (0.1%TFA)=1.36 minutes

[0393] Step 6 A solution of ethyl (S)-2-((1-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperidin-4-ylidene)methyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (60 mg, 103 μmol) and LiOH (0.1 N) (86.5 mg, 2.06 mmol) in THF (10 mL) was stirred at room temperature for 6 h. The resulting mixture was neutralized to pH = 5 with acetic acid and extracted with DCM / MeOH (v / v = 10 / 1, 3 × 10 mL). The combined organic layers were concentrated and purified by preparative HPLC to afford (S)-2-((1-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperidin-4-ylidene)methyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (3.7 mg, 6.5% yield) as a white solid. LCMS: [M+H] + = 555.2, retention time (0.1% FA) = 1.88 min 1 H NMR(400MHz,DMSO-D6)δ8.98(d,J=1.3Hz,1H),8.26(dd,J=8.2,2.1Hz,1H),7.90-7.71(m,1H),7.57(t,J= 7.9Hz,2H),7.48(t,J=8.0Hz,1H),7.35(d,J=8.4Hz,1H),6.27(d,J=8.2Hz,1H),6.16(d,J=7.7Hz,1H),5.5 1(s,1H),5.43(s,2H),5.00(s,1H),4.62(dd,J=15.5,7.4Hz,1H),4.54-4.39(m,2H),4.34(dt,J=8.8,6.0 Hz,1H),3.73(dd,J=25.8,15.9Hz,3H),2.68(d,J=6.8Hz,2H),2.39(dd,J=22.8,14.1Hz,2H),2.10(s,2H).

[0394] (S)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)cyclohexyl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 319) [ka]

[0395] Step 1 Trifluoromethylsulfonyl trifluoromethanesulfonate (2.39 g, 8.46 mmol, 1.42 mL) was added dropwise to a solution of 2,6-ditert-butyl-4-methyl-pyridine (2.17 g, 10.58 mmol) in dichloromethane (16 mL), followed by the dropwise addition of methyl 2-(4-oxocyclohexyl)acetate (1.2 g, 7.05 mmol) in dichloromethane (16 mL). The reaction mixture was stirred at 25 °C for 16 h and then concentrated to give methyl 2-[4-(trifluoromethylsulfonyloxy)cyclohexen-3-en-1-yl]acetate (1.48 g, 66.1% yield) as a colorless oil. LCMS: [M+H] + =591, retention time (10mM NH4HCO3) = 2.35 minutes

[0396] Step 2 A mixture of 2-[4-(trifluoromethylphenyloxy)cyclohex-3-en-1-yl]acetate methyl ester (700 mg, 2.32 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (646.9 mg, 2.55 mmol), Pd(dppf)Cl2 (94.6 mg, 116 μmol), potassium acetate (681.84 mg, 6.95 mmol), and Pd(dppf)Cl2 (64.2 mg, 116 μmol) in dioxane (1 mL) was exchanged in a glovebox. The reaction mixture was stirred at 80 °C for 17 h. LCMS indicated the reaction was complete. Silica gel (3 g) was added to the reaction mixture and evaporated to a dry powder, which was purified by silica gel. Methyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexen-3-en-1-yl]acetate (546 mg, 1.85 mmol, 80.0% yield) was obtained as a light yellow solid. LCMS: [M+H] + =280, retention time (0.01%TFA)=2.16 minutes

[0397] Step 3 A mixture of [4-(2-methoxy-2-oxo-ethyl)cyclohexen-1-yl]boronic acid (443 mg, 2.13 mmol), 2-bromo-6-[(4-chloro-2-fluorophenyl)methoxy]pyridine (672.8 mg, 2.13 mmol), dipotassium carbonate (881.2 mg, 6.38 mmol), and Pd(dppf)Cl2 (77.7 mg, 106 μmol) in dioxane (6 mL) was bubbled with nitrogen for 10 min and then stirred at 80 °C for 16 h. LCMS indicated the reaction was complete. 2-[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]cyclohexen-3-en-1-yl]acetate methyl ester (361 mg, 833 μmol, 39.2% yield) was obtained as a white solid. LCMS: [M+H] + =390, retention time (10mmol NH4HCO3)=2.49min

[0398] Step 4 To a solution of methyl 2-[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]cyclohex-3-en-1-yl]acetate (351 mg, 810 μmol) in methanol (50 mL) was added Raney nickel (0.5 g, 5.84 mmol). The reaction mixture was stirred at 20° C. for 2 hours. LCMS showed the reaction was complete. The reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was evaporated under reduced pressure to give methyl 2-[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]cyclohexyl]acetate (331 mg, 718 μmol, 88.6% yield) as a white solid. LCMS: [M+H] + =392, retention time (0.01%TFA)=2.42 minutes

[0399] Step 5 To a solution of methyl 2-[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]cyclohexyl]acetate (330 mg, 716 μmol) in THF (3 mL) in ice was added a solution of lithium hydroxide hydrate (150.2 mg, 3.58 mmol) in water (3 mL) dropwise. The reaction mixture was stirred at 50° C. for 16 h. 2-[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]cyclohexyl]acetic acid (180 mg, 453 μmol, 63.2% yield) was obtained as a light yellow oil. LCMS: [M+H] + =378, retention time (0.01%TFA)=2.20 minutes

[0400] Step 6 A solution of 2-[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]cyclohexyl]acetic acid (137 mg, 344 μmol), methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (81.38 mg, 344 μmol), 3-hydroxytriazolo[4,5-b]pyridine (56.26 mg, 413 μmol), and 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (79.24 mg, 413 μmol) in DMF (1 mL) was stirred at 25 °C for 1 h. LCMS indicated the reaction was complete. The reaction mixture was diluted with brine (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure to give a residue which was purified on silica gel to give tert-butyl 2-[[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]cyclohexyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (180 mg, 80.1% yield) as a colorless oil. LCMS: [M+H] + =638, retention time (0.01%TFA)=2.41 minutes

[0401] Step 7 A solution of tert-butyl 4-[[2-[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]cyclohexyl]acetyl]amino]-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (175 mg, 261 μmol) in acetic acid (3 mL) was stirred at 60° C. for 2 hours. LCMS showed the reaction was complete. The reaction mixture was slowly flushed with nitrogen until the solvent was removed. Methyl (S)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)cyclohexyl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (127 mg, 74.7% yield) was obtained as a light yellow oil. LCMS: [M+H] + =620, retention time (0.01%TFA)=2.04 minutes

[0402] Step 8 Methyl (S)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)cyclohexyl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (122 mg, 187 μmol) was dissolved in dichloromethane (2 mL) and 2,2,2-trifluoroacetic acid (21.3 mg, 187 μmol). The reaction mixture was stirred at 25° C. for 0.5 h. LCMS showed the reaction was complete. The solvent was completely removed. The residue was basified with saturated ammonium bicarbonate solution to pH=5 and extracted with dichloromethane (3×10 mL). The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. 2-(((1r,4S)-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)cyclohexyl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (60 mg, 54.1% yield) was obtained as a brown solid. LCMS: [M+H] + =564, retention time (0.01%TFA)=1.85 minutes 1 H NMR(400MHz,DMSO-D6)δ8.68(s,1H),8.20(s,1H),7.87(d,J=41.1Hz,2H),7 .61(s,1H),7.47-7.16(m,3H),7.08(s,1H),6.92(d,J=36.3Hz,1H),5.48(s ,2H),5.09(d,J=49.3Hz,2H),4.87(s,1H),4.47(s,2H),3.37(s,1H),2.87( s,1H),2.46-2.36(m,2H),2.08(s,2H),1.91(s,2H),1.68(d,J=67.4Hz,6H).

[0403] (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorophenyl)amino)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 320) [ka]

[0404] Step 1 To a solution of 4-bromo-2-fluoroaniline (3.8 g, 20.00 mmol) in ethanol (40 mL) were added CS2 (4.57 grams, 60.00 mmol, 3.60 mL) and DABCO (13.46 g, 120.00 mmol). The reaction mixture was stirred at room temperature overnight. The resulting precipitate was collected by filtration, washed with ice-cold ethanol, and dried to give a pale yellow solid, which was used in the next step without further characterization or purification. Triphosgene (2.97 g, 10.00 mmol) was slowly added to a solution of the above pale yellow solid in DCM (50 mL) at 0 °C. The reaction mixture was stirred at this temperature for an additional hour, then heated to 40 °C for 4 hours, and the reaction was quenched with water. The crude product was extracted with CHCl (3×50 mL), then dried over MgSO and concentrated, and the residue was purified by flash column chromatography on silica gel eluted with petroleum ether to give 4-bromo-2-fluoro-1-isothiocyanato-benzene (3.6 g, 15.20 mmol, 76.0% yield). Retention time (0.01% TFA) = 2.26 min.

[0405] Step 2 To a suspension of tert-butyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (115 mg, 413 μmol) in DCM (2 mL) was added 4-bromo-2-fluoro-1-isothiocyanatobenzene (108.4 mg, 467 μmol), EDCI (89.5 mg, 467 μmol), and DIEA (60.3 mg, 467 μmol). The reaction mixture was stirred at 40° C. for 16 h until complete by TLC. The reaction mixture was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel eluting with CHCl / MeOH (20:1) to give tert-butyl (S)-2-((4-bromo-2-fluorophenyl)amino)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (99 mg, 50.3% yield) as a pale yellow solid. LCMS: [M+H] + =476, retention time (0.01%TFA)=2.05 minutes

[0406] Step 3 A mixture of tert-butyl (S)-2-((4-bromo-2-fluorophenyl)amino)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 210 μmol), potassium acetate (61.8 mg, 630 μmol), bis(pinacolato)diboron (53.3 mg, 210 μmol), and Pd(DPPF)Cl₂ / DCM complex (8.6 mg, 11 μmol) in anhydrous dioxane (0.5 mL) was stirred at 80°C for 16 h. LCMS showed the reaction was complete, the reaction mixture was filtered through a pad of Celite with EtOAc, washed several times with ethyl acetate and the combined organics were concentrated in vacuo to give crude tert-butyl (S)-2-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (109.9 mg, 209.9 mmol, 82% yield) as a black oil which was used directly in the next step. LCMS: [M+H] +=524, retention time (0.01%TFA)=2.10 minutes

[0407] Step 4 A mixture of tert-butyl (S)-2-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (110 mg, 210 μmol), 4-[(6-bromo-2-pyridyl)oxymethyl]-3-fluorobenzonitrile (64.54 mg, 210 μmol), Pd(DPPF)Cl in DCM (8.6 mg, 11 μmol), and KCO (87.1 mg, 630 μmol) in dioxane (2 mL) was stirred at 80 °C under N for 16 h. The mixture was filtered and concentrated in vacuo to give crude product tert-butyl (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorophenyl)amino)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (120 mg, 91.6% yield) as a black oil. LCMS: [M+H] + =624.1, retention time (0.01%TFA)=2.48 minutes

[0408] Step 5 To a solution of tert-butyl (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorophenyl)amino)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 160 μmol) in DCM (1 mL) at 0° C. was slowly added 2,2,2-trifluoroacetic acid (91.4 mg, 801.7 μmol) and stirred at room temperature for 16 hours. After the reaction was judged complete by LCMS, the reaction mixture was filtered and concentrated in vacuo. The crude product was purified by preparative HPLC and lyophilized to give (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorophenyl)amino)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (27 mg, 29.7% yield) as a white solid. LCMS: [M+H] + =568.1, retention time=1.89 minutes 1 H NMR(400MHz,DMSO-D6-d6)δ 9.36(1H,s),8.47(1H,d,J=8.4),8.07(1H,s),7.96-7.92(3H,m),7.90-7.70(4H,m),7.63(1H,d,J=7.5),7.49(1H, d,J=8.2),6.87(1H,d,J=8.1),5.63(2H,s),5.23(1H,s),4.72-4.44(4H,m),2.82-2.65(1H,m),2.45-2.31(1H,s).

[0409] (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorophenoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 321) [ka]

[0410] Step 1 A mixture of methyl 2-oxo-1,3-dihydrobenzimidazole-5-carboxylate (1.6 g, 8.33 mmol) and phosphoryl trichloride (25.53 g, 166.52 mmol, 15.47 mL) was stirred at 100 °C for 3 hours until LCMS showed the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was cooled to 0 °C, and cold saturated aqueous NaHCO (30 mL) was carefully added. After stirring at room temperature for 15 minutes, the mixture was sonicated, and the resulting residue was filtered to give the title compound, methyl 2-chloro-3H-benzimidazole-5-carboxylate (1.3 g, 67.5% yield), which was used in the next step without further purification. LCMS: [M+H] + =211.1, retention time (0.01%TFA)=1.61 minutes

[0411] Step 2 A mixture of methyl 2-chloro-3H-benzimidazole-5-carboxylate (1 g, 4.32 mmol), 4-bromo-2-fluoro-phenol (2.48 g, 12.96 mmol, 1.42 mL), and N-ethyl-N-isopropyl-propan-2-amine (1.68 g, 12.96 mmol, 2.26 mL) was stirred at 150 °C for 3 h until LCMS showed the reaction was complete. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography (petroleum ether / EtOAc gradient 0-50%) to give the desired product, methyl 2-(4-bromo-2-fluoro-phenoxy)-3H-benzimidazole-5-carboxylate (700 mg, 36.8% yield) as a white solid. LCMS: [M+H] + =365.0, retention time (0.01%TFA)=1.92 minutes

[0412] Step 3 A mixture of methyl 2-(4-bromo-2-fluoro-phenoxy)-3H-benzimidazole-5-carboxylate (843.4 mg, 1.92 mmol) and dipotassium carbonate (397.4 mg, 2.88 mmol) in NMP (9 mL) was stirred at room temperature for 1 hour, and then [(2S)-oxetan-2-yl]methyl 4-methylbenzenesulfonate (696.7 mg, 2.88 mmol) was added to the mixture and stirred at 80° C. for 16 hours. The mixture was purified by preparative HPLC to give (Product 1) methyl 2-(4-bromo-2-fluoro-phenoxy)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (4) (135 mg, 307 μmol, 16.0% yield) (NBK0059-76-P2) and (Product 2) methyl 2-(4-bromo-2-fluoro-phenoxy)-1-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (5) (150 mg, 17.6% yield) (NBK0059-76-P1). Product 1: LCMS: [M+H] + =437.1, retention time (0.01%TFA)=1.91 min Product 2:LCMS:[M+H] + =437.1;Retention time (0.01%TFA)=1.89 minutes

[0413] Step 4 A mixture of methyl 2-(4-bromo-2-fluorophenoxy)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (4) (85 mg, 195 μmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaneboronane (49.6 mg, 195 μmol), potassium acetate (38.3 mg, 391 μmol), and cyclopentyl(diphenyl)phosphane dichloromethane dichloropalladium iron (16.0 mg, 20 μmol) in dioxane (2 mL) was stirred at 90 °C for 2 h until the reaction was complete as indicated by LCMS. The reaction mixture was used in the next step without purification. LCMS: [M+H] += 483.3, retention time = 2.11 min (hydrolyzed corresponding boronic acid [M+H] + = 401.2, retention time = 1.63 min was also observed).

[0414] Step 5 Sodium carbonate (62.0 mg, 585 μmol) (2 M in water) and cyclopentyl(diphenyl)phosphane·dichloromethane·iron dichloropalladium (15.92 mg, 20 μmol) were added to the resulting methyl mixture (S)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, and the mixture was stirred at 90° C. for 2 hours until the reaction was complete as indicated by LCMS. The reaction mixture was filtered through a pad of Celite with EtOAc. The combined organics were concentrated in vacuo and purified on a silica gel column (petroleum ether / EtOAc gradient 0-50%) to give the desired product, methyl (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorophenoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (110 mg, 88.2% yield). LCMS: [M+H] + =583.2, retention time (10mM NH4HCO3)=2.12 minutes

[0415] Step 6 To a stirred solution of methyl 2-[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-phenoxy]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (100 mg, 156 μmol) in THF (5 mL) was added lithium hydroxide hydrate (0.5 M) (65.6 mg, 1.56 mmol). The reaction mixture was stirred at 30° C. for 16 hours, and when judged complete by LCMS, the mixture was acidified with HOAc to approximately pH 6 and purified by preparative HPLC to afford (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorophenoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (34.2 mg, 60 μmol, 38.5% yield) as a white solid. LCMS: [M+H] + =669.2 1 H NMR(400MHz,DMSO-D6)δ8.20(d,J=1.2Hz,1H),8.11(dd,J=12.1,2.0Hz,1H),8.01(d,J=8.4Hz,1H),7.97-7.83(m,2H),7.81-7.67(m,5H),7.46(d ,J=8.4Hz,1H),6.96(d,J=8.2Hz,1H),5.64(s,2H),5.16(s,1H),4.72-4 .41(m,3H),4.33(dt,J=9.0,6.0Hz,1H),2.87-2.66(m,1H),2.53(s,1H).

[0416] (S)-2-((6-((4-cyano-2-fluorobenzyl)oxy)-2'-oxo-[2,4'-bipyridin]-1'(2'H)-yl)methyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 322) [ka]

[0417] Step 1 To a solution of ethyl 4-amino-2-fluoro-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (500 mg, 1.77 mmol) and 2-chloro-1,1,1-trimethoxyethane (288.1 mg, 1.77 mmol) in acetonitrile (5 mL) was added 4-methylbenzenesulfonic acid hydrate (33.7 mg, 177 μmol). The reaction mixture was stirred at 60 °C for 1.5 hours. LCMS showed the reaction was complete. Silica gel (1 g) was added to the reaction mixture, and the mixture was evaporated under reduced pressure to give a dry powder, which was purified on silica gel to give ethyl (S)-2-(chloromethyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (600 mg, 98.5% yield) as a white solid. LCMS: [M+H] + =327, retention time (10mM NH4HCO3) = 1.98 min

[0418] Step 2 A mixture of 4-bromo-1H-pyridin-2-one (124.7 mg, 717 μmol), ethyl 2-(chloromethyl)-4-fluoro-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (239 mg, 717 μmol), and cesium carbonate (233.6 mg, 717 μmol) in DMF (3 mL) was stirred at 25 °C for 2 h. LCMS showed the reaction was complete. The reaction mixture was diluted with saturated ammonium chloride solution and extracted with ethyl acetate (3 × 4 mL). The combined organic layers were washed with brine (3 × 4 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give a residue that was purified on silica gel (petroleum ether / EtOAc gradient 50% to 100%) to give ethyl (S)-2-(chloromethyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (320 mg, 91.3% yield) as a light yellow gum. LCMS: [M+H] + =464 retention time (10mM NH4HCO3) = 1.96 minutes

[0419] Step 3 A mixture of ethyl (S)-2-(chloromethyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (200 mg, 409 μmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (114.3 mg, 450 μmol), potassium acetate (120.5 mg, 1.23 mmol), and bis(triphenylphosphine)palladium(II) chloride (28.7 mg, 41 μmol) in dioxane (5 mL) was charged into a glovebox under nitrogen. The reaction mixture was stirred at 80 °C for 4 h. LCMS showed the reaction was complete, and the reaction mixture was cooled, and 4-[(6-bromo-2-pyridyl)oxymethyl]-3-fluorobenzonitrile (132.3 mg, 409 μmol), dipotassium carbonate (169.7 mg, 1.23 mmol), and Pd(dppf)Cl (29.9 mg, 41 μmol) were added thereto. Nitrogen was bubbled through the reaction mixture for 2 minutes. The resulting mixture was stirred at 80° C. for 16 hours. LCMS showed the reaction was complete. Silica gel (2 g) was added to the reaction mixture, and the solvent was removed under reduced pressure to give a dry powder. This was purified on silica gel (eluent: petroleum ether / ethyl acetate gradient 33-100%) to give ethyl (S)-2-((6-((4-cyano-2-fluorobenzyl)oxy)-2'-oxo-[2,4'-bipyridin]-1'(2'H)-yl)methyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (220 mg, 323.7 μmol, 79.1% yield, 90% purity) as a white solid. LCMS: [M+H] + =612, retention time (10mM NH4HCO3) = 1.98 min

[0420] Step 4 To a solution of ethyl (S)-2-((6-((4-cyano-2-fluorobenzyl)oxy)-2'-oxo-[2,4'-bipyridin]-1'(2'H)-yl)methyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (220 mg, 324 μmol) in THF (5 mL) was added a solution of lithium hydroxide hydrate (67.9 mg, 1.62 mmol) in water (8 mL). LCMS showed the reaction was complete. The reaction mixture was acidified with acetic acid until pH = 5. Tetrahydrofuran was removed under reduced pressure. The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried and evaporated under reduced pressure to give a residue which was purified by preparative HPLC to give (S)-2-((6-((4-cyano-2-fluorobenzyl)oxy)-2'-oxo-[2,4'-bipyridin]-1'(2'H)-yl)methyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (95.5 mg, 49.0% yield). LCMS: [M+H] + =584, retention time (0.01%TFA)=1.84 minutes 1 H NMR(400MHz,DMSO-D6)δ8.04-7.84(m,3H),7.79-7.68(m,3H),7.67-7.54(m,1H),7.40(d,J=8 .5Hz,1H),7.09(d,J=1.7Hz,1H),7.03(d,J=8.2Hz,1H),6.96(dd,J=7.2,1.9Hz,1H),5.50(dd, J=61.4,17.0Hz,4H),5.11(d,J=6.8Hz,1H),4.89(dd,J=15.5,7.0Hz,1H),4.73(d,J=12.8Hz, 1H),4.58-4.46(m,1H),4.40(dd,J=6.1,2.9Hz,1H),2.86-2.70(m,1H),2.44(d,J=9.1Hz,1H).

[0421] (S)-2-((6-((4-chloro-2-fluorobenzyl)oxy)-2'-oxo-[2,4'-bipyridin]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 323) [ka] Prepared in a similar manner to compound 322. LCMS: [M+H] + =575.0, retention time=1.52 minutes 1 H NMR(400MHz,DMSO-D6)δ8.28(s,1H),7.98(d,J=7.2Hz,1H),7.90-7.86(m,1H),7.82-7.79(m,1H) ,7.70(d,J=7.4Hz,1H),7.63-7.59(m,2H),7.50(dd,J=10.0,2.0Hz,1H),7.33(dd,J=8.2,1.7Hz,1 H),7.12-7.11(m,1H),7.01-6.98(m,2H),5.60-5.43(m,4H),5.11-5.07(m,1H),4.88-4.83(m,1H) ),4.74-4.70(m,1H),4.52-4.47(m,1H),4.39-4.34(m,1H),2.75-2.71(m,1H),2.41-2.36(m,1H).

[0422] (S)-2-((6-((4-cyano-2-fluorobenzyl)oxy)-2'-oxo-[2,4'-bipyridin]-1'(2'H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 324) [ka] Prepared in a similar manner to compound 322. LCMS: [M+H] + =567.0, retention time=1.40 minutes 1H NMR(400MHz,DMSO-D6-D6)δ8.09-8.07(d,J=8.0Hz,1H),7.98-7.96(t,J=5.6Hz,2H) ,7.93-7.87(m,2H),7.77-7.70(m,3H),7.08-7.02(m,2H),6.97-6.94(dd,J1=7.2Hz, J2=2.0Hz,1H),5.67-5.49(m,4H),5.18-5.12(m,1H),4.87-4.81(m,1H),4.74-4.69 (m,1H),4.53-4.47(m,1H),4.39-4.33(m,1H),2.77-2.68(m,1H),2.44-2.36(m,1H).

[0423] (S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyrimidin-2-yl)-2-oxopyridin-1(2H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 325) [ka] Prepared in a similar manner to compound 322. LCMS: [M+H] + =586.2, retention time=1.18 minutes 1 H NMR(400MHz,DMSO-D6)δ8.85(d,J=2.8Hz,1H),8.10-7.93(m,4H),7.88-7.73(m,2H),7.29(d, J=1.8Hz,1H),7.11(dd,J=7.1,1.9Hz,1H),5.79(brs,2H),5.68(d,J=16.1Hz,1H),5.53(d,J=1 6.1Hz,1H),5.22-5.09(m,1H),4.84(dd,J=15.0,6.2Hz,1H),4.71(dd,J=15.0,3.2Hz,1H),4. 50(dd,J=13.8,7.6Hz,1H),4.36(dt,J=8.9,6.0Hz,1H),2.78-2.64(m,1H),2.44-2.31(m,1H).

[0424] 2-(4-(6-(4-chloro-2-fluorobenzyloxy)pyridin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-2H-indazole-5-carboxylic acid (Compound 326) [ka]

[0425] Step 1 A mixture of 3,4-dihydro-2H-pyran (327.19 mg, 3.89 mmol), methyl 3-iodo-3a,7a-dihydro-1H-indazole-5-carboxylate (1.18 g, 3.89 mmol), and 4-methylbenzenesulfonic acid hydrate (739.9 mg, 3.89 mmol) in DCM (50 mL) was stirred at 30 °C under N for 12 h until the reaction was complete as indicated by LCMS. The reaction mixture was poured into water, extracted with EtOAc, and the combined organics were concentrated in vacuo and purified by silica gel chromatography (hexanes / EtOAc = 10:1) to give the desired product, methyl 3-iodo-1-tetrahydropyran-2-yl-3a,7a-dihydroindazole-5-carboxylate (0.9 g, 59.6% yield), as a pale yellow solid. LCMS: [M+H] + =387, retention time=2.00 minutes

[0426] Step 2 A mixture of 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (300 mg, 1.79 mmol), methyl 3-iodo-1-tetrahydropyran-2-yl-indazole-5-carboxylate (300 mg, 777 μmol), Pd(dppf)Cl (10 mg), and sodium carbonate (300.0 mg, 2.83 mmol) in water (1 mL) and dioxane (4 mL) was stirred at 100 °C under N for 2 h, and the reaction mixture was monitored by LCMS. The reaction mixture was filtered through a pad of Celite with EtOAc, washed with water, and the combined organics were concentrated in vacuo and purified by silica gel chromatography (hexane / EtOAc = 10:1) to give the desired product, methyl 3-allyl-1-tetrahydropyran-2-yl-indazole-5-carboxylate (170 mg, 72.9% yield), as a pale yellow solid. LCMS: [M+H] + =301, retention time=2.14 minutes

[0427] Step 3 A mixture of 3-chlorobenzenecarboperoxoic acid (2.76 g, 15.98 mmol), methyl 3-allyl-1-tetrahydropyran-2-yl-indazole-5-carboxylate (2.4 g, 7.99 mmol) in DCM (20 mL) was stirred under N at 20 °C for 16 h, and the reaction mixture was monitored by LCMS. The reaction mixture was filtered through a pad of Celite with EtOAc, and the combined organics were concentrated in vacuo and purified by silica gel chromatography (hexane / EtOAc = 5:1) to give the desired product, methyl 3-(oxiran-2-ylmethyl)-1-tetrahydropyran-2-yl-indazole-5-carboxylate (1.4 g, 55.4% yield) as a pale yellow solid. LCMS: [M+H] + =317, retention time=1.78 minutes

[0428] Step 4 A mixture of BLAH methane iodide (3.48 g, 15.81 mmol), potassium 2-methylpropan-2-olate (1.77 g, 15.81 mmol), methyl 3-(oxiran-2-ylmethyl)-1-tetrahydropyran-2-yl-indazole-5-carboxylate (500 mg, 1.58 mmol, 280.37 mL), and copper dichloride (21.3 mg, 158 μmol) in t-BuOH (50 mL) was stirred in an oil bath at 80° C. for 2 hours, and the reaction was monitored by LCMS. The reaction mixture was adjusted to pH=1 with HCl, and the aqueous layer was extracted with DCM, dried over NaSO, concentrated, and purified by preparative HPLC to give the desired product, 3-(oxetan-2-ylmethyl)-1-tetrahydropyran-2-yl-indazole-5-carboxylic acid (200 mg, 24.0% yield) as a pale yellow solid. LCMS: [M+H] + =317, retention time=1.47 minutes

[0429] Step 5 A mixture of 3-(oxetan-2-ylmethyl)-1-tetrahydropyran-2-yl-indazole-5-carboxylic acid (30 mg, 94.8 μmol), iodomethane (14.8 mg, 104.3 μmol, 6.5 μL, 100% pure), and dipotassium carboxylate (39.3 mg, 284.5 μmol, 17.2 μL, 100% pure) in DMF (5 mL) was stirred for 1 hour at RT until the reaction was complete as indicated by LCMS. After stirring at 25 °C under 2 for 1 h in a round-bottom flask, the reaction mixture was filtered through a pad of Celite with EtOAc, and the combined organics were concentrated in vacuo and purified by silica gel chromatography to give the desired product, methyl 3-(oxetan-2-ylmethyl)-1-tetrahydropyran-2-yl-indazole-5-carboxylate (22 mg, 47.8 μmol, 50.4% yield, 71.8% purity) as a colorless oil. LCMS [M+H] + =331.1, retention time (0.01%TFA)=1.82 minutes

[0430] Step 6 A mixture of methyl 3-(oxetan-2-ylmethyl)-1-tetrahydropyran-2-yl-indazole-5-carboxylate (120 mg, 363 μmol) and 2,2,2-trifluoroacetic acid (1.48 g, 12.98 mmol, 1 mL) in DCM (2 mL) was stirred at 20 °C for 2 h and the reaction was monitored by LCMS. The reaction mixture was concentrated to give the desired product, methyl 3-(oxetan-2-ylmethyl)-1H-indazole-5-carboxylate (100 mg, 89.4% yield), as a pale yellow solid. LCMS: [M+H] + =247, retention time=1.47 minutes

[0431] Step 7 A mixture of methyl 3-(oxetan-2-ylmethyl)-1H-indazole-5-carboxylate (100 mg, 406 μmol), 4-bromo-1-(bromomethyl)-2-fluorobenzene (108.8 mg, 406 μmol), and potassium carbonate (168.4 mg, 1.22 mmol) in DMF (10 mL) was stirred in a 60 °C oil bath for 2 h. The reaction was monitored by LCMS. The reaction mixture was filtered through a pad of Celite with EtOAc, and the combined organics were concentrated in vacuo and purified by silica gel chromatography (hexane / EtOAc = 5:1) to give the desired product, methyl 1-[(4-bromo-2-fluorophenyl)methyl]-3-(oxetan-2-ylmethyl)indazole-5-carboxylate (80 mg, 45.5% yield), as a pale yellow liquid. LCMS: [M+H] + =433, retention time=1.47 minutes

[0432] Step 8 A mixture of 2-bromo-6-[(4-chloro-2-fluorophenyl)methoxy]pyridine (1.6 g, 5.05 mmol), butyllithium (356.14 mg, 5.56 mmol, 2.5 mL), and tributyl(chloro)stannane (1.97 g, 6.07 mmol, 1.65 mL) in THF (10 mL) was stirred at 30 °C under N for 16 h. The reaction mixture was monitored by LCMS. The reaction mixture was poured into water, extracted with EtOAc, and the combined organics were concentrated in vacuo and purified by silica gel chromatography (hexane / EtOAc = 10:1) to give the desired product, tributyl-[6-[(4-chloro)-2-fluorophenyl)methoxy]-2-pyridyl]stannane (300 mg, 18.8% yield) as a pale yellow solid. LCMS: [M+H] + =528, retention time=2.14 minutes

[0433] Step 9 A mixture of tributyl-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]stannane (60.8 mg, 115 μmol), methyl 2-[(4-bromo-2-fluoro-phenyl)methyl]-3-(oxetan-2-ylmethyl)indazole-5-carboxylate (50 mg, 115 μmol), and Pd(PPh3)4 (115 μmol) in DMF (1 mL) was stirred at 130 °C under N2 for 2 h, and the reaction mixture was monitored by LCMS. The reaction mixture was filtered through a pad of Celite with EtOAc, and the combined organics were concentrated in vacuo and purified by silica gel chromatography (hexane / EtOAc=2:1) ​​to give the desired product, methyl 2-[[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-phenyl]methyl]-3-(oxetan-2-ylmethyl)indazole-5-carboxylate (50 mg, 73.4% yield) as a pale yellow solid. LCMS: [M+H] + =590, retention time=1.99 minutes

[0434] Step 10 A mixture of methyl 2-[[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-phenyl]methyl]-3-(oxetan-2-ylmethyl)indazole-5-carboxylate (50 mg, 84.7 μmol), lithium hydroxide hydrate (400 mg, 9.53 mmol) in THF (2 mL), methanol (2 mL) and water (2 mL) was stirred under N at 25 °C for 2 h and the reaction mixture was monitored by LCMS. LCMS showed a good result. The reaction mixture was adjusted to pH=1 with HCl, extracted with DCM, and the combined organics were concentrated in vacuo to give the desired product 1-[[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-phenyl]methyl]-3-(oxetan-2-ylmethyl)indazole-5-carboxylic acid (20.3 mg, 35 μmol, 41.6% yield) after purification by preparative HPLC. LCMS: [M+H] + =576, retention time=1.50 minutes 1 H NMR(400MHz,CDCl3)δ8.66(s,1H),8.13(ddd,J=10.3,7.0,1.3Hz,2H),7.60(ddd,J=8.4,7.1,2.0Hz ,1H),7.45(dd,J=8.3,6.6Hz,2H),7.28(d,J=1.1Hz,1H),7.19-7.00(m,3H),6.90(ddd,J=7.1,5.1,0 .9Hz,1H),6.80(d,J=8.4Hz,1H),5.69(s,2H),5.43(s,2H),5.38-5.24(m,1H),4.74-4.61(m,1H),4 .59-4.45(m,1H),3.47(ddd,J=32.1,14.5,6.2Hz,2H),2.72(d,J=5.6Hz,1H),2.57(d,J=8.9Hz,1H).

[0435] 2-((6-((4-chloro-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)methyl)-3-(oxazol-4-ylmethyl)imidazo[1,2-a]pyridine-6-carboxylic acid (Compound 327) [ka]

[0436] Step 1 A mixture of 6-aminopyridine-3-carboxylate (17.62 g, 115.81 mmol), 1,3-dibromopropan-2-one (25 g, 115.81 mmol) in ethanol (400 mL) was stirred at 80 °C under N for 12 h until the reaction was complete as indicated by LCMS. NaHCO was added to the reaction mixture, which was then filtered through a pad of Celite with EtOAc. The combined organics were concentrated in vacuo and purified by silica gel chromatography (hexane: EtOAc = 12:1) to give the desired product, methyl 2-(bromomethyl)imidazo[1,2-a]pyridine-6-carboxylate (5.2 g, 16.7% yield) as a pale yellow solid. LCMS: [M+H] + =269.0, retention time (0.01%TFA)=0.99 minutes

[0437] Step 2 A mixture of 2-(bromomethyl)imidazo[1,2-a]pyridine-6-carboxylate (6.9 g, 25.64 mmol) and potassium acetate (7.55 g, 76.92 mmol, 4.81 mL) in DMF (150 mL) was stirred at 50 °C under N for 2 h until the reaction was complete as indicated by LCMS. The reaction mixture was filtered through a pad of Celite with EtOAc, and the combined organics were concentrated in vacuo and purified by silica gel chromatography (hexane / EtOAc = 5:1) to give the desired product, methyl 2-(acetoxymethyl)imidazo[1,2-a]pyridine-6-carboxylate (5.8 g, 91.1% yield) as a pale yellow solid. LCMS: [M+H] + =249.1, retention time (0.01%TFA)=0.95 minutes

[0438] Step 3 A mixture of phosphoryl trichloride (11.74 g, 76.54 mmol) in DMF (50 mL) was stirred at 0 °C under N for 0.5 h. Then, methyl 2-(acetoxymethyl)imidazo[1,2-a]pyridine-6-carboxylate (3.8 g, 15.31 mmol) was added and the mixture was stirred at room temperature for 2 h until the reaction was complete as indicated by LCMS. The reaction mixture was filtered through a pad of Celite with EtOAc, and the combined organics were concentrated in vacuo and purified by silica gel chromatography (hexane / EtOAc 6:1) to give the desired product, methyl 2-(acetoxymethyl)-3-formyl-imidazo[1,2-a]pyridine-6-carboxylate (2.4 g, 56.78% yield) as a pale yellow solid. LCMS: [M+H] + =277.2, retention time (0.01%TFA)=1.58 minutes

[0439] Step 4 A mixture of methyl 2-(acetoxymethyl)-3-formyl-imidazo[1,2-a]pyridine-6-carboxylate (2.4 g, 8.69 mmol) and potassium carbonate (1.80 g, 13.03 mmol) in MeOH (50 mL) was stirred at room temperature under N for 1.5 hours until the reaction was complete as indicated by LCMS. The reaction mixture was filtered through a pad of Celite with DCM, and the combined organics were concentrated in vacuo and purified by silica gel chromatography (hexanes / EtOAc 2:1) to give the desired product, methyl 3-formyl-2-(hydroxymethyl)imidazo[1,2-a]pyridine-6-carboxylate (2.1 g, 87.7% yield), as a pale yellow solid. LCMS: [M+H] + =235.1, retention time (0.01%TFA)=1.08 minutes

[0440] Step 5 A mixture of methyl 3-formyl-2-(hydroxymethyl)imidazo[1,2-a]pyridine-6-carboxylate (2.1 g, 8.97 mmol), tert-butyl-chloro-diphenyl-silane (2.96 g, 10.76 mmol, 2.76 mL), and imidazole (1.83 g, 26.90 mmol) in DMF (40 mL) was stirred at room temperature under N for 2 h until the reaction was complete as indicated by LCMS. The reaction mixture was filtered through a pad of Celite with EtOAc, and the combined organics were concentrated in vacuo and purified by silica gel chromatography (hexanes / EtOAc = 8:1) to give the desired product, 2-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-formyl-imidazo[1,2-a]pyridine-6-carboxylate methyl ester (5.8 g, 89.0% yield) as a pale yellow solid. LCMS: [M+H] + =473.0, retention time (0.01%TFA)=2.36 minutes

[0441] Step 6 A mixture of oxazole (1.46 g, 21.16 mmol), butyllithium (1.08 g, 16.93 mmol) in THF (30 mL) was stirred at −78° C. under N for 0.5 h, then methyl 2-[[tert-butyl(diphenyl))silyl]oxymethyl]-3-formyl-imidazo[1,2-a]pyridine-6-carboxylate (1 g, 2.12 mmol) was added and the resulting mixture was further stirred at −78° C. under N for 2 h until the reaction was complete as indicated by LCMS. The reaction mixture was filtered through a pad of Celite with EtOAc and the combined organics were concentrated in vacuo and purified by preparative HPLC to give the desired product, methyl 2-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-(oxazol-4-ylmethyl)imidazole[1,2-a]pyridine-6-carboxylate (500 mg, 45.0% yield) as an off-white solid. LCMS: [M+H] + =542.0, retention time (0.01%TFA)=1.75 minutes

[0442] Step 7 A mixture of methyl 2-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-[hydroxy(oxazol-4-yl)methyl]imidazole[1,2-a]pyridine-6-carboxylate (800 mg, 1.48 mmol), triethylsilane (1.72 g, 14.77 mmol, 2.36 mL) in TFA (20 mL) was stirred at 65 °C under N for 16 h until the reaction was complete as indicated by LCMS. The reaction mixture was concentrated and neutralized with NaHCO. The resulting residue was dissolved in DCM and filtered through a pad of Celite with DCM and MeOH. The combined organics were concentrated in vacuo to give the desired product, methyl 2-(hydroxymethyl)-3-(oxazol-4-ylmethyl)imidazo[1,2-a]pyridine-6-carboxylate (105 mg, 24.8% yield), as a pale yellow oil. LCMS: [M+H] + =288.0, retention time=1.30 minutes

[0443] Step 8 To a stirred solution of methyl 2-(hydroxymethyl)-3-(oxazol-4-ylmethyl)imidazo[1,2-a]pyridine-6-carboxylate (30 mg, 104 μmol) in DCM (10 mL) was added methanesulfonic anhydride (21.8 mg, 125 μmol) and TEA (31.7 mg, 313 μmol). The reaction mixture was stirred at room temperature for 3 h. When the reaction was complete as judged by TLC, the mixture was diluted with DCM (50 mL) and allowed to warm to room temperature. The layers were separated, and the aqueous layer was extracted with DMC (2 × 50 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give methyl 2-(methylsulfonyloxymethyl)-3-(oxazol-4-ylmethyl)imidazole[1,2-a]pyridine-6-carboxylate (30 mg, 51.5% yield) as a light yellow liquid. LCMS: [M+H] + =366.0, retention time (10mM NH4HCO3) = 1.38 minutes

[0444] Step 9 A mixture of methyl 2-(bromomethyl)-3-(oxazol-4-ylmethyl)imidazole[1,2-a]pyridine-6-carboxylate (115.0 mg, 49 μmol), 2-[(4-chloro-2-fluoro-phenyl)methoxy]-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridine (18.8 mg, 59 μmol), and N-ethyl-N-isopropyl-propan-2-amine (31.8 mg, 246 μmol) in 1,4-dioxane (12 mL) was stirred at 95° C. under N for 1.5 hours until the reaction was complete as indicated by LCMS. The reaction mixture was filtered through a pad of Celite with EtOAc, and the combined organics were concentrated in vacuo and purified by silica gel chromatography (DCM:MeOH=20:1) to give the desired product, methyl 2-[[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-(oxazol-4-ylmethyl)imidazo[1,2-a]pyridine-6-carboxylate (10 mg, 34.5% yield) as a pale yellow oil. LCMS: [M+H] + =588.0, retention time (0.01%TFA)=2.12 minutes

[0445] Step 10 A mixture of methyl 2-[[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-(oxazol-4-ylmethyl)imidazole[1,2-a]pyridine-6-carboxylate (10 mg, 17 μmol), lithium hydroxide (1.2 mg, 51 μmol) in MeOH (1 mL), HO (3 mL) and THF (3 mL) was stirred at room temperature under N for 2 hours until the reaction was complete as indicated by LCMS. The reaction mixture was filtered through a pad of Celite with EtOAc and the combined organics were concentrated in vacuo and purified by preparative HPLC to give the desired product 2-[[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-(oxazol-4-ylmethyl)imidazo[1,2-a]pyridine-6-carboxylic acid (2 mg, 20.5% yield) as an off-white solid. LCMS: [M+H] + =574.1, retention time=1.56 minutes 1 H NMR(400MHz,DMSO-D6)δ8.79-8.78(brs,1H),8.02(t,J=11.2Hz,1H),7.74-7.64 (m,2H),7.51(ddd,J=12.8,12.0,5.1Hz,3H),7.30(dd,J=8.2,1.8Hz,1H),7.09(d ,J=0.7Hz,1H),7.04(d,J=7.4Hz,1H),6.76-6.62(m,2H),5.39(s,2H),4.76(s,2H) ),3.82(s,2H),3.18-3.17(brs,2H),2.66(t,J=5.5Hz,2H),2.40-2.39(brs,2H).

[0446] (S)-(2-((6-((4-cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)boronic acid (Compound 328) [ka]

[0447] Step 1 A mixture of 4-bromo-2-fluoro-1-nitrobenzene (2 g, 9.09 mmol), 4-methylbenzenesulfonic acid, [(2S)-oxetan-2-yl]methanamine (2.36 g, 9.09 mmol), and N,N-diethylethanamine (4.60 g, 45.46 mmol) in DMF (50 mL) was stirred at 60 °C under N for 2 h until LCMS showed the reaction was complete. The reaction mixture was filtered through a pad of Celite with EtOAc, and the combined organics were concentrated in vacuo and purified by silica gel chromatography to give the desired product, 5-bromo-2-nitro-N-[[(2S)-oxetan-2-yl]methyl]aniline (2.42 g, 7.58 mmol, 83.4% yield, 89.8% purity) as a yellow solid. LCMS: [M+H] + =289.0, retention time (0.01%TFA)=1.72 minutes

[0448] Step 2 A mixture of 5-bromo-2-nitro-N-[[(2S)-oxetan-2-yl]methyl]aniline (2.42 g, 8.44 mmol), iron (3.77 g, 67.54 mmol), and ammonia hydrochloride (3.61 g, 67.54 mmol) in ethanol (16 mL) and water (4 mL) was stirred at 80 °C in a RBF under N for 1.5 h until the reaction was complete as indicated by LCMS. The reaction mixture was filtered through a pad of Celite with EtOAc, and the combined organics were concentrated in vacuo and purified by silica gel chromatography to give the desired product, 4-bromo-N-[[(2S)-oxetan-2-yl]methyl]benzene-1,2-diamine (1.44 g, 5.56 mmol, 65.8% yield, 99.5% purity) as a brown oil. LCMS: [M+H] + =259.1, retention time (0.01%TFA)=1.16 minutes

[0449] Step 3 A mixture of 4-bromo-N2-[[(2S)-oxetan-2-yl]methyl]benzene-1,2-diamine (1.4 g, 5.44 mmol), 2-chloro-1,1,1-trimethoxyethane (925.9 mg, 5.99 mmol), and 4-methylbenzenesulfonic acid hydrate (103.6 mg, 544.5 mol) in ACN (30 mL) was stirred at 60 °C under N2 for 1 h until the reaction was complete by LCMS. The reaction mixture was filtered through a pad of Celite with EtOAc, and the combined organics were concentrated in vacuo and purified by silica gel chromatography to give the desired product, 6-bromo-2-(chloromethyl)-1-[[(2S)-oxetan-2-yl]methyl]benzimidazole (1.04 g, 2.37 mmol, 43.6% yield) as a white solid. LCMS: [M+H] + =317.0, retention time (0.01%TFA)=1.45 minutes

[0450] Step 4 A mixture of 6-bromo-2-(chloromethyl)-1-[[(2S)-oxetan-2-yl]methyl]benzimidazole (500 mg, 1.58 mmol), 3-fluoro-4-[[6-(1,2,3,6-tetrahydropyridin-4-yl)-2-pyridyl]oxymethyl]benzonitrile (735.1 mg, 2.38 mmol), N-ethyl-N-isopropyl-propan-2-amine (1.43 g, 11.09 mmol), and sodium iodide dihydrate (28.8 mg, 158.4 μmol) in dioxane (20 mL) was analyzed by LCMS. After stirring at 90° C. in a RBF under N for 16 hours until completion was indicated, the reaction mixture was filtered through a pad of Celite with EtOAc and the combined organics were concentrated in vacuo and purified by silica gel chromatography to give the desired product 4-[[6-[1-[[6-bromo-1-[[(2S)-oxetan-2-yl]methyl]benzimidazol-2-yl]methyl]-3,6-dihydro-2H-pyridin-4-yl]-2-pyridyl]oxymethyl]-3-fluoro-benzonitrile (800 mg, 869.65 μmol, 54.9% yield) as a white solid. LCMS: [M+H] +=588.0, retention time (10mM NH4HCO3) = 1.82 minutes

[0451] Step 5 4-[[6-[1-[[6-bromo-1-[[(2S)-oxetan-2-yl]methyl]benzimidazol-2-yl]methyl]-3,6-dihydro-2H-pyridin-4-yl]-2-pyridyl]oxymethyl]-3-fluoro-benzonitrile (20 mg, 33.99 μmol), hypoborous acid (9.1 mg, 102 μmol), dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (0.3 mg, 0.7 μmol), XPhos Pd G3 (0.3 mg, 0.34 μmol), and potassium acetate (20 mg, 203.9 μmol) were dissolved in ethanol (3 mL) and ethylene glycol (0.15 mL), and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was purified by HPLC to give the desired product [2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazol-5-yl]boronic acid (2 mg, 2.7 μmol, 8.0% yield) as a white solid. LCMS: [M+H] + =554.1, retention time (0.01%TFA)=1.72 minutes 1H NMR(400MHz,DMSO-D6)δ8.16(s,2H),8.01(s,1H),7.89(d,J=10.4Hz,1H),7.75-7.61(m,4H),7.54(d,J=8.0 Hz,1H),7.10(d,J=7.4Hz,1H),6.77(d,J=8.2Hz,1H),6.71(s,1H),5.49(s,2H),5.14-5.03(m,1H),4.71(dd, J=15.1,7.1Hz,1H),4.57(dd,J=15.1,3.4Hz,1H),4.47(dd,J=14.1,7.1Hz,1H),4.38(dt,J=9.0,6.0Hz,1H), 4.04(d,J=13.3Hz,1H),3.89(d,J=13.3Hz,1H),3.22(d,J=9.2Hz,3H),2.76-2.64(m,3H),2.44-2.30(m,2H).

[0452] (S)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 329) [ka]

[0453] Step 1 A suspension of (4-chloro-2-fluoro-phenyl)methanol (1 g, 6.23 mmol) and potassium 2-methylpropan-2-olate (768.7 mg, 6.85 mmol) in THF (20 mL) was stirred at 0 °C under N for 0.5 h. 3-Bromo-2-fluoro-pyridine (1.21 g, 6.85 mmol) was then added slowly and stirred under N for 1 h. After the reaction was judged complete by LCMS, the reaction mixture was quenched with ice-cold water (20 mL) and extracted with EtOAc (3 × 20 mL). The organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography to give 3-bromo-2-[(4-chloro-2-fluoro-phenyl)methoxy]pyridine (1.4 g, 4.04 mmol, 64.9% yield) as a yellow oil. LCMS: [M+H] + =315.9, retention time (0.01%TFA)=2.30 minutes

[0454] Step 2 A mixture of 3-bromo-2-[(3-chloro-2-fluoro-phenyl)methoxy]pyridine (184.3 mg, 582 μmol), methyl 3-[[(2S)-oxetan-2-yl]methyl]-2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]methyl]benzimidazole-5-carboxylate (272.1 mg, 582 μmol), Pd(dppf)Cl (42.6 mg, 58 μmol), and KCO (241.4 mg, 1.75 mmol) in dioxane (10 mL) and water (2 mL) was stirred at 90 °C under N for 16 h until the reaction was complete by LCMS. The reaction mixture was filtered through a pad of Celite with EtOAc and the combined organics were concentrated in vacuo and purified by silica gel chromatography to give the desired product, methyl 2-[[4-[2-(4-chloro-2-fluoro-phenyl)-2-methyl-1,3-benzodioxol-4-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (200 mg, 227.5 μmol, 39.1% yield, 68.7% purity) as a brown oil. LCMS: [M+H] + =577.3, retention time (0.01%TFA)=1.63 minutes

[0455] Step 3 A mixture of methyl 2-[[4-[2-[(4-chloro-2-fluoro-phenyl)methoxy]-3-pyridyl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (200 mg, 207.96 μmol) and LiOH (43.6 mg, 1.04 mmol) in THF (2.5 mL), methanol (2.5 mL) and water (1.5 mL) was stirred at 25° C. under N for 1.5 h until the reaction was complete as indicated by LCMS. The reaction mixture was purified by HPLC to give the desired product 2-[[4-[2-[(4-chloro-2-fluoro-phenyl)methoxy]-3-pyridyl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid (12.4 mg, 22.02 μmol, 10.6% yield) as a white solid. LCMS: [M+H] + =563.0, retention time (10mM NH4HCO3) = 1.59 minutes 1 H NMR(400MHz,MeOD)δ8.27-8.26(brs,1H),8.05(dd,J=5.0,1.8Hz,1H),7.98(d,J=8.5Hz,1H),7.64(d,J=8.5Hz,1H),7.58(d d,J=7.3,1.8Hz,1H),7.51(t,J=8.1Hz,1H),7.34-7.16(m,2H),6.97(dd,J=7.3,5.0Hz,1H),5.92-5.91(brs,1H),5.43(s,2H) ),5.24(d,J=4.9Hz,1H),4.87(dd,J=15.3,7.1Hz,1H),4.69(dd,J=15.4,2.7Hz,1H),4.60(dd,J=13.7,7.9Hz,1H),4.46(dt, J=9.0,5.9Hz,1H),4.12(d,J=13.6Hz,1H),4.00(d,J=13.6Hz,1H),3.27-3.14(m,2H),2.84-2.68(m,3H),2.60-2.41(m,3H).

[0456] 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydropyridin-1(2H)-yl)methyl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 330) [ka]

[0457] Step 1 To a suspension of 3-bromobenzene-1,2-diol (1.20 g, 6.37 mmol) in toluene (100 mL) was added 1-(4-chloro-2-fluorophenyl)ethanone (1 g, 5.79 mmol) and 4-methylbenzenesulfonic acid hydrate (1.10 g, 5.79 mmol). The reactor was equipped with a Dean-Stark trap and the reaction mixture was heated at 140 °C for 60 h. After that, the solution was concentrated in vacuo and purified by flash chromatography to give 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxole (280 mg, 774.2 μmol, 13.4% yield) as a yellow oil. LCMS [M+H] + =343.0, retention time (0.01%TFA)=2.07 minutes

[0458] Step 2 To a stirred solution of 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxole (100 mg, 291.06 μmol) in 1,4-dioxane (10 mL) and water (2 mL) was added methyl 3-[[(2S)-oxetan-2-yl]methyl]-2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneboron-2-yl)-3,6-dihydro-2H-pyridin-1-yl]methyl]benzimidazole-5-carboxylate (142.8 mg, 305 μmol), Pd(dppf)Cl (21.3 mg, 29 μmol), and KCO (80.3 mg, 582 μmol). The reaction mixture was stirred at 100° C. for 2 h. Once the reaction was judged complete by TLC, the mixture was diluted with EtOAc (100 mL) and allowed to warm to room temperature. The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to afford the crude product, methyl 2-[[4-[2-(4-chloro-2-fluoro-phenyl)-2-methyl-1,3-benzodioxol-4-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (150 mg, 206.2 μmol, 70.9% yield), as a light yellow liquid, which was used directly in the next step. LCMS: [M+H] + =604.0, retention time (10mM NH4HCO3)=2.31min

[0459] Step 3 To a stirred solution of methyl 2-[[4-[2-(4-chloro-2-fluoro-phenyl)-2-methyl-1,3-benzodioxol-4-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (150 mg, 206.2 μmol) in THF (3 mL), MeOH (3 mL), and water (3 mL) was added LiOH·HO (31.3 mg, 744 μmol). The reaction mixture was stirred at room temperature for 8 h. When the reaction was judged complete by TLC, the mixture was diluted with EtOAc (100 mL) and allowed to warm to room temperature. The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC to give 2-[[4-[2-(4-chloro-2-fluoro-phenyl)-2-methyl-1,3-benzodioxol-4-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid (53.9 mg, 91 μmol, 44.3% yield) as a white solid. LCMS: [M+H] + =590.0, retention time (10mM NH4HCO3) = 1.68 minutes 1H NMR(400MHz,MeOD)δ8.35-8.34(brs,1H),8.00(dd,J=8.5,1.4Hz,1H),7.71(d,J=8.5Hz,1H),7.58(t,J=8.3Hz,1H),7.30(dd,J=10. 9,1.9Hz,1H),7.26-7.20(m,1H),6.84(dt,J=15.4,7.2Hz,2H),6.80-6.73(m,1H),6.41-6.40(brs,1H),5.26(d,J=8.1Hz,1H),4.87 -4.86(brs,1H),4.74(d,J=14.0Hz,1H),4.63(dd,J=14.0,7.7Hz,1H),4.48(dd,J=14.7,5.7Hz,1H),4.19(d,J=14.0Hz,1H),4.07(d ,J=13.9Hz,1H),3.32-3.25(m,2H),2.88(d,J=5.7Hz,2H),2.83-2.74(m,1H),2.63-2.62(brs,2H),2.58-2.48(m,1H),2.05(s,3H).

[0460] (S)-2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)thiazol-5-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 331) [ka]

[0461] Step 1 To a mixture of 4-bromothiazole (2 g, 12.19 mmol) and 4-bromothiazole (2 g, 12.2 mmol) was added sodium hydroxide (2.93 g, 73.2 mmol). The mixture was then stirred at 150 °C under a N atmosphere for 4 h. The reaction mixture was diluted with water and then extracted with EtOAc (3 × 50 mL). The organics were concentrated to give a residue that was purified by silica gel chromatography (petroleum ether: EtOAc = 95:5) to give 4-[(4-chloro-2-fluoro-phenyl)methoxy]thiazole (370 mg, 1.52 mmol, 12.5% ​​yield). LCMS: [M+H] + =244.1, retention time (0.01%TFA)=1.77 minutes

[0462] Step 2 To a mixture of 4-[(4-chloro-2-fluorophenyl)methoxy]thiazole (60 mg, 246 μmol) in THF (5 mL) was added 1-bromopyrrolidine-2,5-dione (65.7 mg, 369.3 μmol). The mixture was then stirred at room temperature under a N atmosphere for 3 hours. The reaction mixture was diluted with water, extracted with DCM (3 × 20 mL), and then concentrated to give a residue that was purified by silica gel chromatography (petroleum ether: EtOAc = 98:2) to give 5-bromo-4-[(4-chloro-2-fluorophenyl)methoxy]thiazole (60 mg, 186.0 μmol, 75.5% yield). LCMS: [M+H] + =322.0, retention time (0.01%TFA)=1.96 minutes

[0463] Step 3 To a mixture of 5-bromo-4-[(4-chloro-2-fluorophenyl)methoxy]thiazole (30 mg, 93.00 μmol) and methyl 3-[[(2S)-oxetan-2-yl]methyl]-2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]methyl]benzimidazole-5-carboxylate (52.2 mg, 111.6 μmol) in water (1 mL) and 1,4-dioxane (5 mL) was added Pd(dppf)Cl (6.80 mg, 9.30 μmol) and disodium carbonate (19.7 mg, 186.0 μmol). The mixture was then stirred at 90 °C under a N atmosphere for 2 h. The reaction mixture was concentrated to give a residue, which was purified by silica gel chromatography (PE: EtOAc = 10: 1) to give methyl 2-[[4-[4-[(4-chloro-2-fluoro-phenyl)) methoxy] thiazol-5-yl] -3,6-dihydro-2H-pyridin-1-yl] methyl] -3-[[(2S)-oxetan-2-yl] methyl] benzimidazole-5-carboxylate (20 mg, 34.30 μmol, 36.88% yield). LCMS [M+H] + =583.2, retention time (0.01%TFA)=1.67 minutes

[0464] Step 4 To a mixture of methyl 2-[[4-[4-[(4-chloro-2-fluorophenyl)methoxy]thiazol-5-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (20 mg, 34.3 μmol) in water (2 mL), THF (2 mL), and methanol (2 mL) was added lithium hydroxide (7.2 mg, 171.5 μmol). The mixture was then stirred at 20° C. under a N atmosphere for 3 h. The reaction mixture was concentrated to give a residue which was purified by preparative HPLC to give 2-[[4-[4-[(4-chloro-2-fluoro-phenyl)methoxy]thiazol-5-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid (5 mg, 8.8 μmol, 25.6% yield). LCMS: [M+H] + =568.9, retention time (10mM NH4HCO3)=1.28min 1 H NMR(400MHz,DMSO-D6)δ8.72(s,1H),8.24(s,1H),7.80(d,J=8.8Hz,1H),7.63(d,J=8.4Hz,1H), 7.55-7.44(m,2H),7.36-7.28(m,1H),6.15(s,1H),5.41(s,2H),5.07-5.01(m,1H),4.77(dd,J=1 4.8,7.2Hz,1H),4.62(d,J=12.4Hz,1H),4.45(dd,J=13.2,8.0Hz,1H),4.34(dt,J=12.8,6.0Hz,1 H),4.01(d,J=14.0Hz,1H),3.86(d,J=13.6Hz,1H),3.14(s,2H),2.74-2.63(m,3H),2.41(s,4H).

[0465] (S)-2-((4-(3-(4-chloro-2-fluorobenzyloxy)isothiazol-4-yl)-5,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 332) [ka]

[0466] Step 1 To a stirred solution of isothiazol-3-one (1 g, 9.89 mmol) in DMF (20 mL) was added 1-(bromomethyl)-4-chloro-2-fluorobenzene (2.21 g, 9.89 mmol) and K2CO3 (4.09 g, 29.67 mmol). The reaction mixture was stirred at 40 °C for 8 h, and when the reaction was judged complete by TLC, the mixture was diluted with EtOAc (100 mL) and warmed to room temperature. The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO, hexane / ethyl acetate 10:1) to give 3-[(4-chloro-2-fluoro-phenyl)methoxy]isothiazole (1.6 g, 6.57 mmol, 66.4% yield, 100% purity) as a light yellow liquid. LCMS: [M+H] + =243.9, retention time (0.1%TFA)=2.12 minutes 1 H NMR(400MHz,CDCl3)δ8.52-8.40(m,1H),7.45(t,J=7.9Hz,1H),7.20-7.10(m,2H),6.70-6.58(m,1H),5.46(d,J=11.0Hz,2H).

[0467] Step 2 To a stirred solution of 3-[(4-chloro-2-fluoro-phenyl)methoxy]isothiazole (200 mg, 820.7 μmol) in HOAc (5 mL) was added Br2 (1.05 g, 6.57 mmol). The reaction mixture was stirred at room temperature for 8 h. When the reaction was judged complete by TLC, the mixture was diluted with EtOAc (50 mL) and allowed to warm to room temperature. The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic phases were washed with 1 M NaHCO3 (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC (0.2% TFA) to afford 4-bromo-3-[(4-chloro-2-fluoro-phenyl)methoxy]isothiazole (80 mg, 244.0 μmol, 29.7% yield, 98.4% purity) as a light yellow liquid. LCMS: [M+H] + =322.0, retention time (0.05%TFA)=1.99 minutes 1 H NMR(400MHz,CDCl3)δ8.49-8.35(m,1H),7.49(dd,J=15.0,7.0Hz,1H),7.15(ddd,J=11.5,8.7,1.9Hz,2H),5.48(s,2H).

[0468] Step 3 To a stirred solution of 4-bromo-3-[(4-chloro-2-fluoro-phenyl)methoxy]isothiazole (80 mg, 243.98 μmol) in 1,4-dioxane (10 mL) and water (2 mL) was added methyl 3-[[(2S)-oxetan-2-yl]methyl]-2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneboron-2-yl)-3,6-dihydro-2H-pyridin-1-yl]methyl]benzimidazole-5-carboxylate (125.43 mg, 268.38 μmol), Pd(dppf)Cl (17.8 mg, 24.4 μmol), and KCO (67.3 mg, 488.0 μmol). The reaction mixture was stirred at 100° C. for 2 hours, and when judged complete by TLC, the mixture was diluted with EtOAc (100 mL) and warmed to room temperature. The layers were separated, and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to afford methyl 2-[[4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]isothiazol-4-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (150 mg, 157.6 μmol, 64.6% yield, 61.3% purity) as a brown liquid. LCMS: [M+H] + =583.0, retention time (10mM NH4HCO3)=1.81min

[0469] Step 4 To a stirred solution of methyl 2-[[4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]isothiazol-4-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (150 mg, 157.6 μmol) in THF (3 mL), MeOH (3 mL), and water (3 mL) was added LiOH.HO (33.1 mg, 788.1 μmol). The reaction mixture was stirred at room temperature for 8 hours, and when the reaction was judged complete by TLC, the mixture was diluted with EtOAc (50 mL) and allowed to warm to room temperature. The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 0 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC (NH4HCO3) to give 2-[[4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]isothiazol-4-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid (46.6 mg, 81.89 μmol, 52.0% yield, 100% purity) as a white solid. LCMS: [M+H] + =569.0, retention time (10mM NH4HCO3)=1.61 min 1H NMR(400MHz,DMSO-D6)δ8.70(s,1H),8.25(s,1H),7.80(dd,J=8.5,1.5Hz,1H),7.65(d,J=8.4Hz,1H),7.57(t,J=8.2H) z,1H),7.49(dd,J=10.0,2.0Hz,1H),7.32(dd,J=8.2,1.8Hz,1H),6.39-6.38(brs,1H),5.46(s,2H),5.04(d,J=7.2Hz ,1H),4.77(dd,J=15.3,7.2Hz,1H),4.67-4.58(m,1H),4.45(dd,J=13.5,7.9Hz,1H),4.34(dt,J=8.9,5.9Hz,1H),4.0 2(d,J=13.7Hz,1H),3.87(d,J=13.6Hz,1H),3.15(t,J=13.2Hz,2H),2.65(dd,J=21.6,12.1Hz,3H),2.43-2.33(m,3H).

[0470] (S)-2-((4-(2-(4-cyano-2-fluorobenzyloxy)pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 333) [ka] Prepared in a similar manner to compound 329. LCMS: [M+H] + =554.0, retention time (10mM NH4HCO3)=1.22min 1H NMR(400MHz,DMSO-D6)δ8.26-8.25(brs,1H),8.05(dd,J=4.9,1.8Hz,1H),7.91(d,J=10.0Hz,1H),7.81(dd,J=8.5,1.5Hz ,1H),7.72(dd,J=7.9,1.4Hz,1H),7.68-7.56(m,3H),7.02(dd,J=7.3,4.9Hz,1H),5.98-5.97(brs,1H),5.50(s,2H),5.0 5(d,J=7.3Hz,1H),4.77(dd,J=15.2,7.2Hz,1H),4.63(d,J=12.8Hz,1H),4.44(dd,J=13.8,7.2Hz,1H),4.34(dt,J=11.9, 5.9Hz,1H),4.05(d,J=13.3Hz,1H),3.89(d,J=13.5Hz,1H),3.14(d,J=22.7Hz,2H),2.76-2.58(m,3H),2.45-2.31(m,3H).

[0471] 2-((4-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 334) [ka]

[0472] Step 1 To a stirred solution of 4-bromo-3-fluorobenzonitrile (1 g, 5.00 mmol) in toluene (20 mL) was added tributyl(1-ethoxyvinyl)stannane (2.17 g, 6.00 mmol, 2.03 mL), PdCl(PPh) (351.0 mg, 500 μmol), and TEA (1.52 g, 15.00 mmol). The reaction mixture was stirred at 120 °C for 8 hours, and when the reaction was complete as judged by TLC, the mixture was filtered and concentrated in vacuo. The crude product was dissolved in THF (10 mL) and 4N HCl (10 mL), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc (100 mL) and allowed to warm to room temperature. The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO, hexane / ethyl acetate=7:1) to give 4-acetyl-3-fluoro-benzonitrile (800 mg, 4.90 mmol, 98.1% yield, 100% purity) as a light yellow liquid. LCMS: [M+H] + =164.0, retention time (0.1%TFA)=1.56 minutes

[0473] Step 2 A mixture of 4-acetyl-3-fluorobenzonitrile (800 mg, 4.90 mmol), 3-bromobenzene-1,2-diol (1.02 g, 5.39 mmol), and 4-methylbenzenesulfonic acid (279.8 mg, 1.47 mmol) in toluene (100 mL) was stirred at 140 °C under N for 60 h until LCMS showed the reaction was complete. The reaction mixture was filtered through a pad of Celite with EtOAc, and the combined organics were concentrated in vacuo and purified by silica gel chromatography (hexane / EtOAc = 20:1) to give the desired product, 4-(4-bromo-2-methyl-1,3-benzodioxol-2-yl)-3-fluorobenzonitrile (98 mg, 96.8 μmol, 33% pure), as a colorless oil. LCMS: [M+H] + =336.1, retention time (0.01%TFA)=1.93 minutes

[0474] Step 3 4-(4-Bromo-2-methyl-1,3-benzodioxol-2-yl)-3-fluoro-benzonitrile (40 mg, 119.7 μmol), methyl 3-[[(2S)-oxetan-2-yl]methyl]-2-[[4-(3,3,4,4-tetramethyl-1,2,5-bromadioxolan-1-yl)-3,6-dihydro-2H-pyridin-1-yl]methyl]benzimidazole-5-carboxylate (96.3 mg, 179.6 μmol), Pd(dppf)Cl (8.8 mg, 11.97 μmol), and KCO (33.1 mg, 239.42 μmol) were dissolved in dioxane (3 mL) and water (1 mL). The reaction was stirred at 90 °C under N for 2 hours. The reaction was concentrated to give a residue which was purified by silica gel chromatography (petroleum ether: EtOAc = 3:7) to give methyl 2-[[4-[2-(4-cyano-2-fluoro-phenyl)-2-methyl-1,3-benzodioxol-4-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (40 mg, 67.27 μmol) as a yellow solid. LCMS: [M+H] + =595.0, retention time (0.01%TFA)=1.61 minutes

[0475] Step 4 Methyl 2-[[4-[2-(4-cyano-2-fluoro-phenyl)-2-methyl-1,3-benzodioxol-4-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (40 mg, 67.27 μmol) was dissolved in MeCN (3 mL) and water (1 mL), and then 1,1,3,3-tetramethylguanidine (155.0 mg, 1.35 mmol) was added. The reaction was stirred at 60 °C for 4 h. The mixture was quenched with water (20 mL), the pH was adjusted to 4-5 with HOAc, and then extracted with DCM (3 × 20 mL). The organic phase was concentrated to give a residue which was purified by preparative HPLC to give 2-[[4-[2-(4-cyano-2-fluoro-phenyl)-2-methyl-1,3-benzodioxol-4-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid (12.4 mg, 21.4 μmol, 31.8% yield) as a white solid. LCMS: [M+H] + =581.0, retention time (10mM NH4HCO3)=1.29min 1 H NMR(400MHz,DMSO-D6)δ8.26(s,1H),7.99-7.96(m,1H),7.82-7.70(m,3H),7.6 6-7.64(m,1H),6.89-6.84(m,3H),6.39-6.38(m,1H),5.08-5.06(m,1H),4.78-4 .77(m,1H),4.67-4.63(m,1H),4.47-4.34(m,2H),4.08-4.03(m,1H),3.93-3.8 8(m,1H),3.23-3.21(m,2H),2.76-2.65(m,4H),2.43-2.32(m,2H),2.05(s,3H).

Claims

1. A compound represented by structural formula (II): 【Chemistry 4】 During the ceremony, X １ , X ２ , X ３ , X ４ and X ５ are each independently selected from N and CH; １ , X ２ , X ３ , X ４ and X ５ are N, and ring A does not contain three nitrogen ring atoms in three consecutive positions; W is O, CH ２ and NH; Ring B is a 6-membered heteroaryl or phenyl, where Y １ , Y ３ , Y ４ , and Y ５ are each independently selected from N or CH, where Ring B has three or fewer nitrogen ring atoms and Ring B does not contain three nitrogen ring atoms in three adjacent positions; T ２ is selected from N and C; T ４ , N, NR ４ , O, S, and C.R. ４ Selected from T ６ , T ７ and T ８ are each independently N and CR ４ is selected from Here, T ２ , T ４ , T ６ , T ７ , and T ８ are selected from N, O, and S; EE is -COOH; R ａ is hydrogen, CH ３ , or C.F. ３ and R ｂ is halogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, NR ５ 'R ６ ', 6-10 membered aryl, 5-6 membered heteroaryl, 3-6 membered saturated or partially saturated cycloalkyl, and 3-7 membered saturated or partially saturated heterocyclyl, wherein R ｂ C represented by １ ~C ６ Alkyl or C １ ~C ６ Alkoxy includes halogen, oxo, CN, OH, and C ３ ~C ６ saturated or partially saturated cycloalkyl, where R ｂ or R ｂ In the group represented by the formula: ｂ is non-aromatic), CN, OH, C １ ~C ３ Alkyl (F, OH and OCH ３ and C １ ~C ３ Alkoxy (F, OH and OCH ３ and NR ５’ R ６’ may be substituted with one or more groups selected from R ｃ is hydrogen, halogen, and C optionally substituted with one or more groups selected from halogen and OH; １ ~C ６ alkyl, R ｄ is hydrogen, F, CH ３ , or C.F. ３ and Each R １ is H, deuterium, halogen, -CN, OH, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, NR ５’ R ６’ , 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, and 3-8 membered saturated or partially saturated heterocyclyl, wherein R １ C represented by １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C ２ ~C ６ Alkenyl or C ２ ~C ６ Alkynyl is halogen, oxo, CN, CF ３ , O.H., O.C.H. ３ , O.C.H. ２ CH ３ and saturated or partially saturated C ３ ~C ６ Cycloalkyl (halogen, oxo, CN, CF ３ , O.H., O.C.H. ３ , O.C.H. ２ CH ３ wherein R １ or R １ In the group represented by the formula: １ is non-aromatic), CN, OH, C １ ~C ３ Alkyl (F, OH and OCH ３ and C １ ~C ３ Alkoxy (F, OH and OCH ３ and NR ５’ R ６’ may be substituted with one or more groups selected from Each R ２ and R ３ is H, deuterium, halogen, -CN, OH, oxo, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, NR ５’ R ６’ Independently selected from ２ and / or R ３ C represented by １ ~C ６ Alkyl or C １ ~C ６ Alkoxy is halogen, oxo, CN, CF ３ , O.H., O.C.H. ３ , O.C.H. ２ CH ３ and saturated or partially saturated C ３ ~C ６ Cycloalkyl (halogen, oxo, CN, CF ３ , O.H., O.C.H. ３ , O.C.H. ２ CH ３ and optionally substituted with one or more groups selected from Each R ４ is H, deuterium, halogen, OH, -CN, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy or NR ５’ R ６’ Independently selected from ４ C represented by １ ~C ６ Alkyl and C １ ~C ６ Alkoxy is halogen, oxo, CN, CF ３ , and saturated or partially saturated C ３ ~C ６ Cycloalkyl (halogen, oxo, CN, CF ３ , O.H., O.C.H. ３ , O.C.H. ２ CH ３ and optionally substituted with one or more groups selected from R ５’ and R ６’ are each independently hydrogen and C １ ~C ６ alkyl, m is an integer selected from 0, 1, 2, 3, and 4; n is an integer selected from 0, 1, 2, 3, 4, and 5; o is an integer selected from 0, 1, 2, 3, and 4; or a pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof.

2. The compound is represented by structural formula (III): 【Chemistry 5】 In the formula, R ４ is H, F, Cl, methyl, or methoxy, or a pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof. 【Request 3】 【Chemical 6】 teeth, 【Chemistry 7】 and 2. The compound of claim 1, wherein n is an integer selected from 0, 1, 2, 3, and 4, or a pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof.

4. Ring A is 【Chemistry 8】 and Each R １ is halogen, OH, CN, C １ ~C ４ Alkyl, C １ ~C ４ Haloalkyl, C １ ~C ４ Hydroxyalkyl, C １ ~C ４ Alkoxy, C １ ~C ４ Haloalkoxy, C １ ~C ４ Hydroxyalkoxy, C ２ ~C ４ Alkenyl, C ２ ~C ４ Alkynyl, -NH ２ , -NHC １ ~C ４ Alkyl, -N(C １ ~C ４ Alkyl) ２ and m is an integer selected from 0, 1, and 2, or a pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof.

5. R ｂ but, 【Chemistry 9】 and These are halogen, oxo (R ｂ is non-aromatic), CN, NR ５’ R ６’ , C １ ~C ３ Alkyl, and C １ ~C ３ alkoxy, wherein C １ ~C ３ Alkyl or C １ ~C ３ Alkoxy includes F, OH, and OCH ３ The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, optionally substituted with one or two groups selected from: 【Request 6】 【Chemical 10】 teeth, 【Chemistry 11】 6. The compound according to any one of claims 1 to 5, which is: or a pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof.

7. R ３ is halogen, CN, OH, C １ ~C ４ Alkyl, C １ ~C ４ Haloalkyl, C １ ~C ４ Alkoxy or NR ５’ R ６’ and 7. The compound of any one of claims 1 to 6, or a pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein o is an integer selected from 0, 1, 2, 3, and 4.

8. Each R ２ is halogen, -CN, OH, C １ ~C ２ Alkyl, C １ ~C ２ Haloalkyl, and C １ ~C ２ 8. The compound of any one of claims 1 to 7, wherein n is independently selected from alkoxy and n is an integer selected from 0, 1, 2, 3, and 4, or a pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof.

9. Ring A is 【Chemistry 12】 and Each R １ is halogen, OH, CN, C １ ~C ２ Alkyl, C １ ~C ２ Haloalkyl, C １ ~C ２ Hydroxyalkyl, C １ ~C ２ Alkoxy, C １ ~C ２ Haloalkoxy, C １ ~C ２ Hydroxyalkoxy, and C ２ ~C ４ 9. The compound of any one of claims 1 to 8, or a pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein m is independently selected from alkynyl, aryl, arylsulfates, arylalkyl, arylsulfates ...

10.

13. teeth, 【Chemistry 14】 3. The compound of claim 2, wherein:

11.

15. teeth, 【Chemistry 16】 7. The compound of claim 6, which is: or a pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof.

12. Each R ２ is independently selected from halogen or deuterium, and n is an integer selected from 0, 1, and 2, with the proviso that R ２ 12. The compound of any one of claims 1 to 11, or a pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein when is deuterium, then Ring B is fully substituted with deuterium.

13. Each R ３ is F, Cl, or CH ３ and o is 0, 1, or 2, or a pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof.

14. Ring A is 【Chemistry 17】 The compound according to any one of claims 1 to 3, 5 to 8, and 10 to 13, or a pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof.

15. Ring A is 【Chemistry 18】 15. The compound of claim 14, which is: or a pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof.

16.

19. teeth, 【Chemistry 20】 11. The compound of claim 10, wherein:

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, and a pharma- ceutically acceptable excipient.

18. A pharmaceutical composition according to claim 17 for treating cardiometabolic and related diseases, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt, stereoisomer, solvate or hydrate thereof, wherein the disease is type I diabetes, type II diabetes, prediabetes, idiopathic type I diabetes, latent autoimmune diabetes of adults, early onset type II diabetes, atypical diabetes of the young, maturity onset diabetes of the young, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea, obesity, eating disorders, weight gain due to use of other drugs, excessive sugar craving, dyslipidemia, hyperinsulinemia, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, fibrosis, liver cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease. , peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent stroke, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, A pharmaceutical composition for the prevention or treatment of angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, glucose metabolism disorders, conditions with impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcers, ulcerative colitis, hyperapo B lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive disorders, inflammatory bowel disease, short bowel syndrome Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome, or for the treatment of poisoning.

19. 23. Use of a therapeutically effective amount of a compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, in the manufacture of a medicament for treating a subject in need thereof, the disease being selected from the group consisting of type I diabetes, type II diabetes, prediabetes, idiopathic type I diabetes, latent autoimmune diabetes of adults, early onset type II diabetes, atypical diabetes of the young, maturity onset diabetes of the young, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea, obesity, eating disorders, weight gain due to use of other medications, excessive sugar craving, dyslipidemia, hyperinsulinemia, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, fibrosis, liver cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, Coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent stroke, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, menstruation 2. Use in the prevention or treatment of chronic obstructive pulmonary disease, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, glucose metabolism disorders, conditions with impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcers, ulcerative colitis, hyperapo B lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome, or for the treatment of poisoning.

Images