Glp-1r agonists and uses thereof

Abstract

To provide compounds and pharmaceutical compositions for use in, for example, treating type 2 diabetes mellitus, pre-diabetes, obesity, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and cardiovascular disease; methods for treating cardiometabolic and related diseases; and use of the compounds in the manufacture of a medicament.SOLUTION: There are provided compounds of the formula (I) and pharmaceutical compositions thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application is a joint venture with International Patent Application PCT / CN2019 / The benefit of priority to the above-referenced application is claimed from US Pat. No. 6,238,613, the entire contents of which are hereby incorporated by reference. INCORPORATED INTO THE SPECIFICATION. [Background technology]

[0002] Diabetes mellitus is a major public health concern due to its increasing prevalence and associated health risks. This disease is caused by defects in insulin production, insulin action, or both. Diabetes is characterized by high levels of blood sugar that are caused by the inflammatory bowel disease. The two main forms of diabetes are type 1 and type 2. Type 1 diabetes (T1D) occurs when the body's immune system destroys beta cells in the pancreas. It occurs when the beta cells of the pancreas become sole producers of insulin, a hormone that regulates blood sugar. People with type 1 diabetes need to take insulin by injection or pump to survive. Type 2 diabetes (commonly referred to as T2DM) is usually caused by insulin resistance. when insulin production is insufficient to maintain acceptable glucose levels or It begins.

[0003] Currently, various pharmacological approaches are available to treat hyperglycemia and subsequently T2DM. It is possible (Hampp et al., Use of Antidiabetic Drugs in n the US, 2003~2012, Diabetes Care37:1367- 1374, 2014). These can be grouped into six main classes, each with different It operates through a number of key mechanisms:

[0004] Sulfonylureas (e.g., glipizide, glympride, glyburide), meglitinides ( For example, nateglidin, repaglinide), dipeptidyl peptidase IV (DPP-IV ) inhibitors (e.g., sitagliptin, vildagliptin, alogliptin, alogliptin and glucagon-like peptide-1 receptor (GLP-1R) agonists. (e.g., liraglutide, albiglutide, exenatide, linagliptin, durag Insulin secretagogues, including insulin agonists, act on pancreatic beta cells. Sulfonylureas and meglitinides have been shown to be effective and It has limited tolerability, causes weight gain, and often induces hypoglycemia. The efficacy of IV inhibitors is limited. Commercially available GLP-1R agonists are administered subcutaneously. Liraglutide is a peptide that is administered intravenously. Liraglutide is also approved for the treatment of obesity. do.

[0005] Biguanides (e.g., metformin) primarily act by decreasing hepatic glucose production. Biguanides are often used to treat gastrointestinal disorders and lactic acidosis. and further restrict their use.

[0006] Inhibitors of α-glucosidase (e.g., acarbose) decrease intestinal glucose absorption. These drugs often cause gastrointestinal upset.

[0007] Thiazolidinediones (e.g., pioglitazone, rosiglitazone) affect the liver, muscles, and Acts on a specific receptor (peroxisome proliferator-activated receptor-gamma) in adipose tissue Thiazolidinediones modulate lipid metabolism and subsequently their effects on insulin action. Increased tissue response. Frequent use of these drugs can lead to weight gain, edema, and anemia. This may cause

[0008] Insulin is used in more severe cases, either alone or in combination with the above drugs. Frequent use may lead to weight gain and poses the risk of hypoglycemia.

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

[0010] However, with the exception of GLP-1R agonists and SGLT2 inhibitors, the efficacy of these drugs However, the most important problem, the decline in β-cell function and the associated obesity, have not been addressed. not present.

[0011] Obesity is a chronic disease that is highly prevalent in modern society and is associated with high blood pressure, high cholesterol, and Obesity is also associated with many medical problems, including diabetes, cardiovascular disease, and coronary heart disease. It is highly correlated with DM and insulin resistance, the latter of which is generally characterized by hyperinsulinemia or hypercalcaemia. In addition, T2DM is associated with a two-fold increased risk of coronary artery disease. Currently, the only effective treatment for obesity is weight loss. Pharmacological interventions are generally less effective and have higher costs and risks. , with side effects.

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

[0013] T2DM is most commonly associated with hyperglycemia and insulin resistance, but Other diseases that may be affected include hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, and diabetic nephropathy. , diabetic retinopathy, obesity, dyslipidemia, hypertension, hyperinsulinemia and non-alcoholic lipid This includes fatty liver disease (NAFLD).

[0014] NAFLD is the hepatic manifestation of metabolic syndrome and is characterized by steatosis, nonalcoholic fatty liver disease. A continuum of liver diseases including nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and ultimately hepatocellular carcinoma. NAFLD and NASH account for the largest proportion of individuals with elevated liver lipids. , which is considered the primary fatty liver disease. The severity of NAFLD / NASH is determined by the presence of lipids, inflammation, Based on the degree of hepatic cell infiltration, hepatocyte ballooning, and fibrosis. Not all people will progress to NASH, but a significant proportion will.

[0015] GLP-1 is a 30 amino acid long insulin molecule secreted from L cells in the intestine in response to food intake. GLP-1 is an incretin hormone that acts physiologically and glucose-dependently on insulin. It stimulates glucagon secretion, decreases glucagon secretion, inhibits gastric emptying, decreases appetite, and GLP-1 has been shown to stimulate the proliferation of tumor cells. Stimulates the transcription of genes important for insulin-dependent insulin secretion and promotes beta cell regeneration. and promote continued beta cell performance (Meier et al., Biodrugs, 1 7(2):93-102, 2013).

[0016] In healthy individuals, GLP-1 stimulates glucose-dependent insulin secretion by the pancreas. It plays an important role in regulating postprandial glucose levels by increasing peripheral glucose absorption. GLP-1 also inhibits glucagon secretion and decreases hepatic glucose output. In addition, GLP-1 slows gastric emptying and small intestinal motility, decreasing food intake. In people with T2DM, the normal postprandial rise in GLP-1 is absent , or decreased (Vilsboll et al., Diabetes, 50:609-613, 2001).

[0017] Hoist (Physiol. Rev.87:1409,2007) and Meier ( Nat. Rev. Endocrinol. 8:728, 2012) is a stimulator of GLP-1, GLP-1 receptor agonists such as glutamide and exendin-4 have been shown to be effective in fasting and postprandial By lowering the glucose (FPG and PPG) in the blood, glycemic control in T2DM patients is improved. There are three main pharmacological activities that improve the blood glucose level: (i) increasing glucose-dependent insulin secretion (ii) (ii) glucagon suppression activity under hyperglycemic conditions; (iii) glycemic control; and This explains the slowing of gastric emptying, which slows the absorption of glucose from the blood. .

[0018] Easily administered prophylaxis and / or treatment for cardiometabolic and related disorders is required. It is still needed. Summary of the Invention [Problem to be solved by the invention]

[0019] In one aspect, the present disclosure provides a compound represented by the formula (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 pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof. Provide.

[0020] In another aspect, the present disclosure provides a method for the preparation of a compound comprising administering to a subject in admixture with at least one pharma- ceutically acceptable excipient. , 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 or a pharma- ceutically acceptable salt thereof as defined in any one of the embodiments described herein; Pharmaceutical compositions including stereoisomers, solvates, or hydrates are provided.

[0021] In another aspect, the present disclosure provides a compound of the 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 any one of the compounds of the embodiments described herein. a pharma- ceutically acceptable salt, stereoisomer, solvate thereof as defined in any one of the preceding claims, or Provide a hydrate.

[0022] In another aspect, the present disclosure provides methods for treating and preventing the development of inflammatory bowel disease, including T2DM, pre-diabetes, NASH, and cardiovascular disease. The present invention relates to a method for the prevention and / or treatment of cardiometabolic and related disorders as described herein. The formulas described in the specification (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 pharmacytically acceptable salt thereof, a stereoisomer thereof as defined in any one of the embodiments described herein. The present invention provides isomers, solvates, or hydrates thereof.

[0023] In another aspect, the present disclosure relates to a method for the prevention and treatment of diseases for which an agonist of GLP-1R is indicated. and / or a method for treating a subject in need of treatment, comprising administering to said subject a compound of formula (e.g., For example, 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 any one of the compounds described herein. Any pharma- ceutically acceptable salt, stereoisomer, solvate or other equivalent thereof, as defined in any one of the forms: or a hydrate thereof.

[0024] In another aspect, the present disclosure provides a method for treating a disease or condition for which an agonist of GLP-1R is indicated. For the manufacture of a medicament for treating a disease comprising administering to a patient a compound represented by any one of the formulae (e.g., structural formula (I), (I- 1), (I-2), (II), (III), (IA), (IB), (IC), (I -D), (II-A), (II-B), (II-B'), (II-C), or (II-D )) or any one of the compounds as defined in any one of the embodiments described herein. The present invention provides the use of a pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof. do.

[0025] In another aspect, the present disclosure relates to a method for treating a disease or condition for which an agonist of GLP-1R is indicated. For use in ), (II), (III), (IA), (IB), (IC), (ID), (II -A), (II-B), (II-B'), (II-C), or (II-D) A compound or a pharmaceutical composition thereof as defined in any one of the embodiments described herein. and optionally substituted arylsulfates, arylisopropyl ...

[0026] In another aspect, the present disclosure provides a compound represented by the formula (e.g., structural formula (I), (I-1), (I-2), (II), (III), (IA), (IB), (IC), (ID) , (II-A), (II-B), (II-B'), (II-C), and (II-D) Any one of the compounds or its compounds as defined in any one of the embodiments described herein. GLP-1R, including pharma- ceutically acceptable salts, stereoisomers, solvates, or hydrates of The present invention provides a pharmaceutical composition for the treatment of a disease or condition for which an agonist of

[0027] All examples or pharma- ceutically acceptable salts thereof are either individually claimed or incorporated herein. Any number of each and every embodiment listed may be grouped together in any combination. It is possible.

[0028] The present disclosure also relates to the treatment of diseases, including T2DM, pre-diabetes, NASH, and cardiovascular disease, as defined herein. The present invention relates to a method for treating and / or preventing the cardiometabolic and related diseases. The formulas described in the specification (e.g., structural formulas (I), (I-1), (I-2), (II), (II I), (IA), (IB), (IC), (ID), (II-A), (II-B) , (II-B'), (II-C), or (II-D)), or A pharma- ceutically acceptable salt thereof, a stereochemically acceptable salt thereof, as defined in any one of the embodiments described herein, Pharmaceutical compositions including isomers, solvates, or hydrates are provided.

[0029] In another aspect, the present disclosure relates to diabetes (T1D and / or T2DM, including pre-diabetes), particularly onset T1D (type 1b), latent autoimmune diabetes of adults (LADA), early onset T2D M(EOD), young-onset atypical diabetes (YOAD), maturity-onset diabetes of the young (MODY) ), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance Diabetic renal failure, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease (e.g., acute kidney injury, renal failure) tubule dysfunction, inflammation-induced changes to the proximal tubule), diabetic retinopathy, adipocyte dysfunction, Visceral fat deposition, sleep apnea, obesity (including hypothalamic obesity and monogenic obesity) and Associated comorbidities (e.g., osteoarthritis and urinary incontinence), eating disorders (binge eating disorder, bulimia nervosa) syndrome, Prader-Willi syndrome, Bardet-Biedl syndrome, etc. weight gain due to the use of other medications (e.g., steroids and antipsychotics) use), excessive sugar cravings, dyslipidemia (hyperlipidemia, hypertriglyceridemia, total cholesterol (including elevated cholesterol, high LDL cholesterol, and low HDL cholesterol), high insulin Insulinemia, NAFLD (steatosis, NASH, fibrosis, cirrhosis, and hepatocellular carcinoma) Cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral Vascular disease, hypertension, endothelial dysfunction, vascular compliance disorder, 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 Hypertension, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X , premenstrual syndrome, angina, thrombosis, atherosclerosis, transient ischemic attacks, vascular remodeling Stenosis, impaired glucose metabolism, impaired fasting plasma glucose state, hyperuricemia, gout, erectile dysfunction disorders, 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, Prevention or treatment of colitis, irritable bowel syndrome, polycystic ovarian syndrome, and treatment of poisoning (e.g. Treatment and / or management of cardiometabolic and related disorders, including cardiovascular, cardiovascular, and / or alcohol and / or drug abuse or a compound represented by any one of the formulae 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) Any one of the compounds or its compounds as defined in any one of the embodiments described herein. The present invention provides a pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate of

[0030] In another aspect, the present disclosure provides a compound represented by the formula (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) Any one of the compounds or its compounds as defined in any one of the embodiments described herein. The method includes administering a pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate of , GLP-1R-mediated cAMP signaling accompanied by reduced β-arrestin / arrestin-2 recruitment The present invention provides a method for enhancing or stimulating GLP-1R-mediated signaling, wherein the compounds disclosed herein are Although it is a full agonist of cAMP signaling, the activation GL Maximal β-arrestin recruitment to P-1R was greater than that induced by GLP-1 Activated GLP-1R is associated with a lower Based in part on the surprising discovery that β-arrestin is a partial agonist of recruitment to Such partial and / or biased regulation of GLP-1R for cAMP signaling is Agonists provide more sustained cAMP signaling for better efficacy and fewer side effects. It may provide receptor transduction activity.

[0031] Thus, the disclosed methods are useful in treating the diseases described herein, such as type 2 diabetes (T2D) and related disorders. The compounds can be advantageously used in the treatment of any of the diseases or conditions described herein.

[0032] In certain embodiments, treatment provides relief from associated GI side effects such as nausea, vomiting, or diarrhea. The specific objective of the present invention is to induce glycemic benefits without a corresponding increase, or at least a reduced increase, in the blood sugar level. In embodiments, the treatment involves treating normal or enhanced β-arrestin recruitment (β- These treatments are more tolerable compared to control treatments that involve inhibition of IL-1 expression (e.g., arrestin recruitment). [Brief description of the drawings]

[0033] [Figure 1] FIG. 1 shows dose-response curves for the 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 potency of the test compound normalized to the percentage of the potency exerted by the natural ligand GLP-1(7-37). Compounds 74-91, 93-95, 100, and 101 are compared to GLP-1(7-37) in FIG. 1. [Diagram 2] FIG. 2 shows dose-response curves for the GLP-1R / β-arrestin internalization assay using certain compounds of the 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 due to the natural ligand GLP-1(7-37). The two panels of FIG. 2 compare compounds 74-80, 93-95, 100, and 101 (left panel) and compounds 81-91 (right panel), respectively, to GLP-1(7-37). [Diagram 3] FIG. 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] FIG. 4 shows dose-response curves for the GLP-1R / β-arrestin NanoBit assay using certain compounds of the 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 due to the natural ligand GLP-1(7-37). The two panels of FIG. 4 compare compounds 74-91, 93-95, 100, and 101 to 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 PREFERRED EMBODIMENTS

[0034] 1.Compound In a first embodiment, the present disclosure provides a compound represented by structural formula (I): [ka] or a pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof; During the ceremony, [ka] represents a single bond or a 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 N.R. 5’ is selected from Ring B is a 6-membered heteroaryl, a 6-membered monocyclic heterocyclyl, or a phenyl; Y 1 is N, NH, CH, and CH 2 is selected from Ring C is cyclohexyl, phenyl, or pyridyl; L is for CHR d , O, S, or NR 5’ and Ring D is a bicyclic heteroaryl; EE is -COOH or a carboxylic acid group surrogate, optionally teeth, [ka] R a and R b are hydrogen, deuterium, halogen, -CN, and C, respectively. 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, NR 5 'R 6 ', 6-10 membered aryl, 5-8 membered heteroaryl alkyl, 3-8 membered saturated or partially saturated cycloalkyl, and 3-8 membered saturated or partially saturated hexaaryl. wherein R is independently selected from tetracyclyl, a / R b Represented by C 1 ~C 6 Alkyl or is C 1 ~C 6 Alkoxy includes halogen, oxo, CN, OH, and C 3 ~C 6 Saturation or part partially saturated cycloalkyl, where R a / R b or R a / R b Aryl, heteroaryl, etc., in the group represented by , saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl is Gen, Oxo (if necessary), CN, OH, C 1 ~C 3 Alkyl (F, OH and OCH 3 and C 1 ~C 3Alkoxy (F, OH and OCH 3 Substituted with 1 to 3 groups selected from may be present), and NR 5’ R 6’ and is substituted with one or more groups selected from Also, R c and R d are hydrogen, deuterium, halogen, -CN, and C, respectively. 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, NR 5’ R 6’ , 6-10 membered aryl, 5-8 membered heteroaryl alkyl, 3-8 membered saturated or partially saturated cycloalkyl, and 3-8 membered saturated or partially saturated heptane. R is independently selected from the group consisting of cyclocyclyl, c / R d Represented by C 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, wherein R c / R d or R c / R d In the group represented by the formula: saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclyl is , oxo (optionally), CN, and NR 5’ R 6’ is substituted with one or more groups selected from It may be replaced, Each R 1 H, deuterium, halogen, -CN, OH, C 1 ~C 6 Alkyl, C 1 ~C6 a Lukoxi, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, NR 5’ R 6’ , 6~10 members aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, and 3-8 membered saturated or partially saturated heterocyclyl, 1 Represented by C 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., OCH 3 , O.C.H. 2 CH 3 and optionally substituted with one or more groups selected from may be substituted with one or more groups selected from the group consisting of 1 or R 1 Represented by Among the groups listed above are aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl is halogen, oxo (if necessary), CN, O H, C 1 ~C 3 Alkyl (F, OH and OCH 3 Substituted with 1 to 3 groups selected from (may be included), and C 1 ~C3 Alkoxy (F, OH and OCH 3 Selected from 1 , optionally substituted with 3 groups from 5’ R 6’ One or more items selected from and optionally substituted with a group Each R 2 H, deuterium, halogen, -CN, OH, oxo, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, 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 heteroaryl. cyclyl, wherein R 2 Represented by C 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 may be substituted with one or more groups selected from and R 2 or R 2 Represented by Aryl, heteroaryl, saturated or partially saturated cycloalkyl, or Saturated or partially saturated heterocyclyl is optionally substituted with halogen, oxo, CN, OH, C 1 ~C3 Alkyl (F, OH and OCH 3 and is substituted with 1 to 3 groups selected from (optional), and C 1 ~C 3 Alkoxy (F, OH and OCH 3 Substituted with 1 to 3 groups selected from may be present), and NR 5’ R 6’ and is substituted with one or more groups selected from Also, Each R 3 H, deuterium, halogen, -CN, OH, oxo, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, 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 heterocyclic wherein R is independently selected from the group consisting of 3 Represented by C 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., OCH 3 , O.C.H. 2 CH 3 and optionally substituted with one or more groups selected from may be substituted with one or more groups selected from the group consisting of 3 is expressed as R 3 In table Among the groups listed above, aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl is optionally substituted with halogen, oxo, CN, O.H., C. 1 ~C 3 Alkyl (F, OH and OCH 3 Substituted with 1 to 3 groups selected from (which may be C 1 ~C 3 Alkoxy (F, OH and OCH 3 Substituted with 1 to 3 groups selected from may be present), and NR 5’ R 6’ and is substituted with one or more groups selected from Also, Each R 4 H, deuterium, halogen, OH, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy or NR 5’ R 6’ wherein R 4 Represented by C 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 , OH, OCH 3 , O.C.H. 2 CH 3 may be substituted with one or more groups selected from and optionally substituted with one or more groups selected from R 5 and R 6 are hydrogen, deuterium, halogen, CN, OH, and C, respectively. 1 ~C6 Alki Lu, C 1 ~C 6 Alkoxy, NR 5’ R 6’ , 6-10 membered aryl, 5-8 membered hetero Aryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein R 5 or R 6 Represented by C 1 ~C 6 Alki Ru or C 1 ~C 6 Alkoxy is halogen, oxo, CN, CF 3 , O.H., O.C.H. 3 , O CH 2 CH 3 and saturated or partially saturated C 3 ~C 6 Cycloalkyl (halogen, oxo, CN , C.F. 3 , O.H., O.C.H. 3 , O.C.H. 2 CH 3 is substituted with one or more groups selected from may be substituted with one or more groups selected from 5 or R 6 or R 5 or R 6 Among the groups represented by the formula: Partially saturated cycloalkyl or saturated or partially saturated heterocyclyl is substituted with halogen, oxy, SO (if necessary), CN, OH, C 1 ~C 3 Alkyl (F, OH and OCH 3 Choose from and C 1 ~C 3 Alkoxy (F, OH and OCH 3and NR 5’ R 6’ and optionally substituted with one or more groups selected from R 5’ and R 6’ are each independently hydrogen and C 1 ~C 6 Selected from alkyl , Here, two R 1 ;2 R's 2 ;2 R's 3 ;2 R's 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’ also is R 6 Any of;R a and R 5 R (in the group represented by W) 5’ or R 6 brain Either one of the following;R 2 and R 5 R (in the group represented by W) 5’ or R 6 Any of 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 f Any one of the intervening carbon atoms or together with the heteroatom, phenyl, 5- to 6-membered heteroaryl, 4- to 8-membered saturated or partially saturated cycloalkyl or 4-8 membered saturated or partially saturated heterocyclyl These may be halogen, -CN, -OH, CF 3 , C 1 ~C 6 Alki Lu, C 1 ~C 6 Alkoxy, -NH 2 , -NHC 1 ~C 6 Alkyl, -N(C 1 ~C 6 a Rukill) 2 , oxo, and saturated or partially saturated C 3 ~C 6 1 selected from cycloalkyl may be substituted with one or more groups, where C 1 ~C 6 Alkyl and C 1 ~C 6 Arco Xy is halogen, oxo, CN, CF 3 , O.H., O.C.H. 3 , O.C.H. 2 CH 3 , and saturation or partially saturated C 3 ~C 6 cycloalkyl, Preferably, cycloalkyl is halogen, oxo, CN, CF 3 , O.H., O.C.H. 3 , OCH 2 CH 3 and optionally substituted with one or more groups selected from 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, comprising the structural formula (II ) [ka] or a pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof; During the ceremony, X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from N and CH; Medium, X 1 , X 2 , X 3 , X 4 and X 5 Of these, at most three are N, and ring A has three consecutive does not contain three nitrogen ring atoms at the position 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 no more than three nitrogen rings. atom, 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 CR 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 Up to four of these are from N, O, and S. Be selected.

[0036] In a third embodiment, the present disclosure relates to a compound according to the first or second embodiment, or a pharmaceutical composition thereof. and a physiologically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein W is O, NH, or CH 2 and R a , H, CH 3 , or CF 3 and R b is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, NR 5’ R 6’ , 6~1 0-membered aryl, 5-6 membered heteroaryl, 3-6 membered saturated or partially saturated cycloalkyl and 3-7 membered wherein R is selected from the group consisting of saturated or partially saturated heterocyclyl b Represented by C 1 ~C6A Rukill or C 1 ~C 6 Alkoxy includes halogen, oxo, CN, OH and C 3 ~C 6 saturation or partially saturated cycloalkyl, So, R b or R b Among the groups represented by the formula: Partially saturated cycloalkyl or saturated or partially saturated heterocyclyl is substituted with halogen, oxy, So (R 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’ and optionally substituted with one or more groups selected from R c is selected from hydrogen, halogen, and optionally halogen and hydroxy; C substituted with one or more groups 1 ~C 4 alkyl, R d are H, F, and CH 3 , or CF 3 and Each R 1 H, deuterium, halogen, -CN, OH, C 1 ~C 6 Alkyl, C 1 ~C 6 a Lukoxi, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, NR 5’ R 6’ , 6~10 members aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, and 3-8 membered saturated or partially saturated heterocyclyl, where R 1 in Represented C 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, CF3 , O H, O.C.H. 3 , O.C.H. 2 CH 3 may be substituted with one or more groups selected from wherein R 1 or R 1 in Among the groups represented by the formulae, aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl is halogen, oxo (R 1 is non-aromatic), C.N., O.H., C. 1 ~C 3 Alkyl (F, OH and OCH 3 1 to 3 groups selected from substituted with, and C 1 ~C 3 Alkoxy (F, OH and OCH 3 Choose from , optionally substituted with 1 to 3 groups represented by the formula: 5’ R 6’ Selected from may be substituted with one or more groups; R 2 and R 3 are H, deuterium, halogen, -CN, OH, oxo, and C, respectively. 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy or NR 5’ R 6’ are independently selected from R 2 and / or R 3 Represented by C 1 ~C 6 Alkyl and C 1 ~C 6 Alkoxy is a halogen N, 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 may be substituted with a group, Each R 4 H, deuterium, halogen, OH, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 a Rukoxyl or NR 5’ R 6’ where R 4 Represented by C 1 ~C 6 Alkyl and C 1 ~C 6 Alkoxy is halogen, oxo, CN, CF 3 , and saturated or is 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 and optionally substituted with one or more groups such as o is an integer selected from 0, 1, 2, 3, and 4.

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

[0038] In a fifth embodiment, the present disclosure relates to a compound according to the second, third, or fourth embodiment, or and pharma- ceutically acceptable salts, stereoisomers, solvates, or hydrates thereof, [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 method for manufacturing a semiconductor device according to the first, second, third, fourth, or fifth embodiment. or a pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof. wherein ring A is [ka] and Each R 1 are halogens, 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, C2 ~C 4 Alkynyl, -NH 2 , -NHC 1 ~C 4 Alkyl, -N(C 1 ~C 4 Alkyl) 2 are independently selected from m is an integer selected from 0, 1, and 2.

[0040] In a seventh embodiment, the present disclosure relates to a method for manufacturing a semiconductor device according to the first, second, third, fourth, fifth, or sixth embodiment. or a pharma- ceutically acceptable salt, stereoisomer, solvate, or water thereof. where EE is COOH.

[0041] In an eighth embodiment, the present disclosure provides a first, second, third, fourth, fifth, sixth, or seventh embodiment. The compounds according to the embodiments, or their pharma- ceutically acceptable salts, stereoisomers, solvates, or In one embodiment, R b teeth, [ka] and These are halogen, oxo (R b is non-aromatic), CN, NR 5’ R 6’ , C 1 ~C 4 Alkyl, and C 1 ~C 4 one or two groups selected from alkoxy where R b C in the group represented by 1 ~C 4 Alkyl or C 1 ~C 4 Alkoxy is F, OH, and OCH 3 Substituted with one or two groups selected from It may be possible.

[0042] In a ninth embodiment, the present disclosure relates to a second, third, fourth, fifth, sixth, seventh, or eighth embodiment. The compounds according to the embodiments, or their pharma- ceutically acceptable salts, stereoisomers, solvates, or or a hydrate thereof, wherein [ka] teeth, [ka] It is.

[0043] In a tenth embodiment, the present disclosure provides a first, second, third, fourth, fifth, sixth, seventh, eighth or a compound according to the ninth embodiment, or a pharma- ceutically acceptable salt, stereoisomer thereof; A solvate or hydrate is provided, wherein R 3 are halogens, CN, OH, C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 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 first, second, third, fourth, fifth, sixth, seventh, eighth , 9th, or 10th embodiment of the compound, or a pharma- ceutically acceptable salt thereof, isomers, solvates, or hydrates, wherein each R 2 Deuterium, halogen, - C.N., O.H., C. 1 ~C 2 Alkyl, C 1 ~C2 Haloalkyl and C 1 ~C 2 Alkoxy and n is an integer selected from 0, 1, 2, 3, and 4.

[0045] In a twelfth embodiment, the present disclosure provides a first, second, third, fourth, fifth, sixth, seventh, eighth , 9, 10, or 11, or a pharma- ceutically acceptable form thereof. The present invention provides a salt, stereoisomer, solvate, or hydrate, wherein Ring A is [ka] and Each R 1 are halogens, 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 Hydroxy and C 2 ~C 4 alkynyl, m is 0, 1, or and an integer selected from 2.

[0046] In a thirteenth embodiment, the present disclosure provides the fourth, fifth, sixth, seventh, eighth, ninth, tenth, A compound according to the eleventh or twelfth embodiment, or a pharma- ceutically acceptable salt thereof, a stereoisomer thereof, The present invention provides a monoamine, solvate, or hydrate thereof, wherein [ka] teeth, [ka] It is.

[0047] In a fourteenth embodiment, the present disclosure provides the second, third, fourth, fifth, sixth, seventh, eighth, ninth , 10, 11, 12, or 13, or a pharma- ceutical thereof. providing an acceptable salt, stereoisomer, solvate, or hydrate; [ka] teeth, [ka] It is.

[0048] In a fifteenth embodiment, the present disclosure provides a first, second, third, fourth, fifth, sixth, seventh, eighth , 9th, 10th, 11th, 12th, 13th, or 14th embodiment, or and pharma- ceutically acceptable salts, stereoisomers, solvates, or hydrates thereof, each R 2 is independently selected from halogen (e.g., F) or deuterium, and n is 0, 1, and 2. where R is an integer selected from 2 is deuterium, ring B is fully deuterium-substituted. It has been replaced.

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

[0050] In a seventeenth embodiment, the present disclosure provides a first, second, third, fourth, fifth, sixth, seventh, eighth , 9th, 10th, 11th, 12th, 13th, 14th, 15th, or 16th embodiment or a pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof. wherein ring A is [ka] It is.

[0051] In an eighteenth embodiment, the present disclosure provides a first, second, third, fourth, fifth, sixth, seventh, eighth , 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, or 17th implementation or a pharma- ceutically acceptable salt, stereoisomer, solvate, or provides a hydrate, and ring A is [ka] It is.

[0052] In a nineteenth embodiment, the present disclosure provides a second, third, fourth, fifth, sixth, seventh, eighth, ninth , 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, or 18th The compounds according to the embodiments, or their pharma- ceutically acceptable salts, stereoisomers, solvates, or or a hydrate thereof, wherein [ka] teeth, [ka] It is.

[0053] The present disclosure also relates to a compound represented by structural formula (I-1) or (I-2): [ka] or a pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof. In the formula: [ka] represents a single bond or a double bond, X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from N and CH; Medium, X 1 , X 2 , X 3 , X 4 and X 5 Of these, at most three are N, and ring A has three consecutive does not contain three nitrogen ring atoms at the position W is O, S, CR 5 R 6 , and N.R. 5’ is selected from Ring B is a 5- to 6-membered heteroaryl, a 5- to 6-membered monocyclic heterocyclyl, or a phenyl. and Z 1 and Z 2 are each independently selected from N, C and CH; Z 3 and Z 4 teeth, Bond, CH, and CH 2 , CH=CH, CH 2 CH 2 , C.H. 2 CH, and CHCH 2 are independently selected from Ring C contains up to two double bonds, L is for CHR d , O, S, or NR5’ and Ring D is a bicyclic heteroaryl; EE is -COOH or a carboxylic acid group surrogate, optionally teeth, [ka] R a and R b are hydrogen, deuterium, halogen, -CN, and C, respectively. 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, NR 5 'R 6 ', 6-10 membered aryl, 5-8 membered heteroaryl alkyl, 3-8 membered saturated or partially saturated cycloalkyl, and 3-8 membered saturated or partially saturated hexaaryl. wherein R is independently selected from tetracyclyl, a / R b Represented by C 1 ~C 6 Alkyl or is C 1 ~C 6 Alkoxy includes halogen, oxo, CN, OH, and C 3 ~C 6 Saturation or part partially saturated cycloalkyl, where R a / R b or R a / R b Aryl, heteroaryl, etc., in the group represented by , saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl is Gen, Oxo (if necessary), CN, OH, C 1 ~C 3 Alkyl (F, OH and OCH 3 and C 1~C 3 Alkoxy (F, OH and OCH 3 Substituted with 1 to 3 groups selected from may be present), and NR 5’ R 6’ and is substituted with one or more groups selected from Also, R c and R d are hydrogen, deuterium, halogen, -CN, and C, respectively. 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, NR 5’ R 6’ , 6-10 membered aryl, 5-8 membered heteroaryl alkyl, 3-8 membered saturated or partially saturated cycloalkyl, and 3-8 membered saturated or partially saturated heptane. R is independently selected from the group consisting of cyclocyclyl, c / R d Represented by C 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, wherein R c / R d or R c / R d In the group represented by the formula: saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclyl is , oxo (optionally), CN, and NR 5’ R 6’ is substituted with one or more groups selected from It may be replaced, Each R 1 H, deuterium, halogen, -CN, OH, C 1 ~C 6 Alkyl, C1 ~C 6 a Lukoxi, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, NR 5’ R 6’ , 6~10 members aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, and 3-8 membered saturated or partially saturated heterocyclyl, 1 Represented by C 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., OCH 3 , O.C.H. 2 CH 3 and optionally substituted with one or more groups selected from may be substituted with one or more groups selected from the group consisting of 1 or R 1 Represented by Among the groups listed above are aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl is halogen, oxo (if necessary), CN, O H, C 1 ~C 3 Alkyl (F, OH and OCH 3 Substituted with 1 to 3 groups selected from (may be included), and C1 ~C 3 Alkoxy (F, OH and OCH 3 Selected from 1 , optionally substituted with 3 groups from 5’ R 6’ One or more items selected from and optionally substituted with a group Each R 2 H, deuterium, halogen, -CN, OH, oxo, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, 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 heteroaryl. cyclyl, wherein R 2 Represented by C 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 may be substituted with one or more groups selected from and R 2 or R 2 Represented by Aryl, heteroaryl, saturated or partially saturated cycloalkyl, or Saturated or partially saturated heterocyclyl is optionally substituted with halogen, oxo, CN, OH, C1 ~C 3 Alkyl (F, OH and OCH 3 and is substituted with 1 to 3 groups selected from (optional), and C 1 ~C 3 Alkoxy (F, OH and OCH 3 Substituted with 1 to 3 groups selected from may be present), and NR 5’ R 6’ and is substituted with one or more groups selected from Also, Each R 3 H, deuterium, halogen, -CN, OH, oxo, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, 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 heterocyclic wherein R is independently selected from the group consisting of 3 Represented by C 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., OCH 3 , O.C.H. 2 CH 3 and optionally substituted with one or more groups selected from may be substituted with one or more groups selected from the group consisting of 3 is expressed as R 3 In table Among the groups listed above, aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl is optionally substituted with halogen, oxo, CN, O.H., C. 1 ~C 3 Alkyl (F, OH and OCH 3 Substituted with 1 to 3 groups selected from (which may be C 1 ~C 3 Alkoxy (F, OH and OCH 3 Substituted with 1 to 3 groups selected from may be present), and NR 5’ R 6’ and is substituted with one or more groups selected from Also, Each R 4 H, deuterium, halogen, OH, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy or NR 5’ R 6’ wherein R 4 Represented by C 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 , OH, OCH 3 , O.C.H. 2 CH 3 may be substituted with one or more groups selected from and optionally substituted with one or more groups selected from R 5 and R 6 are hydrogen, deuterium, halogen, CN, OH, and C, respectively. 1 ~C6 Alki Lu, C 1 ~C 6 Alkoxy, NR 5’ R 6’ , 6-10 membered aryl, 5-8 membered hetero Aryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein R 5 or R 6 Represented by C 1 ~C 6 Alki Ru or C 1 ~C 6 Alkoxy is halogen, oxo, CN, CF 3 , O.H., O.C.H. 3 , O CH 2 CH 3 and saturated or partially saturated C 3 ~C 6 Cycloalkyl (halogen, oxo, CN , C.F. 3 , O.H., O.C.H. 3 , O.C.H. 2 CH 3 is substituted with one or more groups selected from may be substituted with one or more groups selected from 5 or R 6 or R 5 or R 6 Among the groups represented by the formula: Partially saturated cycloalkyl or saturated or partially saturated heterocyclyl is substituted with halogen, oxy, SO (if necessary), CN, OH, C 1 ~C 3 Alkyl (F, OH and OCH 3 Choose from and C 1 ~C 3 Alkoxy (F, OH and OCH 3and NR 5’ R 6’ and optionally substituted with one or more groups selected from R 5’ and R 6’ are hydrogen and C, respectively. 1 ~C 6 independently selected from alkyl , Here, two R 1 ;2 R's 2 ;2 R's 3 ;2 R's 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’ also is R 6 Any of;R a and R 5 R (in the group represented by W) 5’ or R 6 brain Either one of the following;R 2 and R 5 R (in the group represented by W) 5’ or R 6 Any of 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 f Any one of the intervening carbon atoms or together with the heteroatom, phenyl, 5- to 6-membered heteroaryl, 4- to 8-membered saturated or partially saturated cycloalkyl or 4-8 membered saturated or partially saturated heterocyclyl Or, -C(R a )-, W, and R 2 is ring B [ka] These are halogen, -CN, , -OH, CF 3 , C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, -NH 2 , -NHC 1 ~C 6 Alkyl, -N(C 1 ~C 6 Alkyl) 2 , oxo, and saturated or partially saturated C 3 ~ C 6 cycloalkyl, where C 1 ~C 6 Alkyl and C 1 ~C 6 Alkoxy is halogen, oxo, CN, CF 3 , O.H., OCH 3 , O.C.H. 2 CH 3 , and saturated or partially saturated C 3 ~C 6 Selected from cycloalkyl The cycloalkyl may be substituted with one or more groups selected from the group consisting of halogen, oxy, and phenyl. Seo, CN, CF 3 , O.H., O.C.H. 3 , O.C.H. 2 CH 3 Substituted with one or more groups selected from It may be possible to 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 a compound of formula A compound represented by (IA), (IB), (IC) or (ID), [ka] or a pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof. In the formula: [ka] represents a single bond or a double bond, X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from N and CH; Medium, X 1 , X 2 , X 3 , X 4 and X 5 Of these, at most three are N, and ring A has three consecutive does not contain three nitrogen ring atoms at the position W is O, S, CR 5 R 6 , and N.R. 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; Y3’ and Y 5’ are each independently selected from N, CH, O, and S; Y 4’ is absent, N or CH; wherein ring B has three or fewer hetero ring atoms, and ring B has three hetero ring atoms at three adjacent positions. does not contain hetero ring atoms, Z 1 and Z 2 are each independently selected from N, C, and CH; Z 1 and Z 2 Few At least one is N and one is Z 3 and Z 4 are each independently a bond, CH, or CH 2 , C H=CH, CH 2 CH 2 , C.H. 2 CH, and CHCH 2 and wherein ring C is selected from Contains a double bond, T 2 , T 3 , and T 4 are each independently N, NR 4 , O, S, C, and CR 4 mosquito Selected from T 6 , T 7 and T 8 are each independently N and CR 4 is selected from Here, T 2 , T 3 , T 4 , T 6 , T 7 , and T 8 Up to four of the following are N, O, and S is selected from The remaining variables are the same as those in the previous embodiment for compounds represented by structural formula (I-1) or (I-2). As defined in the state.

[0055] In some embodiments, the present disclosure provides compounds of structural formula (I-1), (I-2), (IA), ( A compound according to structural formula (II-A), (II-B), (IC), or (ID), A compound represented by the formula II-B), (II-B'), (II-C) or (II-D). [ka] or a pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, Here, the variables are structural formulas (I-1), (I-2), (IA), (IB), (IC), or the compound represented by (ID) is as defined in the previous embodiment.

[0056] In some embodiments, the present disclosure provides compounds of structural formula (I-1), (I-2), (IA), ( IB), (IC), (II-A), (II-B), (II-B'), (II-C), or a pharma- ceutically acceptable salt, stereoisomer, or solvent thereof according to (II-D). wherein ring A is [ka] and Each R 1 are halogens, 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, C2 ~C 4 Alkynyl, -NH 2 , -NHC 1 ~C 4 Alkyl, -N(C 1 ~C 4 Alkyl) 2 are independently selected from m is an integer selected from 0, 1, and 2, and the remaining variables are defined in the previous embodiment. That is exactly what happened.

[0057] In some embodiments, the present disclosure provides compounds of structural formula (I-1), (I-2), (IA), ( IB), (IC), (II-A), (II-B), (II-B'), (II-C), or a pharma- ceutically acceptable salt, stereoisomer, or solvent thereof according to (II-D). wherein ring A is [ka] and Each R 1 are halogens, 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, C 2 ~C 4 Alkenyl, C 2 ~C 4 Independently of alkynyl m is an integer selected from 0, 1, and 2, and the remaining variables are selected from the above embodiments. In certain embodiments, ring A is as defined above. [ka] It is.

[0058] In some embodiments, the present disclosure provides compounds of structural formula (I-1), (I-2), (IA), ( IB), (IC), (II-A), (II-B), (II-B'), (II-C), or a pharma- ceutically acceptable salt, stereoisomer, or solvent thereof according to (II-D). providing a 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] It is.

[0060] In some embodiments, the present disclosure provides compounds of structural formula (I-1), (I-2), (IA), ( IB), (IC), (II-A), (II-B), (II-B'), or (II-C or a pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof. In the process, [ka] teeth, [ka] where R 3 is halogen, CN, OH, oxo, C 1 ~C 4 Alkyl, C 1 ~ C 4 Haloalkyl, C 1 ~C 4 Alkoxy or NR 5’ R 6’ where o is 0, 1, 2, and 3, and the remaining variables are as defined in the previous embodiment. In certain embodiments, [ka] teeth, [ka] where R 3 are independently halogen, C 1 ~C 4 Alkyl or C 1 ~C 4 Ha and o is 0, 1, or 2. In a more specific embodiment, [ka] teeth, [ka] It is.

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

[0062] In some embodiments, the present disclosure provides a compound according to structural formula (II-D), or a pharmaceutical and a commercially available, commercially available, commercially available, and / or commercially available, acceptable salt, stereoisomer, solvate, or hydrate of the compound of formula: [ka] teeth, [ka] It is.

[0063] In one embodiment, the compound, or a pharma- ceutically acceptable salt, stereoisomer, or solvent thereof, The solvates or hydrates are 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. It refers to chlorine dioxide.

[0065] Used alone or as part of a larger moiety such as "alkoxy" or "haloalkyl". As used herein, the term "alkyl" refers to a group of the formula -C n H (2n+1) Saturated aliphatic straight chain or branched chain means a branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has a having up to 4 carbon atoms, i.e. (C 1 ~C 4 ) alkyl. If the 1 ~C 4 An "alkyl" group is one to four carbon atoms in a linear or branched arrangement. It refers to a radical having an atom. Examples include methyl, ethyl, n-propyl, isopropyl, Ropil etc. are included.

[0066] As used herein, the term “alkylene” refers to a group of the formula —C n H 2n- Straight or branched chain "alkyl" refers to a divalent hydrocarbon group having a chain length of 100-150 carbon atoms. Non-limiting examples include ethylene and propylene. can be done.

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

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

[0069] The term "alkoxy" refers to an alkyl group bonded through an oxygen linking atom, represented by -O-alkyl. For example, "(C 1 ~C 4 )Alkoxy" is methoxy , ethoxy, propoxy, and butoxy.

[0070] The terms "haloalkyl" and "haloalkoxy" refer to, where appropriate, one or more haloalkyl groups. It means an alkyl or alkoxy substituted with an halogen atom.

[0071] The terms "hydroxyalkyl" and "hydroxyalkoxy" are sometimes used interchangeably. It means an alkyl or alkoxy substituted with one or more hydroxy groups.

[0072] As used herein, the term "cycloalkyl" refers to a group having at least three carbon atoms. Cyclic hydrocarbon groups (e.g., C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , or C 3~8 or C 3~6 Cycloalkyl means (fully) saturated or partially saturated (i.e. , non-aromatic) and may contain one or more carbon-carbon double bonds. .

[0073] A fully saturated cycloalkyl is represented by the formula C n H (2n-1) Non-limiting examples include: Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0074] The term "heterocyclyl" or "heterocyclic" refers to a ring system having ring carbon atoms and 1 to 4 ring heterocycles. A radical of a non-aromatic ring system having 3 to 12 members, each heteroatom being a nitrogen, independently selected from quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur; ("3- to 12-membered heterocyclyl"). A heterocyclyl group is a 3- to 8-membered non-aromatic ring having ring carbon atoms and 1 to 4 ring heteroatoms. system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("3-8 membered In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment is It can be a carbon or nitrogen atom, where the valence allows. Cyclic ("monocyclic heterocyclyl") or polycyclic (e.g., bicyclic systems ("bicyclic heterocyclyls") a tricyclic system ("tricyclic heterocyclyl"), a polycyclic system may include fused rings, bridged rings, sulphonic acid, Exemplary monocyclic heterocyclyl groups include Azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl , piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, o Xepanyl, thiepanyl, tetrahydropyridinyl, etc. Heterocyclyl polycyclic The system may contain heteroatoms in one or more rings of a polycyclic system. Substituents may be present in one or more rings of a polycyclic system. may exist in

[0075] In general, a cycloalkyl or heterocyclyl may be unsubstituted or may have a valence may be substituted with one or more substituents as permitted by the formula (I), and the substituents are, for example, oxo, -CN, halo, may be independently selected from several groups such as alkyl, alkyl, and alkoxyl, and optionally The alkyl group may be further substituted.

[0076] As used herein, the term "heteroaryl" refers to a heteroaryl group having at least one ring carbon atom. is replaced by a heteroatom independently selected from oxygen, nitrogen, and sulfur; Preferably, heteroaryl refers to a cyclic or polycyclic aromatic hydrocarbon of the formula: C, one or more of which are replaced by heteroatoms 5~8 Based on aryl. Heteroaryl The group may be attached via a ring carbon atom or, if valence allows, a ring nitrogen. The heteroaryl may be attached via any one of the following atoms: or, where valence permits, halogen, OH, alkyl, alkoxyl and amino (e.g., NH 2 , NH alkyl, N(alkyl) 2 ) is one or more substituents independently selected from It may be substituted and optionally the alkyl may be further substituted.

[0077] Specific abbreviations used herein include: room temperature: RT; methanol: MeOH; ethanol: Alcohol: EtOH, isopropanol: iPrOH, ethyl acetate: EtOAc, tetrahydrofuran: Furan: THF, Toluene: PhCH3, Cesium carbonate: Cs 2 CO 3 , Lithium Bis( (trimethylsilyl)amide: LiHMDS, sodium t-butoxide: NaOtBu, Potassium t-butoxide: KotBu, Lithium diisopropylamide: LDA, Triethylene Ethylamine: Et3 N,N,N-Diisopropylethylamine: DIPEA, potassium carbonate M:K 2 CO 3 , dimethylformamide: DMF, dimethylacetamide: DMAc, Methyl sulfoxide: DMSO, N-methyl-2-pyrrolidinone: NMP, sodium hydride Um: NaH, Trifluoroacetic acid: TFA, Trifluoroacetic anhydride: TFAA, Anhydrous acetic acid Acid: Ac 2 O, dichloromethane: DCM, 1,2-dichloroethane: DCE, hydrochloric acid: HC l, 1,8-diazabicyclo[5.4.0]undec-7-ene: DBU, borane-dimethy Thiol sulfide complex: BH 3 -DMS, borane-tetrahydrofuran complex: BH 3 - THF, lithium aluminum hydride: LAH, acetic acid: AcOH, acetonitrile: Me CN, p-toluenesulfonic acid: pTSA, dibenzylideneacetone: DBA, 2,2' -Bis(diphenylphosphino)-1,1'-binaphthalene: BINAP, 1,1'-fu dppf, 1,3-bis(diphenyl Phosphino)propane: DPPP, 3-chloroperbenzoic acid: m-CPBA, tert- Methyl methyl ether: MTBE, methanesulfonyl: Ms, N-methylpyrrolidinone: N MP, thin layer chromatography: TLC, supercritical fluid chromatography: SFC, 4-(di Methylamino)pyridine: DMAP, tert-Butyloxycarbonyl: Boc, 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pi Lysinium 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)diparadiu M:Pd 2 (dba) 3 Includes:

[0078] 1 H nuclear magnetic resonance (NMR) spectra were consistent with the proposed structures in all cases. The characteristic chemical shifts (δ) were consistent with those of the deuterated solvent (CHCl at 7.27 ppm). 3 , 3.31 ppm C.D. 2 HOD, 1.94 ppm MeCN, 2.50 ppm DMS O) for the assignment of the major peaks. with conventional abbreviations, e.g., s for singlet, d for doublet, t for triplet, q for quartet, and m for multiplet. , br is reported using broad; unless otherwise stated, 400 or 600MH With the electric field strength of z 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. do.

[0081] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetates, azides, etc. Pinate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate Salts / sulfates, borates, camsylates, cyclamates, edisylates, esylates, gypsum salts Acid salts, fumarates, gluceptates, gluconates, glucuronates, hexafluorophosphates phosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide salts, isethionates, lactates, malates, maleates, malonates, mesylates, Methyl sulfate, naphthylate, 2-naphthylate, nicotinate, nitrate, orotate, Oxate, palmitate, pamoate, phosphate / hydrogen phosphate / hydrogen phosphate, pyroglucan glutamate, saccharate, saccharate, stearate, stearates, triflate Examples of suitable fluorinated acetate salts include fluoroacetate salts, 1,5-naphthalenedisulfonic acid salts, and xinafoate salts.

[0082] Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum salts. , Arginine, Benzathine, Calcium, Choline, Diethylamine, Bis(2-hydroxy Diethylamine (diolamine), glycine, lysine, magnesium, meglumine, 2- Aminoethanol (Olamine), potassium, sodium, 2-amino-2-(hydroxy methyl)propane-1,3-diol (tris or tromethamine) and zinc salts. do.

[0083] Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts. For a review, see Stahl and Wermuth in the Handbook of Pharmaceutical Salts:Properties,Selectio See, for example, "Publication and Use" (Wiley-VCH, 2002). will be incorporated into the subsection.

[0084] A pharma- ceutically acceptable salt of a compound of any one of the above formulas may be prepared in one of three ways. It can be prepared as described above. (i) by reacting a compound of any one of the above formulas with a desired acid or base , (ii) Removing an acid or base labile protecting group from a suitable precursor of a compound of any one of the above formulas by removing the compound from the body, or by forming a suitable cyclic precursor, e.g., a lactone or lactam, by ring opening using a desired acid or base, or (iii) reacting a salt of a compound of any one of the above formulas with a suitable acid or base; by converting it to another salt by a suitable ion exchange column.

[0085] All three reactions are typically carried out in solution. The resulting salts are precipitated and collected by filtration. The degree of ionization of the resulting salt is , ranging from completely ionized to barely ionized.

[0086] Compounds of any one of the above formulae, and pharma- ceutically acceptable salts thereof, may be unsolvated or soluble. It can exist in solvated form.

[0087] Solvates and hydrates The term "solvate" is used herein to refer to a compound of any one of the above formulae, or and one or more pharma- ceutically acceptable solvent molecules, such as ethanol. It is used to describe a molecular complex that contains

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

[0089] The currently accepted classification system for organic hydrates is based on isolated sites, channels or metal ions. This defines the on-coordinate hydrate, and is described in Polymorph ism in Pharmaceutical Solids(Ed.HGBrit (see Tain, Marcel Dekker, 1995). Isolated site hydrates In the case of the cyclohexane, the water molecules are isolated from each other by the organic molecules that are in between. In channel hydrates, the water molecules are in lattice channels next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion.

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

[0091] Stereoisomers and other variations Compounds of any one of the above formulas may exhibit one or more types of isomerism (e.g., optical isomerism, geometric isomerism, Compounds of any one of the above formulae may also exhibit isomerism, tautomerism, or tautomerism. Such variations may be identified by reference to their structural features. It is implicit in any one of the compounds of the above formulae defined above and therefore falls within the scope of this disclosure. It is inside.

[0092] A compound of any one of the above formulas containing one or more asymmetric carbon atoms may have two or more stereoisomers. The compounds of any of the above formulae may exist in two or more isomers. When an ylene group is contained, geometric (or Z / E) isomers are possible. If they are interconvertible through an energy barrier, tautomeric isomerism ("tautomerism") occurs. This can be achieved, for example, by forming a compound of any one of the above formulae containing an imino, keto, or oxime group. Proton tautomerism in compounds, or so-called valence in compounds containing aromatic moieties They can take the form of tautomers. Thus, a single compound can exhibit more than one type of isomerism. It is possible.

[0093] Compounds that have one or more chiral centers can exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all dimers. Astereomeric, enantiomeric and epimeric forms, as well as racemic and mixtures thereof The term "geometric isomer" refers to compounds that have at least one double bond. The double bond can be cis (also called syn or entgegen (E)) or tri- lance (also called anti or zusammen (Z)) forms and mixtures thereof The disclosed compounds may be named or depicted by structure without indicating stereochemistry. In some cases, the name or structure may refer to one or more of the possible stereoisomers, or geometric isomers, or may encompass any It is understood that the term encompasses mixtures of stereoisomers or geometric isomers.

[0094] When geometric isomers are depicted by name or structure, the named or depicted isomers are distinct. that is, that the named or depicted geometric isomers exist to a greater extent than the The geometric isomeric purity is greater than 50%, for example, at least 60%, 70%, 80%, or more by weight. It should be understood that the compound may be 0%, 90%, 99%, or 99.9% pure by weight. Geometric purity is the weight of the specified or depicted geometric isomer in a mixture. It is determined by dividing 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. A compound with one chiral center can be synthesized without showing the stereochemistry of the chiral center. When named or depicted, the name or structure may include any possible enantiomeric forms of the compound (e.g., enantiomerically pure, enantiomerically enriched, or racemic It is understood that both are included. A compound having two or more chiral centers may be When a compound is named or depicted without indicating its somatic chemistry, the name or structure represents all Possible diastereomeric forms (e.g. diastereomerically pure, diastereomeric diastereomerically enriched and equimolar mixtures of one or more diastereomers (e.g., racemic mixtures). It is understood that the term encompasses the compounds (compounds).

[0096] Enantiomeric and diastereomeric mixtures can be analyzed by chiral phase gas chromatography, chiral crystallization of the compound as a chiral salt complex, or Their component enantiomers can be separated by well-known methods, such as crystallizing the mixture in a chiral solvent. Enantiomers and diastereomers can also be separated into isomers or stereoisomers. Also, diastereomerically or enantiomerically pure intermediates, reagents, and catalysts are available in well-known forms. It can be obtained by asymmetric synthesis of

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

[0098] The stereochemistry of the disclosed compounds is named or indicated by the structures, and the named or depicted structures When R includes two or more stereoisomers (e.g., as in the case of a diastereomeric pair), , one of the stereoisomers included or any mixture of the stereoisomers included It is to be understood that the stereoisomeric purity of the named or depicted stereoisomers is at least 60 fold. %, 70%, 80%, 90%, 99%, or 99.9% by weight. It should be further understood that stereoisomeric purity in this case refers to the stereoisomeric form of the compound included in the name or structure. Determined by dividing the total weight of the mixture of isomers by the total weight of the mixture of all stereoisomers. It is determined.

[0099] Pharmaceutically acceptable salts of compounds of any one of the above formulas also include those which 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 determined by conventional techniques well known to those skilled in the art, such as chromatography and It can be separated by fractional crystallization.

[0101] Conventional techniques for preparing / isolating individual enantiomers include suitable optically pure Chiral synthesis from precursors, or for example using chiral high pressure liquid chromatography (HPLC) Alternatively, the separation of a racemate (or a racemate of a salt or derivative) using (or a racemic precursor) may be reacted with a suitable optically active compound, e.g. an alcohol. or, if the compound of any one of the above formulas contains an acidic or basic moiety, 1-phenylenediamine The resulting diastereomers may be reacted with a base or an acid such as diethylamine or tartaric acid. The mixture can be separated by chromatography and / or fractional crystallization to obtain a dias One or both of the stereoisomers can be purified by means well known to those skilled in the art to produce the corresponding pure enantiomers. The chiral compound of any one of the above formulas (and its chiral derivatives) can be converted to a chiral mer. Precursor) is 0 to 50% by volume, typically 2% to 20% isopropanol, and 0 Hydrocarbons containing 5% by volume of alkylamines, typically 0.1% diethylamine. Chromatography on an asymmetric resin using a mobile phase consisting of nitrogen, typically heptane or hexane. can be obtained in enantiomerically enriched form using purification techniques, typically HPLC. The eluate can be concentrated to obtain a concentrated mixture. In some embodiments of the present disclosure, Suitable chiral chromatography methods are known in the art (see, for example, Smith, R. oger M., Loughborough University, Loughborough, UK, Chromatographic Science Series(1998), 75(Supercritical F luid Chromatography with Packed Columns) (See pages 223-249 and the references cited therein.) Chiral Technologies, West Chester, Pennsylvania, Japan Daicel Chemical Industries, a subsidiary of Daicel Chemical Industries, Inc., located in Tokyo, Japan. It can be obtained from the company.

[0102] As used herein, any one of the compounds of the above formulae may be depicted in a single tautomeric form. It must be emphasized that all possible tautomeric forms are included within the scope of the present disclosure. It won't happen.

[0103] The present disclosure also provides that one or more atoms may have the same atomic number but different atomic masses or mass numbers in a natural Any of the above formulae in which the atomic masses or mass numbers predominant in the field are replaced by atoms different from The present invention includes any one of all pharma- ceutically acceptable isotopically labeled compounds.

[0104] Examples of isotopes suitable for inclusion in the compounds of the present disclosure include: 2 H and 3 Hydrogen such as H 1 1 C. 13 C and 14 Carbon isotopes such as C, 36 Isotopes of chlorine such as Cl, 18 F etc. isotopes of fluorine, 123 I and 125 Iodine isotopes such as I 13 N and 15 N etc. isotopes of nitrogen, 15 O. 17 O and 18 Oxygen isotopes such as O 32 P and other phosphorus equivalents Position, and 35 Examples include isotopes of sulfur such as S.

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

[0106] Deuterium, i.e. 2 Substitution with heavier isotopes such as H results in greater metabolic stability, providing a particular therapeutic advantage, for example resulting from increased in vivo half-life or reduced dosage requirements; possible.

[0107] 11 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes, such as N, can be used to It may be useful in positron emission topography (PET) studies to examine 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 using appropriate isotopically labeled reagents in place of previously used unlabeled reagents. It can be prepared by methods similar to those described in the accompanying examples and preparations.

[0109] Pharmaceutically acceptable solvates according to the present disclosure may include those in which the solvent of crystallization may be isotopically substituted. Good ones, e.g. D 2 O, d 6 -Acetone, d 6 -Contains DMSO.

[0110] Prodrug One method of practicing this disclosure is to provide a compound of any one of the above formulas in the form of a prodrug. Therefore, the above-mentioned substances may have little or no pharmacological activity. Certain derivatives of compounds of any one of the formulas, when administered to or on the body, e.g. Hydrolytic cleavage, especially hydrolytic cleavage promoted by esterase or peptidase enzymes can be converted by cleavage into any one of the compounds of the above formulae having the desired activity. Such derivatives are called "prodrugs." Further information regarding the use of prodrugs is available at: Information provided by Pro-drugs as Novel Delivery Systems ,Volume 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drugs Design, Pergamon Press, 1987 (E.B.Roche, USA) The results can be found in Nature Reviews / Drug Discussion. overy, 7:355, 2008, and Current Opinion in Dr. ug Discovery and Development, 10:550, 2007 You can also refer to:

[0111] Prodrugs according to the present disclosure can be prepared, for example, by the method described by H. Bundgaard (Elsevier, 1999). 85) and D by YM Choi-Sledeski and C G Wermuth esign of Prodrugs, Practice of Medicinal Designing in Chemistry (4th ed.), Chapter 28, 657-696 Prodrugs and Bioprecursors (Elsevier, 2015) As described in, suitable functional groups present in a compound of any one of the above formulas may be by substituting a specific moiety known to those skilled in the art as a "promoiety" It is possible.

[0112] Thus, a prodrug according to the present disclosure comprises: (a) a compound of any one of the above formulae (b) an ester or amide derivative of a carboxylic acid of any one of the compounds of the above formula Ester, carbonate, carbamate, phosphate or ether derivatives of hydroxyl groups conductors, (c) amides, imines of amino groups in compounds forming any one of the above formulas, (d) a carbonyl in any one of the compounds of the above formulae or (e) a carbocyclic compound in any one of the above formulae. The substituents are methyl, primary alcohol, or aldehyde groups that can be metabolically oxidized to carboxylic acids.

[0113] Some specific examples of prodrugs according to the present disclosure include: (i) Any one of the compounds of the above formulas contains a carboxylic acid functional group (-COOH), When the compound of any one of the above formulas contains a carboxylic acid functional group, the hydrogen of the carboxylic acid functional group is C 1 ~ C 8 Alkyl (e.g., ethyl) or (C 1 ~C 8 Alkyl)C(=O)OCH 2 -(example For example, t BuC(=O)OCH 2 -), (ii) A compound of any one of the above formulae has an alcohol functional group (-OH), an ester thereof In the case where the compound contains a cyclic alkyl group, the hydrogen of the alcohol functional group of the compound of any one of the above formulas is -CO( C 1 ~C 8 alkyl) (e.g., methylcarbonyl) or Compounds in which choline is esterified with an amino acid, (iii) Any one of the compounds of the above formulas has an alcohol functional group (-OH), When the compound of any one of the above formulas contains an ether, the hydrogen of the alcohol functional group of the compound is (C 1 ~C 8 Alkyl)C(=O)OCH 2 -or-CH 2 OP(=O)(OH) 2 Replace with Compounds that have been (iv) A compound of any one of the above formulae has an alcohol functional group (-OH), its phosphorus When the compound contains an acid group, the hydrogen of the alcohol functional group of the compound of any one of the above formulas is -P( =O)(OH) 2 or -P(=O)(ONa) 2 or -P(=O)(O - ) 2 Ca 2+ in The compound to be replaced, (v) The compound of any one of the above formulas contains a primary or secondary amino functional group (-NH 2 or -NHR, where R ≠ H), including amides thereof, for example, in some cases, In one or both of the hydrogens of the amino functional group of the compound of any one of the formulae 1 ~C 10 ) Alkanoyl, -COCH 2 NH 2 or the amino group is replaced by an amino acid Compounds that have been derivatized, (vi) The compound of any one of the above formulae contains a primary or secondary amino functional group (-NH 2 or -NHR, where R ≠ H), when it contains an amine, for example, In one or both of the hydrogens of the amino functional group of the compound of any one of the formulas 2 OP(= O)(OH) 2 Compounds which are replaced by (vii) The carboxylic acid group in any one of the compounds of the above formulae is selected from the group consisting of a methyl group, a -CH 2 Compounds in which the OH group or the aldehyde group is substituted.

[0114] A particular compound of any one of the above formulae may itself be any other compound of any one of the above formulae. The compound of any one of the above formulas may act as a prodrug of the compound of the formula: It is also possible to combine them together in the form of a prodrug. In certain circumstances, A prodrug of any one of the compounds may be prepared by, for example, forming a lactone, and the prodrug may be of the formula by internally linking two functional groups in one compound. can be done.

[0115] A reference to a compound of any one of the above formulas includes the compound itself and prodrugs thereof. The present disclosure relates to such compounds of any one of the above formulas, as well as to such compounds The present invention includes pharma- ceutically acceptable salts of the compounds, as well as pharma- ceutically acceptable solvates of the compounds and salts. nothing.

[0116] 3. Administration and Dosing Typically, the compounds of the present disclosure are effective in treating the conditions as described herein. The compounds of the present disclosure may be administered as compounds per se or in a pharma- ceutically acceptable form. In the administration and dosage, the compound itself or its pharmaceutical salt may be administered. The commercially acceptable salts are simply referred to as the compounds of the present disclosure.

[0117] The compounds of the present disclosure may be administered in the form of pharmaceutical compositions adapted for such routes for the intended treatment. The compounds of the present disclosure may be administered by any suitable route in a dose effective for the purpose of treating the condition. The composition may be administered intravenously, vaginally, parenterally, or topically.

[0118] The compounds of the present disclosure can be administered orally. Oral administration allows the compounds to enter the gastrointestinal tract. may involve swallowing, or may use buccal or sublingual administration where the compound enters the bloodstream directly from the mouth. There may be cases where this occurs.

[0119] In another embodiment, the compounds of the present disclosure may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, and urinary. Suitable devices for parenteral administration include intramuscular, intrasternal, intracranial, intramuscular and subcutaneous. These include injectors (including microneedles), needle-free injectors, and injection techniques.

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

[0121] The dosage regimen for the compounds of the present disclosure and / or compositions containing such compounds may vary depending on the type, age, and / or other characteristics of the patient. , weight, sex and medical condition, the severity of the condition, the route of administration, and the activity of the particular compound used. The dosage regimen is based on a variety of factors, including the dosage regimen itself. The total daily dose of the compounds of the present disclosure for the treatment of the indicated conditions discussed herein is Typically, the dosage form is about 0.001 to about 100 mg / kg (i.e., about 0.001 to about 100 mg / kg of body weight of the present disclosure). In another embodiment, the total daily dose of the compounds of the present disclosure is from about 0.01 to about 10 mg of the compound. to about 30 mg / kg, and in another embodiment, from about 0.03 to about 10 mg / kg. and in yet another embodiment, from about 0.1 to about 3 mg / kg. Administration of Compounds of the Disclosure It is not uncommon for this to be repeated multiple times a day (typically up to four times). Depending on the severity, multiple daily doses can usually be used to increase the total daily dose. can.

[0122] For oral administration, the composition may be administered in the form of 0.1, 0.5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 23 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 The drug may be provided in the form of a tablet containing about 0.01 mg to about to 500 mg of active ingredient, or in another embodiment, from about 1 mg to about 100 mg of active ingredient. Intravenously, doses range from about 0.01 to about 10 mg / kg / minute during a constant rate infusion. may be in the range.

[0123] Suitable subjects according to the present disclosure include mammalian subjects, including primates, rodents (mouse, rats, etc.). In one embodiment, the mammalian animal is a human. Human subjects may be of any gender and at any stage of development.

[0124] 4. Pharmaceutical Compositions In another embodiment, the present disclosure includes a pharmaceutical composition. Such a pharmaceutical composition is pharma- ceutical acceptable. The compounds of the present disclosure may be presented together with an acceptable carrier. Other pharmacologically active substances may also be present. possible.

[0125] As used herein, a "pharmaceutical acceptable carrier" refers to a physiologically compatible All solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. Examples of pharma- ceutically acceptable carriers include water, saline, phosphate buffered saline, etc. Saline, dextrose, glycerol, ethanol, etc., and combinations thereof The composition may include one or more of isotonic agents, for example, sugars, sodium chloride, or mannitol. The carrier may include a polyhydric alcohol such as diethanolamine or sorbitol. Storage of Antibodies or Antibody Portions Pharmaceutically acceptable substances, such as wetting agents, which enhance the longevity or effectiveness of the composition, or wetting agents or emulsions. Small amounts of auxiliary substances such as antioxidants, preservatives or buffers.

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

[0127] Exemplary compositions are similar to those commonly used for passive immunization of humans with antibodies. One mode of administration is parenterally (e.g., 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. It is administered.

[0128] Oral administration of solid dosage forms may be, for example, hard or soft capsules, pills, cachets, lozenges, etc. or tablets, each of which may be presented in discrete units, each of which may comprise at least one of the compositions of the present disclosure. In another embodiment, the oral administration is in the form of a powder or granules. In another embodiment, the oral dosage form is sublingual, such as, for example, a troche. In such solid dosage forms, a compound of any one of the above formulas will typically be used in combination with one or more adjuvants. Such capsules or tablets may contain a sustained release formulation. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents or may contain enteric coating agents. It can be prepared using coating.

[0129] In another embodiment, oral administration may be in liquid form. Liquid dosage forms for oral administration include For example, pharmaceutical diluents containing inert diluents commonly used in the art (e.g., water) may be used. These include physiologically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such compositions may also contain wetting agents, emulsifying agents, suspending agents, flavoring agents (e.g., sweetening agents), and / or other additives. Or it may contain an auxiliary agent such as a fragrance.

[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, sternal injection, etc. Injectable preparations (i.e., sterile injectable aqueous or (oil suspensions) may be prepared by the use of suitable dispersing, wetting and / or suspending agents according to the known art. Therefore, it can be formulated.

[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. Compositions for topical administration can also be administered intranasally, intraocularly, or intranasally or by inhalation. Examples include topical gels, sprays, ointments, and creams. Topical preparations are applied to the skin or other affected areas. The compounds disclosed herein may include compounds that enhance absorption or penetration of the active ingredient through a transdermal device. When administered by a system, administration can be by a reservoir and porous membrane type or a solid matrix. This is accomplished using a patch of any of the following types: Gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, fillers films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions Liposomes may also be used. Typical carriers include alcohol, water, mineral oils, etc. Oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene Penetration enhancers can be incorporated, for example, Finnin and and Morgan, J. Pharm. Sci., 88:955-958, 1999. do.

[0134] Formulations suitable for topical administration to the eye include, for example, compositions in which the compounds of the disclosure are dissolved or in a suitable carrier. Exemplary formulations suitable for ocular or aural administration include isotonic, Even in the form of droplets of a micronized suspension or solution in pH-adjusted sterile saline. Other formulations suitable for ocular and otic administration include ointments, biodegradable (i.e., absorbent gels), and the like. sponges, collagen) and non-biodegradable (i.e. silicone) implants, wafers , lenses, and particle or vesicular systems such as niosomes or liposomes. Polymers such as polyacrylic acid, polyvinyl alcohol, and hyaluronic acid, hydroxypropyl Cellulose such as methylcellulose, hydroxyethylcellulose, or methylcellulose A polysaccharide polymer such as a saccharide-based polymer or a heteropolysaccharide polymer such as gellan gum is treated with benzalkonium chloride. Such formulations may also be incorporated with preservatives such as iodine, iodine-4-phosphate dehydrogenase, iodine-5-phosphate dehydrogenase, and iodine-6-phosphate dehydrogenase. can be achieved.

[0135] For administration intranasally or by inhalation, the compounds of the present disclosure may be administered using a suitable propellant, such as: In the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient. Alternatively, it may be conveniently delivered as an aerosol spray from a pressurized container or nebulizer. Formulations suitable for intranasal administration are typically formulated with 1,1,1,2-tetrafluoroethane or Use a suitable propellant such as 1,1,1,2,3,3,3-heptafluoropropane or without the use of dry powder from a dry powder inhaler (alone or as a mixture, e.g. in a dry blend with phosphatidylcholine or as mixed component particles, e.g. or mixed with phospholipids such as phospholipids, etc.) or in pressurized containers, pumps, sprayers, etc. - an atomizer (preferably one that uses electrohydrodynamics to generate a fine mist) It is administered as an aerosol spray from a nebulizer or via a tube. The powder may include a bioadhesive, such as chitosan or cyclodextrin.

[0136] In another embodiment, the present disclosure includes a rectal dosage form. Such a rectal dosage form may be, for example, a suppository. Cocoa butter is a traditional suppository base, but various other suppository bases may be used if desired. Alternatives can be used.

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

[0138] The above considerations regarding effective formulations and administration procedures are well known in the art and are well understood in standard clinical practice. The formulation of drugs is described in, for example, Hoover, John E. , Remington's Pharmaceutical Sciences, Mac K Publishing, Easton, Pennsylvania, 1975. Liberm eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980, and Kibbe et al., eds., Han dbook of Pharmaceutical Excipients (3rd ed.), Discussed in American Pharmaceutical Association, Washington, 1999.

[0139] 5. Simultaneous administration The compounds of the present disclosure may be used alone or in combination with other therapeutic agents. The disclosure provides any of the uses, methods or compositions defined herein, or a pharma- ceutically acceptable salt thereof; Alternatively, a pharma- ceutically acceptable solvate of the compound or salt may be any of the compounds discussed herein. It is used in combination with one or more other therapeutic agents.

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

[0141] "Concurrent administration" (co-administration)" or "simultaneous administration" "administration" and "administered simultaneously" The phrase "combined administration" refers to the compounds being administered in combination. This means that...

[0142] In another embodiment, the present disclosure provides a method for administering a compound of the present disclosure in combination with one or more other agents. and administering to the subject a therapeutically effective amount of one or more of the other agents described herein. may be selected from:

[0143] In one embodiment, the compounds of the present disclosure may be combined with pharma- ceutically acceptable salts of specifically named agents. and biguanides (e.g., methacrylates ... formin), sulfonylureas (e.g., tolbutamide, glibenclamide, gliclazide , chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride , or glipizide), thiazolidinediones (e.g., pioglitazone, rosiglitazone or lobeglitazone), glitazar (e.g., saroglitazar, aleglitazar, muraglitazar, tazar or tesaglitazar), meglitinides (e.g., nateglinide, repaglinide), Dipeptidyl peptidase 4 (DPP-4) inhibitors (e.g., sitagliptin, vildagliptin) Liptin, Saxagliptin, Linagliptin, Gemigliptin, Anagliptin, Tenagliptin Ligliptin, alogliptin, trelagliptin, dutogliptin or omarigliptin tin), glitazones (e.g., pioglitazone, rosiglitazone, balaglitazone, riboglitazone, glitazone or lobeglitazone), sodium-glucose-coupled transporter 2 (SGLT2) inhibitors (e.g., empagliflozin, canagliflozin, dapagliflozin, ipragliflozin Liflozin, Ipragliflozin, Tofogliflozin, Sergliflozin etabonate, Remogliflozin etabonate or ertugliflozin), SGLTL1 inhibitor, GPR 40 agonists (FFAR1 / FFA1 agonists, e.g., fasudimihum), gluco Glucose-dependent insulinotropic peptide (GIP) and its analogs, α-glucosidase inhibitors antidepressants (e.g., voglibose, acarbose, or miglitol), or insulin or administered with antidiabetic drugs, including but not limited to insulin analogs.

[0144] In another embodiment, the compounds of the present disclosure include, but are not limited to, peptide YY or peptides thereof. Analogs of, neuropeptide Y receptor type 2 (NPYR2) agonists, NPYR1 or NPY R5 antagonist, cannabinoid receptor type 1 (CB1R) antagonist, lipase Inhibitors (e.g., orlistat), human islet peptide (HIP), melanocortin receptor Melanin-concentrating hormone receptor 4 agonists (e.g., setomelanotide), melanin-concentrating hormone receptor 1 antagonists agonists, farnesoid X receptor (FXR) agonists (e.g., obeticholic acid), zoni Samidim, phentermine (alone or in combination with topiramate), norepinephrine / Dopamine reuptake inhibitors (e.g., bupropion), opioid receptor antagonists opioids (e.g., naltrexone), norepinephrine / dopamine reuptake inhibitors and opioids Combinations with idiopathic steroid receptor antagonists (e.g., bupropion and naltrexone) combination), GDF-15 analogs, sibutramine, cholecystokinin agonists, myrin and its analogs (e.g., pramlintide), leptin and its analogs (e.g., metholetropin), serotonergic agents (e.g., lorcaserin), methionine aminopeptides MetAP2 inhibitors (e.g., beloranib or ZGN-1061), dimetrazine, diethylpropion, benzphetamine, SGLT2 inhibitors (e.g. Empagliflozin, Canagliflozin, Dapagliflozin, Ipragliflozin, Ipragliflozin Lagliflozin, Tofogliflozin, Sergliflozin etabonate, Remogliflozin etabonate, or ertugliflozin), SGLTL1 inhibitor, dual SGLT2 / SGLT1 inhibitors, fibroblast growth factor receptor (FGFR) modulators, AMP activity AMPK activators, biotin, MAS receptor modulators, or a glucagon receptor agonist (alone or with another GLP-1R agonist, e.g. Liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, or In combination with anti-obesity drugs, including semaglutide, and pharma- ceutically acceptable salts of, as well as pharma- ceutically acceptable solvates of, such agents and salts.

[0145] In another embodiment, the compounds of the present disclosure are administered in the form of pharma- ceutically acceptable forms of the specifically named drugs. PF-05221304, including salts and pharma- ceutically acceptable solvates of said drugs and salts. , FXR agonists (e.g., obeticholic acid), PPARα / δ agonists (e.g., elafibranor), synthetic fatty acid-bile acid conjugates (e.g., aramchol), spase inhibitors (e.g., emricasan), anti-lysyl oxidase homolog 2 (LOXL 2), monoclonal antibodies (e.g., sintuzumab), galectin 3 inhibitors (e.g., G R-MD-02), MAPK5 inhibitors (e.g., GS-4997), chemokine receptor 2 Dual antagonists of CCR2 and CCR5 (e.g., cenicriviroc), fibroblast Follicular growth factor 21 (FGF21) agonists (e.g., BMS-986036), leukotrienes, L-tyrosine D4 (LTD4) receptor antagonists (e.g., tipelukast), niacins analogs (e.g., ARI 3037MO), ASBT inhibitors (e.g., borixibato), Cetyl-CoA carboxylase (ACC) inhibitors (e.g., NDI 010976), Ketoexokinase (KHK) inhibitor, diacylglyceryl acyltransferase 2 (DGAT2) inhibitors, CB1 receptor antagonists, anti-CB1R antibodies, or apoptosis inhibitors and / or other anti-inflammatory drugs to treat NASH, including, but not limited to, inhibitors of signal-regulating kinase 1 (ASK1) It is administered together with a drug for treatment.

[0146] These agents and compounds of the present disclosure may be administered in aqueous solutions such as saline, Ringer's solution, dextrose solution, etc. It can be combined with any pharma- ceutically acceptable excipient. The dosage, timing, and repetition will depend on the particular individual and that individual's medical history.

[0147] Acceptable carriers, excipients, or stabilizers are those that are suitable for use in recipients at the dosages and concentrations employed. buffers such as phosphate, citric acid, and other organic acids; salts; antioxidants including ascorbic acid and methionine; preservatives (octadecyldimethyl chloride) Benzyl ammonium chloride; Hexamethonium chloride; Benzalkonium chloride; Benzyl chloride phenol, butyl or benzyl alcohol; methyl or propyl paraben Any alkyl parabens; catechol; resorcinol; cyclohexanol; 3-penta and m-cresol; low molecular weight (less than about 10 residues) polypeptides; serum aldol proteins such as albumin, gelatin, or Ig; hydrophilic polymers such as polyvinylpyrrolidone; mer; glycine, glutamine, asparagine, histidine, arginine, lysine, etc. Amino acids; monosaccharides, disaccharides, and others, including glucose, mannose, or dextrin carbohydrates; chelating agents such as EDTA; sucrose, mannitol, trehalose, or is a sugar such as sorbitol; a salt-forming counterion such as sodium; a metal complex (e.g., Zn -protein complexes; and / or TWEEN®, PLURONICS® The present invention may include a non-ionic surfactant such as polyethylene glycol (PEG) or a tertiary amine. Liposomes containing these disclosed agents and / or compounds are disclosed in U.S. Pat. No. 4,485,044. Methods known in the art, such as those described in US Pat. Nos. 4,544,545 and 4,544,545. Liposomes with enhanced circulation time are prepared by the method disclosed in U.S. Pat. No. 6. Particularly useful liposomes are those containing phosphatidylcholine, cholesterol, and lipid compositions containing PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes can be produced by reverse phase evaporation using a mixture of 100% glycerol and 100% glycerol. The liposomes are then extruded through filters to yield liposomes with the desired diameter.

[0148] These agents and / or compounds of the present disclosure may also be prepared, for example, by coacervation techniques. or by interfacial polymerization, e.g. hydroxymethyl Cellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules Colloidal drug delivery systems (e.g., liposomes, albumin microspheres) are used in the capsules. , microemulsions, nanoparticles and nanocapsules) or encapsulated in macroemulsions Such techniques are described in Remington, The Science and P The practice of Pharmacy, 20th edition, Mack Publishing This was disclosed in the company (2000).

[0149] Sustained release formulations can be used. Suitable examples of sustained release formulations include those having any of the above formulas. The matrix includes a semipermeable matrix of a solid hydrophobic polymer containing a compound. The matrix is ​​in the form of a shaped article, e.g., a film or a microcapsule. Examples of materials include polyesters, hydrogels (e.g., poly(2-hydroxyethyl) -methacrylate), or "poly(vinyl alcohol)", polylactide (U.S. Pat. No. 3,333,631), ,773,919), a copolymer of L-glutamic acid and 7-ethyl-L-glutamate , non-degradable ethylene-vinyl acetate, used in LUPRON DEPOT™ Degradable lactic acid-glycolic acid copolymers such as lactic acid-glycolic acid copolymers and lactate -Prolide (injectable microspheres), sucrose acetoacetate isobutyrate and Poly-D-(-)-3-hydroxybutyric acid is an example.

[0150] Formulations to be used for intravenous administration must be sterile. This is readily accomplished by filtration through a sterile access port. A container having a stopper that can be penetrated by a hypodermic needle, for example, an intravenous solution container having a stopper that can be penetrated by a hypodermic needle. The sample is placed in a bag or vial.

[0151] Suitable emulsions include Intralipid™, Liposyn™, Infonu Trol(TM), Lipofundin(TM) and Lipiphysan(TM) The active ingredient can be prepared using a commercially available fat emulsion. It may be dissolved in the emulsion composition or may be added to oils (e.g., soybean oil, safflower oil, cottonseed oil, etc. oil, sesame oil, corn oil or almond oil) and phospholipids (e.g. egg phospholipids, Soy phospholipids or soy lecithin) and dissolved in water to form an emulsion. To adjust the tonicity of the emulsion, other ingredients, such as glycerol or It is understood that glucose can be added. A suitable emulsion is typically contains up to 20% oil, for example 5 to 20%. Fat emulsions have a particle size of 0.1 μm to 1. 0 μm, especially 0.1 μm to 0.5 μm, and 5.5 to 8.0 It has a pH range.

[0152] The emulsion composition may comprise a compound of the present disclosure in the form of Intralipid™ or a component thereof. soybean oil, egg phospholipids, glycerol and water) This is also fine.

[0153] Compositions for inhalation or insufflation may be prepared in pharma- ceutically acceptable aqueous or organic solvents or mixtures thereof. The liquid or solid compositions include solutions and suspensions in the mixture, as well as powders. In some embodiments, the composition may include a pharma- ceutically acceptable excipient suitable for topical administration. The drug is administered by the oral or nasal respiratory route for local or systemic effect. Compositions in pharma- ceutically acceptable solvents may be nebulized by use of a gas. The liquid can be breathed directly from the nebulizer or the nebulizer can be attached to a face mask, tent, or or attached to an intermittent positive pressure breathing device. The formulation may be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner. do.

[0154] 6. Kit Another aspect of the present disclosure is a kit comprising a compound of any one of the above formulas or any one of the above compounds of the present disclosure. The present invention provides a pharmaceutical composition comprising a compound of any one of the above formulas. In addition to any one of the compounds, the diagnostic or therapeutic agents of the disclosure or pharmaceutical compositions thereof may be included. The kit may also include instructions for use in a diagnostic or therapeutic method. In one embodiment, the kit comprises a compound of any one of the above formulas, or a pharmaceutical composition thereof, and a diagnostic agent. In another embodiment, the kit comprises a compound of any one of the above formulas, or a pharmaceutical composition thereof. Contains ingredients.

[0155] In yet another embodiment, the present disclosure provides a method for the treatment of cancer, comprising administering to a patient a therapeutically effective amount of a cancer cell. In one embodiment, the kit includes a kit suitable for carrying out the methods of the present disclosure. In another embodiment, the kit comprises a first dosage form comprising a sufficient amount of one or more of the compounds of the present disclosure. The present invention relates to a method for the treatment of a pulmonary artery disease, comprising administering to a subject a sufficient amount of one or more compounds of the present disclosure to a subject in need thereof, and administering to a subject a sufficient amount of one or more compounds of the present disclosure to a subject in need thereof. This includes containers for dispensing medicines and containers for administering medicines.

[0156] 7. Preparation Compounds of any one of the above formulae can be prepared by the general knowledge of a person skilled in the art of synthetic organic chemistry. and can be prepared by the general and specific methods described below. The general knowledge required is the Comprehensive Organic Chemistry y, Barton and Ollis, Elsevier, Comprehensive Or ganic Transformations: A Guide to Function Nal Group Preparations, Larock, John Wiley & Sons Ando Sons, Inc. and the Compendium of Organic Synthetic c Methods, vols. 1-12 (published by Wiley Interscience), etc. The starting materials used herein are commercially available. or can be prepared by conventional methods known in the art.

[0157] In the preparation of a compound of any one of the above formulas, any one of the preparation methods described herein may be used. or a remote functional group (e.g., a primary amine in any one of the precursors of the above formulas, It should be noted that protection of the secondary amines, carboxyls, etc. may be required. The need for such protection will vary depending on the nature of the remote functional group and the conditions of the preparation method. The necessity for such protection / deprotection methods can be readily determined by one of ordinary skill in the art. For a general description of protecting groups and their uses, see Greeley, ne's Protective Groups in Organic Synthesi s, John Wiley & Sons, New York, 1991.

[0158] For example, certain compounds, if left unprotected, may be subject to reactions at other sites on the molecule. They contain primary amine or carboxylic acid functional groups that can interfere with the function of such functional groups. The functional groups may be protected by suitable protecting groups which can be removed in a subsequent step. Suitable protecting groups for carboxylate protection include those commonly used in peptide synthesis (e.g., aryl, aryl, aryl, aryl) and aryl-(aryl) protecting groups. In the case of amine, Nt-butoxycarbonyl (Boc), benzyloxycarbonyl (Cb z) and 9-fluorenylmethyleneoxycarbonyl (Fmoc), and for carboxylic acids lower alkyl or benzyl esters, etc., which are generally suitable for use under the reaction conditions described. under the above conditions, typically without modifying any other functional group in any one of the above compound formulas. It can be removed without altering the biology of the substance.

[0159] The schemes set forth below provide a general illustration of the methodology used to prepare the compounds of the present disclosure. Some of the compounds disclosed herein have the stereochemical designation (R). or (S). The material may be enantiomerically enriched. All synthetic transformations can be carried out in a similar manner, regardless of whether the product is racemic or non-racemic. The decomposition into the desired optically active materials is also apparent to those skilled in the art. At any desired point in the sequence, using well-known methods such as those described in the literature It can be done.

[0160] Amine compounds prepared by the methods described herein include, but are not limited to, D In polar aprotic solvents such as MF, DMAc, DMSO, or NMP, K 2 CO 3 , Et 3 In the presence of a suitable base such as N, NaH or LiHMDS, the protected 2-bromoacetate The compound can be delivered by alkylation with tetraethyl ester. You can go and get the acid. 2 If is t-butyl, TFA / DCM, HCl Standard acidic deprotection conditions such as 1,4-dioxane, HCl / EtOAc or other appropriate conditions The acid can be delivered using protective methods. EXAMPLES

[0161] Activation of the G protein-coupled receptor (GPCR) GLP-1R by its natural ligand GLP-1 Activation leads to the recruitment of multiple intracellular proteins, each of which mediates distinct signaling pathways. It can activate pathways, most notably by activating downstream G proteins (cAMP production) (which can be measured by ELISA), recruitment of β-arrestin, and / or subsequent GPC It induces internalization of the GLP-1R (i.e., GLP-1R)-β-arrestin complex. Unlike GLP-1, specific GLP-1R agonists are able to recruit β-arrestin and / or subsequently within the GPCR (i.e., GLP-1R)-β-arrestin complex. Translocation versus natural signaling pathways such as the G protein activation / cAMP production pathway It is a so-called "biased agonist" in that it preferentially stimulates a subset of The following assays measure various downstream signaling pathways upon activation by a compound of interest: Provide the means to do so.

[0162] Biological Example 1: Demonstrating small molecule compound-mediated GLP-1R / β-arrestin interaction activation GLP-1R / β-arrestin assay and internalization assay for GLP1 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 mediates its effects through a Gαs-coupled pathway. It stimulates the nicotinic acid cyclase pathway, increasing the intracellular concentration of cAMP, which in turn increases insulin secretion. Increased phosphorus synthesis and insulin release. As a result, GLP-1R is a potential treatment for diabetes. has been proposed as a possible target.

[0163] GLP-1R activation after agonist / ligand binding also induces β- This leads to arrestin recruitment, and the GLP-1 receptor binds to, for example, the heterotrimeric G protein G By blocking the binding site on LP-1R to prevent its activation (desensitization), and GLP-1R is transported through coated pits and then into the internal compartment, the endosome. The internalization machinery, including clathrin and the clathrin adaptor AP2, promotes transport to the nucleus. It blocks GLP-1R signaling by binding to the receptor. Either they are directed to the solution compartment (lysosomes) or are recycled to the plasma membrane to be reintegrated. The strength of arrestin-receptor interactions plays a role in this selection. It is believed that the more dense the complex, the greater the probability of receptor degradation ( (Class B), more transient complexes are favorable for recycling (Class A), but this The "rules" are not absolute.

[0164] GLP-1R agonist activity on β-arrestin recruitment was analyzed using PathHunter eXpress GLP1R CHO-K1 β-Arrestin GPCR Assay Kit ( Cell-based detection using DiscoverX (catalog number 93-0300E2CP0M) This can be measured in a functional assay.

[0165] PathHunter β-arrestin GPCR assay technology uses smaller enzyme donors β-galactosyltransferase (ED) and a larger enzyme acceptor (EA) are split into two fragments. These fragments are expressed as EA-β-arrestins and ED-β-gal enzymes. It can be fused to two proteins that may interact with each other, such as GLP-1R. The fusion was the PathHunter CHO-K1 GLP1R β- Arrestin can be stably expressed in a test cell line such as a cell line.

[0166] Independently, these fragment fusions have no β-gal activity, but in solution In vivo or in living cells, the fused proteins are bound together through interactions between them. is encapsulated to form the active β-gal enzyme and thus in the presence of the appropriate β-gal substrate A chemiluminescent signal can be produced.

[0167] In this experiment, the PathHunter CHO-K1 GLP1 assay kit was used. R β-arrestin cells were cultured in 384-well white / clear bottom plates (Greiner Catalog Cells were seeded at a density of 1000 or 2000 cells / 20 μl / well in a 100-well plate (sample number 781098). Rapidly thaw the frozen cells and dissolve them in 10 mL of cell seeding medium (provided by the kit). The cells were incubated in 5% CO 2 Store assays in a 37 °C incubator under The mixture was then maintained for approximately 48 hours until it was ready to be run.

[0168] Reference and test compounds were dissolved in 100% DMSO. Prepared in serum-free DMEM (Thermo Cat. No. 11965). 5 μL of this solution was added to 20 μL of cell culture medium in the assay plate at a final top concentration of 10 μM. The plates were then incubated at 37°C and 5% CO 2 The mixture was incubated under reduced pressure for 90 min.

[0169] After 90 min of incubation, 1 part Galacton Star Substr ate, 5 parts Emerald IITM Solution, and 19 parts PathH The detection reagent is made by combining the respective Cell Assay Buffers. 12.5 μl of detection reagent was added to each well. The plate was then incubated at room temperature in the dark. The plate was then cycled in Envision for 0.1 seconds / second. I read the ell.

[0170] EC 50 The determination was performed using a four-parameter logistic dose-response equation with curve fitting. The results were obtained from agonist dose-response curves analyzed with a linear regression program.

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

[0172] Media and Solutions 1 part Galacton Star® Substrate to 5 parts Emer ald IITM Solution and 19 parts of PathHunter Cell A Prepare the detection standard solution by combining with the assay buffer. To manufacture.

[0173] Once prepared, working solutions are stable at room temperature for at least 24 hours, ensuring assay performance. Sufficient reagents are provided in each kit to perform the number of assays indicated. can be.

[0174] procedure 1. Cell Seeding Cells were seeded at a density of 1000 or 2000 cells / 20 μL / well. The cells were rapidly thawed and added to 10 mL of cell seeding medium. The cells were incubated at 5% CO 2 37 degree ink below The plates were stored in a tubing and left for approximately 48 hours until the assay was ready to be performed.

[0175] 2. Compound Preparation 1) Reference agonist compound GLP1 (7-37): Dissolve in DMSO to make a 1 mM stock The solution was made up and stored in aliquots at -80°C. 2) Test compounds (such as compounds of the present disclosure) were solubilized in 100% DMSO. Prepare 10x concentrations of agonists in EM and add all solutions to the compound plate. Add 2.5 μL of this solution to 20 μL of cell culture medium in the assay plate for a final concentration of 10 μM The plates were incubated at 37°C and 5% CO 2 The mixture was incubated under reduced pressure for 30 min. An additional 2.5 μL of buffer was added to the entire plate for agonist mode and incubated at 37°C. Incubated for an additional 90 minutes.

[0176] 3. Detection Reagents After 90 min incubation, the detection reagent was made up as described. 12.5 μL All wells were then incubated at room temperature in the dark for 60 minutes. The plate was then read on the Envision for 0.1 seconds / well.

[0177] 4. β-Arrestin Assay Data Processing Data analysis: GraphPad Prism6 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 were performed as controls. The results are shown in Figure 1 in comparison with GLP-1 (7-37). The compounds tested included compound 74 ~91, 93~95, 100, 101, 257, 262, 263, 266, 267, 27 1, 276-278, 281, 284, 285, 289-293, 303, 305, 30 7, 308, 310-312, 323, and 331-334. The partial maximum relative activity (at the highest concentration tested in the assay) of the compound tested Effect B max Generally, the B of the natural ligand GLP-1 (7-37) max About 20 to 4 This means it is approaching 0%. [Table 3]

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

[0180] A similar assay was used to assess the degree of signal attenuation due to GLP-1R internalization. This assay can also assess the internalization of activated GLP1R. We engineered endosome-localized untagged GLP1R, enzyme receptor (EA) tag, and Glycated β-arrestin and ProLink™ (PK) tag were co-expressed. Activation of P1R induces β-arrestin recruitment, which is involved in PK-tagged endosomes. This leads to internalization of the receptor / arrestin-EA complex, which then releases two β-galactosidases. The enzyme fragments of ectosidase (EA and PK) are forced to complement each other to hydrolyze the substrate and chemically Functional enzymes that generate a luminescent signal are formed. These cells have no obvious effect on assay performance. It has been modified to prevent long-term growth and spread using a unique compound that has minimal impact on the It is being done.

[0181] Specifically, the Pa thHunter engineered U2OS cells were cultured in 384-well white / clear bottom plates. (Greiner Cat. No. 781098) at a density of 2000 cells / 20 μL / well. The frozen cells were rapidly thawed and seeded in 10 mL of cell seeding medium (provided by the kit). The cells were stored in a 37°C incubator and incubated for 1 h at 4°C for 1 h. It was held for about 48 hours until it was ready.

[0182] Reference and test compounds were dissolved in 100% DMSO. Prepared in serum-free DMEM (Thermo Cat. No. 11965). 5 μL of this solution was added to 20 μL of cell culture medium in the assay plate at a final top concentration of 10 μM. The plates were incubated at 37° C. for 180 minutes.

[0183] After 180 min of incubation, 1 part Galacton Star Subst rate, 5 parts of Emerald IITM Solution, and 19 parts of Path The detection reagents are each combined with Hunter Cell Assay Buffer. 12.5 μL of detection reagent was added to each well. The plate was then incubated at room temperature for 6 The plate was then cycled in Envision for 0.1 seconds / well. I read it.

[0184] EC 50 The determination was performed using a four-parameter logistic dose-response equation with curve fitting. The results were obtained from agonist dose-response curves analyzed with a linear regression program.

[0185] Selected compounds of the present disclosure compared to GLP-1(7-37) as a control The GLP-1R internalization dose-response curves of compound 7 are shown in Figure 2. 4 to 80, 93 to 95, 100, and 101 (left panel), and compounds 81 to 91 ( Right panel) are included. Again, the concentration of the test compound (at the highest concentration tested in the assay) was (Partial maximum relative effect B) max Generally, the B of the natural ligand GLP-1 (7-37) m ax It approaches about 20-30% of the

[0186] Using this assay system, β-arrestin-mediated GLP1R internalization was also assayed using other methods disclosed herein. Selected compounds were measured and the results are summarized in the table below. [Table 4]

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

[0188] Biological Example 2: Small molecule mediated GLP1R and β-arrestin interaction activation NanoBit GLP1R / β-arrestin interaction assay to demonstrate GLP-1R-mediated interaction with β-arrestin upon agonist activity was observed in live cells. NanoL designed to detect the interaction between GLP-1R and β-arrestin uc (registered trademark) Binary Technology (NanoBiT) (Prome This method is determined using a cell-based functional assay using the tandem NanoL can be used for intracellular detection of protein:protein interactions (PPIs) It is a two-subunit system based on uc® luciferase. Large BiT (LgBiT, 17.6 kDa) and Small BiT (Sm These two subunits are known as BiT, 11 amino acids. It is fused to two proteins of interest. When both are expressed, the PPI brings the subunits closer together. Upon contact, they form a functional enzyme that produces a bright luminescent signal.

[0189] More specifically, the human GLP-1R coding sequence (NCBI reference sequence NM_002062 ) and the β-Arrestin2 coding sequence (NCBI reference sequence NM_004313.3) GLP-1R-LgBiT and SmBiT-β-Arrestin2 fusions were generated. Subclone into the transient expression vector provided in the NanoBiT kit so that The natural ligand GLP-1 7~37 HEK293T-based transfection with activation by A total of eight combinations were selected using the transfection method. The combinations are described in the present disclosure. The highest assay window for testing compounds (GLP-1R-LgBiT and We showed that SmBiT-β-arrestin2) was selected.

[0190] NanoBit assays were performed as briefly described herein: HEK29 3T cells (7.5k cells / well) were cultured in heat-inactivated 10% FBS (Biosera Catalog number FB-10581) and DMEM containing 25 mM glucose (Thermo 96-well culture plates (Corning Cat. No. 3) in a 100-well plate (Corning Cat. No. 11965). After 48 hours, the cells were cultured in Lipofectamine 2000 (Th ermo Catalog No. 11668019) according to the manufacturer's assay protocol. GLP-1R-LgBiT and SmBiT-β-Arrestin2 constructs were used to transduce Briefly, GLP-1R-LgBiT and SmBiT-β-arrestin Plasmids encoding the 2-fusions and transfection reagent were added to Opti-MEM ( Thermo Catalog No. 31985-070). P-1R-LgBiT and 50 ng of SmBiT-β-Arrestin2 plasmid constructs The constructs are mixed and the resulting plasmid mixture is 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 incubation, the medium was replaced with 65 μl / well of fresh Opti-MEM.

[0191] The Nano-Glo® Live Cell Substrate was then transferred to the Nano-Glo® L The solution was diluted 1:24 with CS Dilution Buffer. Various concentrations of no-Glo® Live Cell Reagent were added to each well. The mixture (in DMSO) was diluted with Opti-MEM (Sigma catalog no. A7409) to prepare a 10x stock. , was added to each well using a pipette. Luminescence was monitored by EnVision for 4 h. 0, 60 or 120 replicates were measured immediately for 0.25 seconds per well.

[0192] EC 50 The determination was performed using a four-parameter logistic dose-response equation with curve fitting. The results were obtained from agonist dose-response curves analyzed with a linear regression program.

[0193] The present disclosure on GLP-1R / β-arrestin interaction activation or β-arrestin recruitment The effect of small molecule compounds such as one of the compounds described herein can be determined using the assays described herein and commercially available reagents or their equivalents. The reagents and detailed experiment used in this example can be used to demonstrate and measure the The study protocol is further described below. preparation Reagents and consumables: [Table 5] device: [Table 6]

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

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

[0196] 3. Add 1 volume of Nano-Glo® Live Cell Substrate to 24 volumes of Nano-Glo® Live Cell Substrate. Combine with LCS Dilution Buffer (25-fold dilution) and mix at 4x The desired amount of reconstituted Nano-Gl was prepared by preparing a stock and mixing it with cell culture medium. o Prepare the Live Cell Reagent.

[0197] procedure Preparation of compounds: 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] Test compounds were cultured at 1 mM in Opti-MEM containing 1% BSA. The mix was diluted to 100 μM, with a final top concentration of 10 μM, 1 / 4 log (4-fold) dilution, 8 Dilution points, duplicate samples for each dilution. Layout is the same as GLP-1 above. It is.

[0199] Assay procedure: Cell culture and transfection: 1. 96-well plates in DMEM containing 10% FBS (heat inactivated and 25 mM glucose). 7.5k cells / well in 293T 3T culture plates (Corning Cat. No. 3917). The cells were seeded. 2. After 48 hours, perform the procedure according to the Lipofectamine 2000 protocol. Performance transfection was performed. 3. 50 ng Lg-Bit and 50 ng Sm-Bit / well, plasmid The ratio of (μg):Lipofectamine 2000 (μl) is 1:10. 4. 48 hours after transfection, replace the medium with fresh 65 μL of Opti-MEM / Replaced with Well.

[0200] Activation and luminescence measurements: 5. Dilute the NaCl solution using Nano-Glo® LCS Dilution Buffer in a 1:24 ratio. No-Glo® Live Cell Reagent, Dilute Nano-Glo® Live Cell Substrate Prepare. 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. Add. 8. Immediately measure luminescence for 40, 60 or 120 replicates at 0.25 seconds per well. do.

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

[0202] The results show that the time course profile of the natural ligand GLP-1(7-37) and the presently disclosed assay It is clear that there is considerable variation between the compounds.

[0203] Additional test compounds, including compounds 74-91, 93-95, 100, and 101 Also, the NanoBit assay dose at 3 minutes (180 seconds) and 5 minutes (300 seconds) Response curves were generated (Figure 4). In each of these figures, the compound E max of The maximum relative effect is generally the maximum of GLP-1 (7–37) for the highest concentration tested. The relative effectiveness is less than 40% (usually about 20-40%).

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

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

[0206] Biological Example 3: GLP1R to demonstrate small molecule mediated GLP-1R activation cAMP assay HEK293 / GLP-1R / CRE / Luc, Clone 4-cAMP Assay HTRF (homogeneous time-resolved fluorescence) cAMP detection kit for measuring intracellular cAMP levels (cAMP Dynamic2 Assay Kit, CisBio Catalog No. 62AM4P Determine GLP-1R-mediated agonist activity in a cell-based functional assay using EC This method uses natural cAMP produced by cells and exogenous cAMP labeled with the dye d2. This is a competitive immunoassay between cAMP and cryptate-labeled cAMP. Visualized by mAb anti-cAMP. 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 cloned into pcDNA3 The plasmid was subcloned into the .1+ / Hygro vector (Invitrogen) and transformed into HEK2 The 93 / CRE / Luc parental cell line was transfected with 500 ribozymes to produce cells stably expressing the receptor. The strain was isolated. 125 I-GLP-1 7~36 (PerkinElmer) Analysis (filtration assay procedure) 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 in DMSO and initially diluted at 200 × Compound standard dilution solution was obtained, and then 50 nl of compound was added to a white 384 well containing ECHO. The final DMSO concentration was added to a 100 mM NaCl solution in a 100 mM NaCl assay plate (Greiner 784075). was 0.5%. Compound concentration ranges can be adjusted at any time.

[0209] Cells were removed from cryopreservation and resuspended in 5 mL of Dulbecco's Phosphate Buffered Saline (DPBS- Resuspend in 1000 x g (Sigma Cat. No. D8537) and centrifuge at 900 x g for 5 minutes at 22°C. The cell pellet was then transferred to 1 mL of assay buffer [containing 500 μM IBMX]. DPBS (Sigma catalog number I5879) and 0.1% BSA (Sigma catalog number The cells were resuspended in 100% PBS (No. A1933). IBMX and BSA were added fresh on the day of the assay. Count a 10 μL sample of the cell suspension using an Invitrogen Countess II The remaining cell suspension was then added to the assay buffer to determine cell viability and cell number / mL. Prepare the buffer solution and use the Matrix Combi Multidrop reagent dispenser. 1000 viable cells were delivered per well using the 10 μL cell suspension. The mixture was added to each well of the assay plate containing the sample.

[0210] Seal the plate and incubate for 37 o C, 5% CO 2 The mixture was incubated at RT for 30 min.

[0211] After 30 min of incubation, 5 μL of labeled d2 cAMP and 5 μL of anti-cAM were added. P antibodies (both diluted 1:20 in cell lysis buffer, as described in the manufacturer's assay protocol) A 100% PBS solution (as described in the literature) was added to each well of the assay plate. The plate was then placed in a 200-mL PBS-containing well. After 60 minutes of incubation at room temperature, the change in HTRF signal was measured using excitation at 330 nm and Envision Multilabel Platelet Array using 615nm and 665nm emission The raw data was compared with the cAMP standard curve (as described in the manufacturer's assay protocol). ) to nM cAMP by interpolation from the full agonist G LP-1 7~37 Percent efficacy was determined relative to a saturating concentration of (10 nM). EC 50 Determinations were made using a curve fitting program using a four-parameter logistic dose-response equation. The results were obtained from agonist dose-response curves analyzed by HPLC.

[0212] This assay demonstrates whether compounds of the present disclosure inhibit GLP-1R signaling via the cAMP pathway. We demonstrate that the compound activates GLP-1R and therefore behaves as a GLP-1R agonist. Representative commercially available reagents / kits that can be used for such assays are listed 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. Add new one on the day of Say.

[0214] 2) Preparation of cAMP-d2 diluted standard solution a) Reconstitute the lyophilized material with an appropriate amount of distilled water according to the manufacturer's instructions, aliquot and freeze. We created a working stock that can be stored at -20°C. b) Before use, dilute the working stock solution 1:20 with conjugate and lysis buffer. Ta.

[0215] 3) Preparation of anti-cAMP antibody-cryptate standard dilution solution c) Reconstitute the lyophilisate with an appropriate amount of distilled water according to the manufacturer's instructions and freeze in aliquots. A working stock was prepared that could be frozen (-20°C). d) Before use, dilute the working stock solution 1:20 with conjugate and lysis buffer. Ta.

[0216] procedure Cell suspension preparation procedure 1. Frozen cells are frozen in a 37°C water bath under sterile conditions with continuous agitation until the ice is completely melted. Thaw very briefly (approximately 1 min) until just before thawing. Incubation time is increased. Caution was exercised because this can cause cell death. 2. Carefully transfer the thawed cells into a sterile 15 / 50 mL tube and immerse them in 10 mL of pre-warmed 37°C buffer. Fill the tube with ~50 mL of complete medium, let the cells settle for 5 minutes, and then prepare for cell collection. DMSO was removed from the medium by centrifugation at 900 rpm for 5 min. 3. Cells were resuspended in assay buffer. 4. For stable GLP1-R assays, the optimized cell density is 1000 cells / well. Optimization of cell density was important and had to be done in different laboratories. Note that the levels of cAMP produced by the cells were within the linear range of the standard curve. Must be.

[0217] Compound preparation procedure 1) Dissolve the reference agonist compound GLP1 (7-37) in DMSO to make a 1 mM stock. A solution was made which was then aliquoted and stored at -80°C. 2) The reference antagonist compound, exendin (9-39), was dissolved in DMSO. A 2 mM stock solution was made which was then aliquoted and stored at -80°C. 3) Dissolve the test compound in DMSO to make a stock solution, aliquot it, and store it at -80℃. Serial dilutions of the compound solutions were performed using DMSO, starting with 200x compound dilution standard. The diluted standard solution was then transferred to a 384-well plate using ECHO. The final DMSO concentration was 0.5%. Compound concentration ranges can be adjusted at any time. can. 4) IBMX: 500 mM stock solution in DMSO, aliquots, and -20 Store at °C.

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

[0219] Antagonist blocking assay procedure 1) Compound Preparation: Prepare the compound addition plate prior to the assay. Follow the procedure above. Prepare a 200-fold concentration compound dilution standard solution. 2) Cell preparation: Prior to performing the assay, a cell suspension is prepared according to the procedure described above. 3) Compound addition: Add 200x the working concentration of compound to 50nL / well of low volume 384 white Add to assay plate. 4) Cell addition: Add 5 μL of 2X cell suspension to the cells in the assay plate already containing the compounds. Add to each well. 5) Exendin(9-39) antagonist added: Compound and cells already included Add 5 µL of 2x exendin(9-39) to each well of the assay plate. The final concentration of exendin (9–39) is IC80. The plate is sealed and incubated for 37 o C Incubate at 37 °C for 30 min at 5% CO2. 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 diluted standard solution to each well of the assay plate. Add the plate to the wells. Cover the plate with a lid. Incubate at room temperature for 1-4 hours. 8) Use the specified settings to play EnVision with the TRF LASER. The fluorescence is read at 665 nm and 615 nm using a light reader, and the data is stored.

[0220] Setting up EnVision for HTRF cAMP measurements Necessary filters and mirrors Excitation: TRF laser Emission #1: 665nm (CWL665nm BW7.5 nm) Emission #2: 615nm (CWL615nm BW8.5nm) Dichroic mirror: DELFIA / LANCE Dual Enh D400 / D630 Required settings: Delay: 50μsec Window time: 300μs (also called "integration time") Number of sequence windows: 1 Cycle: Default 2000μsec (also called "time between flashes") Time between flashes: 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 The EC50 or IC50 is used to establish a progress curve. was determined by a dose-response equation.

[0222] Using the assay substantially as described above, dose-response curves were obtained for each compound tested below: Each EC 50 The EC values ​​were calculated and tabulated for each compound. 50 The value is the same for the same compound. The cAMP concentration is defined as the concentration of compound that resulted in 50% of the maximal cAMP level achieved in the subject.

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

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

[0225] Two different cell types were used in this assay. In one assay, each compound was incubated with HE The results are shown in Table 1 below. In a separate assay, selected compounds The compound was also tested in CHO cells stably transfected to express the 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 reacted well with the cAMP assay. Nanomolar or subnanomolar (<10 nM) EC 50 This indicates that it has a value. Many of the test compounds also showed Bmax values ​​essentially equal to those of GLP-1(7-37). B max Combined with the fact that many of the test compounds disclosed herein have a c This suggests that it is a full agonist of GLP-1R signaling leading to AMP production. .

[0227] In contrast, the data shown in Examples 1 and 2 above, specifically the compounds listed in the tables, Thus, compounds of the present disclosure generally exhibit potent potency in β-arrestin recruitment assays and in the GLP-1R. In localization assays, with some exceptions, B is close to about 20-40% max In addition, the time course profile of NanoBit The mechanism of action of the agonist is different between the compounds of the present disclosure and the compounds of GLP-1(7-37).

[0228] Example 4 Compound synthesis (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine -2-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H- Benz[d]imidazole-6-carboxylic acid (compound 74) [ka] Step 1. Synthesis of 2-(4-bromo-3-fluorophenyl)acetimidate methyl Growth In a Schlenk tube, 1 2-(4-bromo-3-fluorophenyl)acetonitrile (4 0.24 grams, 19.8 mmol), methanol (600 mg, 19.8 mmol), and A mixture of 1,4-dioxane (20 mL) and HCl gas was bubbled through the reaction until completion. The reaction mixture was filtered to give the title compound, 2-(4-bromo-3-fluoro- Methyl phenyl)acetimidate (2) (4.2 g, 17.1 mmol, yield 86.2 %) as a white solid.

[0229] Step 2. 1-Bromo-2-fluoro-4-(2,2,2-trimethoxyethyl)benzene Synthesis of benzene A mixture of 2 (2.1 g, 8.53 mmol) in methanol (20 mL) was , N 2 The reaction was stirred in a Schlenk flask under atmospheric pressure for 18 hours. The reaction mixture was concentrated in vacuo and then diluted with Et until a large amount of solid precipitated. OAc was added to the reaction mixture. The solid was filtered off and the filtrate was concentrated to give the title compound, 1-bromo-3-(2-(4-methyl-1,2-dihydro-2,4-trimethylphenyl)-2-(2-methylphenyl)-1,2-dihydro-2,4-tetrahydrofuran. The crude product (3 ) as a colorless oil (1.8 g, 6.14 mmol, 72% yield).

[0230] Step 3. Methyl (S)-2-(4-bromo-3-fluorobenzyl)-1-(oxo) cetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate synthesis In acetonitrile (15 mL), 3 (297.8 mg, 1.02 mmol), p- TSA (100 mg, 0.63 mmol) and methyl 4-amino-3-[[(2S)-o Mix 2-methyl-2-oxo-2-ylaminobenzoic acid 4 (150 mg, 0.63 mmol) The combined mixture was then heated to 37° C. 2 The mixture was stirred in a Schlenk flask under atmospheric pressure for 2 hours, and then heated in an oil bath at 85°C. The reaction mixture was transferred to 1000 ml of ethyl acetate and stirred for 3 h until the reaction was complete as indicated by TLC. Concentration in air and purification by SGC (hexane / EtOAc = 5:1-1:1) gave the title compound. The compound methyl(S)-2-(4-bromo-3-fluorobenzyl)-1-(oxetane -2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (5) ( Obtained 180 mg, 0.42 mmol, 65.4% yield as a yellow solid.

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

[0232] Step 5. Methyl (S)-2-(4-(6-((4-chloro-2-fluorobenzyl )oxy)pyridin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-yl Synthesis of (1H-benzo[d]imidazole-6-carboxylate In 1,4-dioxane (3 mL) and water (1 mL), 7 (30 mg, 0.095 mmol) was dissolved in 1,4-dioxane (3 mL) and water (1 mL). l), Pd(dppf)Cl 2 (7.7 mg, 0.0095 mmol) and K 2 CO 3 ( 39.3 mg, 0.28 mmol), as well as the crude product of 6 (68.3 mg, 0.14 mmol). The mixture was mixed with N 2 The mixture was stirred in a Schlenk flask for 3 hours under an atmosphere of 0.5%. The reaction tube was sealed, transferred to a 100° C. oil bath, stirred for 3 h, and the reaction mixture was cooled to room temperature, as shown by TLC and LCMS. The reaction was completed when the reaction mixture was cooled to room temperature. The reaction mixture was filtered and the crude product was purified by TLC to give the following: The title compound, methyl(S)-2-(4-(6-((4-chloro-2-fluorobenzyl )oxy)pyridin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-yl (dimethyl)-1H-benzo[d]imidazole-6-carboxylate (8) (9 mg, Obtained 0.015mmol, 17.9% yield. LCMS: [M+H] + =590.1

[0233] Step 6. (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy) (II) Pyridin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl Synthesis of 1H-benzo[d]imidazole-6-carboxylic acid In a solution of methanol (3 mL), 8 (9 mg, 0.015 mmol) and LiOH (3. 7 mg, 0.15 mmol) was mixed at 25 °C and heated in N 2 Atmosphere, Schlenk The tube was stirred for 3 hours and the reaction was shown by TLC and LCMS. The reaction mixture was diluted 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)pyridine 1-(oxetan-2-ylmethyl)-3-fluorobenzyl H-Benz[d]imidazole-6-carboxylic acid (3.3 mg, 0.006 mmol, yield Yield 37.6%, purity 100%) as a white solid. LCMS: [M+H] + =57 6.1

[0234] (S)-2-(4-(6-(4-cyano-2-fluorobenzyloxy)pyridine-2 -yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[b] Zo[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-yl)methyl (ethyl)-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-(oxetane-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-(oxetane-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-(oxetane-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-phenyl-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H -Benz[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-fluoro (3-fluoropyrimidin-2-yl)-1-(oxetan-2-ylmethyl)-3-fluorobenzyl (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-fluoro (3-fluorobenzyl)-1-(oxetan-2-yl)methylpyrimidin-4-yl (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-fluoro (fluoropyridin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-yl) (ethyl)-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)pyridine -2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H- Benz[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-(oxetane-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-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H -Benz[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-phenyl-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H -Benz[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-fluoro 1-(1-(2-oxetan-2-yl)methyl)-2-fluorobenzyl-1-(pyridin-2-yl)- )-1H-Benz[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-yl)methyl (ethyl)-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-fluoro (fluoropyrimidin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-yl Methyl)-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-fluoro (4-aminopyrimidinyl)-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-fluoro (fluoropyridin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-yl) (ethyl)-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)pyridine -2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H- Benz[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)pyridine -2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]i Midazole-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)pyridine -2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]i Midazole-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-phenyl-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H -Benz[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-fluoro 3-(3-(pyridin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl )-1H-Benz[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-di Fluoropyridin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-yl Methyl)-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) 1H-Pyridin-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzyl 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'-biphenyl Pyridin-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 In dioxane (20 mL), 2-(6-bromo-3-pyridyl)acetonitrile 1( 985mg, 5.0mmol) and methanol (0.30mL, 7.5mmol) were mixed. The mixture was stirred at room temperature in a round bottom flask for 6 h until the reaction was complete as shown by LCMS. HCl (g) was bubbled through the reaction mixture while stirring for 1 hour, and the reaction mixture was concentrated in vacuo to give The desired product, methyl 2-(6-bromo-3-pyridyl)ethaneimidate (2) (1 0.4 g, crude) as a white solid. LCMS: (M+H) + =230.0

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

[0262] Step 3. Methyl (S)-4-(2-(6-bromopyridin-3-yl)acetate Synthesis of (oxetan-2-ylmethyl)amino)benzoate In THF (20 mL), 9 (216 mg, 999.9 umol) and di(imidazo A mixture of 1,2-diphenyl-1-ylmethanone (162.1 mg, 1.0 mol) was heated at 50°C. for 0.5 h, and then methyl 4-amino-3-[[(2S)-oxetane-2- [yl]methylamino]benzoic acid (4) (236.2 mg, 1.0 mmol) was added to the above The mixture was then cooled with N until the reaction was complete as shown by LCMS. 2 Down, 2 more. After stirring for 5 h, 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)acetamide) -3-((oxetan-2-ylmethyl)amino)benzoate (10) (180 mg, 0.42 mol, 41.5% yield) was obtained as a white solid. LCMS: (M+H) + = 435.9

[0263] Step 4. Methyl (S)-2-((6-bromopyridin-3-yl)methyl)-1- (Oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate Synthesis of tetracycline A mixture of 10 (180 mg, 0.41 mmol) in acetic acid (10 mL) was , N until the reaction was complete by LCMS. 2 Below, in a round-bottom flask, 0 The mixture was stirred for 0.5 h, concentrated in vacuo, and dried in vacuo to give the desired product, methionine. (S)-2-((6-bromopyridin-3-yl)methyl)-1-(oxetane-2 -ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (11)(1 (70 mg, crude) was obtained as a pale yellow solid. LCMS: (M+H)+=416.0

[0264] Step 5. 2-Bromo-6-((4-chloro-2-fluorobenzyl)oxy)pyridine Synthesis of gin In toluene (100 mL), (4-chloro-2-fluoro-phenyl)methanol 12 (8.0 g, 49.8 mmol), 2-bromo-6-fluoro-pyridine (8.77 g, 49.8mmol, 5.13mL), 1,4,7,10,13,16-Hexaoxacyl Octadecane (658.4 mg, 2.5 mmol, 0.56 mL), KOH (4.19 g, 74.7 mmol) until the reaction was complete as indicated by LCMS. N 2 The reaction mixture was stirred at room temperature for 18 h in a round-bottom flask and diluted with 50 mL of EtOAc. The combined organic layers were washed with brine and 2 SO 4 and dried in vacuum. Concentrate and purify 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) was obtained as a white solid. LCMS: (M+H) + =316.0

[0265] Step 6. 2-((4-chloro-2-fluorobenzyl)oxy)-6-(tributyrol) Synthesis of rustannyl)pyridine A mixture of 13 (1.58 g, 4.99 mmol) in THF (20 mL) was added. Add n-butyllithium (383.7 mg, 5.99 mmol, 2.4 mL) and add to a round bottom flask. In the flask, N 2 The mixture was stirred at -70°C for 3 hours under reduced pressure, and then Bu 3 SnCl (2.44 g, 7 0.49 mmol, 2.03 mL) was added to the mixture, and after addition, the mixture was further Allow the reaction mixture to warm to room temperature in an ice bath for an hour and when the reaction is complete as indicated by LCMS, saturated NH 4 Quench with Cl and Na 2 SO 4 The organics were concentrated in vacuo and the resulting solution was The desired product, 2-((4-chloro-2-fluorobenzyl)oxy)-6-(trimethylsilyl) Tristanylpyridine (14) (3.5 g, crude) was obtained as a pale yellow liquid, which was Used directly in the next step.

[0266] Step 7. Methyl (S)-2-((6'-((4-chloro-2-fluorobenzyl) Oxy)-[2,2'-bipyridin]-5-yl)methyl)-1-(oxetan-2-yl Synthesis of (1H-benzo[d]imidazole-6-carboxylate In DCM (5 mL), 11 (150 mg, 0.35 mmol), 14 (189.8 mg , 0.36 mmol), Pd(PPh 3 ) 2 Cl 2 (34mg, 0.029mol), C The mixture was mixed with uI (34 mg, 0.178 mol, 6.05 uL) and analyzed by LCMS. Continue stirring until the reaction is complete. 2 The reaction mixture was stirred at 90° C. for 1 h in a RBF under reduced pressure. Filtration and purification by preparative HPLC gave 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) was obtained as a pale yellow solid. LCMS: (M+H) + =573.0

[0267] Step 8. (S)-2-((6'-((4-chloro-2-fluorobenzyl)oxy) )-[2,2'-bipyridine]-5-yl)methyl)-1-(oxetan-2-ylmethyl Synthesis of 1H-benzo[d]imidazole-6-carboxylic acid In a mixture of methanol (1 mL), water (1 mL), and THF (1 mL), 15 (40.0 mg) was added. , 0.070 mmol) and LiOH (117.2 mg, 2.79 mmol, 77.6 u L) was added to the mixture and N was added until the reaction was complete as shown by LCMS. 2 Bottom, RBF medium The mixture was stirred at room temperature for 1 hour, the pH of the reaction mixture was adjusted to 7 with HOAc, and the mixture was fractionated and diluted with HCl. The title compound, (S)-2-((6')-((4-chloro-2-phenylpropanediol), was purified by PLC. (fluorobenzyl)oxy)-[2,2'-bipyridin]-5-yl)methyl)-1-(fluorobenzyl)oxy)-[2,2'-bipyridin]-5-yl)methyl) xetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (6. 9 mg, 0.012 mmol, 17.7% yield) was obtained 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- Benz[d]imidazole-6-carboxylic acid (compound 101) [ka] The title compound was prepared in a similar manner to compound 100 as a white solid. LCMS: M+H) + =558.9

[0269] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine -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 In 16 mL of furic acid, 2-chloro-6-methyl-3-nitro- A stirred solution of pyridine 16 (4.0 g, 23.2 mmol) at room temperature was added to the 2 Cr 2 O 7 (10.2 g, 34.8 mmol) was added. The reaction mixture was stirred at 30° C. for 24 h. Upon completion of the reaction as judged by LCMS, the mixture was washed with water (200 ml) in an ice bath. Dilute the residue (1 μL) and filter the precipitate, wash with water (20 mL) and centrifuge under reduced pressure. After drying, 6-chloro-5-nitropicolinic acid 17 (3.9 g, 19.3 mmol, Yield 83.3%, purity 100%) obtained as a light yellow solid. LCMS: [M+H] + = 203

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

[0272] Step 3. Methyl (S)-5-nitro-6-(oxetan-2-ylmethyl)amine Synthesis of picolinate [(2S)-Oxetan-2-yl]methanamine (663. 7 mg, 7.6 mmol) and 18 (1.50 g, 6.9 mmol) were mixed and stirred. To the solution, N-ethyl-N-isopropyl-propan-2-amine (2.69 g) was added at 25° C. , 20.8 mmol, 3.62 ml) was added. The reaction mixture was stirred at 25° C. for 16 hours. Upon completion of the reaction as judged by LCMS, the mixture was diluted with EtOAc (100 mL). 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) and then with anhydrous Na 2 SO 4 Dry and filter, Concentration in vacuo was performed. The crude product was purified by flash column chromatography (SiO 2 , Petroleum A The mixture was purified with 0% to 40% ethyl acetate to give methyl (S)-5-nitro-6-((oxy) (Cetan-2-ylmethyl)amino)picolinate 19 (1.80 g, 6.5 mmol, Yield 93.3%, purity 96%) obtained as a yellow solid. LCMS: [M+H] + =26 7

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

[0274] Step 5. Methyl (S)-2-(4-bromo-3-fluorobenzyl)-3-(oxo) cetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate Synthesis of tetracycline CH 3 To a stirred solution of 20 (260 mg, 1.10 mmol) in CN (8 mL), 4-methylbenzenesulfonic acid (41.9 mg) at room temperature , 0.22 mmol) and 1-bromo-2-fluoro-4-(2,2,2-trimethoxy Ethyl)benzene (483.7 mg, 1.7 mmol) was added. The reaction mixture was heated to 90°C. The mixture was stirred at 50° C. for 2 h when the reaction was judged complete by LCMS. The mixture was diluted with c (100 mL) and cooled to room temperature. The layers were separated and the aqueous layer was diluted with EtOAc (2×1 The combined organic phase was washed with brine (100 mL) and extracted with anhydrous Na 2 SO 4 The crude product was purified by flash column chromatography. The methyl (S) was purified by filtration (SiO2, petroleum ether / ethyl acetate 5:1). -2-(4-bromo-3-fluorobenzyl)-3-(oxetan-2-ylmethyl)- 3H-Imidazo[4,5-b]pyridine-5-carboxylate 21 (180mg, 0 0.41 mmol, 37.7% yield) was obtained as a white solid. LCMS: [M+H] + = 434

[0275] Step 6. Methyl (S)-2-(3-fluoro-4-(4,4,5,5-tetramethyl) (1,3,2-dioxaborolan-2-yl)benzyl)-3-(oxetane-2-yl) Synthesis of (3H-imidazo[4,5-b]pyridine-5-carboxylate In 1,4-dioxane (1 mL), 21 (20.0 mg, 0.046 mmol) and 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 0.3mmol) was added to a stirred solution at 100°C. 2 (dppf)(5.1m g) and potassium acetate (13.6 mg) were added. The reaction mixture was stirred at 100° C. for 12 hours. When the reaction was judged complete by LCMS, the mixture was diluted with EtOAc (100 mL). L), warm to room temperature and concentrate in vacuo to give crude methyl (S)-2-(3-fluorophenyl) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Benzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine Din-5-carboxylate 22 (22 mg, 0.046 mmol, 99.2% yield) was obtained as a yellow solid which was used in the next step without purification.

[0276] Step 7. Methyl (S)-2-(4-(6-((4-chloro-2-fluorobenzyl )oxy)pyridin-2-yl)-3-fluorobenzyl)-3-(oxetan-2-yl Synthesis of (3H-imidazo[4,5-b]pyridine-5-carboxylate In 1,4-dioxane (2 mL), 22 (22.0 mg, 0.046 mmol) and A stirred solution of 13 (17.4 mg, 0.055 mmol) and 14 (14.2 mmol) was added to the flask at 25 °C. l 2 (dppf) (1.7 mg, 0.002 mmol) and potassium carbonate (19.0 mg The reaction mixture was stirred at 90° C. for 3 h and was When the reaction was judged complete, the mixture was diluted with EtOAc (100 mL) and allowed to warm to room temperature. After warming and concentration in vacuo, the mixture was purified by flash column chromatography (silica gel, petroleum ether). The mixture was purified with 0% to 40% ether / ethyl acetate to give methyl (S)-2-(4-(6-((4 -Chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl (oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine 5-Carboxylate 23 (20.0 mg, 0.034 mmol, 74.0% yield) Obtained as a yellow solid. LCMS: [M+H] + =591

[0277] Step 8. (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy) (II) Pyridin-2-yl)-3-fluorobenzyl)-3-(oxetan-2-ylmethyl Synthesis of 3H-imidazo[4,5-b]pyridine-5-carboxylic acid The above 23 (20.0 mg) was dissolved in water (1 mL), THF (1 mL), and methanol (1 mL). , 0.034 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 1 h and then diluted with LCM. When the reaction was judged complete by S, the mixture was acidified with AcOH to about pH 6 and D Dilute with MF (3 mL) and analyze using reverse-phase HPLC (instrument: Gilson 281 (PHG012); Column: Xtimate C18 10um, 21.2×250mm; Mobile phase: A: water ( 10 mM NH 4 HCO 3 , 0.025%NH 3 H 2 O), B: acetonitrile; gradient : 30% B for 1 min, then 45% B for 7 min, stop at 15 min; Flow rate: 30 mL / min; Detection The corresponding fractions were purified using the following method: wavelength: 214 / 254 nm; retention time: 8.0 min; injection number: 3). The fractions were combined and concentrated under reduced pressure to remove most of the organic solvent, and the aqueous residue was lyophilized. The title compound, (S)-2-(4-(6-((4-chloro-2-fluorobenzene 3-(oxetane-2-yl)oxy)pyridin-2-yl)-3-fluorobenzyl)-3-(oxetane-2-yl) ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (7.0 mg, 0.012 mmol, 35.9% yield) was obtained as a white solid. LCMS: [M+H] + =577

[0278] (S)-2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)thiazo (2H)-yl)methyl)-1-(phenyl-2-yl)-3,6-dihydropyridin-1(2H)-yl)methyl Xetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound Item 246) [ka]

[0279] Step 1 In 1,4-dioxane (40 mL), 2,4-dibromothiazole (2.0 g, 8.2 3mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (2.55 g, 8.23 ​​mmol) and Pd(dppf)Cl 2 (602.42mg, 823.32μmol), Cs 2 CO 3 (5.37g, 16.47mmol) was mixed The mixture was cooled to room temperature with N until the reaction was complete as shown by LCMS. 2 Bottom, in RBF, 10 at 90℃ The reaction mixture was stirred for 1 h, concentrated in vacuo, and purified by silica gel chromatography (hexane / E tOAc=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 The silane (2.2 g, 6.37 mmol, 77.4% yield, 100% purity) was dissolved in a pale yellow solution. LCMS: [M+H] + =291.0, retention time (10mM NH 4 HCO 3 )=1.79 minutes

[0280] Step 2 In toluene (5 mL), tert-butyl 4-(4-bromothiazol-2-yl)- 3,6-Dihydro-2H-pyridine-1-carboxylate (1.0 g, 2.90 mmol) l), (4-chloro-2-fluoro-phenyl)methanol (697.6 mg, 4.34 mmol) and Sphos-PdG3 (225.92mg, 289.64μmol), t The mixture was mixed with -BuONa (835.1 mg, 8.69 mmol) and Continue stirring until the reaction is complete. 2 The reaction mixture was stirred at 60° C. for 16 hours in a RBF under The mixture was filtered through a pad of Celite with EtOAc and the combined organics were concentrated in vacuo and separated. Preparative HPLC purification afforded the desired product, tert-butyl 4-[4-[(4-chlorophenyl) -2-fluorophenyl)methoxy]thiazol-2-yl]-3,6-dihydro2H-pi Lysine-1-carboxylate (30 mg, 70.60 μmmol, 2.4% yield) was dissolved in water. Obtained as a colored oil. LCMS: [M+H] + =425.2, retention time (0.01%T FA) = 2.49 minutes

[0281] Step 3 In dichloromethane (3 mL), 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-trifluoro Acetic acid (1.48 g, 12.98 mmol, 1 mL) was added to the mixture, which was analyzed by LCMS. The reaction was stirred at 16° C. for 3 h until completion was indicated by HCl. The reaction mixture was then 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) was added to a yellow LCMS: [M+H] + =325.0, retention time (10mM NH 4 HCO 3 )=1.58 minutes

[0282] Step 4 In N,N-dimethylformamide (3 mL), 4-[(4-chloro-2-fluoro- phenyl)methoxy]-2-(1,2,3,6-tetrahydropyridin-4-yl)thiazo (15 mg, 46.18 μmol), tert-butyl 2-(chloromethyl)-3- [[(2S)-Oxetan-2-yl]methyl]benzimidazole-5-carboxylate N-ethyl-N-isopropyl-propionate (15.55 mg, 46.18 μmol) Mix Pan-2-amine (29.84 mg, 230.91 μmol, 40.22 μL) The mixture was stirred with N until the reaction was complete as shown by LCMS. 2 Bottom, in RBF, at 50°C After stirring for 4 h, the reaction mixture was concentrated in vacuo to give a residue which was purified by preparative HPLC. and purifying it to give the desired product, tert-butyl 2-[[4-[4-[(4-chloro- 2-Fluoro-phenyl)methoxy]thiazol-2-yl]-3,6-dihydro2H-pyridine 3-[[(2S)-oxetan-2-yl]methyl]benzo[3-(2-oxetan-1 ... Imidazole-5-carboxylate (3 mg, 4.80 μmol, yield 10.39%, 100% pure) was obtained as a yellow solid. LCMS: [M+H] + =625.3, when held (10mM NH 4 HCO 3 )=1.84 minutes

[0283] Step 5 In dichloromethane (4 mL), tert-butyl-2-[[4-[4-[(4-chloro -2-fluorophenyl)methoxy]thiazol-2-yl]-3,6-dihydro2H-pi Lysine-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzene Zimidazole-5-carboxylate (3 mg, 4.80 μmol) and 2,2,2- The mixture was stirred at 4°C for 1 h at 25°C with 1.48 g of trifluoroacetic acid (12.98 mmol, 1 mL). 2 The reaction was stirred at 16°C for 1 h in RBF under reduced pressure until completion was shown by LCMS. The reaction mixture was concentrated in vacuo to give a residue which was purified by preparative HPLC to give the desired product. The compound 2-[[4-[4-[(4-chloro-2-fluoro-phenyl)methoxy]thia 2-[3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[ [(2S)-Oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid(0 0.8 mg, 1.41 μmol, 29.3% yield, 100% purity) was obtained as a white solid. LCMS: [M+H] + =569.2, retention time (10mM NH 4 HCO 3 )=1. 46 minutes, purity = 100% (254nm) 1 H NMR (400MHz, CD 3 OD) 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),4.71-4.63(m,3H),4.43(s,2 H),4.15(d,J=13.6Hz,1H),4.05(d,J=13.6Hz,1 H),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)thiazo (4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(phenyl) Xetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound Item 247) [ka] Prepared in a similar manner to compound 250. LCMS: [M+H] + =568.9, retention time ( 10 mM NH 4 HCO 3 )=1.41 minutes 1 H NMR (400MHz, CD 3 OD) 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),5.28-5.1 4(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(d t,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)oxa 4-yl)-5,6-dihydropyridin-1(2H)-yl)methyl)-1-( oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (chemical Compound 248) [ka] Prepared in a similar manner to compound 250. LCMS: [M+H] + =553.2, retention time ( 0.01% TFA) = 1.50 min 1 H NMR (400 MHz, CDCl 3 ) 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-fluorobenzene (2H)-yl)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 ( 10 mM NH 4 HCO 3 )=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=15.2,7.2Hz,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)thiazo (yl-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxo- 1H-benzo[d]imidazole-6-carboxylic acid (compound 250) [ka]

[0288] Step 1 (5-Chloro-2-pyridyl)methanol (100 mg, 696. 5 μmol) was added to a suspension of sodium hydride (33.4 mg, 1.39 mmol ) was added at 0°C and stirred for 30 minutes. Then, 2,4-dibromothiazole (169.2m g, 696.5 μmol) was added and stirred at 0° C. for 5 hours. The reaction was complete by LCMS. After determining the reaction mixture was quenched with ice-cold water (20 mL) and EtOAc (3×20 mL) was added. The organic phase was washed with brine (50 mL) and extracted with anhydrous Na 2 SO 4 Dry with The crude product was purified by flash chromatography (SiO 2 , Heki Purification with ethyl acetate / ethyl acetate 20:1 gave 4-bromo-2-[(5-chloro-2-pyridyl) (78 mg, 232.4 μmol, yield 33.4%) LCMS: [M+H] + =304.9, retention time (0.01%TF A) = 2.02 minutes

[0289] Step 2 In 1,4-dioxane (3 mL), 4-bromo-2-[(5-chloro-2-pyridyl) A suspension of methyl methoxythiazole (78 mg, 255.25 μmol) was added to the 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. 3mg, 255.3μmol), Pd(dppf)Cl 2 (37.35mg, 51.1μ mol), K 2 CO 3 (105.8 mg, 765.8 μmol, 46.22 μL) and 1 Add 0.3 mL of water at 00°C and immerse in N 2 The reaction was stirred at room temperature for 6 hours. After determining completion, the reaction mixture was quenched with ice-cold water (20 mL) and diluted with EtOAc (3×20 The organic phase was washed with brine (50 mL) and extracted with anhydrous Na 2 SO 4 Dry in The crude product was purified by preparative TLC (dichloromethane / methanol 25:1) to obtain methyl (S)-2-((4-(2-((5-chloropyridine -2-yl)methoxy)thiazol-4-yl)-3,6-dihydropyridine-1(2H )-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imida 6-carboxylate (100 mg, 139.3 μmol, 54.6% yield, pure 78.9%) as a yellow oil. LCMS: [M+H] + =566.1, hold Time (0.01% TFA) = 1.48 min

[0290] Step 3 Methyl (S)-2-((4-(2-((5-chloropyridine)) in MeOH (3 mL) (2-phenyl-2-yl)methoxy)thiazol-4-yl)-3,6-dihydropyridine-1(2 H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imide Suspension of dazole-6-carboxylate (100 mg, 176.7 μmol) 1 mL of sodium hydroxide (80 mg, 2.00 mmol, 37.6 1 μL) was added and stirred for 12 h. After the reaction was judged complete by LCMS, the reaction mixture was The mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (3×10 mL). Wash with brine (20 mL) and add anhydrous Na 2 SO 4 Dry at 40° C., filter, and concentrate in vacuo. The crude product was purified by preparative HPLC to give (S)-2-((4-(2-((5-chlorophenyl)-2-((4-methylphenyl)- ...5-chlorophenyl)-2-( Pyridin-2-yl)methoxy)thiazol-4-yl)-3,6-dihydropyridine- 1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d ]imidazole-6-carboxylic acid (39.1 mg, 70.8 μmol, 40.1% yield) was obtained as a yellow solid. LCMS: [M+H] + =552.0, retention time (0.01% TFA) = 1.45 min 1 H NMR(400MHz,DMSO-D6)δ8.64(d,J=2.1Hz,1 H),8.25(t,J=3.2Hz,1H),7.99(dd,J=8.4,2.5H z,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(br s,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),4.6 4(dd,J=15.2,2.6Hz,1H),4.47(dd,J=14.2,7.0 Hz,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),2.4 6-2.31(m,3H).

[0291] (S)-1-(oxetan-2-ylmethyl)-2-((4-(2-((4-(trifluoromethyl)phenyl)-2-((4-methylphenyl)-2-((4-trifluoromethyl)phenyl)-2-((4-trifluoromethyl)phenyl) (fluoromethoxy)benzyl)oxy)thiazol-4-yl)-3,6-dihydropyridin 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 ( 10 mM NH 4 HCO 3 )=1.63 minutes 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,2 H),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),3.22-3.1 5(m,2H),2.75-2.64(m,3H),2.42-2.35(m,3H).

[0292] (S)-2-((4-(2-((2,4-difluorobenzyl)oxy)thiazole- 4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetane (2-methyl-1H-benzo[d]imidazole-6-carboxylic acid (compound 25 2) [ka] Prepared in a similar manner to compound 250. LCMS: [M+H] + =553.0, retention time ( 10 mM NH 4 HCO3 )=1.54 minutes 1 H 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=1 5.2Hz,1H),4.46(t,J=6Hz,1H),4.39-4.35(m,1 H),4.05(d,J=13.6Hz,1H),3.89(d,J=13.6Hz,1 H),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)thiazo (yl-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxo- 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 ( 10 mM NH 4 HCO 3 )=1.47 minutes 1 H NMR(400MHz,DMSO-D6)δ8.72(d,J=1.9Hz,1 H),8.25(d,J=1.0Hz,1H),8.11(dd,J=8.3,2.4H z,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),4.7 9(dd,J=15.2,7.3Hz,1H),4.64(dd,J=15.2,2.6 Hz,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),2.77-2.5 9(m,3H),2.40(dd,J=18.2,9.4Hz,3H).

[0294] (S)-2-((4-(2-((2-chloro-4-fluorobenzyl)oxy)thiazo (4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(phenyl) Xetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound Item 254) [ka] Prepared in a similar manner to compound 250. LCMS: [M+H] + =569.0, retention time ( 10 mM NH 4 HCO 3 )=1.59 minutes 1 H NMR (400MHz, CD 3 OD) 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)phenyl)-2-((4-methylphenyl)-2-((6- ... (fluoromethyl)pyridin-3-yl)methoxy)thiazol-4-yl)-3,6-dihydro (2H)-Dropyridine-1(2H)-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate Carboxylic acid (compound 255) [ka] Prepared in a similar manner to compound 250. LCMS: [M+H] + =586.3, retention time ( 10 mM NH 4 HCO 3 ) = 1.50 minutes, purity 100% (254nm) 1 H 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,1H),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=1 5.2,2.6Hz,1H),4.47(dd,J=13.6,7.7Hz,1H),4 .36(dt,J=8.9,5.9Hz,1H),4.05(d,J=13.5Hz,1 H),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)phenyl)-2-((4-methylphenyl)-2-((4-trifluoromethyl)phenyl)-2-((4-trifluoromethyl)phenyl) (fluoromethyl)benzyl)oxy)thiazol-4-yl)-3,6-dihydropyridine -1(2H)-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (chemical Compound 256) [ka] Prepared in a similar manner to compound 250. LCMS: [M+H] + =585.0, retention time ( 10 mM NH 4 HCO 3 )=1.61 minutes 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=8.8 Hz,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,1 H),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)pyridine -2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)- 1H-Benz[d]imidazole-6-carboxylic acid (compound 257) [ka]

[0298] Step 1 4-Amino-3-[[(2S)-oxetan-2-yl]methyl in DCM (20 mL) A mixture of methyl aminobenzoate (100 mg, 423 μmol) was added in an ice bath. 2-(4-Bromo-2,5-difluoro-phenyl)acetylacetone in DCM (20 mL) Chloride (228 mg, 847 μmol) was added slowly and the reaction was complete by LCMS. The mixture was stirred at room temperature for 1 h until the reaction mixture was concentrated in vacuo and analyzed by preparative TLC (hexanes). Purification by ethyl acetate / EtOAc (1:2) afforded the desired product, methyl 4-[[2-( 4-Bromo-2,5-difluoro-phenyl)acetyl]amino]-3-[[(2S)- Oxetan-2-yl]methylamino]benzoate (71 mg, 151 μmol, yield 3 5.9%) as a pale yellow solid. LCMS: [M+H] + =469.0, retention time =1.57 minutes

[0299] Step 2 4-[[2-(4-bromo-2,5-difluoro-phenyl)acetamide in AcOH (5 mL) Cetyl]amino]-3-[[(2S)-oxetan-2-yl]methylamino]benzoic acid The mixture was stirred at 120° C. for 30 minutes. The reaction mixture was concentrated in vacuo and columned on silica gel until the reaction was complete as indicated by LCMS. Purification by chromatography (hexane / EtOAc = 20:1) afforded the desired product, methyl (S)-2-(4-bromo-2,5-difluorobenzyl)-1-(oxetane-2 -ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (40 mg, 89 μmol, 58.6% yield) was obtained as a pale yellow solid. LCMS: [M+H] + = 451.1, retention time (0.01%TFA)=1.49 minutes

[0300] Step 3 In a dioxetane (10 mL), (S)-2-(4-bromo-2,5-difluorobenzene (1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate Carboxylates (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 2 (8mg, A mixture of 11 μmol) and KOAc (13 mg, 133 μmol) was added to Argon. The reaction mixture was stirred at 90° C. under reduced pressure for 2 hours until the reaction was complete as indicated by LCMS. 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-(oxetane 42-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate The crude product was obtained without further purification (33.0 mg, yield: 1.0 mg) as a pale yellow solid. It was used as is in the next step. LCMS: [M+H] + =452.9, retention time=1.83 minutes

[0301] Step 4 Dioxane (5 mL) and H 2 Methyl (S)-2-(2,5-difluorophenyl) Oro-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 2 (6 mg, 8 μmol) and K 2 CO 3 (15 mg, 110 μmol) The mixture was heated to 90° C. under argon until the reaction was complete as indicated by LCMS. After stirring for 1 h, the reaction mixture was filtered through a pad of Celite with EtOAc and the combined The material was concentrated in vacuo and purified by silica gel chromatography (hexane / 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 The sylate (12 mg, 20 μmol, 24.0% yield) was obtained as a pale yellow solid. MS: [M+H] + =608.0, retention time=2.28 minutes

[0302] Step 5 Methyl (S)-2-(4-( 6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5- Difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imide A mixture of 13 mg of dazole-6-carboxylate (21 μmol) was added to Li OH (5 mg, 107 μmol) was added and the reaction was heated until completion as shown by LCMS. The mixture was stirred at room temperature for 1 h, concentrated in vacuo and adjusted to pH=7 with aqueous acetic acid (50%). and purified by preparative HPLC to give the desired product, (S)-2-(4-(6-((4-chlorophenyl)-2-(4-phenylphenyl)-2- ...chlorophenyl)-2-(4-chlorophenyl)-2-( 2-fluorobenzyloxypyridin-2-yl-2,5-difluorobenzyloxy Dimethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6- The carboxylic acid (10.1 mg, 17 μmol, 79.5% yield) was obtained as a white solid. LCMS: [M+H] + =594.1, retention time=1.44 minutes 1 H NMR(400MHz,DMSO-D6)δ8.24(brs,1H),7.8 9(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,1 H),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,1 H),2.74-2.67(m,1H),2.45-2.33(m,1H).

[0303] (S)-2-(2-chloro-4-(6-((4-chloro-2-fluorobenzyl)oxy) 1H-Pyridin-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzyl 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), 7.88-7.82(m,1H),7.80-7.77(m,1H),7.68-7.5 5(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,1 H),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-phenyl-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H -Benz[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 1 H NMR(400MHz,MeOD)δ8.61(dd,J=23.8,5.1H z,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=5.9Hz,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-di Fluoropyridin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-yl Methyl)-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 1H NMR(400MHz,DMSO-D6)δ8.22(d,J=0.9Hz,1 H),8.14(t,J=9.9Hz,1H),7.78(dd,J=8.4,1.5H z,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),2.75-2.6 4(m,1H),2.38(dt,J=11.1,7.1Hz,1H).

[0306] (S)-2-(4-(6-(4-chloro-2-fluorobenzyloxy)-3-fluoro 3-(3-(pyridin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl )-1H-Benz[d]imidazole-6-carboxylic acid (compound 261) [ka] Prepared in a similar manner to compound 257. LCMS: [M+H] + =594.1, retention time ( 10 mM NH 4 HCO 3 )=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=2.0 Hz,10.0Hz,1H),7.32-7.36(m,3H),7.02(dd,J= 3.2Hz,9.2Hz,1H),5.38(s,2H),4.97-5.03(m,1 H),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,1 H).

[0307] (S)-2-(4-(6-(4-chloro-2-fluorobenzyloxy)pyridine-2 -yl)-2,3-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H -Benz[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 min 1 H NMR(400MHz,DMSO-D6)δ8.20(s,1H),7.92- 7.86(m,1H),7.82-7.73(m,2H),7.61(t,J=8.2H z,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-fluoro (2-fluoropyrimidinyl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl) (I)-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,1 H),8.12(dd,J=8.0Hz,1.6Hz,1H),8.08-8.02(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-fluoro (fluoropyridin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-yl) (ethyl)-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),2.4 2-2.36(m,1H).

[0310] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyrazine -2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H- Benz[d]imidazole-6-carboxylic acid (compound 265) [ka] Prepared in a similar manner to compound 257. LCMS: [M+H] + =577.7, retention time ( 10 mM NH 4 HCO 3 )=1.55 minutes 1 H 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=5.9,3.1H z,1H),2.77-2.63(m,1H),2.44-2.31(m,1H).

[0311] (S)-2-(4-(4-((4-cyano-2-fluorobenzyl)oxy)-5-fluoro (fluoropyrimidin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-yl Methyl)-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,1 H),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=1.2,10H z,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-fluoropyridine 3-(oxetane-2-ylmethyl)-3-fluorobenzyl H-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 ( 10 mM NH 4 HCO 3 )=1.45 minutes 1 H NMR(400MHz,DMSO-D6)δ8.05(d,J=8.4Hz,1 H),7.97-7.93(m,2H),7.81(dd,J=8.4Hz,10.4H z,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-fluoro (fluoropyridin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-yl) (ethyl)-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 1 H NMR(400MHz,DMSO-D6)δ8.20(s,1H),7.93( d,J=10.2Hz,1H),7.86(dd,J=10.4,9.0Hz,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=15.5,7.0Hz,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)pyridine- 2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1 H-Benz[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),4.63-4.5 8(m,1H),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)pyridine -2-yl)-3-methylbenzyl)-1-(oxetan-2-ylmethyl)-1H-benzyl 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),7.8 3-7.82(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),4.40-4.3 3(m,3H),2.67-2.63(m,1H),2.39-2.29(m,4H).

[0316] (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine -2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)- 1H-Benz[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 1 H 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,1 H).

[0317] (S)-2-(4-(4-((5-chloro-3-fluoropyridin-2-yl)methoxy) (5-fluoropyrimidin-2-yl)-2,5-difluorobenzyl)-1-(phenyl) Xetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound Item 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,1 H),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=15.5,7.0H z,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-(phenyl) Xetan-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,1 H),8.54(d,J=1.3Hz,1H),8.20(dd,J=9.7,2.0H z,1H),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=1 1.0,6.0Hz,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(d d,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,1 H).

[0319] (S)-2-(4-(6-((2,4-difluorobenzyl)oxy)pyridine-2- 1-(oxetan-2-ylmethyl)-2-fluorobenzyl [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 1 H 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=1.2,7.2Hz,1H),7.68(q,J=8.8,8H z,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,2 H),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-fluoro Olopyrimidin-2-yl)-2,5-difluorobenzyl)-1-(oxetane-2-yl) (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,1 H),8.85(d,J=2.8Hz,1H),8.36(dd,J=8.2,2.1H z,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),5.7 9(s,2H),5.06(d,J=7.0Hz,1H),4.81-4.68(m,1 H),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) (ii) Pyridin-2-yl)-2,5-difluorobenzyl)-3-(oxetane-2-yl) (3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 276) [ka]

[0322] Step 1 (5-Chloro-3-fluoro-2-pyridyl)methanol (100 mg, 619 μmol) and 2-bromo-6-fluoro-pyridine (114.4 mg, 6 50 μmol) was slowly added to the suspension at 0°C. 681 μmol) was added, and N 2 The reaction was stirred at room temperature for 2 hours. The reaction was judged complete by LCMS. After digestion, the reaction mixture was quenched with ice-cold water (20 mL) and washed with EtOAc (3×40 mL). The organic phase was washed with brine (50 mL) and extracted with anhydrous Na 2 SO 4 Dry and filter. The crude product was purified by flash chromatography (SiO 2 , hexane / ethyl acetate 10:1) to obtain 2-[(6-bromo-2-pyridyl)oxymethyl ]-5-Chloro-3-fluoro-pyridine (115 mg, 362 μmol) was dissolved in water to give a white solid LCMS: [M+H] + =317.0, retention time (0.01%TFA)=2 .12 minutes

[0323] Step 2 2-(4-bromo-2,5-difluoro-phenyl)acetic acid methyl in dioxane (8 mL) Chill (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 2 (110.4 mg, 151 μmol) The mixture was stirred with N until the reaction was complete as shown by LCMS. 2 Bottom, 95°C at 2 o'clock The reaction mixture was stirred for 1 h and 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), 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 l), Pd(dppf)Cl 2 (50.7 mg, 69 μmol) and Cs 2 CO 3 (twenty two 5.74 mg, 693 μmol) was added to N 2 under Stir for 2 h at 100 °C and filter the reaction mixture through a pad of Celite with EtOAc. The combined organics were concentrated in vacuo and purified by silica gel chromatography (hexane / EtOA / c=10:1) to give the desired product, methyl 2-[4-[6-[(5-chlorophenyl) -3-fluoro-2-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro The resulting solution was concentrated to give the 5'-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 In methanol (3 mL), 2-[4-[6-[(5-chloro-3-fluoro-2-pyridyl) 2-pyridyl)methoxy]-2,5-difluoro-phenyl]methyl acetate (10 0 mg, 237 μmol), LiOH (16.99 mg, 710 μmol) and water (0. 5 mL) was mixed with N 2 At 20° C. until the reaction was complete as indicated by LCMS. The reaction was then quenched by the addition of HOAc and the combined organics were concentrated in vacuo. The product was condensed 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) was obtained as a white solid. S: [M+H] + =409.1, retention time (0.01%TFA)=1.99 minutes

[0326] Step 5 In DCM (8 mL), 2-[4-[6-[(5-chloro-3-fluoro-2-pyridyl )Methoxy]-2-pyridyl]-2,5-difluoro-phenyl]acetic acid (90 mg, 22 0 μmol), methyl 5-amino-6-[[(2S)-oxetan-2-yl]methyla amino]pyridine-2-carboxylate (94.03 mg, 396 μmol), HATU (125.6 mg, 330 μmol) and DIEA (85.4 mg, 661 μmol). The mixture was mixed with N 2 The reaction was stirred at 20° C. for 2 h until the reaction was complete as shown by LCMS. The reaction was quenched by adding water and the combined organics were concentrated in vacuo and washed with silica gel. Purification by chromatography (hexane / EtOAc 1:1) gave the desired product. Methyl 5-[[2-[4-[6-[(5-chloro-3-fluoro-2-pyridyl)meth 2-Pyridyl-2,5-difluorophenylacetylamino [(2S)-Oxetan-2-yl]methylamino]pyridine-2-carboxylate ( 120 mg, 191 μmol, 86.8% yield) was obtained as a pale yellow solid. LCMS: [M+H] + =628.1, retention time (0.01%TFA)=1.77 minutes

[0327] Step 6 Methyl 5-[[2-[4-[6-[(5-chloro-3-fluorophenyl) [O-2-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]a Cetyl]amino]-6-[[(2S)-oxetan-2-yl]methylamino]pyridine 100 mg, 143 μmol) and HOAc (20 drops) were mixed. The mixture was then cooled to 100° C. 2 The mixture was stirred at 60° C. for 2 hours under reduced pressure. Water was added to quench the reaction. The mixture was extracted with EtOAc (3×20 mL). The organic phase was washed with brine (50 mL). And anhydrous Na 2 SO 4 The crude product was purified by flash filtration, dried over low-temperature hexanes, filtered and concentrated in vacuo. Chromatography (SiO 2 , dichloromethane / methanol 15:1) to obtain 2-[[4-[6-[(5-chloro-3-fluoro-2-pyridyl)methoxy]-2 -pyridyl]-2,5-difluoro-phenyl]methyl]-3-[[(2S)-oxetane 2-methyl-2-yl]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 In methanol (3 mL), 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) A mixture of 1000 mol) and water (0.5 mL) was heated in a nitrogen 2 at 20°C under 100°C. The reaction was stirred for 3 h until completion was indicated by the addition of HOAc to quench the reaction. 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, yield 56.3%) as a white solid. LCMS: [M+H] + =596.0, retention time (0.01% TFA) = 1.90 min 1 H NMR(400MHz,DMSO-D6)δ8.53(d,J=1.2Hz,1 H),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(d d,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=8.4H z,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-fluoropyridine 2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3-(oxetane-2-ylmethyl)- H-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 ( 10 mM NH 4 HCO 3 )=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),7.36-7.3 1(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,2 H),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) (ii) Pyridin-2-yl)-2,5-difluorobenzyl)-3-(oxetane-2-yl) (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 ( 10 mM NH 4 HCO 3 )=1.35 minutes 1 H 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)pyridine- 2-yl)-2,5-difluorobenzyl)-3-(oxetan-2-ylmethyl)-3 H-Imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 279) [ka]

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

[0333] Step 2 In DMF (20 mL), tert-butyl 5-amino-6-[[(2S)-oxetane -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 m mol), N-ethyl-N-isopropyl-propan-2-amine (643.6 mg, 4 .98mmol), and [dimethylamino(triazolo[4,5-b]pyridine-3-yl] (1.89 xyloxy)methylene]-dimethylammonium, hexafluorophosphate g, 4.98 mmol) was reacted at 20 °C under N2 by LCMS. Stir for 1 hour until completion is indicated, pour the reaction mixture into water, extract 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, tert-butyl 5-[[2-(4-bromo- 2,5)-Difluoro-phenyl)acetyl]amino]-6-[[(2S)-oxetane -2-yl]methylamino]pyridine-2-carboxylate (1.0 g, 1.95 mm ol, 39.2% yield) was obtained as a pale yellow solid. LCMS: [M+H] + =512, Retention time = 1.92 minutes

[0334] Step 3 tert-Butyl 5-[[2-(4-bromo-2,5-difluorophenyl)- (2S)-oxetan-2-yl)methyl 1.0 g, 1.95 mmol) of pyridine-2-carboxylate was mixed with The mixture was stirred under N2 at 120 °C for 2 h until the reaction was complete as indicated by LCMS. The reaction mixture was then filtered through a pad of Celite with EtOAc and the combined organics were concentrated in vacuo The mixture was concentrated in hexane and purified by silica gel chromatography (hexane / EtOAc 2:1). The desired product, tert-butyl 2-[(4-bromo-2,5-difluoro- 3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5 -b]pyridine-5-carboxylate (430 mg, 870 μmol, 44.6% yield) Obtained as a pale yellow solid. LCMS: [M+H] + =494, retention time (0.01%TF A) = 2.02 minutes

[0335] Step 4 In dioxane (20 mL), tert-butyl 2-[(4-bromo-2,5-difluoro (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-diox Saborolan-2-yl)-13,2-dioxaborolane (184.93 mg, 728 μm ol) and potassium acetate (143.0 mg, 1.46 mmol), Continue eluting with N until the reaction is complete by LCMS. 2 The reaction mixture was stirred at 90° C. for 16 hours under It was filtered through a pad of Celite with EtOAc and used directly in the next step.

[0336] Step 5 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]me ethyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pi Lysine-5-carboxylate (112.0 mg, 207 μmol), and sodium bicarbonate A mixture of sodium (86.87 mg, 1.03 mmol) was 2 Bottom, 110℃, LCM The reaction was stirred for 16 h until completion was indicated by S, at which point water was added to the reaction mixture and EtOAc was added. c) and the combined organics were concentrated in vacuo and purified by silica gel chromatography (hexanes / EtOAc 5:1) to give the desired product, tert-butyl 2-[[4- [6-[(5-cyano-2-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro 3-[[(2S)-oxetan-2-yl]methyl]imidazo [4,5-b]pyridine-5-carboxylate (80 mg, 61.9% yield) was obtained in a pale yellow color. LCMS: [M+H] +=625, retention time=1.77 minutes

[0337] Step 6 CH 2 Cl 2 (2 mL) 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. The mixture was heated at 30°C under N2. The reaction mixture was concentrated in vacuo at rt for 1 h until the reaction was complete as indicated by LCMS. This was then condensed 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) was obtained 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,1 H),8.33(dd,J=8.2,2.1Hz,1H),8.08(d,J=8.2H z,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-fluoro Olopyrimidin-2-yl)-2,5-difluorobenzyl)-3-(oxetane-2-yl) (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,1 H),8.86(d,J=2.8Hz,1H),8.37(dd,J=8.2,2.1H z,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,1H),4.81-4.41(m,6 H),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-pyridine Dimethyl]-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 ( 10 mM NH 4 HCO 3 )=2.94 minutes 1 H NMR(400MHz,DMSO-D6)δ8.06(d,J=8.2Hz,1 H),7.97(d,J=8.2Hz,1H),7.91(dd,J=9.1,5.2H z,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),5.5 2(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=1 5.3,9.1Hz,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)pyridine -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 1 H NMR(400MHz,DMSO-D6)δ7.99(d,J=8.4Hz,1 H),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),2.4 3-2.34(m,1H).

[0341] (S)-2-(4-(6-(4-chloro-2-fluorobenzyloxy)-5-fluoro 3-(oxetan-2-ylmethyl)-2-fluorobenzyl-3-(pyridin-2-yl) )-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,1 H),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),5.18-5.1 0(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-fluoro 3-(oxetan-2-ylmethyl)-2-fluorobenzyl-3-(pyridin-2-yl) )-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,1 H),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(d t,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-fluoro Pyrimidin-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 1 H NMR(400MHz,DMSO-D6)δ8.82-8.76(m,1H), 8.19-8.15(m,1H),8.13-8.03(m,2H),7.99-7.9 4(m,1H),7.78-7.70(m,1H),7.56-7.50(m,1H), 7.41-7.32(m,1H),7.22-7.14(m,1H),5.72(s,2 H),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,1 H).

[0344] (S)-2-(4-(6-((2,4-difluorobenzyl)oxy)pyridine-2- (yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[3H] Zo[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),7.48-7.4 2(m,1H),7.35-7.28(m,1H),7.17-7.08(m,1H), 6.90-6.85(m,1H),5.51(s,2H),5.18-5.10(m,1 H),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,1 H).

[0345] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine -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),7.42-7.3 1(m,5H),7.06(d,1H),5.23(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)pyridine- 2-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-yl Midazo[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),5.6 4(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-fluoro (fluoropyridin-2-yl)-3-fluorobenzyl)-3-(oxetan-2-yl) (ethyl)-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 min 1 H NMR (400 MHz, CDCl 3 ) 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)pyridine-2- 3-(oxetan-2-ylmethyl)-3H-imidazo[3-fluorobenzyl] Zo[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),4.76-4.68(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-fluoro (fluoropyrimidin-4-yl)-2-fluorobenzyl)-3-(oxetan-2-yl Methyl)-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,1 H),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),4.7 6-4.69(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)pyridine -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 1 H NMR (400MHz, CD 3 OD) 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)pyridine -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,1 H),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,2 H),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-(oxetane (2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound Item 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,1 H),8.56(d,J=1.4Hz,1H),8.22(dd,J=9.7,1.9H z,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,1 H).

[0353] (S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine -2-yl)-2-methylbenzyl)-1-(oxetan-2-ylmethyl)-1H-benzyl 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 1 HNMR (400MHz, DMSO-D6): δ8.22(brs,1H),7.9 0(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=1.6 Hz,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)pyridine- 2-yl)-2,5-difluorobenzyl)-3-(oxetan-2-ylmethyl)-3 H-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,1 H),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 Lysine-2-yl)-2,5-difluorobenzyl)-3-(oxetan-2-ylmethyl (I)-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,1 H),8.08-7.84(m,4H),7.79-7.75(m,1H),7.52- 7.49(m,1H),7.42-7.38(m,1H),6.95-6.92(m,1 H),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 1 H NMR(400MHz,DMSO-D6)δ8.58(d,J=2.9Hz,1 H),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=1 1.5,6.1Hz,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=15.4,6.9H z,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-di Fluoropyridin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-yl Methyl)-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),4.3 7-4.32(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-fluoro Olopyrimidin-2-yl)-2,5-difluorobenzyl)-3-(oxetane-2-yl) (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,1 H),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-(oxetane (2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound Item 301) [ka] Prepared in a similar manner to compound 279. LCMS: [M+H] + =588.0, retention time= 1.41 minutes 1 H NMR (400 MHz, CDCl 3 ) 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),5.2 1(s,1H),4.60(ddd,J=29.6,16.5,8.5Hz,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-(oxetane (2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound Item 302) [ka] Prepared in a similar manner to compound 279. LCMS: [M+H] + =587.9, retention time= 1.36 minutes 1 H NMR (400MHz, CD 3 OD): 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,2 H),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-yl) (ethyl)-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,1H),7.85-7.81(m,1H),7.76-7.7 4(m,1H),7.69-7.62(m,4H),7.51(d,J=6.0Hz,1 H),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,1 H).

[0362] (S)-2-(4-(6-((4-(1H-imidazol-1-yl)benzyl)oxy) (II) Pyridin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl (III)-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 1 H NMR(400MHz,DMSO-D6)δ8.25-8.24(brs,1H ),8.06(d,J=8.2Hz,1H),7.99-7.89(m,3H),7.8 8-7.80(m,1H),7.74(t,J=1.3Hz,1H),7.70-7.6 1(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-fluoro (fluoropyridin-2-yl)-3-fluorobenzyl)-3-(oxetan-2-yl) (ethyl)-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,1 H),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=14.9,6.0H z,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-(oxetane-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 = 7.7 Hz, 1H), 2.45 (s, 1H).

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

[0366] Step 1 2-(4-Bromo-3-fluoro-phenyl)acetic acid (220.7 mg, 947 μmol ), ethyl 4-amino-2-fluoro-3-[[(2S)-oxetan-2-yl]methyl Solution of benzoate (231 mg, 861 μmol), EDCI (494.3 μmol) g, 2.58 mmol), DIEA (669.90 mg, 5.18 mmol), The mixture was stirred at 5° C. for 16 hours. 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) and diluted with anhydrous sodium chloride. The mixture was dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate). ethyl acetate / petroleum ether, v / v, 1 / 1) to give 4-[[2-(4-bromo- 3-Fluoro-phenyl)acetyl]amino]-2-fluoro-3-[[(2S)-oxo Ethyl 2-[methylamino]benzoate (82 mg, 15.2% yield) was added to the yellow LCMS: [M+H] + =483.0, retention time=2.27 minutes

[0367] Step 2 4-[[2-(4-bromo-3-fluoro-phenyl)acetyl] ]amino]-2-fluoro-3-[[(2S)-oxetan-2-yl]methylamino] A solution of ethyl benzoate (82 mg, 170 μmol) was stirred at 120°C for 2 hours. 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 adjusted to 0.5% by weight, extracted with ethyl acetate (3 x 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-yl) (ethyl)-1H-benzo[d]imidazole-6-carboxylate (60 mg, yield 68 0.4%) as a yellow solid. LCMS: [M+H] + =465.1, retention time (0 0.01% TFA) = 2.07 min

[0368] Step 3 Ethyl (S)-2-(4-bromo-3-fluorobenzyl)acetate in dioxane (2 mL) -7-Fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazo Mixture of 4,4,5,5- Tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2-yl)-1,3,2-dioxaborolane (63.0 mg, 248 μmol), PdC l 2 (dppf) 2 (36.9 mg, 45 μmol), and KOAc (66.4 mg, 6 The mixture was stirred at 100°C for 16 hours under nitrogen. The 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-dioxaborolane)- 2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imide Dazole-6-carboxylate (227 mg, 204 μmol, 90.31% yield) Obtained as a brown solid and used as is in the next stop. LCMS: [M+H] + =51 3.3, retention time (0.01%TFA) = 2.10 minutes

[0369] Step 4 In dioxane (2 mL), 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-carbo xylate (110 mg, 215 μmol), 4-[(6-bromo-2-pyridyl)oxylate Dimethyl]-3-fluoro-benzonitrile (65.9 mg, 215 μmol), K 2 C O 3 (88.9 mg, 644 μmol), and Pd(dppf)Cl 2 (17.5mg, The mixture was stirred at 90° C. for 3 hours under nitrogen. The mixture was concentrated and purified by silica gel chromatography (ethyl acetate / petroleum ether, v / v, 1 / 1). Elution) to obtain ethyl (S)-2-(4-(6-((4-cyano-2-fluorophenyl)benzene 3-fluorobenzyl)-7-fluoro-1-(2-methylphenyl)oxy)pyridin-2-yl)- ... oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate ( 30 mg, 22.8% yield) was obtained as a white solid. LCMS: [M+H] + =613 .0, retention time=2.33 minutes

[0370] Step 5 Ethyl (S)-2-(4-(6-((4-cyano-2-fluoro) benzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-7-fluoro-1 -(Oxetan-2)-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate A solution of silyl (90 mg, 147 μmol) and 0.5N LiOH (2 mL) was The mixture was neutralized to pH=5 with acetic acid and stirred at 25° C. for 16 h. The mixture was extracted with DCM / MeOH (v / v=10 / 1, 3×10 mL). The organic layer was concentrated and separated using preparative HPLC (column: Xtimate C18 21.2*25 0mm, 10μm; Mobile phase: A: Water (10mM NH 4 HCO 3 &0.025%NH 3 · H 2 O), B:ACN; gradient: 5% B for 3 min, then 50–50% B for 10 min, 18 min Stop at 0.05°C; Flow rate (ml / min): 30.00; Detection wavelength (nm): 214 nm. (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine- 2-yl)-3-fluorobenzyl)-7-fluoro-1-(oxetan-2-ylmethyl (17.3 mg, yield 20.1 4%) 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),4.61-4.31( 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)pyridine -2-yl)-3-fluorobenzyl)-7-fluoro-1-(oxetan-2-yl) (ethyl)-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,1 H),7.84(t,J=7.9Hz,1H),7.61(dd,J=16.3,8.2 Hz,2H),7.46(ddd,J=22.7,13.4,5.1Hz,3H),7. 31(dd,J=10.0,5.9Hz,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)pyridine -2-yl)-2-fluorobenzyl)-7-fluoro-1-(oxetane-2-yl) (ethyl)-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 1 H NMR(400MHz,MeOD)δ7.74(dd,J=11.5,9.2H z,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)pyridine -2-yl)-2-fluorobenzyl)-7-fluoro-1-(oxetane-2-yl) (ethyl)-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=1 6.6,7.0Hz,2H),7.50-7.26(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 7-fluoro-1-(oxetan-2-yl)-2-fluorobenzyl Methyl)-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 min 1 H NMR(400MHz,DMSO-D6)δ8.73(d,J=5.2Hz,1 H),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 .43-7.28(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-fluoro (fluoropyrimidin-2-yl)-2-fluorobenzyl)-7-fluoro-1-(oxetine Tan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 3 12) [ka] Prepared in a similar manner to compound 307. LCMS: [M+H] +=603.9, retention time= 1.53 minutes 1 H NMR (400 MHz, CDCl 3 ) δ8.44-8.43(d,J=2.4H z,1H),8.11-8.05(m,2H),7.93-7.89(t,J=8.0H z,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-fluoro (O-pyrimidin-2-yl)-2,5-difluorobenzyl)-7-fluoro-1-(O-pyrimidin-2-yl)- Xetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound Item 313) [ka] Prepared in a similar manner to compound 307. LCMS: [M+H] + =605.2, retention time ( 10 mM NH 4 HCO 3 )=1.18 minutes

[0377] (S)-2-((1-(6-(4-cyano-2-fluorobenzyloxy)pyridine- 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 In toluene (80 mL), 4-[(6-bromo-2-pyridyl)oxymethyl]-3- Fluoro-benzonitrile (10 g, 30.93 mmol), piperidin-4-one (3 .99g, 40.21mmol), Pd2(dba) 3 (1.13g, 1.55mmol ), BINAP (1.93 g, 3.09 mmol), and Cs2CO3 (15.08 g, 46.40 mmol) was mixed at 110 °C under argon and The reaction was stirred for 18 h until completion was indicated, at which point the reaction mixture was washed with EtOAc through the Celite Filter through a pad, concentrate the combined organics in vacuo, and purify by silica gel chromatography (hexane Purification with ethyl acetate / EtOAc (77:23) gave the desired product 3-fluoro-4- [[6-(4-oxo-1-piperidyl)-2-pyridyl]oxymethyl]benzo The nitrile (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 (400 MHz, CDCl 3 ) δ7.62(t,J=7.6Hz,1H) ,7.50-7.42(m,2H),7.37(dd,J=1.2,8Hz,1H),6 .32(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 tert-Butyl 2-dimethoxyphosphoryl acetate (7.1 A suspension of LDA (3.98 g, 37.3 mmol) was added at room temperature. 12 mmol, 19 mL) was slowly added and stirred under Ar for 10 min. mL) 3-fluoro-4-[[6-(4-oxo-1-piperidyl)-2-pyridyl] A solution of 1.00g of 10.60mmol of 1,000g of oxymethylbenzonitrile was dissolved in the solution. The reaction was judged complete by LCMS, after which the reaction mixture was poured into ice-cold water. (10 mL) and extracted with EtOAc (3×20 mL). The organic phase was washed with brine. (50 mL), and washed with anhydrous Na 2 SO 4 The crude product was dried over 1000 ml of ethyl acetate, filtered and concentrated in vacuo. The product was subjected to flash chromatography (SiO 2 , purified with hexane / ethyl acetate 10:1 It is prepared by 2-[1-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2- tert-Butyl pyridyl-4-piperidylidene acetate (2.2 g, yield 36 0.1%) as a colorless liquid. LCMS: [M+H] + =424.2, retention time=1 .98 minutes

[0380] Step 3 tert-Butyl 2-[1-[6-[(4-cyano-2-fluoro) 2-Pyridyl)-4-piperidylidene]acetate (2.2 g, 5.20 mmol) was added to the mixture. l, 7 mL) and stirred at room temperature for 1 hour until the reaction was complete as indicated by LCMS. The reaction mixture was added with DCM (160 mL) and NaHCO 3 Aqueous solution of Sat.) (2 x 30 mL), dried, evaporated and flash-coated with silica gel. Purification by chromatography (PE:EA / 0%-66%) afforded the desired product 2. -[1-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl] [0,4-diphenyldiamine]acetic acid (1.78 g, 4.44 mmol, 85.5% yield) was Obtained as a colored solid. LCMS: [M+H] + =368.1, retention time=1.25 minutes

[0381] Step 4 2-[1-[6-[(4-cyano-2-fluoro-phenyl)methyl]phenyl]propanediol in THF (30 mL) [2-pyridyl]-4-piperidylidene]acetic acid (723 mg, 1.97 mmol) The mixture was stirred and cooled on a salt-ice bath. Then, isobutyl chloroformate (52 5.00 mg, 3.84 mmol) and N-methylmorpholine (598 mg, 5.91 mmol) mol, 0.65 mL) was added and the reaction was stirred in a salt-ice bath for 20 minutes. 5-Amino-6-[[(2S)-oxetan-2-yl]methylamino]pyridine-2- Carboxylate (500 mg, 1.79 mmol) was dissolved in pyridine (6.85 g, 86.5 5 mmol, 7 mL) and dissolved in N-methylmorpholine (598 mg, 5.91 mmol) (0.65 mL) was added to the reaction mixture on an ice bath while stirring at 0° C. for 1 hour. After completion, the solvent was evaporated in vacuo and the remaining residue was dissolved in DCM (50 mL) and water (20 mL). The DCM layer was washed once with brine and partitioned with anhydrous Na 2 SO 4 Dry and filter, Evaporation in vacuo gave the crude product, which was purified by silica gel chromatography (Hexa The desired product, tert-butyl 5-[[ 2-[1-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl ]-4-piperidylidene]acetyl]amino]-6-[[(2S)-oxetane-2-yl [methylamino]pyridine-2-carboxylate (168 mg, 13.35% yield) was obtained as a pale yellow solid. LCMS: [M+H] + =629.1, retention time=2.12 minutes

[0382] Step 5 In toluene (4 mL), 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) were mixed The mixture was stirred at 60° C. for 1.5 h until the reaction was complete as indicated by LCMS. 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-[[(2 S)-Oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxamide The sylate (5 mg, 8.0% yield) was obtained as a pale yellow oil. LCMS: [M+H] + =612.3, retention time (0.01%TFA)=2.04 minutes

[0383] Step 6 tert-Butyl 2-[[1-[6-[(4-cyano-2-fluoro) 2-pyridyl]-4-piperidylidene]methyl]-3-[[ (2S)-Oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxamide A mixture of 1.48 g of TFA (13. 0 mmol, 1 mL) was added and the reaction was stirred at room temperature for 1 h until the reaction was complete by LCMS. The reaction mixture was stirred, concentrated in vacuo, dissolved in THF (1.5 mL) and purified by preparative HPLC. Purification affords the desired product, 2-[[1-[6-[(4-cyano-2-fluoro- (2S) -oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylic acid ( Obtained 1.1 mg, 23.3% yield) as a white solid. LCMS: [M+H] + =55 5.0, retention time=1.51 minutes 1 H NMR(400MHz,DMSO-D6-d6)δ8.16-8.09(m,1 H),7.68(t,J=8Hz,1H),7.62-7.55(m,2H),7.52 (t,J=8Hz,1H),6.70(s,1H),6.41(d,J=8.4Hz,1 H),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)pyridine-2-yl) (III)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 min 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 .77-4.76(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)pyridine -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 min 1 H NMR (400 MHz, CDCl 3 ) 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),3.95-3.83(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-phenyl-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 1 H 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=8.2 Hz,1H),6.10(d,J=7.8Hz,1H),5.57-5.53(brs, 1H),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)pyridine -2-yl)piperidin-4-ylidene)methyl)-7-fluoro-1-(oxetane- 2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 318) [ka]

[0388] Step 1 tert-Butyl 4-(2-ethoxy)acetate in THF (10 mL) and ethanol (8 mL) -2-oxo-ethylidene)piperidine-1-carboxylate (1.0 g, 3.71 m Lithium hydroxide hydrate (779 mg, 18.56 mol) in water (7 mL) was dissolved. The mixture was stirred at 50° C. for 16 h, and the mixture was neutralized with acetic acid to pH= The mixture was extracted with EtOAc (2×50 mL). The combined organic layers were concentrated. Condensed, 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 Ethyl 4-amino-2-fluoro-3-[[(2S)-oxetanediol in DMF (5 mL) Ethyl 2-(phenyl-2-yl)methylamino]benzoate (207 mg, 772 μmol), Solution of 1-tert-butoxycarbonyl-4-piperidylidene in acetic acid (204.79m g, 889 μmol), T 3 P (736.08 mg, 2.31 mmol), and Et 3 N (311.72 mg, 3.09 mmol) was dissolved and the mixture was heated at 30° C. for 16 h. The mixture was poured into water and extracted with ethyl acetate (3×20 mL). The organic layer was washed with brine (2×50 mL), dried over anhydrous sodium sulfate and concentrated. , by silica gel chromatography (eluted with ethyl acetate / petroleum ether, v / v, 3 / 2). After purification, tert-butyl (S)-4-(2-((4-(ethoxycarbonyl)-3- Fluoro-2-((oxetan-2-ylmethyl)amino)phenyl)amino)-2-oxo xoethylidene)piperidine-1-carboxylate (135 mg, yield 27.4%) Obtained as a yellow oil. LCMS: [M+H] + =492.3, retention time (0.01% TFA) = 2.07 min

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

[0391] Step 4 Ethyl (S)-2-((1-(tert-butoxycarbonyl)pyridinyl)acetate in DCM (5 mL) Peridine-4-ylidene)methyl)-7-fluoro-1-(oxetan-2-ylmethyl )-1H-benzo[d]imidazole-6-carboxylate (20 mg, 41 μmol To the solution of 1,2-dichlorophenyl ether (1,2-dichlorophenyl ether), TFA (8.5 mg, 75 μmol) was added. The mixture was heated at room temperature. The mixture was stirred at rt for 2 h. The resulting mixture was concentrated and adjusted to about pH 8 with saturated sodium bicarbonate. Extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate to give ethyl (S)-7 -Fluoro-1-(oxetan-2-ylmethyl)-2-(piperidin-4-ylidene ethyl)-1H-benzo[d]imidazole-6-carboxylate (10 mg, 27 μm ol, 65.8% yield) was obtained as a yellow oil. LCMS: [M+H] + =374. 2. Retention time (0.1%TFA) = 0.89 minutes

[0392] Step 5 In a glove box, ethyl (S)-7-fluoro-1-( Oxetan-2-ylmethyl)-2-(piperidin-4-ylidenemethyl)-1H-benzo[b]pyridin-2-ylmethyl Zo[d]imidazole-6-carboxylate (40 mg, 107 μmol), 6-[( 6-Bromo-2-pyridyl)oxymethyl]pyridine-3-carbonitrile (31.08 mg, 107 μmol), Pd 2 (dba) 3 (9.8 mg, 11 μmol), BINA P (13.3mg, 21μmol) and Cs 2 CO 3 (104.8 mg, 321 μmol The solution containing l) was stirred at 110° C. for 16 hours. The resulting solution was filtered and The product was purified by column chromatography (eluted with ethyl acetate / petroleum ether, v / v, 4 / 1) to give Ethyl (S)-2-((1-(6-((5-cyanopyridin-2-yl)methoxy)pyri (2-yl)piperidin-4-ylidene)methyl)-7-fluoro-1-(oxetane 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 In THF (10 mL), ethyl (S)-2-((1-(6-((5-cyanopyridine 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 The solution in which 1,2-dichlorophenyl ether (1 mg, 2.06 mmol) was dissolved was stirred at room temperature for 6 hours. Neutralize with acetic acid to pH = 5 and dissolve in DCM / MeOH (v / v = 10 / 1, 3 x 10 mL). The combined organic layers were concentrated and purified by preparative HPLC to give (S)-2-((1 -(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperidinyl 7-fluoro-1-(oxetan-2-ylmethyl)-1-phenyl-4-ylidenemethyl H-Benzo[d]imidazole-6-carboxylic acid (3.7 mg, 6.5% yield) was obtained as a white Obtained as a solid. LCMS: [M+H] + =555.2, retention time (0.1%FA)=1 .88 minutes 1 H NMR(400MHz,DMSO-D6)δ8.98(d,J=1.3Hz,1 H),8.26(dd,J=8.2,2.1Hz,1H),7.90-7.71(m,1 H),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),5.51(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=8.8,6.0Hz,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-phenyl-2-yl)cyclohexyl)methyl)-1-(oxetan-2-ylmethyl)-1H -Benz[d]imidazole-6-carboxylic acid (compound 319) [ka]

[0395] Step 1 Trifluoromethylsulfonyl trifluoromethanesulfonate (2.39 g, 8.4 6mmol, 1.42mL) in dichloromethane (16mL) Add dropwise ethyl-4-methyl-pyridine (2.17 g, 10.58 mmol) to the solution. Then, 2-(4-oxocyclohexyl)methyl acetate was dissolved in dichloromethane (16 mL). The reaction mixture was stirred at 25° C. for 1 hour. Stir for 6 h, then concentrate to give methyl 2-[4(trifluoromethylsulfonyloxy)phenyl]phenyl cyclohexen-3-en-1-yl]acetate (1.48g, yield 66.1%) ) was obtained as a colorless oil. LCMS: [M+H] + =591, retention time (10mM NH 4 HCO 3 )=2.35 minutes

[0396] Step 2 In dioxane (1 mL), 2-[4-(trifluoromethylphenyloxy)silyl] [Clohex-3-en-1-yl]acetate methyl (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. 55mmol), Pd(dppf)Cl 2 (94.6 mg, 116 μmol), potassium acetate (681.84 mg, 6.95 mmol), Pd(dppf)Cl 2 (64.2mg The mixture was exchanged in a glove box. The mixture was stirred at 80° C. for 17 hours. LCMS showed the reaction was complete. Silica gel (3 g) was added and evaporated to give a dry powder, which was purified on silica gel. [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)silyl cyclohexen-3-en-1-yl]acetate methyl (546 mg, 1.85 mmol) , 80.0% yield) as a light yellow solid. LCMS: [M+H] + =280, hold Time (0.01% TFA) = 2.16 min

[0397] Step 3 In dioxane (6 mL), [4-(2-methoxy-2-oxo-ethyl)cyclohexene 1-phenyl]boronic acid (443 mg, 2.13 mmol), 2-bromo-6-[(4- Mixture of chloro-2-fluoro-phenyl)methoxy]pyridine (672.8 mg, 2 .13mmol), dipotassium carbonate (881.2mg, 6.38mmol), Pd(dp pf)Cl 2 The mixture was then bubbled with nitrogen for 10 min. The mixture was stirred at 80° C. for 16 hours. LCMS showed the reaction was complete. 2-[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridin methyl]cyclohexen-3-en-1-yl]acetate (361 mg, 833 μm ol, 39.2% yield) was obtained as a white solid. LCMS: [M+H] + =390, Retention time (10mmol NH 4 HCO 3 )=2.49 minutes

[0398] Step 4 2-[4-[6-[(4-chloro-2-fluoro-phenyl) )Methoxy]-2-pyridyl]cyclohex-3-en-1-yl]acetate methyl ( A solution of Raney nickel (0.5 g, 5.84 μmol) was added to the solution. The reaction mixture was stirred at 20° C. for 2 h. LCMS showed the reaction was complete. The reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. Evaporate with ethyl acetate to obtain methyl 2-[4-[6-[(4-chloro-2-fluoro-phenyl)methacrylate [2-pyridyl]cyclohexyl]acetate (331 mg, 718 μmol, yield Yield 88.6%) as a white solid. LCMS: [M+H] + =392, retention time ( 0.01% TFA) = 2.42 min

[0399] Step 5 Methyl 2-[4-[6-[(4-chloro-2-fluoro- phenyl)methoxy]-2-pyridyl]cyclohexyl]acetate (330 mg, 716 A solution of lithium hydroxide hydrate (150.2 mg, The reaction mixture was stirred at 50° C. for 16 hours. 2-[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridin [cyclohexyl]acetic acid (180 mg, 453 μmol, 63.2% yield) was obtained as a bright yellow Obtained as an oil. LCMS: [M+H] + =378, retention time (0.01%TFA)= 2.20 minutes

[0400] Step 6 In DMF (1 mL), 2-[4-[6-[(4-chloro-2-fluoro-phenyl)methyl] [2-pyridyl]cyclohexyl]acetic acid (137 mg, 344 μmol), To a solution of 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoyl Zoate (81.38 mg, 344 μmol), 3-hydroxytriazolo[4,5-b ]pyridine (56.26 mg, 413 μmol), 3-(ethyliminomethyleneamino) -N,N-Dimethyl-propan-1-amine hydrochloride (79.24 mg, 413 μmol) The solution was stirred at 25° C. for 1 h. LCMS showed 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 Purify on silica gel to obtain tert-butyl 2-[[4-[6-[(4-chloro-2-fluoro )Methoxy]-2-pyridyl]cyclohexyl]methyl]-3-(phenyl) -[[(2S)-Oxetan-2-yl]methyl]benzimidazole-5-carboxy The rate (180 mg, 80.1% yield) was obtained as a colorless oil. LCMS: [M+H ] + =638, retention time (0.01%TFA)=2.41 minutes

[0401] Step 7 Acetic acid (3 mL) with tert-butyl 4-[[2-[4-[6-[(4-chloro-2-furan) Fluoro-phenyl)methoxy]-2-pyridyl]cyclohexyl]acetyl]amino]- 3-[[(2S)-Oxetan-2-yl]methylamino]benzoate (175 mg, The solution 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, yield 74. 7%) as a light yellow oil. LCMS: [M+H] + =620, retention time (0. 01% TFA) = 2.04 min

[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 1 l) was dissolved in dichloromethane (2 mL) and 2,2,2-trifluoroacetic acid (21.3 mg, 1 The reaction mixture was stirred at 25° C. for 0.5 h. LCMS showed that the reaction The reaction was shown to be complete. The solvent was completely removed. The residue was dissolved in saturated ammonium bicarbonate solution. The mixture was basified to pH=5 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) 1-(((S)-oxetan-2-yl)methyl)-1H-benzyl 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 1H NMR(400MHz,DMSO-D6)δ8.68(s,1H),8.20( s,1H),7.87(d,J=41.1Hz,2H),7.61(s,1H),7.4 7-7.16(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),1.6 8(d,J=67.4Hz,6H).

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

[0404] Step 1 4-Bromo-2-fluoroaniline (3.8 g, 20.00 mL) in ethanol (40 mL) CS was dissolved in a solution of 10 mmol. 2 (4.57 g, 60.00 mmol, 3.60 The reaction mixture was stirred for 10 min at 40° C. for 24 hours at 40° C. for 1 hour and then cooled to 37° C. The mixture was stirred at room temperature overnight, and the resulting precipitate was collected by filtration, washed with ice-cold ethanol, and dried. Drying gave a pale yellow solid which was carried on to the next step without further characterization or purification. Triphosgene (2.97 g, 10.00 mmol) was dissolved in DCM (5 The reaction mixture was slowly added to the solution of the above pale yellow solid in 0.0 mL of water. The mixture was stirred at rt for an additional hour and then heated at 40° C. for 4 hours, and the reaction was quenched with water. CH 2 Cl 2 (3×50 mL) and then MgSO 4 The residue was dried and concentrated at 40°C. was purified by flash column chromatography on silica gel, eluting with petroleum ether to give 4-Bromo-2-fluoro-1-isothiocyanato-benzene (3.6 g, 15.20 m mol, yield 76.0%). Retention time (0.01% TFA) = 2.26 min.

[0405] Step 2 4-Amino-3-[[(2S)-oxetan-2-yl]methylamine in DCM (2 mL) A suspension of tert-butylaminobenzoate (115 mg, 413 μmol) was added to the 4-Bromo-2-fluoro-1-isothiocyanatobenzene (108.4 mg, 467 μ mol), EDCI (89.5 mg, 467 μmol), and DIEA (60.3 mg, The reaction mixture was stirred at 40° C. until completion as indicated by TLC. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in CH 2 Cl 2 / M Purification by flash column chromatography on silica gel eluted with eOH (20:1) tert-Butyl (S)-2-((4-bromo-2-fluorophenyl)amino) -1-(Oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carbo The xylate (99 mg, 50.3% yield) was obtained as a pale yellow solid. LCMS: [M+ H] + =476, retention time (0.01%TFA)=2.05 minutes

[0406] Step 3 In anhydrous dioxane (0.5 mL) was added 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, 2 10 μmol), Pd(DPPF)Cl 2 and DCM complex (8.6 mg, 11 μmol The mixture was stirred at 80° C. for 16 hours. LCMS showed the reaction was complete. The reaction mixture was filtered through a pad of Celite with EtOAc and washed several times with ethyl acetate. The combined organics were concentrated in vacuo to give crude tert-butyl (S)-2-((2-phenyl)- Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl (phenyl)amino)-1-(oxetan-2-ylmethyl)-1H-benzo[d]i Midazole-6-carboxylate (109.9 mg, 209.9 mmol, 82% yield) ) was obtained as a black oil and used directly in the next step. LCMS: [M+H] + =5 24, retention time (0.01%TFA) = 2.10 minutes

[0407] Step 4 In dioxane (2 mL), tert-butyl (S)-2-((2-fluoro-4-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)a 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6- Carboxylate (110 mg, 210 μmol), 4-[(6-bromo-2-pyridyl )oxymethyl]-3-fluoro-benzonitrile (64.54 mg, 210 μmol) , Pd(DPPF)Cl 2 and DCM complex (8.6 mg, 11 μmol), and K 2 C O 3 (87.1 mg, 630 μmol) was mixed with N 2 Down, 80℃, 4pm The mixture was filtered and concentrated in vacuo to give the crude product, tert-butyl (S )-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2 -yl)-2-fluorophenyl)amino)-1-(oxetan-2-ylmethyl)-1 H-Benzo[d]imidazole-6-carboxylate (120 mg, 91.6% yield) was obtained as a black oil. LCMS: [M+H] + =624.1, retention time (0.01 % TFA) = 2.48 min

[0408] Step 5 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-carbo A solution of 2,2,2-tetraoxyl (100 mg, 160 μmol) was dissolved in 2,2,2-tetraoxyl Trifluoroacetic acid (91.4 mg, 801.7 μmol) was slowly added and the mixture was 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-fluoro (fluorophenyl)amino)-1-(oxetan-2-ylmethyl)-1H-benzo[d] Imidazole-6-carboxylic acid (27 mg, 29.7% yield) was obtained 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)pyridine -2-yl)-2-fluorophenoxy)-1-(oxetan-2-ylmethyl)-1H -Benz[d]imidazole-6-carboxylic acid (compound 321) [ka]

[0410] Step 1 Methyl 2-oxo-1,3-dihydrobenzimidazole-5-carboxylate(1 .6g, 8.33mmol) and phosphoryl trichloride (25.53g, 166.52mmol 15.47 mL) at 100° C. until the reaction was complete as indicated by LCMS. The mixture was stirred at rt for 3 h and the reaction mixture was concentrated in vacuo. The residue was cooled to 0° C. and diluted with cold NaHC O 3Saturated aqueous solution (30 mL) was carefully added. After stirring at room temperature for 15 min, the mixture was After sonication, the resulting residue was filtered to give the title compound, methyl 2-chloro-3H-benzenediamine. 1.3 g (67.5% yield) of 5-phenylenediimidazole-5-carboxylate was obtained, which was Used in next step without further purification. LCMS: [M+H] + =211. 1. Retention time (0.01%TFA) = 1.61 minutes

[0411] Step 2 2-Chloro-3H-benzimidazole-5-carboxylate methyl (1g, 4.3 2mmol), 4-bromo-2-fluoro-phenol (2.48g, 12.96mmol l, 1.42 mL) and N-ethyl-N-isopropyl-propan-2-amine (1.6 A mixture of 8 g, 12.96 mmol, 2.26 mL) was heated at 150° C. and analyzed by LCMS. The reaction was stirred for 3 h until completion was indicated, at which point the reaction mixture was concentrated in vacuo and purified by silica gel chromatography. Purification by chromatography (petroleum ether / EtOAc gradient 0-50%) gave the desired product. Methyl 2-(4-bromo-2-fluoro-phenoxy)-3H-benzimidazo L-5-carboxylate (700 mg, 36.8% yield) was obtained as a white solid. CMS:[M+H] + =365.0, retention time (0.01%TFA)=1.92 minutes

[0412] Step 3 In NMP (9 mL), methyl 2-(4-bromo-2-fluoro-phenoxy)-3H- Benzimidazole-5-carboxylate (843.4 mg, 1.92 mmol) and The mixture was mixed with dipotassium carbonate (397.4 mg, 2.88 mmol) at room temperature for 1 h. The mixture is then added with [(2S)-oxetan-2-yl]methyl 4-methylbenzene Add benzene sulphonate (696.7 mg, 2.88 mmol) and heat at 80°C for 16 h. The mixture was purified by preparative HPLC to give (Product 1) methyl 2-(4-bromophenyl bromo-2-fluoro-phenoxy)-3-[[(2S)-oxetan-2-yl]methyl ] Benzimidazole-5-carboxylate (4) (135 mg, 307 μmol, yield (Product 2) Methyl 2-(4-bromophenyl)propanediol (16.0%) (NBK0059-76-P2) and (Product 3) Methyl 2-(4-bromophenyl)propanediol (16.0%). bromo-2-fluoro-phenoxy)-1-[[(2S)-oxetan-2-yl]methyl ] benzimidazole-5-carboxylate (5) (150 mg, 17.6% yield) NBK0059-76-P1) was obtained. Product 1: LCMS: [M+H] + =437.1 , retention time (0.01%TFA)=1.91 min Product 2:LCMS:[M+H] + =4 37.1; Retention time (0.01%TFA)=1.89 minutes

[0413] Step 4 In dioxane (2 mL), methyl 2-(4-bromo-2-fluoro-phenoxy)-3 -[[(2S)-Oxetan-2-yl]methyl]benzimidazole-5-carboxy Rate (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 -Dioxaneborolane (49.6 mg, 195 μmol), potassium acetate (38.3 mg , 391 μmol), and cyclopentyl(diphenyl)phosphane·dichloromethane· The mixture was mixed with dichloropalladium iron (16.0 mg, 20 μmol) and analyzed by LCMS. The reaction mixture was stirred at 90° C. for 2 hours until completion, as indicated by the addition of 100 mL of 100 mL of 100% ethanol. Used in the next step. LCMS: [M+H] + =483.3, retention time=2.1 1 min (hydrolyzed corresponding boronic acid [M+H] + =401.2, retention time=1.63 minutes were also observed).

[0414] Step 5 Sodium carbonate (62.0 mg, 585 μmol) (2 M in water) and cyclopentyl ( Diphenyl)phosphane dichloromethane dichloropalladium iron (15.92 mg, 2 0 μmol) 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 silane and the mixture was stirred at 90° C. for 2 h until the reaction was complete as indicated by LCMS. After stirring for 1 h, the reaction mixture was filtered through a pad of Celite with the aid of EtOAc. The material was concentrated in vacuo and purified by 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 The ester (110 mg, yield 88.2%) was obtained. LCMS: [M+H] + =583.2, Retention time (10mM NH 4 HCO 3 )=2.12 minutes

[0415] Step 6 Methyl 2-[4-[6-[(4-cyano-2-fluorophenyl) )Methoxy]-2-pyridyl]-2-fluoro-phenoxy]-3-[[(2S)-oxy 100 mg of 5-methyl-2-phenyl-1,2-diphenyl-1,2-diphenyl-2,3-dimethyl-1,2-dimethyl-2,4 ... A stirred solution of 156 μmol of lithium hydroxide hydrate (0.5 M) (65.6 The reaction mixture was stirred at 30° C. for 16 hours and LCMS showed When the reaction was deemed complete, the mixture was acidified with HOAc to about pH 6 and separated. Purification by HPLC gave (S)-2-(4-(6-((4-cyano-2-fluorobenzyl )oxy)pyridin-2-yl)-2-fluorophenoxy)-1-(oxetane-2- ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (34.2 mg, 60 mol, 38.5% yield) was obtained as a white solid. LCMS: [M+H] + =669 .2 1 H NMR(400MHz,DMSO-D6)δ8.20(d,J=1.2Hz,1 H),8.11(dd,J=12.1,2.0Hz,1H),8.01(d,J=8.4 Hz,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),5.6 4(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'-oxy So-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-7-fluoro-1- (Oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid ( Compound 322) [ka]

[0417] Step 1 In acetonitrile (5 mL), 4-amino-2-fluoro-3-[[(2S)-oxo Ethyl 2-methyl-2-methylaminobenzoate (500 mg, 1.77 mmol), -Chloro-1,1,1-trimethoxy-ethane (288.1 mg, 1.77 mmol) The solution was diluted with 4-methylbenzenesulfonic acid hydrate (33.7 mg, 177 The reaction mixture was stirred at 60° C. for 1.5 h. LCMS showed that the reaction was complete. Silica gel (1 g) was added to the reaction mixture, and the mixture was evaporated under reduced pressure. Evaporation gave a dry powder, which was purified on silica gel to give ethyl (S)-2-(chloromethyl) (1H-benzo[d]imidazo[3-yl]phenyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazo[3-yl]phenyl The zole-6-carboxylate (600 mg, 98.5% yield) was obtained as a white solid. LCMS: [M+H] + =327, retention time (10mM NH 4 HCO 3 )=1.98 minutes

[0418] Step 2 In DMF (3 mL), 4-bromo-1H-pyridin-2-one (124.7 mg, 71 7 μmol), ethyl 2-(chloromethyl)-4-fluoro-3-[[(2S)-oxo Tan-2-yl]methyl]benzimidazole-5-carboxylate (239 mg, 7 A mixture of 17 μmol) and cesium carbonate (233.6 mg, 717 μmol) was The mixture was stirred at 25° C. for 2 hours. LCMS showed the reaction was complete. The mixture was diluted with ammonium chloride solution and extracted with ethyl acetate (3×4 mL). The layer was washed with brine (3×4 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc gradient 50% to 100%). ) to obtain ethyl (S)-2-(chloromethyl)-7-fluoro-1-(oxopropyl) Tan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (3 20 mg, 91.3% yield) was obtained as a light yellow gum. LCMS: [M+H] + =46 4 retention times (10mM NH 4 HCO 3 )=1.96 minutes

[0419] Step 3 In dioxane (5 mL), ethyl (S)-2-(chloromethyl)-7-fluoro -1-(Oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carbo xylate (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 m g, 1.23 mmol), bis(triphenylphosphine)palladium(II) chloride The mixture (28.7 mg, 41 μmol) was loaded into a glove box under nitrogen. The reaction mixture was stirred at 80° C. for 4 h. LCMS showed the reaction was complete and the reaction mixture was Cool and add 4-[(6-bromo-2-pyridyl)oxymethyl]-3-fluoro - Benzonitrile (132.3 mg, 409 μmol), dipotassium carbonate (169.7 m g, 1.23 mmol), Pd(dppf)Cl 2 (29.9 mg, 41 μmol) was added. The reaction mixture was bubbled with nitrogen for 2 minutes. The resulting mixture was stirred at 80° C. for 16 hours. LCMS showed the reaction was complete. The reaction mixture was washed with silica gel (2 g). The solvent was removed under reduced pressure to obtain a dry powder, which was then separated by silica gel (eluent: petroleum ether / Purify with ethyl (S)-2-((6-((4-cyano) Ano-2-fluorobenzyl)oxy)-2'-oxo-[2,4'-bipyridine]-1 '(2'H)-yl)methyl)-7-fluoro-1-(oxetan-2-ylmethyl)- 1H-Benzo[d]imidazole-6-carboxylate (220 mg, 323.7 μm ol, 79.1% yield, 90% purity) was obtained as a white solid. LCMS: [M+H] + =612, retention time (10mM NH 4 HCO 3 )=1.98 minutes

[0420] Step 4 Ethyl (S)-2-((6-((4-cyano-2-fluorobenzene) (2,4'-bipyridine)-1'(2'H)-yl)methyl (1H-benzo[d]imidazo[3-yl]phenyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazo[3-yl]phenyl A solution of 220 mg of 6-carboxylate (324 μmol) was added to water ( 8 mL) dissolved in lithium hydroxide hydrate (67.9 mg, 1.62 mmol) LCMS showed the reaction was complete. The reaction mixture was stirred until pH=5. The mixture was acidified with acetic acid at rt. Tetrahydrofuran was removed under reduced pressure. The aqueous phase was washed with ethyl acetate (3× The combined organic layers were dried and evaporated under reduced pressure to give a residue which was This was purified by preparative HPLC to give (S)-2-((6-((4-cyano-2-fluorophenyl)benzene. (2'H)-yl)methyl)-2'-oxo-[2,4'-bipyridine]-1'(2'H)-yl)methyl 7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imide Dazole-6-carboxylic acid (95.5 mg, yield 49.0%) was obtained. 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,1 H),4.58-4.46(m,1H),4.40(dd,J=6.1,2.9Hz,1 H),2.86-2.70(m,1H),2.44(d,J=9.1Hz,1H).

[0421] (S)-2-((6-((4-chloro-2-fluorobenzyl)oxy)-2'-oxy So-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-1-(oxetane 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, 1H), 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'-oxy So-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-3-(oxetane 2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 3 twenty four) [ka] Prepared in a similar manner to compound 322. LCMS: [M+H] + =567.0, retention time= 1.40 minutes 1 H 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,2 H), 6.97-6.94(dd,J 1 =7.2Hz,J 2 =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-carboxylate 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,1 H),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= 16.1Hz,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),4.5 0(dd,J=13.8,7.6Hz,1H),4.36(dt,J=8.9,6.0H z,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 In DCM (50 mL), 3,4-dihydro-2H-pyran (327.19 mg, 3.8 9mmol), methyl 3-iodo-3a,7a-dihydro-1H-indazole-5-carboxylate Carboxylate (1.18 g, 3.89 mmol), 4-methylbenzenesulfonyl The mixture was analyzed by LCMS using 100% ethyl acetate (739.9 mg, 3.89 mmol). Continue stirring until the reaction is complete. 2 The mixture was stirred at 30° C. for 12 hours, and the reaction mixture was poured into water. Extract with EtOAc, concentrate the combined organics in vacuo, and purify using silica gel chromatography ( Purification with hexane / EtOAc (10:1) gave the desired product, methyl 3-iodo- 1-Tetrahydropyran-2-yl-3a,7a-dihydroindazole-5-carboxylate The sylate (0.9 g, 59.6% yield) was obtained as a pale yellow solid. LCMS: [M+H ] + =387, retention time=2.00 minutes

[0426] Step 2 2-Allyl-4,4,5,5-tetramethylphenyl in water (1 mL) and dioxane (4 mL) 1,3,2-dioxaborolane (300 mg, 1.79 mmol), methyl 3-iodo Do-1-tetrahydropyran-2-yl-indazole-5-carboxylate (300 mg, 777 μmol), Pd(dppf)Cl 2 (10 mg), and sodium carbonate ( The mixture was mixed with N 2 Stir at 100℃ for 2 hours. The reaction mixture was stirred and monitored by LCMS. The reaction mixture was washed with EtOAc on Celite. The combined organics were concentrated in vacuo and purified by silica gel chromatography. The desired product, methyl 3, was obtained by purifying the product by chromatography (hexane / EtOAc 10:1). -Allyl-1-tetrahydropyran-2-yl-indazole-5-carboxylate ( Obtained 170 mg, 72.9% yield) as a pale yellow solid. LCMS: [M+H] + =3 01, retention time = 2.14 minutes

[0427] Step 3 In DCM (20 mL) was added 3-chlorobenzenecarboperoxoic acid (2.76 g, 15. 98mmol), methyl 3-allyl-1-tetrahydropyran-2-yl-indazole The mixture was mixed with 1,000 mL of ... The reaction mixture was stirred at 20° C. for 16 hours and monitored by LCMS. The combined organics were concentrated in vacuo and purified by filtration through a pad of Celite using silica gel chromatography. Purification by chromatography (hexane / EtOAc 5:1) afforded the desired product, methyl 3-(oxiran-2-ylmethyl)-1-tetrahydropyran-2-yl-indazoline The resulting mixture was concentrated to give 1.4 g (55.4% yield) of aryl-5-carboxylate as a pale yellow solid. LCMS: [M+H] + =317, retention time=1.78 minutes

[0428] Step 4 In t-BuOH (50 mL), BLAH methane iodide (3.48 g, 15.81 mm ol), potassium 2-methylpropane-2-oleate (1.77 g, 15.81 mmol) ), and methyl 3-(oxiran-2-ylmethyl)-1-tetrahydropyran-2-yl Indazole-5-carboxylate (500 mg, 1.58 mmol, 280.3 A mixture of copper chloride (21.3 mg, 158 μmol) and copper chloride (21.3 mg, 158 μmol) was heated at 80°C. The reaction was stirred in an oil bath for 2 hours and monitored by LCMS. The reaction mixture was adjusted to pH 5. = 1, and the aqueous layer was extracted with DCM and 2 SO 4 Dry, concentrate and prep HPLC The desired product, 3-(oxetan-2-ylmethyl)-1-tetrahydrofuran, was obtained by purification using Ropyran-2-yl-indazole-5-carboxylic acid (200 mg, 24.0% yield) Obtained as a pale yellow solid. LCMS: [M+H] + =317, retention time=1.47 minutes

[0429] Step 5 In DMF (5 mL), 3-(oxetan-2-ylmethyl)-1-tetrahydropyran -2-yl-indazole-5-carboxylic acid (30 mg, 94.8 μmol), iodomethane tannin (14.8 mg, 104.3 μmol, 6.5 μL, 100% purity) and mixture Potassium carboxylate (39.3 mg, 284.5 μmol, 17.2 μL, purity 1 The mixture was stirred in a round bottom flask under N2 until the reaction was complete as shown by LCMS. The reaction mixture was stirred at 25 °C for 1 h in a razor and then purified by elution with EtOAc on a pad of Celite. After filtration, 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, yield 50.4%, purity 71.8%) as a colorless oil. LCMS [M+H] + =33 1.1, retention time (0.01%TFA) = 1.82 minutes

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

[0431] Step 7 Methyl 3-(oxetan-2-ylmethyl)-1H-indazoline in DMF (10 mL) 4-bromo-1-(bromo) (108.8 mg, 406 μmol)-2-fluorobenzene, and potassium carbonate. The mixture was heated in an oil bath at 60 °C. The reaction was stirred for 2 h and monitored by LCMS. The reaction mixture was washed with EtOAc to give a column of 100 mL of ethyl acetate. The combined organics were concentrated in vacuo and purified by silica gel chromatography ( Purification with hexane / EtOAc (5:1) gave the desired product, methyl 1-[(4-bromophenyl)- bromo-2-fluoro-phenyl)methyl-3-(oxetan-2-ylmethyl)indane The sol-5-carboxylate (80 mg, 45.5% yield) was obtained as a pale yellow liquid. LCMS: [M+H] + =433, retention time=1.47 minutes

[0432] Step 8 In THF (10 mL), 2-bromo-6-[(4-chloro-2-fluoro-phenyl) Methoxy]pyridine (1.6 g, 5.05 mmol), butyllithium (356.14 m g, 5.56 mmol, 2.5 mL), and tributyl(chloro)stannane (1.97 g, 6.07 mmol, 1.65 mL) was mixed with N 2 16 hours at 30℃ The reaction mixture was stirred and monitored by LCMS. 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 / Et OAc=10:1) to give the desired product, tributyl-[6-[(4-chlorophenyl)- )-2-Fluoro-phenyl)methoxy]-2-pyridyl]stannane (300 mg, yield The product was obtained as a pale yellow solid (yield 18.8%). LCMS: [M+H] + =528, retention time =2.14 minutes

[0433] Step 9 In DMF (1 mL), 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) (50 mg, 115 μmol) indazole-5-carboxylate and Pd(P Ph 3 ) 4 (115 μmol) was mixed with N 2 The mixture was stirred at 130°C for 2 hours. The reaction mixture was monitored by LCMS. The reaction mixture was padded with EtOAc onto Celite. The combined organics were concentrated in vacuo and purified by silica gel chromatography (hexanes / EtOAc=2:1) ​​to give the desired product, methyl 2-[[4-[6-[( 4-Chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro- phenylmethyl]-3-(oxetan-2-ylmethyl)indazole-5-carboxy The leut (50 mg, 73.4% yield) was obtained as a pale yellow solid. LCMS: [M+H] + =590, retention time=1.99 minutes

[0434] Step 10 In THF (2 mL), methanol (2 mL) and water (2 mL), methyl 2-[[4-[ 6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro [O-phenyl]methyl]-3-(oxetan-2-ylmethyl)indazole-5-carboxylate Carboxylate (50 mg, 84.7 μmol), lithium hydroxide hydrate (400 mg, 9.53 mmol) was mixed with N 2 The reaction mixture was stirred for 2 h at 25 °C under The reaction mixture was monitored by LCMS. LCMS shows good results. The reaction mixture was diluted with HCl to pH= 1, extracted with DCM, the combined organics were concentrated in vacuo and purified by preparative HPLC. After that, the desired product, 1-[[4-[6-[(4-chloro-2-fluoro- phenyl)methoxy]-2-pyridyl]-2-fluoro-phenyl]methyl]-3-(oxy cetan-2-ylmethyl)indazole-5-carboxylic acid (20.3 mg, 35 μmol LCMS: [M+H] + =576, retention time=1.50 minutes 1 H NMR (400 MHz, CDCl 3 ) δ8.66(s,1H),8.13(dd d,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),4.7 4-4.61(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 1'(2'H)-yl)methyl)-3-(oxazole -4-ylmethyl)imidazo[1,2-a]pyridine-6-carboxylic acid (compound 327) [ka]

[0436] Step 1 In ethanol (400 mL) was added 6-aminopyridine-3-carboxylate (17.6 2g, 115.81mmol), 1,3-dibromopropan-2-one (25g, 115 The mixture was stirred with N until the reaction was complete as shown by LCMS. 2 The reaction mixture was stirred at 80 °C for 12 h under reduced pressure and then added NaHCO 3 Add EtOAc and eluate. Filter through a pad of light, concentrate the combined organics in vacuo, and chromatograph on silica gel. The desired product, methyl 2-(bromophenyl)acetate, was obtained by purification with hexane:EtOAc 12:1. bromomethyl)imidazo[1,2-a]pyridine-6-carboxylate (5.2 g, yield 16.7%) as a pale yellow solid. LCMS: [M+H] + =269.0, when held Interval (0.01% TFA) = 0.99 min

[0437] Step 2 In DMF (150 mL), 2-(bromomethyl)imidazo[1,2-a]pyridine-6 -carboxylate (6.9 g, 25.64 mmol) and potassium acetate (7.55 g, The reaction was confirmed to be complete by LCMS. N until indicated 2The reaction mixture was stirred at 50° C. for 2 hours under reduced pressure, and then diluted with EtOAc to give a cellophane. The combined organics were concentrated in vacuo and purified by silica gel chromatography ( Purification with hexane / EtOAc (5:1) gave the desired product, methyl 2-(acetoxy) (dimethyl)imidazo[1,2-a]pyridine-6-carboxylate (5.8 g, yield 9 1.1%) as a pale yellow solid LCMS: [M+H] + =249.1, retention time ( 0.01% TFA) = 0.95 min

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

[0439] Step 4 Methyl 2-(acetoxymethyl)-3-formyl-imidazolium chloride in MeOH (50 mL) [1,2-a]pyridine-6-carboxylate (2.4 g, 8.69 mmol) and charcoal The mixture was mixed with potassium phosphate (1.80 g, 13.03 mmol) and analyzed by LCMS. Continue stirring until the reaction is complete. 2 The reaction mixture was stirred at room temperature for 1.5 hours under reduced pressure, and then diluted with DCM. The combined organics were concentrated in vacuo and subjected to silica gel chromatography. The desired product, methyl 3-hydroxybenzoate, was obtained by elution with hexane / EtOAc (2:1). 2-(hydroxymethyl)imidazo[1,2-a]pyridine-6-carboxylate The ester (2.1 g, 87.7% yield) was obtained as a pale yellow solid. LCMS: [M+H] + =235.1, retention time (0.01%TFA)=1.08 minutes

[0440] Step 5 In DMF (40 mL), 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 m A mixture of imidazole (1.83 g, 26.90 mmol) and LC Continue stirring until the reaction is complete as indicated by MS. 2 The reaction mixture was stirred at room temperature for 2 h under Filter through a pad of Celite with OAc and concentrate the combined organics in vacuo and rinse with silica gel. Purification by column chromatography (hexane / EtOAc 8:1) gave the desired product. 2-[[tert-Butyl(diphenyl)silyl]oxymethyl]-3-formyl-imide Dazo[1,2-a]pyridine-6-carboxylate methyl (5.8 g, yield 89.0%) ) was obtained as a pale yellow solid. LCMS: [M+H] + =473.0, retention time (0.0 1% TFA) = 2.36 min

[0441] Step 6 In THF (30 mL), oxazole (1.46 g, 21.16 mmol), butyl riboflavin (1.0 g, 21.16 mmol) The mixture was mixed with 1.08 g of N 2 Bottom, -78℃ 0 Stir for 0.5 h, then add methyl 2-[[tert-butyl(diphenyl))silyl]oxy Dimethyl]-3-formyl-imidazo[1,2-a]pyridine-6-carboxylate ( 1 g, 2.12 mmol) was added and the resulting mixture was cooled to room temperature until the reaction was complete as indicated by LCMS. Until then, N 2 The reaction mixture was stirred at −78° C. for 2 hours. Filter through a pad of Celite, concentrate the combined organics in vacuo, and purify by preparative HPLC. The desired product, methyl 2-[[tert-butyl(diphenyl)silyl]oxymethyl ethyl]-3-(oxazol-4-ylmethyl)imidazole[1,2-a]pyridine- The 6-carboxylate (500 mg, 45.0% yield) was obtained as a pale white solid. LC MS: [M+H] + =542.0, retention time (0.01%TFA)=1.75 minutes

[0442] Step 7 Methyl 2-[[tert-butyl(diphenyl)silyl]oxy]- Dimethyl]-3-[hydroxy(oxazol-4-yl)methyl]imidazole [1, 2-a]pyridine-6-carboxylate (800 mg, 1.48 mmol), triethyl The mixture was mixed with ruthenium (1.72 g, 14.77 mmol, 2.36 mL) and purified by LC Continue stirring until the reaction is complete as indicated by MS. 2 The reaction mixture was stirred at 65° C. for 16 hours. Concentrate and add NaHCO 3 The resulting residue was dissolved in DCM and mixed with MeO H and the combined organics were concentrated in vacuo to give the desired product. The compound methyl 2-(hydroxymethyl)-3-(oxazol-4-ylmethyl)imide Dazo[1,2-a]pyridine-6-carboxylate (105 mg, 24.8% yield) Obtained as a pale yellow oil. LCMS: [M+H] + =288.0, retention time=1.30 minutes

[0443] Step 8 A solution of methyl 2-(hydroxymethyl)-3-(oxazole-4) in DCM (10 mL) -ylmethyl)imidazo[1,2-a]pyridine-6-carboxylate (30 mg, 1 A stirred solution of methanesulfonic anhydride (21.04 μmol) was added to the reaction solution. 8 mg, 125 μmol) and TEA (31.7 mg, 313 μmol) were added to the reaction mixture. The mixture was stirred at room temperature for 3 h, and when the reaction was judged complete by TLC, the mixture was diluted with DCM ( The layers were separated and the aqueous layer was diluted with DMC (2×50 mL). The combined organic phase was washed with brine (50 mL) and extracted with anhydrous Na 2 SO 4 Dry with The mixture was then filtered and concentrated in vacuo to give methyl 2-(methylfonyloxymethyl) -3-(Oxazol-4-ylmethyl)imidazole[1,2-a]pyridine-6-carboxylate The carboxylate (30 mg, 51.5% yield) was obtained as a light yellow liquid. LCMS: M+H] + =366.0, retention time (10mM NH 4 HCO 3 )=1.38 minutes

[0444] Step 9 In 1,4-dioxane (12 mL), methyl 2-(bromomethyl)-3-(oxazolidinediamine) (1-4-ylmethyl)imidazole[1,2-a]pyridine-6-carboxylate (1 15.0 mg, 49 μmol), 2-[(4-chloro-2-fluoro-phenyl)meth 1,2,3,6-tetrahydropyridin-4-yl)pyridine (18.8m g, 59 μmol), N-ethyl-N-isopropyl-propan-2-amine (31.8 mg, 246 μmol) until the reaction was complete as indicated by LCMS. , N 2 The mixture was stirred at 95° C. for 1.5 hours under reduced pressure. The reaction mixture was filtered through Celite with EtOAc. 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)imidazoline Zo[1,2-a]pyridine-6-carboxylate (10 mg, 34.5% yield) was dissolved in a pale yellow solution. Obtained as a colored oil. LCMS: [M+H] + =588.0, retention time (0.01%T FA) = 2.12 minutes

[0445] Step 10 MeOH (1 mL), H 2 In a mixture of 2-(4-(2-methyl-2-phenylindole)-2-(2,4-dimethylphenyl)-2,4-dimethyl-1,5-dimethyl-2,5-dimethyl-1,6 ... [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 μm A mixture of 1.2 mg (51 μmol) and lithium hydroxide was analyzed by LCMS. Continue until the reaction is complete. 2 The reaction mixture was stirred at room temperature for 2 hours under 50° C. The reaction mixture was diluted with EtOAc. Filter through a pad of Celite and concentrate the combined organics in vacuo using preparative HPLC. 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) was obtained as a pale 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(ddd,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-(o Xetan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)boronic acid ( Compound 328) [ka]

[0447] Step 1 In DMF (50 mL) was added 4-bromo-2-fluoro-1-nitrobenzene (2 g, 9. 09 mmol), 4-methylbenzenesulfonic acid, [(2S)-oxetane-2 -yl]methanamine (2.36 g, 9.09 mmol), N,N-diethylethaneamine The reaction was confirmed to be complete by LCMS. N until 2 The reaction mixture was stirred at 60° C. for 2 hours under reduced pressure. Filter through a pad of light, concentrate the combined organics in vacuo, and chromatograph on silica gel. The desired product, 5-bromo-2-nitro-N-[[(2S)-oxo- Tan-2-yl]methyl]aniline (2.42 g, 7.58 mmol, 83.4% yield, (89.8%) as a yellow solid. LCMS: [M+H] + =289.0, hold Time (0.01% TFA) = 1.72 min

[0448] Step 2 In ethanol (16 mL) and water (4 mL), 5-bromo-2-nitro-N-[[(2 S)-Oxetan-2-yl]methyl]aniline (2.42 g, 8.44 mmol), iron (3.77 g, 67.54 mmol) and ammonium hydrochloride (3.61 g, 67.54 mmol) ol) was added to N until the reaction was complete as shown by LCMS. 2 Bottom, RBF The reaction mixture was stirred at 80° C. for 1.5 hours. The reaction mixture was filtered through a pad of Celite with EtOAc. After filtration, the combined organics were concentrated in vacuo and purified by silica gel chromatography to give The desired product, 4-bromo-N2-[[(2S)-oxetan-2-yl]methyl]benzene, Benzene-1,2-diamine (1.44 g, 5.56 mmol, yield 65.8%, purity 99 0.5%) as a brown oil. LCMS: [M+H] + =259.1, retention time ( 0.01% TFA) = 1.16 min

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

[0450] Step 4 In dioxane (20 mL), 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) l) and sodium iodide dihydrate (28.8 mg, 158.4 μmol) were mixed. The mixture was cooled to room temperature with N until the reaction was complete as shown by LCMS. 2 Bottom, in RBF, 16 at 90℃ The reaction mixture was stirred for 1 h, filtered through a pad of Celite with EtOAc, and the combined organic layer was The material was 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]be 2H-Pyridin-4-yl]methyl-3,6-dihydro-2H-pyridin-4-yl ]-2-pyridyl]oxymethyl]-3-fluoro-benzonitrile (800 mg, 86 9.65 μmol, 54.9% yield) was obtained as a white solid. LCMS: [M+H] + =588.0, retention time (10mM NH 4 HCO 3 )=1.82 minutes

[0451] Step 5 In ethanol (3 mL) and ethylene glycol (0.15 mL), 4-[[6-[1 -[[6-Bromo-1-[[(2S)-oxetan-2-yl]methyl]benzimidazo 2-pyridinyl]methyl]-3,6-dihydro-2H-pyridin-4-yl]-2-pyridinyl Dimethyl]oxymethyl]-3-fluoro-benzonitrile (20 mg, 33.99 μmol ) and hypoboric acid (9.1 mg, 102 μmol), dicyclohexyl-[2-(2,4 ,6-triisopropylphenyl)phenyl]phosphane (0.3 mg, 0.7 μmol ), XPhos Pd G 3 (0.3 mg, 0.34 μmol), potassium acetate (20 m g, 203.9 μmol) was dissolved and the mixture was stirred at 60° C. for 3 hours. The product was purified by HPLC to give the desired product, [2-[[4-[6-[(4-cyano-2 -Fluoro-phenyl)methoxy]-2-pyridyl]-3,6-dihydro-2H-pyridyl 3-[[(2S)-oxetan-2-yl]methyl]benzyl [midazol-5-yl]boronic acid (2 mg, 2.7 μmol, 8.0% yield) was obtained as a white solid. LCMS: [M+H...

Claims

1. A compound represented by structural formula (I): 【Chemistry 1】 During the ceremony, 【Chemistry 2】 represents a single bond or a 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 N.R. ５’ is selected from Ring B is a 6-membered heteroaryl, a 6-membered monocyclic heterocyclyl, or a phenyl; Y １ is N, NH, CH, and CH ２ is selected from 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, optionally a carboxylic acid group surrogate teeth, 【Chemistry 3】 R ａ and R ｂ are hydrogen, deuterium, halogen, -CN, and C, respectively. １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, NR ５ 'R ６ ', 6- to 10-membered aryl, 5- to 8-membered heteroaryl alkyl, 3- to 8-membered saturated or partially saturated cycloalkyl, and 3- to 8-membered saturated or partially saturated hexaaryl. R is independently selected from tetracyclyl, ａ / R ｂ C represented by １ ~C ６ Alkyl or is C １ ~C ６ Alkoxy includes halogen, oxo, CN, OH, and C ３ ~C ６ Saturation or part partially saturated cycloalkyl, where R ａ / R ｂ or R ａ / R ｂ Aryl, heteroaryl, etc., in the group represented by , saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl is Gen, oxo (if necessary), 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 and R ｄ are hydrogen, deuterium, halogen, -CN, and C, respectively. １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, NR ５’ R ６’ , 6- to 10-membered aryl, 5- to 8-membered heteroaryl alkyl, 3- to 8-membered saturated or partially saturated cycloalkyl, and 3- to 8-membered saturated or partially saturated heptyl. and independently selected from the group consisting of cyclocyclyl, ｃ / R ｄ 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, wherein R ｃ / R ｄ or R ｃ / R ｄ In the group represented by the formula: saturated or partially saturated cycloalkyl or saturated or partially saturated heterocyclyl is , oxo (optionally), CN, and NR ５’ R ６’ is substituted with one or more groups selected from It may be replaced, Each R １ is H, deuterium, halogen, -CN, OH, C １ ~C ６ Alkyl, C １ ~C ６ a Lukoxi, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, NR ５’ R ６’ , 6-10 members aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, and 3-8 membered saturated or partially saturated heterocyclyl, １ Represented by C 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, C F ３ , O.H., O.C.H. ３ , O.C.H. ２ CH ３ and may be substituted with one or more groups selected from may be substituted with one or more groups selected from １ Is it expressed as , R １ In the group represented by the formula: alkyl, or saturated or partially saturated heterocyclyl is optionally substituted with halogen, oxo (as appropriate); ), C.N., O.H., C. １ ~C ３ Alkyl (F, OH and OCH ３ 1 to 3 selected from and C １ ~C ３ Alkoxy (F, OH and OCH ３ from and NR ５’ R ６’ Selected from and may be substituted with one or more groups selected from the group consisting of Each R ２ is H, deuterium, halogen, -CN, OH, oxo, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, NR ５’ R ６’ , 6-10 membered aryl, 5-8 membered heteroaryl , 3- to 8-membered saturated or partially saturated cycloalkyl and 3- to 8-membered saturated or partially saturated heterocyclic wherein R is independently selected from the group consisting of aryl, ２ C represented by １ ~C ６ Alkyl, C １ ~C ６ a Alkoxy is halogen, oxo, CN, CF ３ , O.H., O.C.H. ３ , O.C.H. ２ CH ３ And tiredness sum or partial saturation C ３ ~C ６ Cycloalkyl (halogen, oxo, CN, CF ３ , O.H., O. CH ３ , O.C.H. ２ CH ３ and optionally substituted with one or more groups selected from wherein R ２ Is expressed as R ２ Represented by Among the groups listed above are aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl is selected from halogen, oxo (optionally), CN, O H.C. １ ~C ３ Alkyl (F, OH and OCH ３ Substituted with 1 to 3 groups selected from may be present), and C １ ~C ３ Alkoxy (F, OH and OCH ３ One selected from , and NR ５’ R ６’ One or more selected from and optionally substituted with a group Each R ３ is H, deuterium, halogen, -CN, OH, oxo, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, NR ５’ R ６’ , 6- to 10-membered aryl , 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered wherein R is independently selected from saturated or partially saturated heterocyclyl ３ C represented by １ ~ C ６ Alkyl or C １ ~C ６ Alkoxy is halogen, oxo, CN, CF ３ , O.H., O. CH ３ , O.C.H. ２ CH ３ and saturated or partially saturated C ３ ~C ６ Cycloalkyl (halogen, o K.S., CN, CF ３ , O.H., O.C.H. ３ , O.C.H. ２ CH ３ is substituted with one or more groups selected from and optionally substituted with one or more groups selected from ３ Is expressed as R ３ In the group represented by Partially saturated cycloalkyl or saturated or partially saturated heterocyclyl is substituted with halogen, oxy, SO (as needed), CN, OH, C １ ~C ３ Alkyl (F, OH and OCH ３ Choose from and C １ ~C ３ Alkoxy (F, OH and O.C.H. ３ and NR ５’ R ６’ may be 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 a rucoxyl, or NR ５’ R ６’ Independently selected from the following: ４ C represented by １ ~C ６ Alkyl and C １ ~C ６ Alkoxy includes halogen, oxo, CN, CF3, and saturated or Partial saturation 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 may be substituted with one or more groups; R ５ and R ６ are hydrogen, deuterium, halogen, CN, OH, and C, respectively. １ ~C ６ Alki Lu, C １ ~C ６ Alkoxy, NR ５’ R ６’ , 6-10 membered aryl, 5-8 membered hetero Aryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein R ５ Or R ６ C represented by １ ~C ６ Alki Ru or C １ ~C ６ Alkoxy is halogen, oxo, CN, CF ３ , O.H., O.C.H. ３ , O CH ２ CH ３ and saturated or partially saturated C ３ ~C ６ Cycloalkyl (halogen, oxo, CN , C.F. ３ , O.H., O.C.H. ３ , O.C.H. ２ CH ３ is substituted with one or more groups selected from may be substituted with one or more groups selected from ５ Or R ６ or R ５ Or R ６ Among the groups represented by the formula: Partially saturated cycloalkyl or saturated or partially saturated heterocyclyl is substituted with halogen, oxy, SO (as needed), CN, OH, C １ ~C ３ Alkyl (F, OH and OCH ３ Choose from and C １ ~C ３ Alkoxy (F, OH and O.C.H. ３ and NR ５’ R ６’ may be substituted with one or more groups selected from R ５’ and R ６’ are each independently hydrogen and C １ ~C ６ Selected from 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’ also is R ６ Any of the following: R ａ and R ５ R (in the group represented by W) ５’ Or R ６ brain Either one of the following; R ２ and R ５ R (in the group represented by W) ５’ Or R ６ Any of KA;R ５ and R ６ ;R ｃ , R ｄ , R ｅ and R ｆ any two groups selected from: R ４ And R ｃ , R ｄ , R ｅ and R ｆ Any one of the intervening carbon atoms or together with the heteroatom, phenyl, 5- to 6-membered heteroaryl, 4- to 8-membered saturated or partially saturated cycloalkyl or 4- to 8-membered saturated or partially saturated heterocyclyl; These may be halogen, —CN, —OH, and CF ３ , C １ ~C ６ Alki Lu, C １ ~C ６ Alkoxy, -NH ２ , -NHC １ ~C ６ Alkyl, -N(C １ ~C ６ a Rukill) ２ , oxo, and saturated or partially saturated C ３ ~C ６ 1 selected from cycloalkyl may be substituted with one or more groups, where C １ ~C ６ Alkyl and C １ ~C ６ Arco Xy is halogen, oxo, CN, CF ３ , O.H., O.C.H. ３ , O.C.H. ２ CH ３ , and saturation or partially saturated C ３ ~C ６ cycloalkyl, Preferably, cycloalkyl is halogen, oxo, CN, CF ３ , O.H., O.C.H. ３ , OCH ２ CH ３ may be substituted with one or more groups selected from 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; A physiologically acceptable salt, stereoisomer, solvate, or hydrate.

2. The compound is 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; Medium, X １ , X ２ , X ３ , X ４ and X ５ Of these, up to three are N, and ring A has three consecutive does not contain three nitrogen ring atoms at the position 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 up to three nitrogen rings. atom, 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 Up to four of these are from N, O, and S. A compound according to claim 1 or a pharma- ceutically acceptable salt or stereoisomer thereof. , solvates, or hydrates.

3. W is O, NH, or CH ２ and R ａ is H, CH ３ , or C.F. ３ and R ｂ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, NR ５’ R ６’ , 6~1 0-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered saturated or partially saturated cycloalkyl and 3- to 7-membered saturated or partially saturated heterocyclyl, where R ｂ Represented by RuC １ ~C ６ Alkyl or C １ ~C ６ Alkoxy includes halogen, oxo, CN, OH and C ３ ~C ６ cycloalkyl, substituted with one or more groups selected from saturated or partially saturated cycloalkyl. where R ｂ or R ｂ Among the groups represented by the formula: Cycloalkyl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl is Halogen, oxo (R ｂ is non-aromatic), CN, OH, C １ ~C ３ Alkyl (F, OH and OCH ３ is substituted with 1 to 3 groups selected from may be used), and C １ ~C ３ Alkoxy (F, OH and OCH ３ One selected from and NR ５’ R ６’ One or more selected from may be substituted with a group, R ｃ is selected from hydrogen, halogen, and optionally halogen and hydroxy; C substituted with one or more groups １ ~C ４ alkyl, R ｄ is H, 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 a Lukoxi, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, NR ５’ R ６’ , 6-10 members aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl, and 3-8 membered saturated or partially saturated heterocyclyl, where R １ in Represented by C 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 (Ha rogen, oxo, CN, CF ３ , O.H., O.C.H. ３ , O.C.H. ２ CH ３ One or more selected from and optionally substituted with one or more groups selected from the group consisting of Here, R １ or R １ Among the groups represented by the formula: or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl is halogen, Oxo (R １ is non-aromatic), CN, OH, C １ ~C ３ Alkyl (F, OH and OC H ３ and C １ ~C ３ Alcoki Si (F, OH and OCH ３ and And NR ５’ R ６’ may be substituted with one or more groups selected from R ２ and R ３ are H, deuterium, halogen, -CN, OH, oxo, and C, respectively. １ ~C ６ Alkyl, C １ ~C ６ Alkoxy or NR ５’ R ６’ are independently selected from R ２ and / or R ３ C represented by １ ~C ６ Alkyl and C １ ~C ６ Alkoxy is a halogen N, 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 may be substituted with a group, Each R ４ is H, deuterium, halogen, OH, -CN, C １ ~C ６ Alkyl, C １ ~C ６ a rucoxyl, or NR ５’ R ６’ where R ４ C represented by １ ~C ６ Alkyl and C １ ~C ６ Alkoxy is halogen, oxo, CN, CF ３ , and saturated or is 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 and optionally substituted with one or more groups such as 3. The compound according to claim 1 or 2, wherein o is an integer selected from 0, 1, 2, 3, and 4. or a pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof.

4. The compound is represented by structural formula (III): 【Chemistry 5】 In the formula, R ４ is H, F, Cl, methyl, or methoxy. A compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt, stereoisomer, solvate, or Hydrate. 【Request 5】 【Chemical 6】 teeth, 【Chemistry 7】 and In the formula, n is an integer selected from 0, 1, 2, 3, and 4. The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt, stereoisomer, solvate, or Often hydrated.

6. 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 m is an integer selected from 0, 1, and 2. or a pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof.

7. A compound according to any one of claims 1 to 6, or a pharmaceutical composition thereof, wherein EE is COOH. Acceptable salts, stereoisomers, solvates, or hydrates thereof.

8. R ｂ but, 【Chemistry 9】 and These are halogen, oxo (R ｂ is non-aromatic), CN, NR ５’ R ６’ , C １ ~C ４ Alkyl, and C １ ~C ４ one or two groups selected from alkoxy where R ｂ In the group represented by １ ~C ４ Alkyl or C １ ~C ４ Alkoxy includes F, OH, and OCH ３ Substituted with one or two groups selected from The compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, Salts, stereoisomers, solvates, or hydrates thereof. 【Request 9】 【Chemical 10】 teeth, 【Chemistry 11】 The compound according to any one of claims 2 to 8, or a pharma- ceutically acceptable salt thereof, Stereoisomers, solvates, or hydrates.

10. 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 10. The compound according to claim 1, wherein o is an integer selected from 0, 1, 2, 3, and 4. or a pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof.

11. Each R ２ is halogen, -CN, OH, C １ ~C ２ Alkyl, C １ ~C ２ Haloalkyl, and C １ ~C ２ alkoxy, and n is selected from 0, 1, 2, 3, and 4. The compound according to any one of claims 1 to 10, wherein R is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 2

12. 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 Hydroxy and C ２ ~C ４ alkynyl, m is 0, 1, or 12. The compound according to claim 1, wherein R is an integer selected from R1 and R2, or A pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate of

13.

13. teeth, 【Chemistry 14】 The compound according to any one of claims 4 to 12, or a pharma- ceutically acceptable salt thereof, , stereoisomers, solvates, or hydrates.

14.

15. teeth, 【Chemistry 16】 The compound according to any one of claims 2 to 13, or a pharma- ceutically acceptable salt thereof, , stereoisomers, solvates, or hydrates.

15. Each R ２ is independently selected from halogen (e.g., F) or deuterium; n is 0, 1, and 2, where R ２ is deuterium, ring B is completely deuterium The compound according to any one of claims 1 to 14, or a pharma- ceutical thereof, Acceptable salts, stereoisomers, solvates, or hydrates.

16. Each R ３ is F, Cl, or CH ３ and o is 0, 1, or 2.

5. A compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof. product, or hydrate.

17. Ring A is 【Chemistry 17】 17. The compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, , stereoisomers, solvates, or hydrates.

18. Ring A is 【Chemistry 18】 18. The compound according to any one of claims 1 to 17, which is: , stereoisomers, solvates, or hydrates.

19.

19. teeth, 【Chemistry 20】 19. The compound according to any one of claims 2 to 18, or a pharma- ceutically acceptable salt thereof, , stereoisomers, solvates, or hydrates.

20. A compound selected from any one of compounds 74 to 102 and 246 to 334 in Table 1. or a pharma- ceutically acceptable salt, stereoisomer, solvate, or hydrate thereof.

21. The compound according to any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof, A pharmaceutical composition comprising the isomer, solvate, or hydrate, and a pharma- ceutically acceptable excipient.

22. A method for treating cardiometabolic and related disorders, comprising administering to a subject in need of such treatment. a therapeutically effective amount of a compound according to any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof and administering to the patient a salt, stereoisomer, solvate, or hydrate of said compound, 1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, nutrition Malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, tolerance Glucose disorder, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction Harm, visceral fat deposition, sleep apnea, obesity, eating disorders, weight gain due to use of other drugs, Excessive sugar craving, dyslipidemia, hyperinsulinemia, NAFLD, NASH, fibrosis, cirrhosis , hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension Pressure, endothelial dysfunction, vascular compliance disorder, congestive heart failure, myocardial infarction, stroke, hemorrhagic Stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent cerebral Stroke, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease Meningeal disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, Tabooic syndrome, Syndrome X, Premenstrual syndrome, Angina, Thrombosis, Atheroma Atherosclerosis, Transient ischemic attack, Vascular restenosis, Glucose metabolism disorder, Fasting plasma glucose conditions, 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 ovarian syndrome The methods are prevention or treatment, and treatment of addiction.

23. In the manufacture of medicines for the treatment of subjects in need thereof suffering from cardiometabolic and related disorders A therapeutically effective amount of a compound according to any one of claims 1 to 20, or a pharma- ceutical acceptable salt thereof, The use of an acceptable salt, stereoisomer, solvate or hydrate thereof, wherein the disease is T1 D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, nutrition Ataxia-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, glucose tolerance impairment, 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, NAFLD, NASH, fibrosis, cirrhosis, Hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension Pressure, endothelial dysfunction, vascular compliance disorder, congestive heart failure, myocardial infarction, stroke, hemorrhagic Stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent cerebral Stroke, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease Meningeal disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, Tabooic syndrome, Syndrome X, Premenstrual syndrome, Angina, Thrombosis, Atheroma Atherosclerosis, Transient ischemic attack, Vascular restenosis, Glucose metabolism disorder, Fasting plasma glucose conditions, 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 ovarian syndrome Uses that are preventive or therapeutic, and treatment of addiction.

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