GLP-1 receptor agonists and uses thereof

Abstract

The present invention provides novel benzimidazole compounds that act as GLP-1 receptor agonists, as well as methods for preparing such compounds and methods for administering such compounds to mammals in need thereof. The compounds of the present invention exhibit strong GLP-1 receptor agonist effects and good metabolic stability, and have strong specificity for the GLP-1 receptor and pharmaceutical safety.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and specifically relates to a novel benzimidazole compound as a GLP-1 receptor agonist, a method for preparing the compound, and a method for administering the compound to a mammal in need. Technical Background

[0002] Diabetes is a metabolic disease characterized by high blood sugar levels, characterized by defects or dysfunction in insulin production, insulin action, or both, which can further lead to chronic damage or dysfunction of organs and tissues such as the eyes, kidneys, heart, blood vessels, and nerves. Depending on the pathogenesis, diabetes is divided into type I and type II. Type I diabetes (T1D) develops when the body's immune system destroys pancreatic beta cells, which are the only cells in the body that produce insulin, which has the effect of regulating blood sugar. The treatment of type I diabetes is mainly through injection or pump administration of insulin. Type II diabetes (commonly known as T2DM) often begins with insulin resistance or when the function of pancreatic beta cells decreases, resulting in insufficient insulin production to maintain acceptable glucose levels. It is the main type of diabetes.

[0003] There are currently different pharmacological approaches for the treatment of hyperglycemia and T2DM (Diabetes Care 2014, 37, 1367-1374). These drugs can be divided into six major categories based on their different mechanisms of action: (1) Biguanides (such as metformin), which act primarily by reducing hepatic glucose production and often cause gastrointestinal disturbances and lactic acidosis, limiting their further use. (2) α-glucosidase inhibitors (such as acarbose), which act by reducing intestinal glucose absorption but can cause gastrointestinal disturbances. (3) Thiazolidinediones (such as pioglitazone and rosiglitazone), which act primarily on peroxisome proliferator-activated receptor γ in the liver, muscle, and adipose tissue, regulating lipid metabolism and increasing the response of these tissues to insulin. However, frequent use of these drugs can induce edema, anemia, and weight gain. (4) Insulin alone or in combination with drugs with other mechanisms of action can lead to the risk of hypoglycemia and obesity. (5) Sodium-glucose linked transporter cotransporter 2 (SGLT2) inhibitors (such as dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, etc.). These drugs mainly inhibit the reabsorption of glucose in the kidneys, thereby reducing the glucose content in the blood. However, these drugs may be associated with ketoacidosis and urinary tract infections. (6) Insulin secretagogues, which increase insulin secretion by acting on pancreatic β cells, include sulfonylureas (glipizide, glimepiride, glyburide), meglitinides (such as nateglidine, repaglinide), dipeptidyl peptidase 4 (DPP-IV) inhibitors (sitagliptin, vildagliptin, alogliptin, etc.). logliptin, dutogliptin, linagliptin, saxogliptin), glucagon-like peptide-1 receptor (GLP-1R) agonists (e.g., liraglutide, albiglutide, exenatide, lixisenatide, dulaglutide, semaglutide).Sulfonylureas and meglitinides have limited efficacy and tolerability, often inducing hypoglycemia and causing weight gain. DPP-IV inhibitors have limited efficacy, and GLP-1 receptor agonists are all large-molecule peptide drugs, usually administered by subcutaneous injection. Although oral semaglutide developed by Novo Nordisk was launched in 2019, it is subject to multiple unfavorable limitations such as administration time, dosage, and gastrointestinal disturbance, and has low oral bioavailability.

[0004] T2DM is most commonly associated with hyperglycemia and insulin resistance, and is also associated with other diseases including obesity, coronary artery disease, hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, dyslipidemia, hypertension, hyperinsulinemia, and non-alcoholic fatty liver disease (NAFLD). Bariatric surgery, a highly effective treatment for obesity, is expensive and risky, while pharmacological interventions are generally less effective and associated with significant side effects. Therefore, there is an urgent need to develop more effective, less side-effect, and conveniently administered weight loss drugs. NAFLD is the hepatic manifestation of metabolic syndrome, including steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and ultimately hepatocellular carcinoma. The severity of NAFLD / NASH is based on the presence of lipids, inflammatory cell infiltration, hepatocyte ballooning, and the degree of fibrosis. Although not all individuals with steatosis progress to NASH, a large proportion do. In addition to GLP-1 receptor agonists and SGLT2 inhibitors, other diabetes-related drugs have limited efficacy and fail to address β-cell dysfunction and related obesity. GLP-1 receptor agonists have been approved for the treatment of obesity, and a variety of T2DM-related indications are currently in clinical trials.

[0005] The GLP-1 receptor belongs to the G protein-coupled receptor B family. Its natural agonist ligand, GLP-1, is a 30-amino acid incretin secreted by intestinal L cells in response to food intake. GLP-1 stimulates insulin secretion, reduces glucagon secretion, inhibits gastric emptying, reduces appetite, and stimulates β-cell proliferation in a physiological and glucose-dependent manner. In nonclinical trials, GLP-1 promotes sustained β-cell capacity by stimulating the transcription of genes important for glucose-dependent insulin secretion and by promoting β-cell regeneration (Biodrugs. 2003; 17(2): 93-102). In healthy individuals, GLP-1 plays an important role in regulating postprandial blood glucose levels by stimulating glucose-dependent insulin secretion from the pancreas, leading to increased peripheral glucose absorption. At the same time, it inhibits glucagon secretion, resulting in reduced hepatic glucose output, delayed gastric emptying, and slowed small intestinal motility, thereby delaying food absorption. In people with T2DM, the normal postprandial rise in GLP-1 is absent or reduced (Diabetes. 2001. 50; 609-613). GLP-1 receptor agonists improve glycemic control in patients with T2DM by lowering fasting and postprandial glucose (FPG and PPG) through three main pharmacological activities: (i) increased glucose-dependent insulin secretion (improved first and second phases), (ii) glucagon inhibitory activity under hyperglycemic conditions, and (iii) delayed gastric emptying, resulting in delayed absorption of meal-derived glucose (Physiol. Rev. 2007, 87, 1409; Nat. Rev. Endocrinol. 2012, 8, 728).

[0006] In recent years, researchers have discovered that small-molecule compounds can modulate the function of the GLP-1 receptor, leading to the development of small-molecule GLP-1 receptor agonists, including low-molecular-weight flavonoids and nitrogen-containing heterocyclic compounds, as well as peptide-mimicking compounds such as Boc-4 and S4P (Journal of Diabetes Research, 2012, 2012: 344-350). However, existing small-molecule agonists have limited structural types, weak specificity for the GLP-1 receptor, and low safety. Therefore, it is necessary to develop agonists with new structural types that are specific for the GLP-1 receptor. Pfizer Pharmaceuticals has reported a series of GLP-1 receptor agonists with a 6-carboxyaryl imidazole structure, of which the active compounds PF-06882961 (WO2018109607A1) and PF-07081532 (WO2019239319A1) are currently in clinical trials. Summary of the Invention

[0007] The present invention provides a novel benzimidazole compound as a GLP-1 receptor agonist, which exhibits a strong GLP-1 receptor agonist effect and good metabolic stability, and has strong specificity and pharmaceutical safety for the GLP-1 receptor.

[0008] The present invention provides a compound of formula (I) or formula (II) or (III) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0009]

[0010] Wherein, ring A is selected from substituted or unsubstituted: phenyl, pyridyl, quinoline,

[0011] Each R 1 and R 2 independently selected from H, halogen, -CN, -OH, C 2-6 Alkynyl, C 2-6 Alkenyl, C 1-6 Alkyl, -OC 1-6 Alkyl, halogenated C 1-6 alkyl;

[0012] R 3 Selected from C 1-6 alkyl, wherein the alkyl group may be substituted by 1 to 3 halogens, -CN, -OC 1-6 Alkyl substitution;

[0013] Z1 is selected from CH or N;

[0014] n and m are each independently selected from 0, 1, 2, 3, and 4.

[0015] In some preferred embodiments, ring A is selected from phenyl, quinoline; each R 1 Independently selected from halogen, -CN; each R 2 Independently selected from H, halogen.

[0016] In some preferred embodiments, R 3 Selected from

[0017] In some embodiments, the compound is selected from one of the following:

[0018]

[0019]

[0020]

[0021]

[0022] Another aspect of the present invention provides a pharmaceutical composition comprising the above-mentioned compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0023] Another aspect of the present invention provides a method for treating cardiometabolic diseases and related diseases, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the above-mentioned compound, wherein the disease is T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, renal disease, diabetic retinopathy, adipocyte dysfunction, visceral adipocyte accumulation, sleep apnea, obesity, eating disorders, weight gain caused by the use of other agents, excessive sugar cravings, dyslipidemia, hyperinsulinemia, NAFLD, NASH, fibrosis, sclerosis. , hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipidemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina, thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, impaired glucose metabolism, impaired fasting glucose conditions, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcers, ulcerative colitis, high apo Prevention or treatment of beta-lipoproteinemia, Alzheimer's disease, schizophrenia, impaired cognitive function, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome, and treatment of addiction. Specific embodiments

[0024] Example 1

[0025] Synthesis of 2-({4-[2-(4-chloro-2-fluorophenyl)-2H-1,3-benzodioxetane-4-yl]-2,6-difluorophenyl}methyl)-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (1)

[0026]

[0027] Step 1: Synthesis of methyl 4-[2-(4-bromo-2,6-difluorophenyl)acetamide]-3-({[(2S)-oxetan-2-yl]methyl}amino)benzoate (1-3)

[0028] 1-2 (200.00 mg, 0.847 mmol) was dissolved in 5 mL of DMF, and compound 1-1 (211.75 mg, 0.847 mmol), DIEA (543.09 mg, 4.210 mmol), and HATU (805.60 mg, 2.120 mmol) were added thereto and allowed to react at room temperature for two hours. After the reaction was completed as monitored by TLC, 20 mL of water was added to the system, and the mixture was extracted with 20 mL of ethyl acetate. The organic phase was washed with 20 mL of saturated sodium chloride, separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain a black oily crude compound 1-3 (300 mg, yield: 80%). The crude product was used directly in the next step without further purification. [M+H] + :469.05.

[0029] Step 2: Synthesis of methyl-2-[(4-bromo-2,6-difluorophenyl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylate (1-4)

[0030] 1-3 (300.00 mg, 0.641 mmol) was dissolved in 6 mL of glacial acetic acid and reacted at 60°C for 2 hours. After the reaction was completed, the glacial acetic acid was dried and purified by column chromatography (V PE :V EA =2:1), to give compound 1-4 as a yellow solid (200.00 mg, yield: 69%), [M+H] + :451.04.

[0031] Step 3: Synthesis of methyl-2-{[2,6-difluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylate (1-5)

[0032] 1-4 (200.00 mg, 0.444 mmol) was added to a single-necked bottle, followed by B2(Pin)2 (135.48 mg, 0.533 mmol), pd(dppf)Cl2 (36.26 mg, 0.044 mmol), potassium acetate (117.60 mg, 1.200 mmol), and 1,4-dioxane (5 mL). The mixture was reacted at 100°C overnight. After LCMS showed that the reaction was complete, the mixture was cooled and filtered, and the filtrate was collected and dried to obtain 300 mg of crude 1-5, which was directly used in the next reaction without further purification. [M+H]+ :499.21.

[0033] Step 4: Synthesis of methyl 2-({4-[2-(4-chloro-2-fluorophenyl)-2H-1,3-benzodioxetane-4-yl]-2,6-difluorophenyl}methyl)-1-{[(2S)-oxetane-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylate (1-7)

[0034] The crude product 1-5 (300.00 mg, 0.602 mmol) was added to a single-necked bottle, followed by compound 1-6 (120.00 mg, 0.366 mmol), pd(dppf)Cl2 (29.86 mg, 0.037 mmol), cesium carbonate (390.96 mg, 1.200 mmol), and 1,4-dioxane (6 mL). The mixture was reacted at 90°C overnight. After LCMS showed that the reaction was complete, the mixture was filtered, and the filtrate was concentrated and purified by column chromatography (V PE :V EA =2:1) to give a white solid 1-7 (120 mg, yield: 33%), [M+H] + :621.13.

[0035] Step 5: Synthesis of 2-({4-[2-(4-chloro-2-fluorophenyl)-2H-1,3-benzodioxetane-4-yl]-2,6-difluorophenyl}methyl)-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (1)

[0036] 1-7 (120.00 mg, 0.193 mmol) was added to a single-necked bottle, and 5 mL of methanol, 2 mL of water, and lithium hydroxide (12.00 mg, 0.500 mmol) were added thereto. The reaction was allowed to proceed overnight at room temperature. After LCMS showed that the reaction was complete, the methanol was dried and the pH of the system was adjusted to 5 with 1N HCl. The solid precipitated and was filtered to collect the filter cake to obtain 1 (60 mg, yield: 51%) as a white solid. [M+H] + :607.12.

[0037] 1H NMR (400MHz, DMSO-d6) δ12.78 (s, 1H), 8.24 (d, 1H), 7.76 (dd, 1H), 7.73 (s, 1H), 7.63 (dd, 1H), 7.59–7.49 (m, 4H), 7.43 (dd, 1H), 7.33 (dd, 1 H), 7.10–7.01(m, 2H), 5.11(td, 1H), 4.79(dd, 1H), 4.66(dd, 1H), 4.59–4.38(m, 3H), 4.34(dt, 1H), 2.79–2.66(m, 1H), 2.43–2.32(m, 1H).

[0038] Example 2

[0039] Synthesis of 2-({4-[2-(4-chloro-2-fluorophenyl)-2H-1,3-benzodioxetane-4-yl]-2-fluorophenyl}methyl)-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (2)

[0040]

[0041] Step 1: Synthesis of methyl 4-[2-(4-bromo-2-fluorophenyl)acetamide]-3-({[(2S)-oxetan-2-yl]methyl}amino)benzoate (2-3)

[0042] 1-2 (200.00 mg, 0.847 mmol) was dissolved in 5 mL of DMF, and compound 2-1 (196.50 mg, 0.847 mmol), DIEA (543.09 mg, 4.210 mmol), and HATU (805.60 mg, 2.120 mmol) were added thereto and allowed to react at room temperature for two hours. After the reaction was completed, 20 mL of water was added to the system, and the mixture was extracted once with 20 mL of ethyl acetate. The organic phase was washed with 20 mL of saturated sodium chloride aqueous solution. After separation, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain a black oily crude product 2-3 (300.00 mg, yield: 77%). The product was directly used in the next step without further purification. [M+H] + :451.05.

[0043] Step 2: Synthesis of methyl-2-[(4-bromo-2-fluorophenyl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylate (2-4)

[0044] The crude product 2-3 (300.00 mg, 0.667 mmol) was dissolved in 6 mL of glacial acetic acid and reacted at 60°C for 2 hours. After the reaction was completed by TLC monitoring, the glacial acetic acid was dried and purified by column chromatography (V PE :V EA =2:1) to give a yellow solid 2-4 (200 mg, yield: 69%), [M+H] + :433.05.

[0045] Step 3: Synthesis of (3-fluoro-4-{[6-(methoxycarbonyl)-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazol-2-alkyl]methyl}phenyl)boronic acid (2-5)

[0046] 2-4 (200.00 mg, 0.444 mmol) was added to a single-necked bottle, and B2(Pin)2 (135.48 mg, 0.533 mmol), pd(dppf)Cl2 (36.26 mg, 0.044 mmol), potassium acetate (117.60 mg, 1.200 mmol), and 1,4-dioxane (5 mL) were added thereto. The mixture was reacted at 100°C overnight. After LCMS showed that the reaction was complete, the system was cooled and filtered. The filtrate was collected and dried to give crude product 2-5 (300 mg, yield: 100%). It was directly used in the next reaction without further purification. [M+H] + :481.22.

[0047] Step 4: Synthesis of methyl-2-({4-[2-(4-chloro-2-fluorophenyl)-2H-1,3-benzodioxetane-4-yl]-2-fluorophenyl}methyl)-1-{[(2S)-oxetane-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylate (2-7)

[0048] 2-5 (300.00 mg, 0.754 mmol) was added to a single-necked bottle, and compound 1-6 (120.00 mg, 0.366 mmol), pd(dppf)Cl2 (29.86 mg, 0.037 mmol), cesium carbonate (390.96 mg, 1.200 mmol), 1,4-dioxane (6 mL) were added thereto and reacted at 90°C overnight. After LCMS showed that the reaction was complete, the mixture was filtered, and the filtrate was spin-dried and column chromatography (V PE :V EA =2:1) to give a white solid 2-7 (120 mg, yield: 26%), [M+H] + :603.14.

[0049] Step 5: Synthesis of 2-({4-[2-(4-chloro-2-fluorophenyl)-2H-1,3-benzodioxetane-4-yl]-2-fluorophenyl}methyl)-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (2)

[0050] 2-7 (120.00 mg, 0.193 mmol) was added to a single-necked flask, and 5 mL of methanol, 2 mL of water, and lithium hydroxide (12.00 mg, 0.500 mmol) were added thereto. The reaction was allowed to proceed overnight at room temperature. After LCMS showed that the reaction was complete, the methanol was dried and the pH of the system was adjusted to 5 with 1N HCl. The solid precipitated and was filtered to collect the filter cake to obtain a white solid 2 (50 mg, yield: 42%). [M+H] + :589.13.

[0051] 1 H NMR (400MHz, DMSO-d6) δ12.75 (s, 1H), 8.24 (s, 1H), 7.78 (d, 1H), 7.68 (t, 1H), 7.62 (dd, 2H), 7.57 (d, 2H), 7.49 (s, 1H), 7.42 (dd, 2H), 7.2 5(p, 1H), 7.02(d, 2H), 5.04(d, 1H), 4.72(dd, 1H), 4.59(dd, 1H), 4.49(q, 2H), 4.41–4.35(m, 1H), 4.33(d, 1H), 2.70(p, 1H), 2.37(p, 1H).

[0052] Example 3

[0053] Synthesis of 2-({4-[2-(4-chloro-2-fluorophenyl)-2H-1,3-benzodioxetane-4-yl]-2,5-difluorophenyl}methyl)-1-{[(2S)-oxetane-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (3)

[0054]

[0055] Step 1: Synthesis of methyl 4-[2-(4-bromo-2,5-difluorophenyl)acetamide]-3-({[(2S)-oxetan-2-yl]methyl}amino)benzoate (3-3)

[0056] 1-2 (200.00 mg, 0.847 mmol) was dissolved in 5 mL of DMF, and compound 3-1 (211.75 mg, 0.847 mmol), DIEA (543.09 mg, 4.210 mmol), and HATU (805.60 mg, 2.120 mmol) were added thereto and allowed to react at room temperature for two hours. After the reaction was completed as monitored by TLC, 20 mL of water was added to the system, and the mixture was extracted once with 20 mL of ethyl acetate. The organic phase was washed with 20 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain a black oily crude product 3-3 (300 mg, yield: 94%). The product was directly used in the next step without further purification. [M+H] + :469.05.

[0057] Step 2: Synthesis of methyl-2-[(4-bromo-2,5-difluorophenyl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylate (3-4)

[0058] 3-3 (300.00 mg, 0.641 mmol) was dissolved in 6 mL of glacial acetic acid and reacted at 60°C for 2 hours. After the reaction was completed by TLC monitoring, the glacial acetic acid was dried and purified by column chromatography (V PE :V EA =2:1) to give a yellow solid 3-4 (200 mg, yield: 69%), [M+H] + :451.04.

[0059] Step 3: Synthesis of methyl-2-{[2,5-difluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylate (3-5)

[0060] 3-4 (200.00 mg, 0.444 mmol) was added to a single-necked bottle, and B2(Pin)2 (135.48 mg, 0.533 mmol), pd(dppf)Cl2 (36.26 mg, 0.044 mmol), potassium acetate (117.60 mg, 1.200 mmol), and 1,4-dioxane (5 mL) were added thereto. The mixture was reacted at 100°C overnight. After LCMS showed that the reaction was complete, the system was cooled and filtered, and the filtrate was collected and dried to give the crude product 3-5 (300 mg, yield: calculated as 100%), [M+H] + :499.21.

[0061] Step 4: Synthesis of methyl-2-({4-[2-(4-chloro-2-fluorophenyl)-2H-1,3-benzodioxetane-4-yl]-2,5-difluorophenyl}methyl)-1-{[(2S)-oxetane-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylate (3-7)

[0062] 3-5 (300.00 mg, 0.602 mmol) was added to a single-necked bottle, and compound 1-6 (120.00 mg, 0.366 mmol), pd(dppf)Cl2 (29.86 mg, 0.037 mmol), cesium carbonate (390.96 mg, 1.200 mmol), 1,4-dioxane (6 mL) were added thereto and reacted at 90°C overnight. After LCMS showed that the reaction was complete, the mixture was filtered, and the filtrate was spin-dried and column chromatography (V PE :V EA =2:1) to give a white solid 3-7 (120 mg, yield: 32%), [M+H] + :621.13.

[0063] Step 5: Synthesis of 2-({4-[2-(4-chloro-2-fluorophenyl)-2H-1,3-benzodioxetane-4-yl]-2,5-difluorophenyl}methyl)-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (3)

[0064] 3-7 (120.00 mg, 0.193 mmol) was added to a single-necked bottle, and 5 mL of methanol, 2 mL of water, and lithium hydroxide (12.00 mg, 0.500 mmol) were added thereto. The reaction was allowed to proceed overnight at room temperature. After LCMS showed that the reaction was complete, the methanol was dried and the pH of the system was adjusted to 5 with 1N HCl. The solid precipitated and was filtered to collect the filter cake to obtain 3 (60 mg, yield: 51%) as a white solid. [M+H] + :607.12.

[0065] 1 H NMR (400MHz, DMSO-d6) δ12.77(s, 1H), 8.25(d, 1H), 7.78(dd, 1H), 7.67(t, 1H), 7.64–7.58(m, 2H), 7.48–7.39(m, 2H), 7.36(dd, 1H), 7.10–6.98(m, 3H), 5.06(d, 1H), 4.74(dd, 1H), 4.61(dd, 1H), 4.55–4.41(m, 3H), 4.41–4.26(m, 2H), 2.76–2.65(m, 1H), 2.38(t, 1H).

[0066] Example 4

[0067] Synthesis of 2-[(4-{1-[(4-chloro-2-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl}-2-fluorophenyl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (4)

[0068]

[0069] Step 1: Synthesis of 6-chloro-1-[(4-chloro-2-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine (4-3)

[0070] 4-1 (300.00 mg, 1.970 mmol) was dissolved in DMF (5 mL), and NaH (87.00 mg, 2.170 mmol) was added at 0°C, stirred for 10 min, and then 4-2 (465.00 mg, 2.17 mmol) was added. The system was stirred at room temperature (30°C) for 2 h. After the reaction was complete, water (5 mL) was added to quench the reaction, filtered, and the filter cake was washed with water (2 mL). The filter cake was dried to obtain a white solid product 4-3 (571 mg, yield: 98%), [M+H] + :295.01.

[0071] Step 2: Synthesis of methyl-2-[(4-{1-[(4-chloro-2-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl}-2-fluorophenyl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylate (4-4)

[0072] 4-3 (310.00 mg, 1.050 mmol), 2-5 (420.00 mg, 0.875 mmol), pd(dppf)Cl2 (64.00 mg, 0.088 mmol), Na2CO3 (278.00 mg, 2.630 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 100 ° C for 5 h under nitrogen. The reaction solution was filtered through celite (10 g), the filter cake was washed with EA (5 mL), and the filtrate was concentrated to give a crude product, which was purified by column chromatography (V PE :V EA =1:1) to give a white solid product 4-4 (150 mg, yield: 53%), [M+H] + :613.06.

[0073] Step 3: Synthesis of 2-[(4-{1-[(4-chloro-2-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl}-2-fluorophenyl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (4)

[0074] 4-4 (150.00 mg, 0.245 mmol) was added to THF (5 mL), and H2O (1 mL) and LiOH (20.00 mg, 0.490 mmol) were added. The system was stirred at room temperature (35°C) for 20 h. After the reaction was complete, THF was concentrated to dryness, H2O (5 mL) was added, and the pH was adjusted to 6-7 with 1N HCl solution. The product was extracted with EA (5 mL×3), washed with saturated sodium chloride (10 mL), and the organic phase was concentrated and purified by prep-TLC (V DCM :V MeOH =10:1) to give a white solid product 4 (50 mg, yield: 34%), [M+H] + :599.03.

[0075] 1 H NMR (400MHz, DMSO-d6) δ8.25 (s, 1H), 8.07 (d, 1H), 8.00-7.95 (m, 2H), 7.80-7. 76(m, 2H), 7.67(d, 1H), 7.61(d, 1H), 7.48–7.40(m, 2H), 7.30–7.23(m, 2H), 6.5 7(d, 1H), 5.60(s, 2H), 5.06-5.04(m, 1H), 4.76–4.72(m, 1H), 4.62-4.54(m, 1H ), 4.50–4.37(m, 3H), 4.36-4.35(m, 1H), 2.71-2.67(m, 1H), 2.34-2.33(m, 1H).

[0076] Example 5

[0077] Synthesis of 2-[(4-{1-[(4-chloro-2-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl}-2,5-difluorophenyl)methyl ester]-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (5)

[0078]

[0079] Step 1: Synthesis of methyl-2-[(4-{1-[(tetrachloro-2-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl}-2,5-difluorophenyl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylate (5-1)

[0080] 4-3 (64 mg, 0.216 mmol), 3-5 (90 mg, 0.216 mmol), Cs2CO3 (211 mg, 0.648 mmol), pd(dppf)Cl2 (18 mg, 0.0216 mmol) were added to dioxane / H2O (4 mL: 1 mL), nitrogen was replaced, and the system was stirred at 110 ° C for 10 h. After the reaction was complete, it was filtered with diatomaceous earth, and the filter cake was washed with EA (20 mL). The filtrate was concentrated and dissolved with EA and filtered, and the filtrate was concentrated again. The crude product was purified by column chromatography (V PE :V EA =3:1), the product was obtained as a light yellow oil 5-1 (80 mg, yield: 60%), [M+H] + :631.

[0081] Step 2: Synthesis of 2-[(4-{1-[(4-chloro-2-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl}-2,5-difluorophenyl)methyl ester]-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (5)

[0082] At room temperature, 5-1 (80 mg, 0.127 mmol) was added to THF / H2O (5 mL:5 mL) system, and LiOH (10 mg, 0.381 mmol) was added and stirred at room temperature. After the reaction was complete, THF was concentrated to dryness, the pH was adjusted to 4, and EA (10 mL × 3) was used for extraction. After concentration, the crude product was obtained, which was slurried with MeOH to obtain product 5 (30 mg, yield: 40%), [M+H] + :617.5.

[0083] 1H NMR (400MHz, DMSO-d6) δ8.28(s,1H),8.12(d,J=8.2Hz,1H),7.84(dd,J=18.2,8.6Hz,2H),7.72(d ,J=3.5Hz,1H),7.67–7.60(m,2H),7.47(d,J=10.0Hz,1H),7.38(t,J=8.8Hz,1H),7.25(d,J=4.2H z,2H),6.60(d,J=3.5Hz,1H),5.60(s,2H),5.08(d,J=7.5Hz,1H),4.78(dd,J=15.7,7.0Hz,1H),4 .64(d,J=15.4Hz,1H),4.59–4.43(m,3H),4.41–4.33(m,1H),2.73(s,1H),2.42(d,J=9.1Hz,1H).

[0084] Example 6

[0085] Synthesis of 2-({4-[2-(4-chloro-2-fluorophenyl)-2H-1,3-benzodioxetane-4-yl]-2,3,6-trifluorophenyl}methyl)-1-{[(2S)-oxetane-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (6)

[0086]

[0087] Step 1: Synthesis of methyl 4-[2-(4-bromo-2,3,6-trifluorophenyl)acetamide]-3-({[(2S)-oxetan-2-yl]methyl}amino)benzoate (6-3)

[0088] 1-2 (265 mg, 1.12 mmol) was dissolved in 5 mL of DMF, and compound 6-1 (300 mg, 1.12 mmol), DIEA (433 mg, 3.36 mmol), and HATU (638 mg, 1.68 mmol) were added. The mixture was allowed to react at room temperature for two hours. TLC monitored the reaction completion. 20 mL of water was added to the system, and the mixture was extracted with 20 mL of ethyl acetate. The organic phase was washed once with 20 mL of saturated sodium chloride solution. The organic phase was separated, dried over anhydrous sodium sulfate, and then spin-dried to obtain a pale yellow solid crude product 6-3 (520 mg, yield: 95%). This was used directly in the next reaction without further purification. [M+H] + :487.3.

[0089] Step 2: Synthesis of methyl-2-[(4-bromo-2,3,6-trifluoropropyl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylate (6-4)

[0090] Dissolve 6-3 (520 mg, crude) in 10 mL of glacial acetic acid and react at 60°C for 2 hours. The reaction is complete after monitoring by TLC. PE :V EA =2:1) to give yellow solid 6-4 (246 mg, yield: 49%), [M+H] + :469.3.

[0091] Step 3: Synthesis of methyl-1-{[(2S)-oxetan-2-yl]methyl}-2-{[2,3,6-trifluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1H-1,3-benzodiazole-6-carboxylate (6-5)

[0092] 6-4 (200 mg, 0.426 mmol) was added to a single-necked bottle, and B2(Pin)2 (129.79 mg, 0.511 mmol), Pd(dppf)Cl2 (31.17 mg, 0.0426 mmol), potassium acetate (117.6 mg, 1.2 mmol), and 5 mL of dioxane were added. The mixture was reacted at 100°C overnight. LCMS showed that the reaction was complete. The system was cooled and filtered, and the filtrate was collected and dried to give crude product 6-5 (400 mg, yield: 100%). It was directly used in the next reaction without further purification. [M+H] + :517.2.

[0093] Step 4: Synthesis of methyl 2-({4-[2-(4-chloro-2-fluorophenyl)-2H-1,3-benzodioxetane-4-yl]-2,3,6-trifluorophenyl}methyl)-1-{[(2S)-oxetane-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylate (6-7)

[0094] 6-5 (400 mg, crude) was added to a single-necked bottle, and 1-6 (120 mg, 0.366 mmol), Pd(dppf)Cl2 (29.86 mg, 0.0366 mmol), cesium carbonate (390.96 mg, 1.20 mmol), and dioxane 6 mL were added thereto. The mixture was heated at 90°C overnight. LCMS showed that the reaction was complete, and the mixture was filtered and the filtrate was purified by column chromatography (V PE :V EA =3:1) to give a white solid 6-7 (100 mg, yield: 36%), [M+H] + :639.3.

[0095] Step 5: Synthesis of 2-({4-[2-(4-chloro-2-fluorophenyl)-2H-1,3-benzodioxetane-4-yl]-2,3,6-trifluorophenyl}methyl)-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (6)

[0096] 6-7 (100 mg, 0.157 mmol) was added to a single-necked bottle, and 5 mL of methanol, 2 mL of water, and lithium hydroxide (12 mg, 0.500 mmol) were added. The mixture was allowed to stand at room temperature overnight. LCMS indicated that the reaction was complete. The methanol was dried and the pH of the system was adjusted to 5 with 1N HCl. A solid precipitated and was filtered to collect the filter cake to obtain 6 (60 mg, yield: 73%) as a white solid. [M+H] + :625.2.

[0097] 1 H NMR (400MHz, DMSO-d6) δ8.28(s,1H),8.12(d,J=8.0Hz,1H),7.84(t,J=8.0Hz ,1H),7.63-7.57(m,2H),7.48-7.35(m,3H),7.13-7.04(m,3H),5.12(d,J=8.0 Hz,1H),4.79(dd,J=16.0,8.0Hz,1H),4.64(t,J=16.0Hz,2H),4.52(s,1H),4. 49(d,J=8.0Hz,1H),4.35–4.30(m,1H),2.78-2.71(m,1H),2.42-2.34(m,1H).

[0098] Example 7

[0099] Synthesis of 2-[(4-{1-[(4-chloro-2-fluorophenyl)methyl]-2,3-dihydro-1H-indol-6-yl}-2,6-difluorophenyl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (7)

[0100]

[0101] Step 1: Synthesis of 6-bromo-1-[(4-chloro-2-fluorophenyl)methyl]-2,3-dihydro-1H-indole (7-2)

[0102] 7-1 (100 mg, 0.51 mmol) was dissolved in 5 mL of DMF, and NaH (50 mg, 1.26 mmol) was added. The reaction was allowed to proceed at 0°C for 10 min. Compound 4-2 (113 mg, 0.51 mmol) was then added and allowed to react overnight at room temperature. TLC monitored the reaction completion. 20 mL of water was added to the system, and the mixture was extracted with 20 mL of ethyl acetate. The organic phase was washed once with 20 mL of saturated sodium chloride solution, dried, and spin-dried to give a pale yellow oily crude product 7-2 (140 mg, yield: 81%). This was used directly in the next step without purification. [M+H] + :340.3.

[0103] Step 2: Synthesis of methyl-2-[(4-{1-[(4-chloro-2-fluorophenyl)methyl]-2,3-dihydro-1H-indol-6-yl}-2,6-difluorophenyl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylate (7-3)

[0104] 7-2 (140 mg, crude) was added to a single-necked bottle, and 1-5 (200 mg, crude), Pd(dppf)Cl2 (22 mg, 0.028 mmol), cesium carbonate (270 mg, 0.83 mmol), and dioxane / H2O (4 mL / 1 mL) were added thereto. The mixture was allowed to stand at 100°C overnight. LCMS showed that the reaction was complete. The mixture was filtered and the filtrate was purified by column chromatography to give 7-3 (80 mg, yield: 31%) as a white solid. [M+H] + :632.3.

[0105] Step 3: Synthesis of 2-[(4-{1-[(4-chloro-2-fluorophenyl)methyl]-2,3-dihydro-1H-indol-6-yl}-2,6-difluorophenyl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (7)

[0106] 7-3 (80 mg, 0.127 mmol) was added to a single-necked bottle, and 5 mL of methanol, 2 mL of water, and lithium hydroxide (12 mg, 0.500 mmol) were added. The mixture was allowed to stand at room temperature overnight. LCMS showed that the reaction was complete. The methanol was dried and the pH of the system was adjusted to 5 with 1N HCl. The solid precipitated and was filtered to collect the filter cake to obtain 7 (50 mg, yield: 64%) as a white solid. [M+H] + :618.2.

[0107] 1H NMR (400MHz, DMSO-d6) δ8.18(s,1H),8.03(d,J=8.0Hz,1H),7.82(d,J=18.0Hz,1H),7.36(t,J=8.0Hz,1H),7.16–7.12(m,5H),6.86(d,J=8.0Hz,1 H),6.62(s,1H),5.22(s,1H),4.69-4.40(m,6H),4.34(s,2H),3.46(t,J= 8.4Hz,2H),3.05(t,J=8.0Hz,2H),2.78-2.73(m,1H),2.47-2.43(m,1H).

[0108] Example 8

[0109] Synthesis of 2-[(4-{1-[(4-cyano-2-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl}-2,6-difluorophenyl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (8)

[0110]

[0111] Step 1: Synthesis of 4-(6-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl}methyl)-3-fluorobenzonitrile (8-2)

[0112] 4-1 (50 mg, 0.327 mmol) was dissolved in DMF (3 mL). NaH (14 mg, 0.359 mmol) was added at 0°C. The system was stirred at 0°C for 10 min, followed by the dropwise addition of 8-1 (77 mg, 0.359 mmol). The reaction was allowed to react at room temperature for 1 h. After completion, the reaction was quenched with water, filtered, and the filter cake was washed with water and dried to afford the product 8-2 (110 mg, 100% yield) as a white solid.

[0113] Step 2: Synthesis of methyl-2-(4-{1-[(4-cyano-2-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl}-2,6-difluorophenyl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylate (8-3)

[0114] 8-2 (63 mg, 0.222 mmol), 1-5 (150 mg, 0.222 mmol), Pd (dppf) Cl2 (16 mg, 0.032 mmol), Cs2CO3 (93 mg, 0.671 mmol) were dissolved in dioxane / H2O (5 mL / 1 mL) and stirred at 80 ° C for 2 h under nitrogen. The reaction solution was filtered through celite, the filter cake was washed with EA, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by column chromatography (V hexane :V EA =1:1) to give yellow oil 8-3 (64 mg, yield: 47%), [M+H] + :622.62.

[0115] Step 3: Synthesis of 2-[(4-{1-[(4-cyano-2-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl}-2,6-difluorophenyl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (8)

[0116] Compound 8-3 (59 mg, 0.095 mmol) was added to ACN (10 mL), followed by H2O (2 mL) and LiOH (20 mg, 0.476 mmol), and stirred at room temperature at 30°C for 16 h. After the reaction was complete, H2O (5 mL) was added, and the pH was adjusted to <3 with 1N HCl. The mixture was extracted with EA, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The product was purified by prep-TLC to obtain the white solid product 8 (20 mg, yield: 35%). [M+H] + :608.59.

[0117] 1 H NMR(400MHz,DMSO-d6)δ8.14-8.12(m,2H),7.92-7.85(m,4H),7.76-7.34(m,2H),7 .66(dd,J=7.6Hz,J=1.6Hz,1H),7.45(d,J=8.4Hz,1H),7.36(d,J=7.6Hz,1H),6.62( d,J=3.6Hz,1H),5.72(s,2H),5.13(d,J=7.6Hz,1H),4.77-4.72(m,1H),4.65-4.60( m,1H),4.55-4.49(m,2H),4.44-4.33(m,2H),2.74-2.68(m,1H),2.45-2.41(m,1H).

[0118] Example 9

[0119] Synthesis of 2-[(2,6-difluoro-4-{6-[(7-fluoroquinolin-6-yl)methoxy]pyridin-2-yl}phenyl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (9)

[0120]

[0121] Step 1: Synthesis of 7-fluoroquinoline-6-carbaldehyde (9-2)

[0122] At room temperature, 9-1 (200 mg, 0.889 mmol) was dissolved in THF (5 mL), cooled to -78 ° C, and n-BuLi (0.65 mL, 9.8 mmol) was slowly added dropwise under nitrogen atmosphere. The mixture was stirred at -78 ° C for 0.5 h. DMF (78 mg, 1.067 mmol) was then added. After the reaction was complete, saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with 30 mL of EA, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product, which was purified by column chromatography (V hexane :V EA =3:1) to give a white solid product 9-2 (62 mg, yield: 40%), [M+H] + :176.16.

[0123] Step 2: Synthesis of (7-fluoroquinolin-6-yl)methanol (9-3)

[0124] 9-2 (310 mg, 1.771 mmol) was added to MeOH (10 mL), and sodium borohydride (74 mg, 1.949 mmol) was slowly added at 0°C. After the addition, the mixture was stirred at room temperature for 1 h. After the reaction was complete, water was added to quench the mixture, and the mixture was filtered. The filter cake was washed with water and dried to obtain a yellow solid product 9-3 (281 mg, yield: 90%). [M+H] + :178.79.

[0125] Step 3: Synthesis of 6-{[(6-bromopyridin-2-yl)oxy]methyl}-7-fluoroquinoline (9-5)

[0126] 9-3 (100 mg, 0.565 mmol) was dissolved in DMF (5 mL), and NaH (27 mg, 0.678 mmol) was added at 0°C. The system was stirred at 0°C for 10 min, and 9-4 (109 mg, 0.565 mmol) was added dropwise at 0°C. The reaction was allowed to react at room temperature for 1 h. After the reaction was complete, water was added to quench the reaction, and the mixture was filtered. The filter cake was washed with water and dried to give the white solid product 9-5 (80 mg, yield: 43%). [M+H] + :334.16.

[0127] Step 4: Synthesis of methyl-2-[(2,6-difluoro-4-{6-[(7-fluoroquinolin-6-yl)methoxy]pyridin-2-yl}phenyl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylate (9-6)

[0128] 9-5 (57 mg, 0.321 mmol), 1-5 (160 mg, 0.321 mmol), RuPhos Pd G2 (25 mg, 0.032 mmol), RuPhos (15 mg, 0.032 mmol), K2CO3 (133 mg, 0.966 mmol) were dissolved in dioxane / H2O (5 mL / 1 mL) and stirred at 80°C for 2 h under nitrogen. The reaction solution was filtered through celite, the filter cake was washed with EA (10 mL), and the filtrate was concentrated to dryness to obtain the crude product, which was purified by column chromatography (V hexane :V EA =1:1) to give a white solid product 9-6 (84 mg, yield: 42%), [M+H] + :625.62.

[0129] Step 5: Synthesis of 2-[(2,6-difluoro-4-{6-[(7-fluoroquinolin-6-yl)methoxy]pyridin-2-yl}phenyl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (9)

[0130] 9-6 (84 mg, 0.135 mmol) was added to THF (5 mL), and H2O (1 mL) and LiOH (28 mg, 0.673 mmol) were added. The mixture was stirred at room temperature at 35°C for 20 h. After the reaction was completed, THF was concentrated to dryness, H2O (5 mL) was added, and the pH was adjusted to <3 with 1N HCl. The mixture was extracted with EA, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The product was stirred with EA (2 mL) for 2 h, and the filter cake was filtered and dried to obtain a white solid product 9 (4 mg, yield: 5%). [M+H] + :611.59.

[0131] 1H NMR (400MHz, DMSO-d6) δ8.93(d,J=4.4Hz,1H),8.42(d,J=8.4Hz,1H),8.27(s,1H),8.25(s,1H),7.92-7.73(m,6H),7.56-7.52(m,2H) ,7.00(d,J=8.0Hz,1H),5.75(s,2H),5.13-5.11(m,1H),4.83-4.77(m,1H),4.69-4.33(m,5H),2.77-2.72(m,1H),2.42-2.37(m,1H).

[0132] Example 10

[0133] Synthesis of 2-({2,6-difluoro-4-[2-(7-fluoroquinolin-6-yl)-2H-1,3-benzodioxetane-4-yl]phenyl}methyl)-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (10)

[0134]

[0135] Step 1: Synthesis of 2-bromo-6-[(7-fluoroquinolin-6-yl)(hydroxy)methyl]phenol (10-3)

[0136] 9-1 (500 mg, 2.21 mmol) was added to (10 mL) Et2O, and a THF solution of n-BuLi (1.3 mL, 1.99 mmol) was added dropwise at -78°C under a nitrogen atmosphere. After the reaction for 1 h, compound 10-2 (222 mg, 1.11 mmol) was added and the reaction was continued for 3 h. TLC showed that the raw material 9-1 was completely reacted. The mixture was warmed to room temperature and saturated ammonium chloride solution was added to quench the reaction solution. EA was added for extraction and the crude product was obtained by concentration. The crude product was purified by column chromatography (V hexane :V EA =15:1) to give a yellow solid product 10-3 (210 mg, yield: 27%), [M+H] + :348.2.

[0137] Step 2: Synthesis of 6-(4-bromo-2H-1,3-benzodioxetyl)-7-fluoroquinoline (10-4)

[0138] 10-3 (210 mg, 0.61 mmol) and NaIO4 (324 mg, 1.51 mmol) were dissolved in MeOH (2.5 mL) and H2O (0.5 mL) and reacted at room temperature under nitrogen atmosphere for 24 h. TLC showed that the reaction of the raw material 10-3 was complete. The reaction solution was filtered through celite, the filter cake was washed with EA, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by column chromatography (Vhexane :V EA =50:1) to give a white solid product 10-4 (180 mg, yield: 86%), [M+H] + :346.2.

[0139] Step 3: Synthesis of methyl-2-({2,6-difluoro-4-[2-(7-fluoroquinolin-6-yl)-2H-1,3-benzodioxetane-4-yl]phenyl}methyl)-1-{[(2S)-oxetane-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylate (10-6)

[0140] 10-4 (180 mg, 0.52 mmol), 1-5 (239 mg, 0.57 mmol), Pd(dppf)Cl2 (53 mg, 0.05 mmol), Cs2CO3 (340 mg, 1.04 mmol) were dissolved in Dioxane / H2O (10 mL / 2 mL) and refluxed at 90°C for 10 h under a nitrogen atmosphere. TLC showed that the reaction of the raw material 10-4 was complete. The reaction solution was filtered through celite, the filter cake was washed with EA, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by column chromatography (V hexane :V EA =1:1) to give a white solid product 10-6 (55 mg, yield: 18%), [M+H] + :638.2.

[0141] Step 4: Synthesis of 2-({2,6-difluoro-4-[2-(7-fluoroquinolin-6-yl)-2H-1,3-benzodioxetane-4-yl]phenyl}methyl)-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (10)

[0142] 10-6 (55 mg, 0.09 mmol) was added to MeOH (2 mL), and H2O (0.5 ml) and KOH (10 mg, 0.18 mmol) were added. The system was stirred at 40°C for 5 h. After the reaction was complete, MeOH was concentrated to dryness, H2O (2 mL) was added, and the pH was adjusted to 6-7 with 1N HCl. The crude product was extracted and concentrated with EA and purified by prep-TLC (V DCM :V MeOH =10:1) to give a white solid product (15 mg, yield: 28%), [M+H] + :624.2

[0143] 1H NMR (400MHz, DMSO-d6) δ9.01 (s, 1H), 8.57 (d, J = 8.4Hz, 1H), 8.42 (d, J = 7.8Hz, 1H), 8.15(s,1H),7.93(d,J=11.9Hz,1H),7.73(s,1H),7.69(s,1H),7.59(dd,J=13.9,8. 7Hz,3H),7.48(s,1H),7.35(d,J=7.8Hz,1H),7.09(dt,J=15.7,7.7Hz,2H),5.40(br s,1H),4.48-4.30(m,4H),4.01(s,1H),3.74(s,1H),2.03(brs,1H),1.93(brs,1H).

[0144] Example 11

[0145] Synthesis of 2-[(4-{1-[(4-chloro-2-fluorophenyl)methyl]-1H,2H,3H-pyrrolo[2,3-b]pyridin-6-yl}-2,6-difluorophenyl)methyl ester]-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (11)

[0146]

[0147] Step 1: Synthesis of 6-chloro-1-[(4-chloro-2-fluorophenyl)methyl]-1H,2H,3H-pyrrolo[2,3-b]pyridine (11-2)

[0148] Compound 4-3 (100 mg, 0.340 mmol) was dissolved in triethylsilane (5 mL) and stirred at 70°C for 12 h. The mixture was quenched with water, extracted with EA, dried over anhydrous sodium sulfate, and concentrated to obtain a colorless oily product 11-2 (115 mg), which was used directly in the next reaction without further purification.

[0149] Step 2: Synthesis of methyl-2-[(4-{1-[(4-chloro-2-fluorophenyl)methyl]-1H,2H,3Hpyrrolo[2,3-b]pyridin-6-yl}-2,6-difluorophenyl)methyl ester]-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylate (11-3)

[0150] 11-2 (115 mg, 0.387 mmol), 1-5 (212 mg, 0.426 mmol), Pd(dppf)Cl2 (28 mg, 0.039 mmol), Cs2CO3 (379 mg, 1.162 mmol) were dissolved in Dioxane / H2O (10 mL / 2 mL), and the system was reacted at 100 ° C for 16 h under nitrogen. The reaction solution was filtered through celite, the filter cake was washed with EA, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by column chromatography (V hexane :V EA =1:1) to give a white solid product 11-3 (16 mg, yield: 7%), [M+H] + :634.06.

[0151] Step 3: Synthesis of 2-[(4-{1-[(4-chloro-2-fluorophenyl)methyl]-1H,2H,3Hpyrrolo[2,3-b]pyridin-6-yl}-2,6-difluorophenyl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (11)

[0152] 11-3 (16 mg, 0.025 mmol) was added to THF (2 mL), and H2O (0.5 mL) and LiOH (5 mg, 0.126 mmol) were added. The system was stirred at room temperature (35°C) for 20 h. After the reaction was complete, THF was concentrated to dryness, H2O (5 mL) was added, and the pH was adjusted to 3-5 with 1N HCl. The product was extracted with EA and concentrated to obtain a crude product, which was purified by prep-TLC (V hexane :V EA =2:1) to give a white solid product 11 (1.5 mg, yield: 9%), [M+H] + :620.03.

[0153] 1H NMR(400MHz, DMSO-d6)δ8.24(d,J=1.6Hz,1H),7.78-7.75(m,3H),7.56(d,J=2.4Hz,1H),7.52 -7.39(m,3H),7.30(dd,J=8.4Hz,J=2.0Hz,1H),7.22(d,J=7.2Hz,1H),6.51(s,1H),5.12-5.09 (m,1H),4.82-4.76(m,1H),4.67-4.63(m,2H),4.55-4.51(m,2H),4.44-4.40(m,1H),4.38-4. 23(m,1H),3.54(t,J=8.4Hz,2H),3.04(t,J=8.4Hz,2H),2.76-2.68(m,1H),2.42-2.33(m,1H).

[0154] Example 12

[0155] Synthesis of 2-[(4-{1-[(4-chloro-2-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl}-2,6-difluorophenyl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (12)

[0156] Step 1: Synthesis of methyl-2-[(4-{1-[(tetrachloro-2-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl}-2,6-difluorophenyl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylate (12-1)

[0157] Compound 4-3 (53 mg, 0.181 mmol), 1-5 (90 mg, 0.181 mmol), Pd(dppf)Cl2 (13 mg, 0.018 mmol), Cs2CO3 (177 mg, 0.542 mmol) were dissolved in Dioxane / H2O (10 mL / 2 mL), and the system was reacted at 100 ° C for 5 h under nitrogen. The reaction solution was filtered through celite, the filter cake was washed with EA, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by column chromatography (V hexane :V EA =1:1) to give a white solid product 12-1 (40 mg, yield: 35%), [M+H] + :632.01.

[0158] Step 2: Synthesis of 2-[(4-{1-[(4-chloro-2-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl}-2,6-difluorophenyl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (12)

[0159] 12-1 (40 mg, 0.063 mmol) was added to MeOH (5 mL), and H2O (1 mL) and LiOH (13 mg, 0.317 mmol) were added. The system was stirred at room temperature (35°C) for 20 h. After the reaction was complete, MeOH was concentrated to dryness, H2O (5 mL) was added, and the pH was adjusted to 3-5 with 1N HCl. The product was extracted with EA and concentrated to obtain a crude product, which was purified by prep-TLC (V hexane :V EA =2:1) to give a white solid product 12 (18 mg, yield: 46%), [M+H] + :618.03.

[0160] 1 H NMR (400MHz, DMSO-d6) δ8.24(d,J=1.6Hz,1H),8.12(d,J=8.4Hz,1H),7.94(d,J=8.8Hz,2H) ,7.86(d,J=8.0Hz,1H),7.78-7.76(m,2H),7.56(d,J=8.4Hz,1H),7.48(dd,J=10.0Hz,J=2. 0Hz, 1H), 7.32-7.24 (m, 2H), 6.59 (d, J = 3.6Hz, 1H), 5.62 (s, 2H), 5.13 (d, J = 6.8Hz, 1H), 4.8 2-4.77(m,1H),4.65-4.58(m,1H),4.52-4.34(m,4H),2.77-2.73(m,1H),2.43-2.41(m,1H).

[0161] Example 13

[0162] Synthesis of 2-[(2,6-difluoro-4-{1-[(7-fluoroquinolin-6-yl)methyl]-1H-pyrrolo[2,3-b]pyridin-6-alkyl}phenyl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (13)

[0163]

[0164] Step 1: Synthesis of (7-fluoroquinolin-6-yl)methanol (13-2)

[0165] 13-1 (500 mg, 2.86 mmol) was dissolved in MeOH (10 mL). NaBH4 (326 mg, 8.57 mmol) was added in small portions in an ice-water bath. After 10 minutes of reaction, TLC showed that the reaction of the starting material was complete. Saturated ammonium chloride solution was added to quench the reaction. The reaction was extracted with DCM. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to give a yellow-white solid 13-2 (490 mg, yield: 97%). [M+H] + :178.16.

[0166] Step 2: Synthesis of 6-(6-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl}methyl)-7-fluoroquinoline (13-4)

[0167] 13-2 (490 mg, 2.77 mmol), 13-3 (597 mg, 3.05 mmol), Ph3P (943 mg, 3.60 mmol) were dissolved in THF (8 mL), and the system was stirred in an ice-water bath under a nitrogen atmosphere. A THF solution of DEAD (650 mg, 3.74 mmol) was slowly added dropwise. After 6 h of reaction, TLC showed that most of the reaction of the raw material 13-2 was complete. The reaction solution was quenched with saturated ammonium chloride solution and extracted with EA. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain the crude product, which was purified by column chromatography (V hexane :V EA =10:1) to give a white solid product 13-4 (370 mg, yield: 38%), [M+H] + :356.21.

[0168] Step 3: Synthesis of methyl-2-[(2,6-difluoro-4-{1-[(7-fluoroquinolin-6-yl)methyl]-1H-pyrrolo[2,3-b]pyridin-6-alkyl}phenyl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylate (13-6)

[0169] 13-4 (370 mg, 1.04 mmol), 1-5 (478 mg, 1.15 mmol), Pd(dppf)Cl2 (85 mg, 0.11 mmol), Cs2CO3 (680 mg, 2.08 mmol) were dissolved in Dioxane / H2O (5 mL / 1 mL) and the system was refluxed at 90°C for 8 h under a nitrogen atmosphere. TLC showed that the reaction of the raw material 13-4 was almost complete. The reaction solution was filtered through celite, the filter cake was washed with EA, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by column chromatography (V hexane :V EA=1:1) to give a white solid product 13-6 (210 mg, yield: 31%), [M+H] + :648.36.

[0170] Step 4: Synthesis of 2-[(2,6-difluoro-4-{1-[(7-fluoroquinolin-6-yl)methyl]-1H-pyrrolo[2,3-b]pyridin-6-alkyl}phenyl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazole-6-carboxylic acid (13)

[0171] 13-6 (210 mg, 0.32 mmol) was added to MeOH (3 mL), and H2O (0.6 mL) and KOH (36 mg, 0.65 mmol) were added. The system was stirred at 40°C for 6 h. After TLC showed that the reaction of the raw material 13-6 was complete, the MeOH was concentrated to dryness, H2O (3 mL) was added, and the pH was adjusted to 6-7 with 1N HCl. The product was extracted with EA and concentrated to obtain the crude product, which was purified by prep-TLC (V DCM :V MeOH =10:1) to give a white solid product 13 (120 mg, yield: 58%), [M+H] + :634.11.

[0172] 1 H NMR (400MHz, DMSO-d6) δ8.89(d,J=4.1Hz,1H),8.33(d,J=8.3Hz,1H),8.22(s,1H),8.13(d,J=8.2H z,1H),7.92(t,J=7.9Hz,3H),7.86(d,J=8.2Hz,1H),7.81(d,J=11.4Hz,1H),7.81–7.71(m,2H),7.5 7–7.44(m,2H),6.63(d,J=3.5Hz,1H),5.83(s,2H),5.42(d,J=5.8Hz,1H),4.51(dd,J=15.5,9.4Hz, 2H),4.45–4.27(m,1H),4.03(s,1H),3.80(dq,J=18.0,10.0,7.9Hz,2H),2.08(s,1H),1.95(s,1H).

[0173] Biological test cases

[0174] The GLP-1 receptor agonist efficacy of the compounds of the present invention was tested.

[0175] Cells, reagents, and consumables are as follows:

[0176]

[0177]

[0178] Experimental methods

[0179] Compound EC in CRE-Luc / GLP1R / HEK293 agonist mode 50 Determination (by Fire-Lumi TM Luciferase Assay Kit was used for detection. HEK293 / CRE-Luc / GLP1R cells in the logarithmic growth phase were harvested, counted, and resuspended in complete culture medium (DMEM + 10% FBS + 400 μg / mL G418 + 200 μg / mL Hygromycin B). The cells were adjusted to the appropriate concentration and seeded into a 384-well plate, with 20 μL of cell suspension added to each well. The cells were incubated overnight in a 37°C, 100% relative humidity, 5% CO2 incubator. The test compound was diluted in culture medium to the desired concentration and 20 μL was added to each well. The final concentration and dilution gradient of the test compound were determined based on specific requirements, e.g., 100 μM, 4-fold dilution, 9 concentrations, and 2 replicates. The cells were incubated in a 37°C, 100% relative humidity, 5% CO2 incubator for 6 h. 40 μL / well of One-Glo detection solution was added. After gentle shaking, the cells were measured on an ENVISION 2104 microplate reader. The curves were fitted and the EC values were calculated using the professional software Graphpad Prisma. 50 .

[0180] The experimental results show that the compound of the present invention exhibits a strong GLP-1 receptor agonist effect;

[0181] The experimental results of some compounds in the general structural formula of formula (I) and their closest structural formula (control group 1; preparation method refers to patent CN112533674A) are shown in Table 1:

[0182]

[0183] Table 1 GLP-1 receptor agonist effects of some compounds in the general structural formula (I)

[0184]

[0185] The experimental results of some compounds in the general structural formula of formula (II) and their closest structural formula (control group 2; preparation method refers to patent CN113227068A) are shown in Table 2:

[0186]

[0187]

[0188] Table 2 GLP-1 receptor agonist effects of some compounds in the general structural formula (II)

[0189]

[0190] The experimental results of some compounds in the general structural formula of formula (III) and their closest structural formula (control group 3; preparation method refers to patent WO2022068772A1) are shown in Table 3:

[0191]

[0192] Table 3 shows the agonist effects of some compounds in the general structural formula (III) on GLP-1 receptor.

[0193]

[0194] Liver microparticle stability test

[0195] Prepare liver microsomes of the desired species (e.g., mouse, rat, dog, monkey, or human). Prepare a 10 mM concentration of the test sample and positive control stock solutions using DMSO as the diluent. Then dilute all stock solutions to a working concentration of 0.25 mM with 70% acetonitrile. The cofactor used in this study is an NADPH regeneration system consisting of 6.5 mM NADP, 16.5 mM G-6-P, and 3 U / mL G-6-PD. The quenching reagent is an acetonitrile solution containing tolbutamide and propranolol. The buffer used in this study is 100 mM potassium phosphate buffer. A mixture containing 0.2 mg / mL liver microsomal protein and 1 μM test article / positive control is incubated in 100 mM potassium phosphate buffer.

[0196] 80 μL of each incubation solution was added to 300 μL of quenching reagent to precipitate proteins, preparing a 0-minute sample. After vortexing, 20 μL of NADPH regeneration system was added. The reaction was initiated by adding 130 μL of NADPH regeneration system to 520 μL of each incubation solution. The final incubation conditions in 650 μL were: 0.2 mg / mL microsomal protein, 1 μM band / positive control, 1.3 mM NADP, 3.3 mM glucose-6-phosphate, and 0.6 U / mL glucose-6-phosphate dehydrogenase. The mixture was placed in a 37°C water bath and gently shaken. At 0, 5, 10, 30, and 60 minutes, 100 μL of the mixture was aliquoted onto a 96-well plate containing 300 μL of quenching reagent to precipitate proteins and centrifuged (5000 × g, 10 minutes). 80 μL of the supernatant was added to a 96-well assay plate pre-filled with 160 μL of ultrapure water and analyzed by LC-MS / MS. Data processing to obtain the elimination half-life (T1 / 2 , T 1 / 2 =0.693 / K) and in vitro clearance (Cl int ).

[0197] The stability results of some compounds of the present invention in SD rat liver microsomes are shown in the following table (Table 4);

[0198] Table 4: Stability results of some compounds of the present invention in SD rat liver microsomes

[0199]

[0200] The experiment found that the compound of the present invention has a T 1 / 2 (min)>80min, preferably T 1 / 2 (min)>100min, with good liver microparticle metabolic stability.

[0201] Pharmacokinetic experiments

[0202] The compound under study is administered orally or intravenously (solvent 5% DMSO + 10% Solutol (HS-15) + 85% saline) to animals (such as mice, rats, dogs or monkeys) and blood is collected at fixed time points. Immediately after blood sample collection, the test tube is gently inverted at least 5 times to ensure sufficient mixing and then placed on ice. The blood is anticoagulated with heparin and then centrifuged at 8000rpm for 5 minutes to separate the serum from the red blood cells. The serum is aspirated with a pipette and transferred to a 2mL polypropylene tube, labeled with the name of the compound and the time point, and stored in a -40°C refrigerator before LC-MS analysis. High-concentration samples are diluted with blank plasma for measurement. After sample processing, the substances in the plasma are quantitatively analyzed by LCMS / MS. The plasma concentration / time curve obtained in this way is used to calculate the pharmacokinetic parameters using a validated pharmacokinetic computer program. The experiment found that the compounds of the present invention all have good pharmacokinetic properties.

[0203] After oral administration of the compounds listed in Table 5 (equimolar doses in each group, with the vehicle consisting of 5% DMSO + 10% Solutol (HS-15) + 85% saline, 3 rats per group), blood samples were collected at fixed time points for analysis. The pharmacokinetic parameters of the unmodified free molecules in rat plasma for some of the compounds of this invention are shown in Table 5.

[0204] Table 5: Pharmacokinetic parameters of prototype free molecules of some compounds of the present invention in rat plasma.

[0205]

[0206] The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, not all possible combinations of the technical features in the above-mentioned embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0207] The above-described embodiments merely illustrate several implementations of the present invention, and while their descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the patent. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the patent for this invention shall be determined by the appended claims.

Claims

1. A compound of formula (II) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in, Ring A is selected from phenyl, pyridyl, and quinoline; Each R 1 and R 2 independently selected from H, halogen, -CN, -OH, C 2-6 Alkynyl, C 2-6 Alkenyl, C 1-6 Alkyl, -OC 1-6 Alkyl, halogenated C 1-6 alkyl; R 3 Selected from C 1-6 alkyl, wherein the alkyl group may be substituted by 1 to 3 halogens, -CN, -OC 1-6 Alkyl substitution; Z1 is selected from CH or N; n and m are each independently selected from 0, 1, 2, 3, and 4.

2. The compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that: in, Ring A is selected from phenyl, quinoline; each R 1 Independently selected from halogen, -CN; each R 2 Independently selected from H, halogen.

3. The compound according to claim 1 or its stereoisomer, or its pharmaceutically acceptable salt, characterized in that: where R 3 Selected from 4. The compound according to claim 1 or its stereoisomer, or its pharmaceutically acceptable salt, characterized in that: The compound is selected from any of the following structures:

5. A pharmaceutical composition comprising a compound of formula (II) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

6. Use of the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 5, in the preparation of a medicament for treating cardiometabolic diseases and related diseases, wherein the disease is T2DM or obesity.

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