Method for producing GLP-1R agonist, intermediate and use thereof

Abstract

The invention relates to a preparation method and an intermediate for preparing a GLP-1R agonist compound as shown in a formula (I) or a pharmaceutically acceptable salt of the GLP-1R agonist compound. According to the method, the defects in the prior art are overcome, the cost is greatly reduced, the obtained product is good in purity and high in yield, the process operability is high, and the process safety is also greatly improved. Therefore, the preparation method and the application thereof are suitable for industrial application.

Description

GLP-1R agonist manufacturing method and intermediates and their uses

[0001] This application claims priority to a prior application, patent application number 202310105038.4, filed with the State Intellectual Property Office of China on January 19, 2023, entitled "Methods for producing GLP-1R agonists, intermediates thereof, and uses thereof." The entirety of that prior application is incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of medicinal chemistry and specifically relates to a method for producing a novel GLP-1R agonist and intermediates thereof. The present invention also relates to a method for preparing a medicament comprising such a compound for treating or preventing diseases associated with GLP1 / GLP1R. Technical Background

[0003] Diabetes is a chronic disease characterized by high blood sugar levels, caused by insufficient insulin secretion (relative or absolute) or impaired insulin action. According to the 9th edition of the World Diabetes Atlas, published by the International Diabetes Federation (IDF), approximately 463 million adults (aged 20-79) worldwide suffered from diabetes in 2019, and the number is projected to reach 578 million by 2030. If this trend continues, there will be 700 million people with diabetes worldwide by 2045. Therefore, diabetes has become one of the most serious global health issues of the 21st century.

[0004] Various pharmacological approaches are currently used to treat hyperglycemia and the accompanying T2DM (Hampp et al., Use of Antidiabetic Drugs in the US, 2003-2012, Diabetes Care 37:1367-1374, 2014). These approaches can be divided into six main categories, each of which works through a different primary mechanism.

[0005] Insulin secretagogues, including sulfonylureas, dipeptidyl peptidase IV (DPP-IV) inhibitors, and glucagon-like peptide-1 receptor (GLP-1R) agonists, increase insulin secretion by acting on pancreatic beta cells. Sulfonylureas have limited efficacy and tolerability, causing weight gain and often inducing hypoglycemia. DPP-IV inhibitors have limited efficacy. Marketed GLP-1R agonists are peptides administered by subcutaneous injection. Liraglutide is also approved for the treatment of obesity.

[0006] Biguanides (eg, metformin) are thought to act primarily by reducing hepatic glucose production. Biguanides often cause gastrointestinal upset and lactic acidosis, further limiting their use.

[0007] Alpha-glucosidase inhibitors (e.g., acarbose) reduce intestinal glucose absorption. These agents often cause gastrointestinal discomfort.

[0008] Thiazolidinediones (e.g., pioglitazone, rosiglitazone) act on specific receptors in the liver, muscle, and adipose tissue. They modulate lipid metabolism and subsequently enhance the responsiveness of these tissues to insulin. Frequent use of these drugs can lead to weight gain and may induce edema and anemia.

[0009] Insulin, alone or in combination with the above agents, is used in more severe cases, and regular use may also lead to weight gain and carries the risk of hypoglycemia.

[0010] Sodium-glucose linked cotransporter 2 (SGLT2) inhibitors (e.g., dapagliflozin, empagliflozin, canagliflozin, ertugliflozin) inhibit glucose reabsorption in the kidneys, thereby lowering blood glucose levels. This class of drugs may be associated with ketoacidosis and urinary tract infections.

[0011] In addition to diabetes, with the improvement of material living standards, overweight or obesity is becoming more and more common. The number of patients with complications caused by obesity, such as diabetes and fatty liver, is increasing. A report released by the World Health Organization (WHO) and Zhiyan Consulting predicts that by 2030, the number of obese patients in the world will reach 3.26 billion; by 2029, the number of global diabetes patients will exceed 500 million; and the number of global non-alcoholic fatty liver disease patients will exceed 1.5 billion. Currently, there is no effective treatment for fatty liver; there are only six FDA-approved drugs for the treatment of obesity, and most of them are controlled drugs with weak efficacy and significant side effects; although many drugs for the treatment of type 2 diabetes have been approved for marketing, the blood sugar-lowering rate of existing hypoglycemic drugs (<7%) has always been low, and even the most active compound has a target-lowering rate of only around 45%. Therefore, whether it is fatty liver, obesity, or diabetes, new drugs need to be developed to meet the needs of a wider range of patients.

[0012] GLP-1 is a 30-amino acid incretin hormone secreted by intestinal L cells in response to food intake. GLP-1 has been shown to stimulate insulin secretion, reduce glucagon secretion, inhibit gastric emptying, reduce appetite, and stimulate beta-cell proliferation in a physiological and glucose-dependent manner. In nonclinical studies, GLP-1 has been shown to promote sustained beta-cell capacity by stimulating the transcription of genes important for glucose-dependent insulin secretion and by promoting beta-cell neogenesis.

[0013] Scientific research has led to structural modifications and alterations of GLP-1 to increase its half-life and thus prolong its biological effects in vivo. However, long-acting GLP-1 analogs currently in clinical use, such as liraglutide and exenatide, are peptides with poor stability, requiring refrigeration and portability. Frequent, multiple injections lead to poor patient compliance, and compared to small molecules, they are expensive and impose a significant burden on patients. Therefore, the development of small-molecule GLP-1R agonists holds broad clinical market potential, aiming to improve patient compliance, ease of portability and administration, and reduce side effects and costs.

[0014] Mindrank AI Ltd., a subsidiary of Hangzhou Mindrank AI, has developed a novel small molecule compound with GLP-1R agonist activity during its early research. The relevant patent application number is PCT / CN2022 / 075295. The structures of its representative compounds I-1 and I-2 are as follows:

[0015] The chemical name of compound I-1 is (S)-2-(4-(6-(4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0016] The chemical name of compound I-2 is (S)-2-(4-(6-(4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0017] This type of compound can significantly activate the GLP-1R target and is an excellent GLP1R agonist. Its maximum agonistic effect can reach or even exceed that of the GLP1 polypeptide.

[0018] Existing methods for preparing Compound I-1 or Compound I-2 have low yields (total yields of only approximately 7%-9%), are not optimized, and require post-processing by column chromatography, which is costly and complex, making scale-up difficult and severely limiting industrial production. Successful drug development typically requires simple operation, mild conditions, stable quality, and processes suitable for industrial production. To meet the needs of clinical research and marketed pharmaceutical preparations, there is an urgent need for a cost-effective manufacturing method suitable for industrial production.

[0019] Summary of the Invention

[0020] To address the problems existing in the prior art, the inventors have developed a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof during a long research and development process. The method has simpler operation, significantly improved yield (total yield can reach 50%), lower cost, mild reaction conditions, mature process, stable quality, and is very suitable for industrial application.

[0021] In the first aspect of the present invention, a compound represented by Formula III or an acid salt thereof having the following structure is provided:

[0022] Wherein, R1 is selected from chlorine or cyano, R2 is selected from hydrogen atom or amino protecting group, and the acid salt is a salt formed by the compound and an acid, such as hydrobromide, hydrochloride, sulfate, bisulfate, sulfite, phosphate, borate, acetate, trifluoroacetate, oxalate, valerate, benzoate, lactate, toluate, citrate, malate, maleate, fumarate, succinate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.

[0023] According to an embodiment of the present invention, the amino protecting group is benzyloxycarbonyl, tert-butoxycarbonyl, allylcarbonyl, fluorenylmethyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, trimethylsilylethoxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, o-nitrobenzenesulfonyl, p-nitrobenzenesulfonyl, pivaloyl, benzoyl, trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl or benzyl, preferably benzyloxycarbonyl, tert-butoxycarbonyl or benzyl.

[0024] According to an embodiment of the present invention, the compound represented by formula III has the following structure:

[0025] According to an embodiment of the present invention, the acid salt of the compound represented by formula III has the following structure:

[0026] The present invention also provides a compound represented by Formula II or an acid salt thereof having the following structure:

[0027] wherein R1 is selected from chlorine or cyano;

[0028] R3 is selected from C 1-20 Alkyl, C 6-14 Aryl, C 6-14 Aryl C 1-20 Alkyl, wherein the C 1-20 Alkyl, C 6-14 Aryl, C 6-14 Aryl C 1-20 The alkyl groups are each independently optionally substituted with halogen, C 1-20 Alkyl, halogenated C 1-20 Alkyl, C 1-20 Alkoxy, halogenated C 1-20 Alkoxy, cyano, amino, nitro, hydroxy, oxo (=O), carboxyl and hydroxy-C 1-20 The alkyl group is substituted by one or more substituents, and R3 is preferably methyl, ethyl, tert-butyl or benzyl;

[0029] According to an embodiment of the present invention, R3 is selected from C 1-10 Alkyl or C 6-14 Aryl C 1-10 Alkyl, the C 1-10 Alkyl or C 6-14 Aryl C 1-10 The alkyl groups are each independently optionally substituted with halogen, C 1-10 Alkyl, halogenated C 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkoxy, carboxyl and hydroxy-C 1-10 The alkyl group is substituted by one or more substituents.

[0030] According to an embodiment of the present invention, R3 is selected from C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, tert-butyl.

[0031] According to an embodiment of the present invention, R3 is selected from C 6-14 Aryl C 1-6 Alkyl groups, such as benzyl.

[0032] According to an embodiment of the present invention, the compound shown in Formula II has the following structure:

[0033] The present invention further provides a method for preparing the compound represented by formula I or a pharmaceutically acceptable salt thereof:

[0034] The method comprises the following steps: hydrolyzing a compound represented by formula II or an acid salt thereof with a suitable base, wherein the suitable base is selected from lithium hydroxide, sodium hydroxide or potassium hydroxide.

[0035] wherein R1 is selected from chlorine or cyano;

[0036] R3 is selected from C 1-20 Alkyl, C 6-14 Aryl or C 6-14 Aryl C 1-10 Alkyl, wherein the C 1-20 Alkyl, C 6-14 Aryl or C 6-14 Aryl C 1-10 The alkyl groups are each independently optionally selected from halogen, C 1-20 Alkyl, halogenated C 1-20 Alkyl, C 1-20 Alkoxy, halogenated C 1-20 Alkoxy, cyano, amino, nitro, hydroxy, oxo (=O), carboxyl and hydroxy-C 1-20 The alkyl group is substituted by one or more substituents, preferably methyl, ethyl or tert-butyl.

[0037] According to an embodiment of the present invention, R3 is selected from C 1-10 Alkyl or C 6-14 Aryl C 1-10 Alkyl, the C 1-10 Alkyl or C 6-14 Aryl C 1-10 The alkyl groups are each independently optionally substituted with halogen, C 1-10 Alkyl, halogenated C 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkoxy, carboxyl and hydroxy-C 1-10 According to an embodiment of the present invention, R3 is selected from C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, tert-butyl.

[0038] According to an embodiment of the present invention, R3 is selected from C 6-14 Aryl C 1-6 Alkyl groups, such as benzyl.

[0039] The present invention also provides another method for preparing the compound represented by formula I or a pharmaceutically acceptable salt thereof:

[0040] The method comprises the steps of subjecting a compound represented by formula IIIa or its acid salt to a nucleophilic substitution reaction with a compound represented by formula IV to prepare a compound represented by formula I or a pharmaceutically acceptable salt thereof.

[0041] wherein R1 is selected from chlorine or cyano; and X represents a suitable leaving group, in particular chlorine, bromine, iodine, mesylate, triflate or p-toluenesulfonate.

[0042] In some aspects, the present invention provides a method wherein the nucleophilic substitution reaction is carried out in the presence of a suitable base, wherein the base is selected from one or more of potassium phosphate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, morpholine, N-methylmorpholine or pyridine, preferably potassium carbonate, sodium bicarbonate or triethylamine.

[0043] The present invention further provides a method for preparing the compound represented by formula II or its acid salt:

[0044] The method comprises the following steps: a compound represented by formula IIIa or its acid salt undergoes a nucleophilic substitution reaction with a compound represented by formula V to generate a compound represented by formula II or its acid salt.

[0045] wherein R1 is selected from chlorine or cyano;

[0046] R3 is selected from C 1-20 Alkyl, C 6-14 Aryl or C 6-14 Aryl C 1-10 Alkyl, wherein the C 1-20 Alkyl, C 6-14 Aryl or C 6-14 Aryl C 1-10 The alkyl groups are each independently optionally selected from halogen, C 1-20 Alkyl, halogenated C 1-20 Alkyl, C 1-20 Alkoxy, halogenated C 1-20 Alkoxy, cyano, amino, nitro, hydroxy, oxo (=O), carboxyl and hydroxy-C 1-20 The alkyl group is substituted by one or more substituents.

[0047] According to an embodiment of the present invention, R3 is selected from C 1-10 Alkyl or C 6-14 Aryl C 1-10 Alkyl, the C 1-10 Alkyl or C 6-14 Aryl C 1-10 The alkyl groups are each independently optionally substituted with halogen, C 1-10 Alkyl, halogenated C 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkoxy, carboxyl and hydroxy-C 1-10 The alkyl group is substituted by one or more substituents.

[0048] According to an embodiment of the present invention, R3 is selected from C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, tert-butyl.

[0049] According to an embodiment of the present invention, R3 is selected from C 6-14 Aryl C 1-6 Alkyl groups, such as benzyl.

[0050] In some aspects, the present invention provides a method wherein the nucleophilic substitution reaction is carried out in the presence of a suitable base, wherein the base is selected from one or more of potassium phosphate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, morpholine, N-methylmorpholine or pyridine, preferably potassium carbonate, sodium bicarbonate or triethylamine.

[0051] The present invention also provides a method for preparing the compound represented by IIIa:

[0052] The method comprises the following steps: deprotecting a compound represented by formula IIIb or an acid salt thereof to generate a compound represented by formula IIIa or an acid salt thereof.

[0053] Wherein, R1 is selected from chlorine or cyano; R2 is selected from benzyloxycarbonyl, tert-butyloxycarbonyl, allylcarbonyl, methyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, trimethylsilylethoxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, o-nitrobenzenesulfonyl, p-nitrobenzenesulfonyl, pivaloyl, benzoyl, trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl or benzyl, preferably benzyloxycarbonyl, tert-butyloxycarbonyl or benzyl.

[0054] The present invention further provides a method for preparing a compound represented by formula III or an acid salt thereof:

[0055] The method comprises the following steps: subjecting a compound represented by formula VI to a compound represented by formula VII through Mitsunobu reaction to obtain a compound represented by formula III or an acid salt thereof.

[0056] Wherein, R1 is selected from chlorine or cyano, and R2 is selected from hydrogen atom or amino protecting group.

[0057] In some aspects, the amino protecting group is benzyloxycarbonyl, tert-butoxycarbonyl, allylcarbonyl, fluorenylmethyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, trimethylsilylethoxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, o-nitrobenzenesulfonyl, p-nitrobenzenesulfonyl, pivaloyl, benzoyl, trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl or benzyl, preferably benzyloxycarbonyl, tert-butoxycarbonyl or benzyl.

[0058] The present invention further provides a method for preparing a compound represented by formula III or an acid salt thereof:

[0059] The method comprises the following steps: subjecting a compound represented by formula VIII to a substitution reaction with a compound represented by formula IX to obtain a compound represented by formula III or an acid salt thereof.

[0060] wherein R1 is selected from chlorine or cyano, and R2 is selected from a hydrogen atom or an amino protecting group. In some aspects, the amino protecting group is benzyloxycarbonyl, tert-butyloxycarbonyl, allylcarbonyl, fluorenylmethyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, trimethylsilylethoxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, o-nitrobenzenesulfonyl, p-nitrobenzenesulfonyl, pivaloyl, benzoyl, trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl, or benzyl, preferably benzyloxycarbonyl, tert-butyloxycarbonyl, or benzyl; and X represents a suitable leaving group, particularly chlorine, bromine, iodine, methanesulfonate, trifluoromethanesulfonate, or p-toluenesulfonate.

[0061] The present invention further provides a method for preparing a compound represented by formula III or an acid salt thereof:

[0062] The method comprises the steps of subjecting a compound represented by formula VI to a substitution reaction with a compound represented by formula X to obtain a compound represented by formula III or an acid salt thereof.

[0063] Wherein, R1 is selected from chlorine or cyano, and R2 is selected from hydrogen atom or amino protecting group.

[0064] In some aspects, the amino protecting group is benzyloxycarbonyl, tert-butyloxycarbonyl, allylcarbonyl, fluorenylmethyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, trimethylsilylethoxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, o-nitrobenzenesulfonyl, p-nitrobenzenesulfonyl, pivaloyl, benzoyl, trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl or benzyl, preferably benzyloxycarbonyl, tert-butyloxycarbonyl or benzyl. R represents a suitable leaving group, in particular chlorine, bromine, iodine, methanesulfonate, trifluoromethanesulfonate or p-toluenesulfonate.

[0065] The present invention also provides a method for preparing the compound represented by formula VII:

[0066] The method comprises the steps of generating a compound represented by formula VII by a nucleophilic substitution reaction between a compound represented by formula IX and a compound represented by formula XI.

[0067] Wherein, R2 is selected from benzyloxycarbonyl, tert-butoxycarbonyl, allylcarbonyl, fluorenylmethyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, trimethylsilylethoxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, o-nitrobenzenesulfonyl, p-nitrobenzenesulfonyl, pivaloyl, benzoyl, trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl or benzyl, preferably benzyloxycarbonyl, tert-butoxycarbonyl or benzyl; X' is selected from fluorine, chlorine, bromine, iodine, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, methanesulfonyloxy, p-nitrobenzenesulfonyloxy, preferably chlorine, bromine or methanesulfonyloxy.

[0068] The present invention further provides another method for preparing the compound represented by formula VII:

[0069] The method comprises the steps of first subjecting a compound represented by formula IX to a nucleophilic substitution reaction with a compound represented by formula XII to generate a compound represented by formula XIII, and then reacting the reaction in the presence of a reducing agent to obtain a compound represented by formula VII.

[0070] wherein R2 and X' are the same as described above; the reducing agent is selected from lithium aluminum hydride, lithium borohydride, sodium borohydride, potassium borohydride, borane and tetrahydrofuran, borane and dimethyl sulfide, borane and diphenyl sulfide, borane and dibenzyl sulfide, borane and dioxane, a complex of borane and 1,4-oxathiazole, or a complex of BH2Cl and dimethyl sulfide, preferably a complex of sodium borohydride, borane and tetrahydrofuran, or borane and dimethyl sulfide.

[0071] In addition, the present invention provides a pharmaceutical composition comprising the aforementioned compound I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0072] The present invention further provides a use of the aforementioned compound I or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating metabolic diseases, tumors, autoimmune diseases or metastatic diseases.

[0073] The present invention also provides the aforementioned compound I or a pharmaceutically acceptable salt thereof, which is used as a drug for treating metabolic diseases, tumors, autoimmune diseases or metastatic diseases.

[0074] The present invention further provides a compound I or a pharmaceutically acceptable salt thereof for use in treating 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, NAS, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction, stroke, Drugs for the prevention or treatment of hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipidosis, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome XI, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, poor glucose metabolism, impaired fasting blood glucose conditions, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcers, ulcerative colitis, hyperapoB 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 the treatment of addiction.

[0075] As a preferred embodiment, the aforementioned compound I or a pharmaceutically acceptable salt thereof is used as a drug for treating 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, obesity, eating disorders, weight gain caused by the use of other agents, excessive sugar addiction, dyslipidemia, and hyperinsulinemia.

[0076] The technical solution of the present invention does not require column chromatography during the synthesis of the compound of formula I, the reaction conditions are mild, the yield is significantly improved, and the use of precious metal catalysts can be avoided in the entire process, effectively reducing the reaction cost, facilitating the scale-up of the reaction, and being more suitable for industrial production.

[0077] Definition and Description

[0078] Unless otherwise stated, the following terms used in the specification and claims have the following meanings. A particular phrase or term should not be considered ambiguous or unclear without a specific definition, but should be understood according to its ordinary meaning.

[0079] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0080] As used herein, "salt" refers to a compound prepared by reacting an organic acid or base drug with a pharmaceutically acceptable inorganic or organic acid or base.

[0081] Unless otherwise indicated, numerical ranges recited in this specification and claims are equivalent to reciting at least each specific integer value therein. For example, the numerical range "1-20" is equivalent to reciting each integer value in the numerical range "1-10", namely, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and each integer value in the numerical range "11-20", namely, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.

[0082] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0083] The term "C 1-20 "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched saturated monovalent hydrocarbon groups of 1 to 20 carbon atoms. Preferably, the alkyl group (C 1-10 More preferred are lower alkyl groups (C 1-6 alkyl), such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or tert-butyl, pentyl, heptyl, and the like.

[0084] The term "C 3-20 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (such as condensed, bridged, spiro) hydrocarbon ring or tricyclic alkane having 3 to 20 carbon atoms, preferably "C 3-10 Cycloalkyl", more preferably "C 3-8 Cycloalkyl". The term "C 3-10 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (eg bridged, spiro) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. 3-10The cycloalkyl group may be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as borneol, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonyl, 2,6-diazaspiro[3,4]octyl, or a tricyclic hydrocarbon group such as adamantyl.

[0085] The term "C 1-20 "Alkoxy" refers to -O-(C 1-20 alkyl) and ‐O‐(C 3-20 cycloalkyl), wherein C 1-20 Alkyl and C 3-20 Cycloalkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0086] The term "C 6-14 "Aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, preferably a 6- to 10-membered (C 6-10 aryl), such as phenyl and naphthyl.

[0087] The "amino protecting group" of the present invention is a group known in the art that can be used to protect amino groups, see the literature ("Protective Groups in Organic Synthesis", 5 Th .Ed.TW Greene & P.GMWuts). As an example, the amino protecting group is selected from tert-butyloxycarbonyl, acetyl, benzyl, allyl or p-methoxybenzyl, or the amino protecting group together with the nitrogen atom to which it is bound forms a lactam, such as phthaloyl. The method of removing the protecting group can also be referred to the literature ("Protective Groups in Organic Synthesis", 5 ThThe methods for removing amino protecting groups are described in [Ed. T. W. Greene & P. ​​G. M. Wuts], and the relevant content is incorporated herein. As an example, the benzyl group is removed using hydrogen / metal catalyst, wherein the metal catalyst is selected from, but not limited to, at least one of palladium on carbon, palladium hydroxide, platinum oxide, palladium, palladium on alumina, platinum on activated carbon, and Raney nickel, preferably palladium on carbon or palladium hydroxide. The tert-butyloxycarbonyl (Boc) group is removed under acidic conditions, wherein the reagent providing the acidic conditions is preferably selected from methanesulfonic acid, hydrochloric acid, and trifluoroacetic acid.

[0088] As used herein, the term "room temperature" or "RT" refers to an ambient temperature of 20 to 25°C.

[0089] The intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0090] The chemical reactions of the present invention are carried out in suitable solvents that are compatible with the chemical transformations of the present invention and the reagents and materials required. To obtain the compounds of the present invention, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0091] The present invention will be described in detail below through examples, which are not intended to limit the present invention in any way.

[0092] All solvents used in the present invention were commercially available and used without further purification.

[0093] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring, the solvent is a dry solvent, and the temperature unit is degrees Celsius (°C).

[0094] Methods and Materials

[0095] The structures of the compounds were determined by nuclear magnetic resonance (NMR). NMR shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker avance-400 MHz NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (MeOD-d4). The internal standard was tetramethylsilane (TMS). Chemical shifts were expressed in 10 -6 ppm) as the unit.

[0096] HPLC determination was performed using an Agilent 1260 high performance liquid chromatograph or a high performance liquid chromatograph of equivalent performance (Sunfire C18 150×4.6m column or a column of equivalent performance).

[0097] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm. DETAILED DESCRIPTION

[0098] The present invention is further described in detail and completely by the following examples, which are only used to illustrate specific embodiments of the present invention and should not be interpreted as limiting the scope of the present invention in any way. Unless otherwise stated, all percentages, ratios, proportions, or parts are by weight. The monitoring of the reaction process in the examples is performed by thin layer chromatography (TLC).

[0099] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0100] Example 1: Preparation of tert-butyl 4-(6-(hydroxymethyl)pyridin-2-yl)oxy)piperidine-1-carboxylate:

[0101] To a solution of N-tert-butoxycarbonyl-4-hydroxypiperidine (10.0 g, 0.05 mol) in tetrahydrofuran (100 mL) was added potassium tert-butoxide (1 M tetrahydrofuran solution, 100 mL, 0.1 mol). The internal temperature was controlled to be <30°C. After the addition was completed, the mixture was stirred at room temperature for 2 hours. A solution of 6-bromopyridine-2-methanol (9.4 g, 0.05 mol) in tetrahydrofuran (30 mL) was slowly added dropwise. The internal temperature was controlled to be <20°C. After the addition was completed, the mixture was heated to 50°C and stirring was continued for 6 hours. Ethyl acetate (100 mL) was added to the reaction system for dilution, cooled to 0-10° C., and quenched by adding dropwise saturated aqueous ammonium chloride solution (50 mL). Formic acid was added dropwise to adjust the pH to 6. The layers were separated, and the aqueous phase was extracted twice with ethyl acetate (100 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was added with ethyl acetate (20 mL) and n-hexane (100 mL), cooled to 0° C., stirred for 2 hours, filtered, and the filter cake was dried in vacuo to give tert-butyl 4-(6-(hydroxymethyl)pyridin-2-yl)oxy)piperidine-1-carboxylate (9.3 g, yield: 60.4%). 1H NMR (400MHz, DMSO-d6) δ7.67(t,J=7.8Hz,1H),7.02(d,J=7.2Hz,1H),6.62(d,J=8.2Hz,1H),5.32(s,1H),5.21-5.08(m ,1H),4.44(s,2H),3.66(dt,J=10.1,4.5Hz,2H),3.25-3.08(m,2H),1.95-1.87(m,2H),1.60-1.48(m,2H),1.41(s,9H).

[0102] Example 2: Preparation of tert-butyl 4-(6-(hydroxymethyl)pyridin-2-yl)oxy)piperidine-1-carboxylate:

[0103] 1) Preparation of 6-(1-(tert-butyloxycarbonyl)piperidin-4-yl)oxy)picolinic acid:

[0104] To tetrahydrofuran (400 mL) dissolved with N-tert-butyloxycarbonyl-4-hydroxypiperidine (20.1 g, 0.1 mol) was added 60% sodium hydride (10.0 g, 0.25 mol) in portions, and the internal temperature was controlled to be <25°C. After the addition was completed, the mixture was stirred at room temperature for 2 hours. 6-bromopyridine-2-carboxylic acid (20.2 g, 0.1 mol) was added in portions. After the addition was completed, the temperature was raised to 60°C and stirring was continued for 12 hours. Ethyl acetate (300 mL) was added to the reaction system for dilution, cooled to 0-10° C., and added dropwise to a saturated aqueous ammonium chloride solution (100 mL) for quenching. A 1 M aqueous hydrochloric acid solution was added dropwise to adjust the pH to 4. The layers were separated, and the aqueous phase was extracted twice with ethyl acetate (200 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 6-(1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)picolinic acid (26.4 g, yield: 82.0%). 1 H NMR (400MHz, CDCl3) δ7.83-7.82(m,2H),7.02(d,J=7.2Hz,1H),5.26-5.20(m,1H),3.7 6-3.70(m,2H),3.42-3.37(m,2H),2.02-1.97(m,2H),1.82-1.79(m,2H),1.48(s,9H).

[0105] 2) Preparation of tert-butyl 4-(6-(hydroxymethyl)pyridin-2-yl)oxy)piperidine-1-carboxylate:

[0106] Dissolve 6-(1-(tert-Butyloxycarbonyl)piperidin-4-yl)oxy)picolinic acid (25.8 g, 0.08 mol) in tetrahydrofuran (200 mL), cool to 0°C, add sodium borohydride (5.7 g, 0.15 mol) in batches, and then add boron trifluoride ether solution (45 mL) dropwise. Control the internal temperature to <25°C. After addition, react at room temperature for 3 hours. The reaction system was cooled to 0°C and quenched by adding saturated aqueous sodium bicarbonate solution (100 mL). Water (100 mL) and ethyl acetate (300 mL) were added, the layers were separated, the aqueous phase was extracted with ethyl acetate (200 mL), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, the filter cake was dried under vacuum, filtered and concentrated, ethyl acetate (20 mL) and n-hexane (100 mL) were added to the crude product, the temperature was cooled to 0°C, the mixture was stirred for 2 hours, filtered, and the filter cake was dried under vacuum to give tert-butyl 4-(6-(hydroxymethyl)pyridin-2-yl)oxy)piperidine-1-carboxylate (19.9 g, yield: 80.6%).

[0107] Example 3: Preparation of (6-(piperidin-4-oxy)pyridin-2-yl)methanol hydrochloride

[0108] To tert-butyl 4-(6-(hydroxymethyl)pyridin-2-yl)oxy)piperidine-1-carboxylate (30.8 g, 0.1 mol) dissolved in ethyl acetate (150 mL) was added dropwise 3 M ethyl acetate hydrochloride (100 mL, 0.3 mol), and the internal temperature was controlled to <25°C. After the addition was completed, the mixture was stirred at room temperature for 12 hours, filtered, and the filter cake was washed twice with ethyl acetate (100 mL). The filter cake was dried in vacuo to give (6-(piperidin-4-oxy)pyridin-2-yl)methanol hydrochloride (22.6 g, yield: 92.4%).

[0109] Example 4: Preparation of 2-(4-chloro-2-fluorophenoxy)methyl)-6-(piperidin-4-oxy)pyridine

[0110] (6-(Piperidin-4-oxy)pyridin-2-yl)methanol hydrochloride (19.5 g, 0.08 mol) and 2-fluoro-4-chlorophenol (11.7 g, 0.08 mol) were added to tetrahydrofuran (200 mL). The temperature was lowered to 0°C, and triphenylphosphine (41.9 g, 0.16 mol) and diisopropyl azodicarboxylate (32.4 g, 0.16 mol) were added sequentially. After addition, the mixture was warmed to room temperature and reacted for 12 hours. Ethyl acetate (200 mL) and saturated aqueous sodium chloride solution (100 mL) were added to the reaction system. The layers were separated, and the aqueous phase was extracted twice with ethyl acetate (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was added to a mixture of petroleum ether and ethyl acetate (10:1) (250 mL), stirred at room temperature for 12 hours, filtered, and the filtrate was concentrated to obtain the crude product. A mixed solution of petroleum ether and ethyl acetate (3:1) (100 mL) was added, followed by anhydrous magnesium chloride (7.6 g, 0.08 mol). The temperature was raised to 35°C and stirred for 6 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give 2-(4-chloro-2-fluorophenoxymethyl)-6-(piperidin-4-oxy)pyridine (19.6 g, yield: 72.9%). 1 H NMR (400MHz, DMSO-d6) δ8.77(br,1H),7.77(t,J=7.8Hz,1H),7.46(dd,J=11.2,2.3Hz,1H),7.28(t,J=8.9Hz,1H),7.24-7.18(m,1H),7.1 1(d,J=7.3Hz,1H),6.79(d,J=8.2Hz,1H),5.22-5.10(m,3H),3.31-3.21(m,2H),3.19-3.04(m,2H),2.18-2.04(m,2H),1.94-1.75(m,2H).

[0111] Example 5: Preparation of 2-(4-cyano-2-fluorophenoxy)methyl)-6-(piperidin-4-oxy)pyridine

[0112] (6-(Piperidin-4-oxy)pyridin-2-yl)methanol hydrochloride (19.5 g, 0.08 mol) and 2-fluoro-4-cyanophenol (11.0 g, 0.08 mol) were added to tetrahydrofuran (200 mL). The temperature was lowered to 0°C, and triphenylphosphine (41.9 g, 0.16 mol) and diisopropyl azodicarboxylate (32.4 g, 0.16 mol) were added sequentially. After addition, the mixture was warmed to room temperature and reacted for 12 hours. Ethyl acetate (200 mL) and saturated aqueous sodium chloride solution (100 mL) were added to the reaction system. The layers were separated, and the aqueous phase was extracted twice with ethyl acetate (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was added to a mixture of petroleum ether and ethyl acetate (10:1) (250 mL), stirred at room temperature for 12 hours, filtered, and the filtrate was concentrated to obtain the crude product. A mixed solution of petroleum ether and ethyl acetate (3:1) (100 mL) was added, and anhydrous magnesium chloride (7.6 g, 0.08 mol) was added. The temperature was raised to 35°C and stirred for 6 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give 2-(4-cyano-2-fluorophenoxymethyl)-6-(piperidin-4-oxy)pyridine (21.0 g, yield: 80.2%). 1 H NMR (400MHz, DMSO-d6) δ8.78(br,1H),7.89(dd,J=11.3,2.0Hz,1H),7.81-7.76(m,1H),7.68(d,J=8.6Hz,1H),7.45(t,J=8.6Hz,1H),7.12(d,J= 7.3Hz,1H),6.81(d,J=8.2Hz,1H),5.31(s,2H),5.19-5.10(m,1H),3.32 -3.23(m,2H),3.09-3.03(m,2H),2.15-2.04(m,2H),1.88-1.79(m,2H).

[0113] Example 6: Preparation of 2-(4-chloro-2-fluorophenoxy)methyl)-6-(piperidin-4-oxy)pyridine hydrochloride

[0114] 1) Preparation of tert-butyl 4-(6-(4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidine-1-carboxylate:

[0115] tert-Butyl 4-(6-(hydroxymethyl)pyridin-2-yl)oxy)piperidine-1-carboxylate (15.4 g, 0.05 mol) and 2-fluoro-4-chlorophenol (7.3 g, 0.05 mol) were added to tetrahydrofuran (150 mL). The temperature was lowered to 0°C, and triphenylphosphine (26.2 g, 0.1 mol) and diisopropyl azodicarboxylate (20.2 g, 0.1 mol) were added sequentially. After addition, the mixture was warmed to room temperature and reacted for 12 hours. Ethyl acetate (100 mL) and saturated aqueous sodium chloride solution (100 mL) were added to the reaction system. The layers were separated, and the aqueous phase was extracted twice with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was added to a mixture of petroleum ether and ethyl acetate (10:1) (250 mL), stirred at room temperature for 12 hours, filtered, and the filtrate was concentrated to obtain the crude product. A mixed solution of petroleum ether and ethyl acetate (3:1) (100 mL) was added, followed by anhydrous magnesium chloride (4.8 g, 0.05 mol), and the temperature was raised to 35°C and stirred for 6 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl 4-(6-(4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidine-1-carboxylate (18.2 g, yield: 83.3%). 1 H NMR (400MHz, CDCl3) δ7.61-7.56(m,1H),7.13(dd,J=10.8,2.4Hz,1H),7.06-6.98(m,2H),6.93(t,J=8.7Hz,1H),6.64(d,J=8.2H z,1H),5.24-5.15(m,1H),5.10(s,2H),3.82-3.69(m,2H),3.34-3.23(m,2H),2.00-1.88(m,2H),1.80-1.64(m,2H),1.48(s,9H).

[0116] 2) Preparation of 2-(4-chloro-2-fluorophenoxy)methyl)-6-(piperidin-4-oxy)pyridine hydrochloride:

[0117] To tert-butyl 4-(6-(4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidine-1-carboxylate (16.0 g, 0.037 mol) dissolved in ethyl acetate (80 mL) was added dropwise 3 M hydrochloric acid ethyl ester (30 mL, 0.1 mol), and the internal temperature was controlled to <25°C. After the addition was completed, the mixture was stirred at room temperature for 12 hours, filtered, and the filter cake was washed twice with ethyl acetate (30 mL). The filter cake was dried in vacuo to give 2-(4-chloro-2-fluorophenoxy)methyl)-6-(piperidin-4-oxy)pyridine hydrochloride (12.9 g, yield: 93.5%). 1H NMR (400MHz, DMSO-d6) δ8.90(br,2H),7.77(t,J=7.8Hz,1H),7.47(dd,J=11.2,2.4Hz,1H),7.27(t,J=8.9Hz,1H),7.21(d,J=8.8Hz,1H),7. 10(d,J=7.3Hz,1H),6.79(d,J=8.3Hz,1H),5.24–5.09(m,3H),3.21-3.17(m,2H),3.07-3.06(m,2H),2.17-2.06(m,2H),2.01-1.79(m,2H).

[0118] Example 7: Preparation of 2-(4-cyano-2-fluorophenoxy)methyl)-6-(piperidin-4-oxy)pyridine hydrochloride

[0119] 1) Preparation of tert-butyl 4-(6-(4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidine-1-carboxylate:

[0120] tert-Butyl 4-(6-(hydroxymethyl)pyridin-2-yl)oxy)piperidine-1-carboxylate (15.4 g, 0.05 mol) and 2-fluoro-4-cyanophenol (6.9 g, 0.05 mol) were added to tetrahydrofuran (150 mL). The temperature was lowered to 0°C, and triphenylphosphine (26.2 g, 0.1 mol) and diisopropyl azodicarboxylate (20.2 g, 0.1 mol) were added sequentially. After addition, the mixture was warmed to room temperature and reacted for 12 hours. Ethyl acetate (100 mL) and saturated aqueous sodium chloride solution (50 mL) were added to the reaction system. The layers were separated, and the aqueous phase was extracted twice with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was added to a mixture of petroleum ether and ethyl acetate (10:1) (250 mL), stirred at room temperature for 12 hours, filtered, and the filtrate was concentrated to obtain the crude product. A mixed solution of petroleum ether and ethyl acetate (3:1) (100 mL) was added, and anhydrous magnesium chloride (4.8 g, 0.05 mol) was added. The temperature was raised to 35 ° C. and stirred for 6 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure and dried to obtain the product tert-butyl 4-(6-(4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidine-1-carboxylate (16.8 g, yield: 78.5%). 1H NMR (400MHz, DMSO-d6) δ7.88(dd,J=11.3,1.7Hz,1H),7.74(t,J=7.8Hz,1H),7.67(d,J=8.6Hz,1H),7.45(t,J=8.6Hz,1H),7.08(d,J=7.3Hz,1H),6.75 (d,J=8.3Hz,1H),5.31(s,2H),5.12-4.97(m,1H),3.67(dt,J=9.6,4.5Hz, 2H),3.18-3.03(m,2H),1.92-1.79(m,2H),1.58-1.44(m,2H),1.41(s,9H).

[0121] 2) Preparation of 2-(4-cyano-2-fluorophenoxy)methyl)-6-(piperidin-4-oxy)pyridine hydrochloride:

[0122] To tert-butyl 4-(6-(4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidine-1-carboxylate (16.8 g, 0.039 mol) dissolved in ethyl acetate (80 mL) was added dropwise 3 M hydrochloric acid ethyl ester (30 mL, 0.1 mol), and the internal temperature was controlled to <25°C. After the addition was completed, the mixture was stirred at room temperature for 12 hours, filtered, and the filter cake was washed twice with ethyl acetate (30 mL). The filter cake was dried in vacuo to give 2-(4-cyano-2-fluorophenoxy)methyl)-6-(piperidin-4-oxy)pyridine hydrochloride (13.2 g, yield: 93.1%).

[0123] Example 8: Preparation of tert-butyl 4-(6-(4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidine-1-carboxylate

[0124] To tetrahydrofuran (400 mL) dissolved with N-tert-butyloxycarbonyl-4-hydroxypiperidine (20.0 g, 0.1 mol) was added 60% sodium hydride (10.0 g, 0.25 mol) in portions, and the internal temperature was controlled to <25°C. After the addition was complete, the mixture was stirred at room temperature for 2 hours. 2-Chloro-6-((4-chloro-2-fluorophenoxy)methyl)pyridine (27.2 g, 0.1 mol) was added in portions. After the addition was complete, the temperature was raised to 60°C and stirring was continued for 12 hours. Ethyl acetate (200 mL) was added to the reaction system for dilution, cooled to 0-10° C., and quenched by adding dropwise to a saturated aqueous ammonium chloride solution (200 mL). The layers were separated, and the aqueous phase was extracted twice with ethyl acetate (100 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and slurried with n-hexane / ethyl acetate (5 / 1), filtered, and dried to give tert-butyl 4-(6-(4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidine-1-carboxylate (37.3 g, yield: 85.4%).

[0125] Example 9: Preparation of tert-butyl 4-(6-(4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidine-1-carboxylate

[0126] To a solution of 2-fluoro-4-chlorophenol (7.3 g, 0.05 mol) in DMF (50 mL) was added potassium carbonate (13.8 g, 0.1 mol). The internal temperature was controlled to <25°C. After the addition was complete, tert-butyl 4-((6-(chloromethyl)pyridin-2-yl)oxy)piperidine-1-carboxylate (16.3 g, 0.05 mol) was added. After the addition was complete, the temperature was raised to 50°C and stirring was continued for 12 hours. Ethyl acetate (100 mL) and water (100 mL) were added to the reaction system for dilution, the layers were separated, the aqueous phase was extracted twice with ethyl acetate (100 mL), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated, slurried with n-hexane / ethyl acetate (5 / 1), filtered and dried to give tert-butyl 4-(6-(4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidine-1-carboxylate (17.5 g, yield: 80.3%)

[0127] Example 10: Preparation of (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0128] A mixture of (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (7.5 g, 26.7 mmol), 2-(4-chloro-2-fluorophenoxy)methyl)-6-(piperidin-4-oxy)pyridine hydrochloride (10.0 g, 26.8 mmol) and sodium bicarbonate (5.6 g, 66.7 mmol) in N,N-dimethylformamide (150 mL) was dissolved in water. The mixture was stirred at 40°C for 6 hours, then diluted with water (250 mL), and formic acid was added dropwise to adjust the pH to 5. After stirring at room temperature for 2 hours, the mixture was filtered and dried in vacuo to give (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (14.4 g, yield: 90.0%). 1 HNMR (400MHz, CD3OD): δ8.20(s,1H),7.94(dd,J=8.4,1.3Hz,1H),7.68-7.62(m,1H),7.58(d,J=8.4Hz,1H),7. 19(dd,J=11.0,2.4Hz,1H),7.16-7.02(m,3H),6.66(d,J=8.2Hz,1H),5.31-5.23(m,1H),5.12(s,1H),5.08-4. 99(m,1H),4.90-4.85(m,2H),4.75-4.59(m,2H),4.46(dt,J=9.1,5.9Hz,1H),4.00(d,J=13.7Hz,1H),3.90(d, J=13.6Hz,1H),2.87-2.72(m,3H),2.61-2.48(m,1H),2.47-2.35(m,2H),2.02-1.99(m,2H),1.77-1.76(m,2H).

[0129] Example 11: Preparation of (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0130] A solution of (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (7.5 g, 26.7 mmol), 2-(4-cyano-2-fluorophenoxy)methyl)-6-(piperidin-4-oxy)pyridine hydrochloride (9.7 g, 26.7 mmol) and sodium bicarbonate (5.6 g, 66.7 mmol) in N,N-dimethylformamide (100 mL) was prepared. The mixture was stirred at 45°C for 16 hours, then diluted with water (250 mL), and formic acid was added dropwise to adjust the pH to 5. After stirring at room temperature for 2 hours, the mixture was filtered and dried in vacuo to give (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (13.9 g, yield: 90.8%). 1 HNMR (400MHz, CD3OD): δ8.20 (s, 1H), 7.94 (dd, J = 2.0Hz, 8.6Hz, 1H), 7.66 (dd, J = 1.6, 8.5Hz, 1H), 7.64-7. 54(m,2H),7.51-7.50(m,1H),7.32(t,J=8.5Hz,1H),7.04(d,J=7.6Hz,1H),6.68(d,J=8.5Hz,1H),5.27-5. 24(m,3H),5.10-5.08(m,1H),4.90-4.88(m,1H),4.73-4.62(m,2H),4.47-4.45(m,1H),4.00(d,J=13.5Hz ,1H),3.90(d,J=13.5Hz,1H),2.81-2.77(m,3H),2.51-2.41(m,3H),1.91-1.89(m,2H),1.79-1.76(m,2H).

[0131] Example 12: Preparation of (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid:

[0132] 1) Preparation of (S)-methyl 2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate:

[0133] A mixture of (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (7.9 g, 26.8 mmol), 2-(4-chloro-2-fluorophenoxy)methyl)-6-(piperidin-4-oxy)pyridine hydrochloride (10.0 g, 26.8 mmol) and sodium bicarbonate (5.6 g, 66.7 mmol) was stirred for 1 0 minutes. The mixed solution was stirred at 40 ° C for 16 hours, then washed with water (250 mL), stirred at room temperature for 2 hours, filtered, and dried in vacuo to give (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (14.8 g, yield: 93.1%). 1 H NMR (400MHz, CDCl3) δ8.17(s,1H),7.97(dd,J=8.5,1.2Hz,1H),7.74(d,J=8.5Hz,1H),7.57(t,J =7.8Hz,1H),7.12(dd,J=10.8,2.4Hz,1H),7.05-6.91(m,3H),6.63(d,J=8.3Hz,1H),5.30-5.19 (m,1H),5.10(s,2H),5.07-5.04(m,1H),4.81-4.60(m,3H),4.41(dt,J=9.2,5.9Hz,1H),3.97(s ,2H),3.95(s,3H),2.82-2.73(m,3H),2.51-2.39(m,3H),2.03-2.01(m,2H),1.80-1.73(m,2H).

[0134] 2) Synthesis of (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid:

[0135] To a solution (200 mL) of a mixture of (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (10.0 g, 16.8 mmol) in tetrahydrofuran:water (1:1) was added sodium hydroxide (2.0 g, 50.0 mmol) and the mixture was stirred at room temperature. The mixture was stirred for 12 hours, water (100 mL) was added, the reaction solution was adjusted to pH 4-5 with formic acid, filtered, the filter cake was washed with water, and dried in vacuo to give (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (9.2 g, yield: 94.3%).

[0136] Example 13: Preparation of (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid:

[0137] 1) Preparation of (S)-methyl 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate:

[0138] A mixture of (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (8.1 g, 27.5 mmol), 2-(4-cyano-2-fluorophenoxy)methyl)-6-(piperidin-4-oxy)pyridine hydrochloride (10.0 g, 27.5 mmol) and sodium bicarbonate (5.8 g, 68.8 mmol) was stirred for 1 hr in N,N-dimethylformamide (100 mL). The mixed solution was stirred at 40°C for 16 hours, then water (250 mL) was added, and after stirring at room temperature for 2 hours, it was filtered and dried in vacuo to give (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (14.6 g, yield: 90.7%). 1H NMR(400MHz,DMSO-d6)δ8.33(s,1H),7.95-7.83(m,2H),7.82-7.71(m,2H),7.70-7.64(m,1H) ),7.45(t,J=8.6Hz,1H),7.08(d,J=7.3Hz,1H),6.76(d,J=8.3Hz,1H),5.31(s,2H),5.11-4.9 4(m,2H),4.83(dd,J=15.6,7.3Hz,1H),4.72-4.58(m,1H),4.52-4.47(m,1H),4.39-4.32(m,1 H),3.89(s,2H),3.85-3.78(m,3H),2.77-2.63(m,2H),2.42-2.33(m,3H),2.03-1.69(m,5H).

[0139] 2) Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid:

[0140] To a solution (200 mL) of a mixture of (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (10.0 g, 17.1 mmol) in tetrahydrofuran:water (1:1) was added sodium hydroxide (2.0 g, 50.0 mmol) and the mixture was stirred at room temperature. The mixture was stirred at room temperature for 12 hours, water (100 mL) was added, and the reaction solution was adjusted to pH 4-5 with formic acid, filtered, and the filter cake was washed with water and dried in vacuo to give (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (9.0 g, yield: 92.1%).

[0141] All documents mentioned herein are incorporated herein by reference as if each document were individually incorporated by reference. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the appended claims.

Claims

1. A compound of formula III or its acid addition salt: Among them, R1 is selected from chlorine or cyano; R2 is selected from a hydrogen atom or an amino-protecting group; The acid addition salt is a salt formed by the compound and an acid, such as hydrobromide, hydrochloride, sulfate, bisulfate, sulfite, phosphate, borate, acetate, trifluoroacetate, oxalate, valerate, benzoate, lactate, tolylbenzoate, citrate, malate, maleate, fumarate, succinate, tartrate, mesylate, benzenesulfonate, p-toluenesulfonate.

2. The compound or its acid addition salt according to claim 1, wherein the amino-protecting group is selected from benzyloxycarbonyl, tert-butoxycarbonyl, allylcarbonyl, fluorenylmethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, trimethylsilylethoxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, o-nitrobenzenesulfonyl, p-nitrobenzenesulfonyl, pivaloyl, benzoyl, triphenylmethyl, 2,4-dimethoxybenzyl, p-methoxybenzyl or benzyl; Preferably, the compound shown in Formula III has the following structure: Preferably, the acid salt of the compound shown in Formula III has the following structure:

3. The compound represented by Formula II or its acid addition salt: Among them, The definition of R1 and its acid addition salt is as described in claim 1; Among them, R3 is selected from C 1-20 alkyl, C 6-14 aryl or C 6-14 aryl C 1-10 alkyl, wherein the C 1-20 alkyl, C 6-14 aryl or C 6-14 aryl C 1-10 alkyl are each independently optionally substituted by one or more substituents selected from halogen, C 1-20 alkyl, halo C 1-20 alkyl, C 1-20 alkoxy, halo C 1-20 alkoxy, cyano, amino, nitro, hydroxy, oxo(=O), carboxyl and hydroxy-C 1-20 alkyl; Preferably, R3 is selected from C 1-10 alkyl or C 6-14 aryl C 1-10 alkyl, wherein the C 1-10 alkyl or C 6-14 aryl C 1-10 alkyl is each independently optionally substituted by one or more substituents selected from halogen, C 1-10 alkyl, halo C 1-10 alkyl, C 1-10 alkoxy, halo C 1-10 alkoxy, carboxyl, and hydroxy-C 1-10 alkyl. Preferably, R3 is selected from C 1-6 alkyl, such as methyl, ethyl, isopropyl, tert-butyl; According to an embodiment of the present invention, R3 is selected from C 6-14 aryl C 1-6 alkyl, such as benzyl. Preferably, the compound shown in Formula II has the following structure:

4. A method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof, characterized in that, Comprising the following steps: The compound represented by Formula II or its acid salt as described in Claim 3 undergoes a hydrolysis reaction with a suitable base to obtain the compound represented by Formula I or its pharmaceutically acceptable salt; Wherein, the definition of R1 and its acid addition salt is as described in claim 1; the definition of R3 is as described in claim 3; The suitable base is selected from inorganic bases, such as: lithium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate or potassium hydroxide, potassium phosphate, sodium phosphate.

5. A method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof, characterized in that, Comprising the following steps: The compound shown by formula IIIa or its acid salt undergoes a nucleophilic substitution reaction with the compound shown by formula IV to prepare the compound shown by formula I or its pharmaceutically acceptable salt, Wherein, the definition of R1 is as described in claim 1; Wherein, X represents a suitable leaving group, such as selected from chlorine, bromine, iodine, methanesulfonate, trifluoromethanesulfonate or p-toluene sulfonate.

6. A process for preparing the compound of formula II or its acid addition salt according to claim 3, characterized in that, The method includes the step of nucleophilic substitution reaction of the compound shown by formula IIIa or its acid salt with the compound shown by formula V to generate the compound shown by formula II or its acid salt. Wherein, the definition of R1 is as described in claim 1; Wherein, the definition of R3 is as described in claim 3; the definition of X is as described in claim 5.

7. The preparation method according to claim 5 or 6, wherein the nucleophilic substitution reaction is carried out in the presence of a base, and the base is selected from one or more of potassium phosphate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, morpholine, N-methylmorpholine or pyridine, preferably potassium carbonate, sodium bicarbonate or triethylamine.

8. The preparation method according to claim 5, characterized in that, The method further includes the step of deprotecting the compound represented by Formula IIIb or its acid salt to generate the compound represented by Formula IIIa. Wherein, the definitions of R1 and R2 are as described in claim 1.

9. A method for preparing the compound represented by Formula III or its acid addition salt according to claim 1, comprising the following steps: The compound shown by Formula VI and the compound shown by Formula VII are subjected to a Mitsunobu reaction to obtain the compound shown by Formula III or its acid salt. Wherein, the definitions of R1 and R2 are as described in claim 1.

10. A method for preparing the compound of formula III or its acid salt according to claim 1, which comprises obtaining the compound of formula III or its acid salt by subjecting the compound of formula VIII to a substitution reaction with the compound of formula IX, Among them, The definitions of R1 and R2 are as described in claim 1, and X represents a suitable leaving group, such as selected from chlorine, bromine, iodine, methanesulfonate, trifluoromethanesulfonate or p-toluenesulfonate.

11. A method for preparing the compound of formula III or its acid salt according to claim 1, which is obtained by subjecting the compound of formula VI and the compound of formula X to a substitution reaction to obtain the compound of formula III or its acid salt. Among them, The definitions of R1 and R2 are as described in claim 1; Wherein, R0 represents a suitable leaving group, especially chlorine, bromine, iodine, methanesulfonate, trifluoromethanesulfonate or p-toluenesulfonate.

12. A pharmaceutical composition, which comprises the compound of formula I shown in claim 4 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

13. Use of the compound of formula I or a pharmaceutically acceptable salt thereof according to claim 4 in the preparation of a medicament for preventing or treating a disease related to the GLP1R target and its corresponding signaling pathway, wherein the disease is selected from 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 craving, dyslipidemia, hyperinsulinemia, NAFLD, NAS, 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 lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome XI, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, glucose metabolism disorder, impaired fasting glucose condition, hyperuricemia, gout, erectile dysfunction, skin and connective tissue abnormalities, psoriasis, foot ulcer, ulcerative colitis, Alzheimer's disease, schizophrenia, impaired cognitive function, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome.

Images