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WO2024153041A1 - Glp-1r激动剂的制造方法与中间体及其用途 - Google Patents

Glp-1r激动剂的制造方法与中间体及其用途 Download PDF

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WO2024153041A1
WO2024153041A1 PCT/CN2024/072393 CN2024072393W WO2024153041A1 WO 2024153041 A1 WO2024153041 A1 WO 2024153041A1 CN 2024072393 W CN2024072393 W CN 2024072393W WO 2024153041 A1 WO2024153041 A1 WO 2024153041A1
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alkyl
acid salt
disease
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张龙
胡杨
牛张明
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杭州德睿智药科技有限公司
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Definitions

  • the present invention belongs to the field of pharmaceutical chemistry, and specifically relates to a method for preparing a novel GLP-1R agonist and an intermediate thereof.
  • the present invention also relates to a method for preparing a drug containing such a compound for treating or preventing diseases related to GLP1/GLP1R.
  • Diabetes is a chronic disease characterized by high blood sugar due to insufficient insulin secretion (relative or absolute) or insulin dysfunction in the human body.
  • IDF International Diabetes Federation
  • 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, cause weight gain and often induce hypoglycemia.
  • DPP-IV inhibitors have limited efficacy.
  • the commercially available GLP-1R agonists are peptides administered by subcutaneous injection, and liraglutide is also approved for the treatment of obesity.
  • Biguanides eg, metformin
  • Biguanides are thought to act primarily by reducing hepatic glucose production. Biguanides often cause gastrointestinal upset and lactic acidosis, further limiting their usefulness.
  • ⁇ -Glucosidase inhibitors e.g., acarbose
  • Thiazolidinedione acts on specific receptors in liver, muscle and adipose tissue. They modulate lipid metabolism and subsequently enhance the response of these tissues to the action of insulin. Frequent use of these drugs may lead to weight gain and may induce edema and anemia.
  • 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 a risk of hypoglycemia.
  • Sodium-glucose linked transporter cotransporter 2 (SGLT2) inhibitors e.g., dapagliflozin, empagliflozin, canagliflozin, ertugliflozin
  • SGLT2 inhibitors inhibit glucose reabsorption in the kidneys, thereby lowering blood glucose levels, and this drug class may be associated with ketoacidosis and urinary tract infections.
  • 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 trials, GLP-1 promotes sustained beta cell capacity by stimulating the transcription of genes important for glucose-dependent insulin secretion and by promoting beta cell neogenesis.
  • GLP-1R agonists will start from the purpose of improving patient compliance, portability and convenience of medication, and reducing drug side effects and costs, and has broad clinical market prospects.
  • 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.
  • compound I-2 is (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.
  • 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.
  • the inventors have developed a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof during a long-term research and development process.
  • the method is simpler to operate, has a significantly improved yield (the total yield can reach 50%), has a low cost, mild reaction conditions, a mature process, and stable quality, and is very suitable for industrial application.
  • R1 is selected from chlorine or cyano
  • R2 is selected from hydrogen atom or amino protecting group
  • 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.
  • an acid such as hydrobromide, hydrochloride, sulfate, bisulfate, sulfite, phosphate, borate, acetate, trifluoroacetate, oxalate, valerate, benzoate, lactate, toluate, citrate, malate, maleate, fumarate, succinate, tartrate, methan
  • the amino protecting group is benzyloxycarbonyl, tert-butoxycarbonyl, allylcarbonyl, fluorenylmethoxycarbonyl, 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.
  • the compound represented by formula III has the following structure:
  • the acid salt of the compound represented by formula III has the following structure:
  • the present invention also provides a compound represented by Formula II or an acid salt thereof having the following structure:
  • R 1 is selected from chlorine or cyano
  • R3 is selected from C1-10 alkyl or C6-14 arylC1-10 alkyl, and the C1-10 alkyl or C6-14 arylC1-10 alkyl is each independently optionally substituted with one or more substituents selected from halogen, C1-10 alkyl, halogenated C1-10 alkyl, C1-10 alkoxy, halogenated C1-10 alkoxy, carboxyl and hydroxy- C1-10 alkyl.
  • R 3 is selected from C 1-6 alkyl, such as methyl, ethyl, isopropyl, tert-butyl.
  • R 3 is selected from C 6-14 aryl C 1-6 alkyl, such as benzyl.
  • the compound shown in Formula II has the following structure:
  • the present invention further provides a method for preparing the compound of formula I or a pharmaceutically acceptable salt thereof:
  • the method comprises the following steps: hydrolyzing the compound represented by formula II or its acid salt with a suitable base, wherein the suitable base is selected from lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • R 1 is selected from chlorine or cyano
  • the present invention is substituted by a substituent, preferably a methyl group, an ethyl group or a tert-butyl group.
  • R 3 is selected from C 1-10 alkyl or C 6-14 aryl C 1-10 alkyl, and the C 1-10 alkyl or C 6-14 aryl C 1-10 alkyl is each independently optionally substituted by one or more substituents of 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 alkyl.
  • R 3 is selected from C 1-6 alkyl, such as methyl, ethyl, isopropyl, tert-butyl.
  • R 3 is selected from C 6-14 aryl C 1-6 alkyl, such as benzyl.
  • the present invention also provides another method for preparing the compound represented by formula I or a pharmaceutically acceptable salt thereof:
  • the method comprises the steps of subjecting a compound represented by 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.
  • R 1 is selected from chlorine or cyano; and X represents a suitable leaving group, in particular chlorine, bromine, iodine, mesylate, triflate or p-toluenesulfonate.
  • 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.
  • 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 triethyl
  • the present invention further provides a method for preparing the compound represented by formula II or its acid salt:
  • 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.
  • R 1 is selected from chlorine or cyano
  • R3 is selected from C1-10 alkyl or C6-14 arylC1-10 alkyl, and the C1-10 alkyl or C6-14 arylC1-10 alkyl is each independently optionally substituted with one or more substituents selected from halogen, C1-10 alkyl, halogenated C1-10 alkyl, C1-10 alkoxy, halogenated C1-10 alkoxy, carboxyl and hydroxy- C1-10 alkyl.
  • R 3 is selected from C 1-6 alkyl, such as methyl, ethyl, isopropyl, tert-butyl.
  • R 3 is selected from C 6-14 aryl C 1-6 alkyl, such as benzyl.
  • 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.
  • 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 triethyl
  • the present invention also provides a method for preparing the compound represented by IIIa:
  • 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.
  • R 1 is selected from chlorine or cyano
  • R 2 is selected from benzyloxycarbonyl, tert-butyloxycarbonyl, allylcarbonyl, methoxycarbonyl, 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.
  • the method comprises the following steps: preparing a compound represented by formula III or an acid salt thereof by subjecting a compound represented by formula VI to a compound represented by formula VII through Mitsunobu reaction.
  • R1 is selected from chlorine or cyano
  • R2 is selected from hydrogen atom or amino protecting group.
  • the amino protecting group is benzyloxycarbonyl, tert-butoxycarbonyl, allylcarbonyl, fluorenylmethoxycarbonyl, 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.
  • the present invention further provides a method for preparing a compound represented by formula III or an acid salt thereof:
  • the method comprises the following steps: subjecting a compound represented by formula VIII to a compound represented by formula IX through a substitution reaction to obtain a compound represented by formula III or an acid salt thereof.
  • R 1 is selected from chlorine or cyano
  • R 2 is selected from hydrogen atom or amino protecting group.
  • 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;
  • X represents a suitable leaving group, in particular chlorine, bromine, iodine, methanethan
  • the present invention further provides a method for preparing a compound represented by formula III or an acid salt thereof:
  • the method comprises the following steps: subjecting a compound represented by formula VI to a compound represented by formula X through a substitution reaction to obtain a compound represented by formula III or an acid salt thereof.
  • R1 is selected from chlorine or cyano
  • R2 is selected from hydrogen atom or amino protecting group.
  • 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 0 represents a suitable leaving group, in particular chlorine, bromine, iodine, mesylate, trifluoromethanesulfonate or p-toluenesulfon
  • the present invention also provides a method for preparing the compound represented by formula VII:
  • 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.
  • R 2 is selected from 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; X 'is selected from fluorine, chlorine, bromine, iodine, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, me
  • the present invention further provides another method for preparing the compound represented by formula VII:
  • the method comprises first subjecting the compound represented by formula IX to a nucleophilic substitution reaction with the compound represented by formula XII to generate the compound represented by formula XIII, and then reacting the reaction in the presence of a reducing agent to obtain the compound represented by formula VII.
  • 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 di A complex of oxane, borane and 1,4-oxathiinane, or a complex of BH 2 Cl and dimethyl sulfide, preferably a complex of sodium borohydride, borane and tetrahydrofuran, or borane and dimethyl sulfide.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the aforementioned compound I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • 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.
  • 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.
  • the present invention further provides a compound I or a pharmaceutically acceptable salt thereof, which is used 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, 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 addiction, 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, and out Drugs for the prevention or treatment of hemorr
  • 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.
  • 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, the use of precious metal catalysts can be avoided in the entire process, the reaction cost is effectively reduced, the reaction is easy to scale up, and it is more suitable for industrial production.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and 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, facilitate the absorption of the active ingredient, and thus exert biological activity.
  • salt refers to a compound prepared by reacting an organic acid or base drug with a pharmaceutically acceptable inorganic or organic acid or base.
  • the numerical ranges recorded in this specification and claims are equivalent to recording at least each specific integer value therein.
  • the numerical range “1-20” is equivalent to recording 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.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • C 1-20 alkyl refers to a saturated aliphatic hydrocarbon group, including straight and branched saturated monovalent hydrocarbon groups of 1 to 20 carbon atoms.
  • alkyl groups having 1 to 10 carbon atoms such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl or pentyl.
  • More preferred are lower alkyl groups having 1 to 6 carbon atoms (C 1-6 alkyl), such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or tert-butyl, pentyl, heptyl, etc.
  • 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 a "C 3-10 cycloalkyl", more preferably a "C 3-8 cycloalkyl".
  • C 3-10 cycloalkyl is understood to mean a saturated monovalent monocyclic, bicyclic (such as bridged, spiro) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • the C3-10 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]nonanyl, 2,6-diaza
  • 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 are as defined above.
  • Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • C6-14 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 ⁇ 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 6 to 10 members ( C6-10 aryl), such as phenyl and naphthyl.
  • amino protecting group of the present invention is a group known in the art that can be appropriately used for amino protection, see the amino protecting group in the literature ("Protective Groups in Organic Synthesis", 5 Th . Ed. TW Greene & P. GMWuts).
  • 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 combined therewith forms a lactam, such as phthaloyl.
  • the method of removing the protecting group can also refer to the method of removing the amino protecting group in the literature ("Protective Groups in Organic Synthesis", 5 Th . Ed.
  • the benzyl group is removed by hydrogen/metal catalyst, wherein the metal catalyst is selected from but not limited to at least one of palladium carbon, palladium hydroxide, platinum oxide, palladium, palladium on alumina, platinum on activated carbon and Raney nickel, preferably palladium carbon and palladium hydroxide; the tert-butyloxycarbonyl (Boc) group is removed under acidic conditions, and the reagent providing the acidic conditions is preferably selected from methanesulfonic acid, hydrochloric acid and trifluoroacetic acid.
  • the metal catalyst is selected from but not limited to at least one of palladium carbon, palladium hydroxide, platinum oxide, palladium, palladium on alumina, platinum on activated carbon and Raney nickel, preferably palladium carbon and palladium hydroxide
  • the tert-butyloxycarbonyl (Boc) group is removed under acidic conditions, and the reagent providing the acidic conditions is preferably selected from me
  • room temperature or "RT” refers to an ambient temperature of 20 to 25°C.
  • the intermediate compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the following: The specific embodiments listed, the embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods known to those skilled in the art, and preferred embodiments include but are not limited to the embodiments of the present invention.
  • NMR nuclear magnetic resonance
  • HPLC determination uses Agilent 1260 high performance liquid chromatograph or high performance liquid chromatograph of equivalent performance (Sunfire C18 150 ⁇ 4.6m column or column of equivalent performance).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.
  • the reaction system was cooled to 0°C, quenched by adding saturated aqueous sodium bicarbonate solution (100 mL), water (100 mL) and ethyl acetate (300 mL), 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 obtained crude product, cooled to 0°C, stirred at this temperature for 2 hours, filtered, and the filter cake was dried under vacuum to obtain tert-butyl 4-(6-(hydroxymethyl)pyridin-2-yl)oxy)piperidine-1-carboxylate (19.9 g, yield: 80.6%).
  • N,N-dimethylformamide (100 g, 26.8 mmol) containing (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 added.
  • N,N-dimethylformamide 100 g, 27.5 mmol
  • (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 added.

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Abstract

本发明涉及用于制备式（I）所示GLP-1R激动剂类化合物或其可药用盐的制备方法和中间体。本发明方法克服了现有技术中存在的缺陷，大大缩减了成本，所得产物纯度好、收率高，工艺可操作性强，工艺安全性也得到大幅提高。因此，本发明制备方法及其应用适合工业化应用。

Description

GLP-1R激动剂的制造方法与中间体及其用途
本发明要求享有于2023年1月19日向中国国家知识产权局提交的，专利申请号为202310105038.4，名称为“GLP-1R激动剂的制造方法与中间体及其用途”的在先申请的优先权。该在先申请的全文通过引用的方式结合于本发明中。
技术领域
本发明属于医药化学领域，具体涉及一种新型GLP-1R激动剂的制造方法与中间体。本发明还涉及包含该类化合物应用于制备治疗或预防与GLP1/GLP1R相关的疾病的药物的方法。
技术背景
糖尿病是由于人体胰岛素分泌(相对或绝对)不足或者胰岛素作用障碍导致的以高血糖为特征的慢性疾病。根据国际糖尿病-联盟(International diabetes federation,IDF)最新颁布的第九版世界糖尿病地图显示，2019年全球约有4.63亿成人(20-79岁)患糖尿病,预计到2030年糖尿病患病人数将达到5.78亿。若按照此趋势持续下去,2045年全球将有7亿糖尿病患者。因此，糖尿病已成为21世纪全球范围内面临的最为严峻的社会健康问题之一。
目前已有各种药理学方法用来治疗高血糖症及伴随发生的T2DM(Hampp等人，《美国抗糖尿病药物的使用(Use of Antidiabetic Drugs in the U.S.)》,2003‐2012,Diabetes Care 37:1367‐1374,2014)。这些方法可分成六个主要类别，每个类别是通过不同的主要机制起作用。
胰岛素促分泌素，包含磺酰脲类、二肽基肽酶IV(DPP-IV)抑制剂以及类升糖素肽-1受体(GLP-1R)激动剂，其通过在胰脏β细胞上作用而提高胰岛素分泌。磺酰脲的功效及耐受性有限,引起增重且常诱发低血糖症。DPP-IV抑制剂的功效有限。市场上销售的GLP-1R激动剂是经皮下注射给药的肽，利拉鲁肽同时被批准用于治疗肥胖症。
双胍(例二甲双胍(metformin))被认为主要通过降低肝脏葡萄糖生产而起作用双胍常引起胃肠不适及乳酸中毒，进一步限制了其用途。
α-葡萄糖苷酶抑制剂(例如阿卡波糖(acarbose))会降低肠道葡萄糖吸收。这些药剂常引起胃肠不适。
噻唑烷二酮(thiazolidinedione)(例如匹格列酮(pioglitazone)、罗格列酮(rosiglitazone))是在肝、肌肉及脂肪组织的特定受体上起作用。它们调节脂质代谢且随后増强这些组织对胰岛素作用的反应。常使用这些药物可能导致增重且可能诱发水肿及贫血。
胰岛素单独或与上述药剂组合而用于更严重的病例，且常使用也可能导致增重且带有低血糖症风险。
钠-葡萄糖连结的转运蛋白共转运蛋白2(SGLT2)抑制剂(例如达格列净(dapagliflozin)、恩格列净(empagliflozin)、卡格列净(canagliflozin)、依格列净(ertugliflozin)抑制葡萄糖在肾脏中的再吸收，从而降低血液中的葡萄糖含量，这种药物类别可能与酮酸中毒及尿道感染相关联。
除了糖尿病外，随着物质生活水平的提高，超重或肥胖现象也越来越普遍。由肥胖导致的并发症如糖尿病、脂肪肝等患者人群日益增多。来自世界卫生组织(WHO)和智研咨询发布的报告预测显示：至2030年全球肥胖患者将达32.6亿；至2029年全球糖尿病患者将超5亿；全球非酒精性脂肪肝患者将超15亿。目前脂肪肝尚未有有效治疗药物；FDA批准的治疗肥胖的药物只有6个，且多数属于管制类药物，疗效弱、副作用大；尽管已经有不少治疗2型糖尿病的药物获批上市，但现有降糖药降糖达标率(<7％)一直不高，即使活性最好的复方达标率也仅在45％左右。因此，无论是脂肪肝、肥胖、还是糖尿病均需要研发新的药物，以满足更广大患者的需求。
GLP-1是肠内L细胞在反应食物摄取时所分泌的30个氨基酸长度的肠促胰岛素激素。已显示GLP-1以生理及葡萄糖依赖性方式刺激胰岛素分泌、降低升糖素分泌、抑制胃排空、降低食欲及刺激β细胞増生。在非临床试验中，GLP-1通过刺激对葡萄糖依赖性胰岛素分泌重要的基因转录，及通过促进β细胞新生而促进持续的β细胞能力。
科学研究已经对GLP-1的结构进行相应的改造和修饰，以增加其半衰期进而延长体内生物学效应。然而，目前临床上投入使用的长效GLP-1类似物如利拉鲁肽、艾塞那肽等均为多肽，稳定性差，需要冷藏，携带不变；频繁多次注射给药导致患者的依从性较差，且相较于小分子而言，价格昂贵，患者负担严重。因此小分子GLP-1R激动剂的开发将从提高患者的依从性、携带及用药方便性以及降低药物副作用和成本的目的出发，具有广阔的临床市场前景。
杭州德睿智药科技有限公司(Mindrank AI Ltd.)在前期的研究过程中发明了一种结构新颖的具有GLP-1R激动效果的小分子化合物，相关专利申请号为PCT/CN2022/075295，其代表性化合物I-1和化合物I-2的结构如下：
化合物I-1的化学名称为(S)-2-(4-(6-(4-氯-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸。
化合物I-2的化学名称为(S)-2-(4-(6-(4-氰基-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸。
该类化合物能显著激活GLP-1R靶点，是优秀的GLP1R激动剂，其最大激动作用可以达到甚至是超过GLP1多肽。
现有的化合物I-1或化合物I-2的制备方法产率较低(总收率仅约7％-9％)，制备方法没有经过优化，后处理需要柱层析纯化，成本较高，操作复杂，很难放大，严重限制了工业化生产。作为药物的成功开发通常要具有简便的操作，条件温和，质量稳定，可适用于工业化生产的工艺，为满足临床研究以及上市药物制剂的需要，迫切需要开发一种能够成本低廉并适合工 业化生产的制造方法。
发明内容
为了解决现有技术中存在的问题，发明人在长期的研发过程中开发出一种制备式I化合物或其可药用盐的方法，其操作更为简便，收率明显提高(总收率可达50％)，成本较低，反应条件温和，工艺成熟，质量稳定，非常适于工业应用。
本发明的第一方面，提供了具有以下结构的式III所示化合物或其酸式盐：
其中，R1选自氯或氰基，R2选自氢原子或氨基保护基，所述酸式盐为所述化合物与酸形成的盐，例如氢溴酸盐、盐酸盐、硫酸盐、硫酸氢盐、亚硫酸盐、磷酸盐、硼酸盐、乙酸盐、三氟乙酸盐、草酸盐、戊酸盐、苯甲酸盐、乳酸盐、甲苯甲酸盐、柠檬酸盐、苹果酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐等。
根据本发明的实施方案，所述氨基保护基为苄氧羰基、叔丁氧羰基、烯丙基羰基、芴甲氧羰基、甲氧羰基、乙氧羰基、三甲基硅乙氧羰基、邻苯二甲酰基、对甲苯磺酰基、三氟乙酰基、邻硝基苯磺酰基、对硝基苯磺酰基、特戊酰基、苯甲酰基、三苯甲基、2,4‐二甲氧基苄基、对甲氧基苄基或苄基，优选苄氧羰基、叔丁氧羰基或苄基。
根据本发明的实施方案，式III所示化合物具有如下结构：
根据本发明的实施方案，式III所示化合物的酸式盐具有如下结构：
本发明还提供了具有以下结构的式II所示化合物或其酸式盐：
其中，R1选自氯或氰基；
R3选自C1-20烷基、C6-14芳基、C6-14芳基C1-20烷基，其中所述的C1-20烷基、C6-14芳基、C6-14芳基C1-20烷基各自独立地任选被卤素、C1-20烷基、卤代C1-20烷基、C1-20烷氧基、卤代C1-20烷氧基、氰基、氨基、硝基、羟基、氧代(＝O)、羧基和羟基-C1-20烷基中的一个或多个取代基所取代，R3优选甲基、乙基或叔丁基或苄基；
根据本发明的实施方案，R3选自C1-10烷基或C6-14芳基C1-10烷基，所述C1-10烷基或C6-14芳基C1-10烷基各自独立地任选被卤素、C1-10烷基、卤代C1-10烷基、C1-10烷氧基、卤代C1-10烷氧基、羧基和羟基-C1-10烷基中的一个或多个取代基所取代。
根据本发明的实施方案，R3选自C1-6烷基，例如甲基、乙基、异丙基、叔丁基。
根据本发明的实施方案，R3选C6-14芳基C1-6烷基，例如苄基。
根据本发明的实施方案，式II所示化合物具有如下结构：
本发明进一步提供了一种制备式I所示化合物或其可药用盐的方法：
其包括由式II所示化合物或其酸式盐与合适的碱发生水解反应制得，其中所述合适的碱选自氢氧化锂、氢氧化钠或氢氧化钾等。
其中，R1选自氯或氰基；
R3选自C1-20烷基、C6-14芳基或C6-14芳基C1-10烷基，其中所述的C1-20烷基、C6-14芳基或C6-14芳基C1-10烷基各自独立地任选被选自卤素、C1-20烷基、卤代C1-20烷基、C1-20烷氧基、卤代C1-20烷氧基、氰基、氨基、硝基、羟基、氧代(＝O)、羧基和羟基-C1-20烷基中的一个或多 个取代基所取代，优选甲基、乙基或叔丁基。
根据本发明的实施方案，R3选自C1-10烷基或C6-14芳基C1-10烷基，所述C1-10烷基或C6-14芳基C1-10烷基各自独立地任选被卤素、C1-10烷基、卤代C1-10烷基、C1-10烷氧基、卤代C1-10烷氧基、羧基和羟基-C1-10烷基中的一个或多个取代基所取代。根据本发明的实施方案，R3选自C1-6烷基，例如甲基、乙基、异丙基、叔丁基。
根据本发明的实施方案，R3选C6-14芳基C1-6烷基，例如苄基。
本发明还提供了另一种制备式I所示化合物或其可药用盐的方法：
其包括由IIIa所示化合物或其酸式盐与式IV所示化合物发生亲核取代反应制备式I所示化合物或其可药用盐。
其中，R1选自氯或氰基；X代表合适的离去基团，特别是氯、溴、碘、甲磺酸酯、三氟甲磺酸酯或对甲苯磺酸酯。
在一些方面，本发明提供了其中所述的亲核取代反应在合适的碱存在下进行，所述的碱选自磷酸钾、碳酸钾、碳酸钠、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、三乙胺、N,N-二异丙基乙胺、4-二甲氨基吡啶、吗啉、N-甲基吗啉或吡啶中的一种或几种，优选碳酸钾、碳酸氢钠或三乙胺。
本发明进一步提供了一种制备式II所示化合物或其酸式盐的方法：
其包括式IIIa所示化合物或其酸式盐与式V所示化合物发生亲核取代反应生成式II所示化合物或其酸式盐。
其中，R1选自氯或氰基；
R3选自C1-20烷基、C6-14芳基或C6-14芳基C1-10烷基，其中所述的C1-20烷基、C6-14芳基或C6-14芳基C1-10烷基各自独立地任选被选自卤素、C1-20烷基、卤代C1-20烷基、C1-20烷氧基、卤代C1-20烷氧基、氰基、氨基、硝基、羟基、氧代(＝O)、羧基和羟基-C1-20烷基中的一个或多个取代基所取代。
根据本发明的实施方案，R3选自C1-10烷基或C6-14芳基C1-10烷基，所述C1-10烷基或C6-14芳基C1-10烷基各自独立地任选被卤素、C1-10烷基、卤代C1-10烷基、C1-10烷氧基、卤代C1-10烷氧基、羧基和羟基-C1-10烷基中的一个或多个取代基所取代。
根据本发明的实施方案，R3选自C1-6烷基，例如甲基、乙基、异丙基、叔丁基。
根据本发明的实施方案，R3选C6-14芳基C1-6烷基，例如苄基。
在一些方面，本发明提供了其中所述的亲核取代反应在合适的碱存在下进行，所述的碱选自磷酸钾、碳酸钾、碳酸钠、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、三乙胺、N,N-二异丙基乙胺、4-二甲氨基吡啶、吗啉、N-甲基吗啉或吡啶中的一种或几种，优选碳酸钾、碳酸氢钠或三乙胺。
本发明还提供了一种IIIa所示化合物的制备方法：
其包括式IIIb所示化合物或其酸式盐经脱保护生成式IIIa所示化合物或其酸式盐。
其中，R1选自氯或氰基；R2选自选自苄氧羰基、叔丁氧羰基、烯丙基羰基、笏甲氧羰基、甲氧羰基、乙氧羰基、三甲基硅乙氧羰基、邻苯二甲酰基、对甲苯磺酰基、三氟乙酰基、邻硝基苯磺酰基、对硝基苯磺酰基、特戊酰基、苯甲酰基、三苯甲基、2,4‐二甲氧基苄基、对甲氧基苄基或苄基，优选苄氧羰基、叔丁氧羰基或苄基。
本发明进一步提供了一种式III所示化合物或其酸式盐的制备方法：
其包括由式VI所示化合物与式VII所示化合物经Mitsunobu反应制得式III所示化合物或其酸式盐。
其中，R1选自氯或氰基，R2选自氢原子或氨基保护基。
在一些方面，所述氨基保护基为苄氧羰基、叔丁氧羰基、烯丙基羰基、芴甲氧羰基、甲氧羰基、乙氧羰基、三甲基硅乙氧羰基、邻苯二甲酰基、对甲苯磺酰基、三氟乙酰基、邻硝基苯磺酰基、对硝基苯磺酰基、特戊酰基、苯甲酰基、三苯甲基、2,4‐二甲氧基苄基、对甲氧基苄基或苄基，优选苄氧羰基、叔丁氧羰基或苄基。
本发明进一步提供了一种式III所示化合物或其酸式盐的制备方法：
其包括由式VIII所示化合物与式IX所示化合物经取代反应制得式III所示化合物或其酸式盐。
其中，R1选自氯或氰基，R2选自氢原子或氨基保护基。在一些方面，所述氨基保护基为苄氧羰基、叔丁氧羰基、烯丙基羰基、芴甲氧羰基、甲氧羰基、乙氧羰基、三甲基硅乙氧羰基、邻苯二甲酰基、对甲苯磺酰基、三氟乙酰基、邻硝基苯磺酰基、对硝基苯磺酰基、特戊酰基、苯甲酰基、三苯甲基、2,4‐二甲氧基苄基、对甲氧基苄基或苄基，优选苄氧羰基、叔丁氧羰基或苄基；X代表合适的离去基团，特别是氯、溴、碘、甲磺酸酯、三氟甲磺酸酯或对甲苯磺酸酯。
本发明进一步提供了一种式III所示化合物或其酸式盐的制备方法：
其包括由式VI所示化合物与式X所示化合物经取代反应制得式III所示化合物或其酸式盐。
其中，R1选自氯或氰基，R2选自氢原子或氨基保护基。
在一些方面，所述氨基保护基为苄氧羰基、叔丁氧羰基、烯丙基羰基、芴甲氧羰基、甲氧羰基、乙氧羰基、三甲基硅乙氧羰基、邻苯二甲酰基、对甲苯磺酰基、三氟乙酰基、邻硝基苯磺酰基、对硝基苯磺酰基、特戊酰基、苯甲酰基、三苯甲基、2,4‐二甲氧基苄基、对甲氧基苄基或苄基，优选苄氧羰基、叔丁氧羰基或苄基。R0代表合适的离去基团，特别是氯、溴、碘、甲磺酸酯、三氟甲磺酸酯或对甲苯磺酸酯。
本发明还提供了一种式VII所示化合物的制备方法：
其包括由式IX所示化合物与式XI所示化合物发生亲核取代反应生成式VII所示化合物。
其中，R2选自苄氧羰基、叔丁氧羰基、烯丙基羰基、芴甲氧羰基、甲氧羰基、乙氧羰基、三甲基硅乙氧羰基、邻苯二甲酰基、对甲苯磺酰基、三氟乙酰基、邻硝基苯磺酰基、对硝基苯磺酰基、特戊酰基、苯甲酰基、三苯甲基、2,4‐二甲氧基苄基、对甲氧基苄基或苄基，优选苄氧羰基、叔丁氧羰基或苄基；X’选自氟、氯、溴、碘、对甲苯磺酰基氧基、三氟甲磺酰基氧基、甲磺酰基氧基、对硝基苯磺酰基氧基，优选氯、溴或甲磺酰基氧基。
本发明进一步提供了另一种式VII所示化合物的制备方法：
其包括由式IX所示化合物与式XII所示化合物先发生亲核取代反应生成式XIII所示化合物，再经在还原剂的存在下反应制得式VII所示化合物。
其中，R2和X’同前所述；所述还原剂选自氢化铝锂、硼氢化锂、硼氢化钠、硼氢化钾、甲硼烷和四氢呋喃、甲硼烷和二甲硫醚、甲硼烷和二苯硫醚、甲硼烷和二苄硫醚、甲硼烷和二 氧六环、甲硼烷和1，4氧硫杂环己烷的复合物、或BH2Cl与二甲硫醚的复合物，优选硼氢化钠、甲硼烷和四氢呋喃、或甲硼烷和二甲硫醚的复合物。
此外，本发明提供了一种药物组合物，包括前述化合物I或其可药用盐及可药用的载体。
本发明进一步提供了一种前述化合物I或其可药用盐在制备治疗代谢性疾病、肿瘤、自身免疫性疾病或转移性疾病药物中的应用。
本发明还提供一种前述化合物I或其可药用盐，其用作治疗代谢性疾病、肿瘤、自身免疫性疾病或转移性疾病的药物。
本发明进一步提供一种前述化合物I或其可药用盐，其用作治疗T1D、T2DM、糖尿病前期、特发性T1D、LADA、EOD、YOAD、MODY、营养不良相关性糖尿病、妊娠糖尿病、高血糖症、胰岛素抗性、肝脏胰岛素抗性、葡萄糖耐受不良、糖尿病神经病变、糖尿病肾病变、肾疾病、糖尿病视网膜病变、脂肪细胞功能障碍、内脏脂肪细胞囤积、睡眠窒息症、肥胖症、进食障碍、使用其它药剂导致的体重增加、过度嗜糖、血脂异常症、高胰岛素血症、NAFLD、NAS、纤维变性、硬化、肝细胞癌、心血管疾病、动脉粥样硬化、冠状动脉疾病、外周血管疾病、高血压、内皮功能障碍、受损的血管顺应性、充血心力衰竭、心肌梗塞、中风、出血性中风、缺血性中风、创伤性脑损伤、肺性高血压、血管成形术后再狭窄、间歇性跛行、餐后脂血症、代谢性酸中毒、酮体症、关节炎、骨质疏松症、帕金森病、左心室肥大、外周动脉疾病、黄斑变性、白内障、肾小球硬化、慢性肾衰竭、代谢综合征、综合征Ⅺ、经前综合征、心绞痛、血栓症、动脉粥样硬化、短暂性脑缺血发作、血管再狭窄、葡萄糖代谢不良、受损的空腹血糖病况、高尿酸血症、痛风、勃起功能障碍、皮肤和结缔组织异常、牛皮癣、足部溃疡、溃疡性结肠炎、高apoB脂蛋白血症、阿尔茨海默病、精神分裂症、认知功能受损、炎性肠病、短肠征、克隆病、结肠炎、肠易激综合征、多囊性卵巢综合征的预防或治疗及成瘾的治疗的药物。
作为优选的方案，前述化合物I或其可药用盐，其用作治疗T1D、T2DM、糖尿病前期、特发性T1D、LADA、EOD、YOAD、MODY、营养不良相关性糖尿病、妊娠糖尿病、高血糖症、胰岛素抗性、肝脏胰岛素抗性、葡萄糖耐受不良、糖尿病神经病变、糖尿病肾病变、肥胖症、进食障碍、使用其它药剂导致的体重增加、过度嗜糖、血脂异常症、高胰岛素血症的药物。
本发明的技术方案在合成式I化合物的过程中，全程无需进行柱层析，反应条件温和，收率明显提高，整个工艺流程中可以避免使用贵金属催化剂，有效降低了反应成本，便于放大反应，更加适合工业化生产。
定义和说明
除非有相反陈述，下列用在说明书和权利要求书中的术语具有下述含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照普通的含义去理解。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
本文应用的“盐”是指通过有机酸或碱类药物与可药用无机或有机酸或碱反应制备的化合物。
除非另有说明，本说明书和权利要求书记载的数值范围相当于至少记载了其中每一个具体的整数数值。例如，数值范围“1-20”相当于记载了数值范围“1-10”中的每一个整数数值即1、2、3、4、5、6、7、8、9、10，以及数值范围“11-20”中的每一个整数数值即11、12、13、14、15、16、17、18、19、20。
术语“卤素”表示氟、氯、溴和碘。
术语“C1-20烷基”指饱和的脂族烃基团，包括1至20个碳原子的直链和支链基团饱和一价烃基。优选含有1至10个碳原子的烷基(C1-10烷基)，例如甲基、乙基、丙基、2‐丙基、正丁基、异丁基、叔丁基或戊基等。更优选的是含有1至6个碳原子的低级烷基(C1-6烷基)，例如甲基、乙基、丙基、2‐丙基、正丁基、异丁基或叔丁基、戊基、庚基等。
术语“C3-20环烷基”应理解为表示饱和的一价单环、二环(如稠环、桥环、螺环)烃环或三环烷烃，其具有3～20个碳原子，优选“C3-10环烷基”，更优选“C3-8环烷基”。术语“C3-10环烷基”应理解为表示饱和的一价单环、双环(如桥环、螺环)烃环或三环烷烃，其具有3、4、5、6、7、8、9或10个碳原子。所述C3-10环烷基可以是单环烃基，如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基，或者是双环烃基如龙脑基、吲哚基、六氢吲哚基、四氢萘基、十氢萘基、二环[2.1.1]己基、二环[2.2.1]庚基、二环[2.2.1]庚烯基、6,6-二甲基二环[3.1.1]庚基、2,6,6-三甲基二环[3.1.1]庚基、二环[2.2.2]辛基、2,7-二氮杂螺[3,5]壬烷基、2,6-二氮杂螺[3,4]辛烷基，或者是三环烃基如金刚烷基。
术语“C1-20烷氧基”指‐O‐(C1-20烷基)和‐O‐(C3-20环烷基)，其中C1-20烷基和C3-20环烷基的定义如上所述。非限制性实施例包含甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。
术语“C6-14芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，具有6、7、8、9、10、11、12、13或14个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环，优选为6至10元(C6-10芳基)，例如苯基和萘基。
本发明所述“氨基保护基”是本领域已知的可适当的用于氨基保护的基团，参见文献(“Protective Groups in Organic Synthesis”,5Th.Ed.T.W.Greene&P.G.M.Wuts)中的氨基保护基团。作为示例，该氨基保护基选自叔丁氧羰基、乙酰基、苄基、烯丙基或对甲氧苄基，或者，该氨基保护基连同与之结合的氮原子一起，形成内酰胺，如邻苯二甲酰基。脱除保护基的方式也可参照文献(“Protective Groups in Organic Synthesis”，5Th.Ed.T.W.Greene&P.G.M.Wuts)中氨基保护基团去除的方式，并将相关内容引入本说明书中。作为示例，通过氢气/金属催化剂脱除苄基，所述金属催化剂选自但不限于钯碳、氢氧化钯、氧化铂、钯、附氧化铝上的钯、在活性炭上的铂和兰尼镍的中至少一种，优选为钯炭、氢氧化钯；在酸性条件下脱除叔丁氧羰基(Boc)，提供酸性条件的试剂优选自甲磺酸、盐酸、三氟乙酸。
本文所用的术语"室温"或"RT"是指20至25℃的环境温度。
本发明的中间体化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面 列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，有时需要本领域技术人员在已有实施方式的基础对合成步骤或者反应流程进行修改或选择。
下面会通过实施例具体描述本发明，这些实施例并不意味着对本发明的任何限制。
本发明所使用的所有溶剂是市售的，无需进一步纯化即可使用。
在无特殊说明的情况下，本发明的所有反应均在连续的磁力搅拌下，溶剂为干燥溶剂，温度单位为摄氏度(℃)。
方法和材料
化合物的结构是通过核磁共振(NMR)来确定的。NMR位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用Bruker avance-400MHz核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(MeOD-d4)，内标为四甲基硅烷(TMS)，化学位移是以10-6ppm)作为单位。
HPLC的测定使用Agilent 1260高效液相色谱仪或效能相当的高效液相色谱仪(Sunfire C18 150×4.6m色谱柱或效能相当的色谱柱)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
具体实施方式
通过以下实施例对本发明做进一步详细、完整地说明，其仅用于阐明本发明的特定实施方案，而不应被解读为以任何方式限制本发明的范围。除非另外说明，否则所有的百分数、比率、比例、或份数按重量计。实施例中的反应进程的监测采用薄层色谱法(TLC)。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例1：4-(6-(羟甲基)吡啶-2-基)氧基)哌啶-1-甲酸叔丁酯的制备：
向溶有N-叔丁氧羰基-4-羟基哌啶(10.0g，0.05mol)的四氢呋喃(100mL)中，加入叔丁醇钾(1M四氢呋喃溶液，100mL，0.1mol)，控制内温<30℃，加毕，室温搅拌2小时，缓慢滴加6-溴吡啶-2-甲醇(9.4g，0.05mol)的四氢呋喃溶液(30mL)，控制内温<20℃，加毕，升温至50℃，继续搅拌6小时。向反应体系中加入乙酸乙酯(100mL)进行稀释，冷至0-10℃，滴加到饱和氯化铵水溶液(50mL)中进行淬灭，滴加甲酸调节pH＝6，分层，水相用 乙酸乙酯(100mL)萃取两次，合并有机相，用饱和食盐水(50mL)洗涤后，加入无水硫酸钠干燥，过滤并浓缩，所得粗品加入乙酸乙酯(20mL)和正己烷(100mL)，降温至0℃，保温搅拌2小时，过滤，滤饼真空干燥，得4-(6-(羟甲基)吡啶-2-基)氧基)哌啶-1-甲酸叔丁酯(9.3g，收率：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).
实施例2：4-(6-(羟甲基)吡啶-2-基)氧基)哌啶-1-甲酸叔丁酯的制备：
1)6-(1-(叔丁氧羰基)哌啶-4-基)氧基)吡啶甲酸的制备：
向溶有N-叔丁氧羰基-4-羟基哌啶(20.1g，0.1mol)的四氢呋喃(400mL)中，分批加入60％氢化钠(10.0g，0.25mol)，控制内温<25℃，加毕，室温搅拌2小时，分批加入6-溴吡啶-2-甲酸(20.2g，0.1mol)，加毕，升温至60℃，继续搅拌12小时。向反应体系中加入乙酸乙酯(300mL)进行稀释，冷至0-10℃，滴加到饱和氯化铵水溶液(100mL)中进行淬灭，滴加1M盐酸水溶液，调节pH＝4，分层，水相用乙酸乙酯(200mL)萃取两次，合并有机相，用饱和食盐水(100mL)洗涤后，加入无水硫酸钠干燥，过滤并浓缩，得6-(1-(叔丁氧羰基)哌啶-4-基)氧基)吡啶甲酸(26.4g，收率：82.0％)。1H NMR(400MHz,CDCl3)δ7.83-7.82(m,2H),7.02(d,J＝7.2Hz,1H),5.26-5.20(m,1H),3.76-3.70(m,2H),3.42-3.37(m,2H),2.02-1.97(m,2H),1.82-1.79(m,2H),1.48(s,9H).
2)4-(6-(羟甲基)吡啶-2-基)氧基)哌啶-1-甲酸叔丁酯的制备：
将6-(1-(叔丁氧羰基)哌啶-4-基)氧基)吡啶甲酸(25.8g,0.08mol)溶于四氢呋喃(200mL)，降温至0℃，分批加入硼氢化钠(5.7g，0.15mol)，随后滴加三氟化硼乙醚溶液(45mL)，控制内温<25℃，加毕，室温反应3小时。将反应体系降温至0℃，滴加饱和碳酸氢钠水溶液(100mL)淬灭，加入水(100mL)和乙酸乙酯(300mL),分层，水相用乙酸乙酯(200mL)萃取，合并有机相,用饱和食盐水(100mL)洗涤后，加入无水硫酸钠干燥，过滤，滤饼真空干燥，过滤并浓缩，所得粗品加入乙酸乙酯(20mL)和正己烷(100mL)，降温至0℃，保温搅拌2小时，过滤，滤饼真空干燥，得4-(6-(羟甲基)吡啶-2-基)氧基)哌啶-1-甲酸叔丁酯(19.9g，收率：80.6％)。
实施例3：(6-(哌啶-4-氧基)吡啶-2-基)甲醇盐酸盐的制备
向溶有4-(6-(羟甲基)吡啶-2-基)氧基)哌啶-1-甲酸叔丁酯(30.8g，0.1mol)的乙酸乙酯(150mL)中，滴加入3M的盐酸乙酸乙酯(100mL，0.3mol)，控制内温<25℃，滴毕， 室温搅拌12小时，过滤，滤饼用乙酸乙酯(100mL)洗涤两次，滤饼真空干燥，得(6-(哌啶-4-氧基)吡啶-2-基)甲醇盐酸盐(22.6g，收率：92.4％)。
实施例4：2-(4-氯-2-氟苯氧基)甲基)-6-(哌啶-4-氧基)吡啶的制备
将(6-(哌啶-4-氧基)吡啶-2-基)甲醇盐酸盐(19.5g，0.08mol)和2-氟-4-氯苯酚(11.7g，0.08mol)加入到四氢呋喃(200mL)中，降温至0℃，依次加入三苯基磷(41.9g，0.16mol)和偶氮二甲酸二异丙酯(32.4g，0.16mol)，加毕，升至室温反应12小时，向反应体系中加入乙酸乙酯(200mL)和饱和氯化钠水溶液(100mL)，分层，水相用乙酸乙酯(100mL)萃取两次。合并有机相，无水硫酸钠干燥，过滤并浓缩，所得残留物加入石油醚：乙酸乙酯(10:1)混合溶液(250mL)，室温搅拌12小时，过滤，滤液浓缩得粗品。加入石油醚：乙酸乙酯(3:1)混合溶液(100mL)，加入无水氯化镁(7.6g,0.08mol),升温至35℃搅拌6小时，过滤，滤液减压浓缩后，得2-(4-氯-2-氟苯氧基)甲基)-6-(哌啶-4-氧基)吡啶(19.6g，收率：72.9％)。1H 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),7.11(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).
实施例5：2-(4-氰基-2-氟苯氧基)甲基)-6-(哌啶-4-氧基)吡啶的制备
将(6-(哌啶-4-氧基)吡啶-2-基)甲醇盐酸盐(19.5g，0.08mol)和2-氟-4-氰基苯酚(11.0g，0.08mol)加入到四氢呋喃(200mL)中，降温至0℃，依次加入三苯基磷(41.9g，0.16mol)和偶氮二甲酸二异丙酯(32.4g，0.16mol)，加毕，升至室温反应12小时，向反应体系中加入乙酸乙酯(200mL)和饱和氯化钠水溶液(100mL)，分层，水相用乙酸乙酯(100mL)萃取两次。合并有机相，无水硫酸钠干燥，过滤并浓缩，所得残留物加入石油醚：乙酸乙酯(10:1)混合溶液(250mL)，室温搅拌12小时，过滤，滤液浓缩得粗品。加入石油醚：乙酸乙酯(3:1)混合溶液(100mL)，加入无水氯化镁(7.6g,0.08mol),升温至35℃搅拌6小时，过滤，滤液减压浓缩后，得2-(4-氰基-2-氟苯氧基)甲基)-6-(哌啶-4-氧基)吡啶(21.0g，收率：80.2％)。1H 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).
实施例6：2-(4-氯-2-氟苯氧基)甲基)-6-(哌啶-4-氧基)吡啶盐酸盐的制备
1)4-(6-(4-氯-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-甲酸叔丁酯的制备：
将4-(6-(羟甲基)吡啶-2-基)氧基)哌啶-1-甲酸叔丁酯(15.4g，0.05mol)和2-氟-4-氯苯酚(7.3g，0.05mol)加入到四氢呋喃(150mL)中，降温至0℃，依次加入三苯基磷(26.2g，0.1mol)和偶氮二甲酸二异丙酯(20.2g，0.1mol)，加毕，升至室温反应12小时，向反应体系中加入乙酸乙酯(100mL)和饱和氯化钠水溶液(100mL)，分层，水相用乙酸乙酯(50mL)萃取两次。合并有机相，无水硫酸钠干燥，过滤并浓缩，所得残留物加入石油醚：乙酸乙酯(10:1)混合溶液(250mL)，室温搅拌12小时，过滤，滤液浓缩得粗品。加入石油醚：乙酸乙酯(3:1)混合溶液(100mL)，加入无水氯化镁(4.8g,0.05mol),升温至35℃搅拌6小时，过滤，滤液减压浓缩后，得4-(6-(4-氯-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-甲酸叔丁酯(18.2g，收率：83.3％)。1H 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＝8.2Hz,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).
2)2-(4-氯-2-氟苯氧基)甲基)-6-(哌啶-4-氧基)吡啶盐酸盐的制备：
向溶有4-(6-(4-氯-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-甲酸叔丁酯(16.0g，0.037mol)的乙酸乙酯(80mL)中，滴加入3M的盐酸乙酸乙酯(30mL，0.1mol)，控制内温<25℃，滴毕，室温搅拌12小时，过滤，滤饼用乙酸乙酯(30mL)洗涤两次，滤饼真空干燥，得2-(4-氯-2-氟苯氧基)甲基)-6-(哌啶-4-氧基)吡啶盐酸盐(12.9g，收率：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).
实施例7：2-(4-氰基-2-氟苯氧基)甲基)-6-(哌啶-4-氧基)吡啶盐酸盐的制备
1)4-(6-(4-氰基-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-甲酸叔丁酯的制备：
将4-(6-(羟甲基)吡啶-2-基)氧基)哌啶-1-甲酸叔丁酯(15.4g，0.05mol)和2-氟-4-氰基苯酚(6.9g，0.05mol)加入到四氢呋喃(150mL)中，降温至0℃，依次加入三苯基磷(26.2g，0.1mol)和偶氮二甲酸二异丙酯(20.2g，0.1mol)，加毕，升至室温反应12小时， 向反应体系中加入乙酸乙酯(100mL)和饱和氯化钠水溶液(50mL)，分层，水相用乙酸乙酯(50mL)萃取两次。合并有机相，无水硫酸钠干燥，过滤并浓缩，所得残留物加入石油醚：乙酸乙酯(10:1)混合溶液(250mL)，室温搅拌12小时，过滤，滤液浓缩得粗品。加入石油醚：乙酸乙酯(3:1)混合溶液(100mL)，加入无水氯化镁(4.8g,0.05mol),升温至35℃搅拌6小时，过滤，滤液减压浓缩后，干燥得产品4-(6-(4-氰基-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-甲酸叔丁酯(16.8g，收率：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).
2)2-(4-氰基-2-氟苯氧基)甲基)-6-(哌啶-4-氧基)吡啶盐酸盐的制备：
向溶有4-(6-(4-氰基-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-甲酸叔丁酯(16.8g，0.039mol)的乙酸乙酯(80mL)中，滴加入3M的盐酸乙酸乙酯(30mL，0.1mol)，控制内温<25℃，滴毕，室温搅拌12小时，过滤，滤饼用乙酸乙酯(30mL)洗涤两次，滤饼真空干燥，得2-(4-氰基-2-氟苯氧基)甲基)-6-(哌啶-4-氧基)吡啶盐酸盐(13.2g，收率：93.1％)。
实施例8：4-(6-(4-氯-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-甲酸叔丁酯的制备
向溶有N-叔丁氧羰基-4-羟基哌啶(20.0g，0.1mol)的四氢呋喃(400mL)中，分批加入60％氢化钠(10.0g，0.25mol)，控制内温<25℃，加毕，室温搅拌2小时，分批加入2-氯-6-((4-氯-2-氟苯氧基)甲基)吡啶(27.2g，0.1mol)，加毕，升温至60℃，继续搅拌12小时。向反应体系中加入乙酸乙酯(200mL)进行稀释，冷至0-10℃，滴加到饱和氯化铵水溶液(200mL)中进行淬灭，分层，水相用乙酸乙酯(100mL)萃取两次，合并有机相，用饱和食盐水(100mL)洗涤后，加入无水硫酸钠干燥，过滤并浓缩，用正己烷/乙酸乙酯(5/1)打浆，过滤后干燥，得4-(6-(4-氯-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-甲酸叔丁酯(37.3g，收率：85.4％)
实施例9：：4-(6-(4-氯-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-甲酸叔丁酯的制备
向溶有2-氟-4-氯苯酚(7.3g，0.05mol)的DMF(50mL)中，加入碳酸钾(13.8g，0.1mol)，控制内温<25℃，加毕，加入4-((6-(氯甲基)吡啶-2-基)氧基)哌啶-1-甲酸叔丁酯(16.3g， 0.05mol)，加毕，升温至50℃，继续搅拌12小时。向反应体系中加入乙酸乙酯(100mL)和水(100mL)进行稀释，分层，水相用乙酸乙酯(100mL)萃取两次，合并有机相，用饱和食盐水(100mL)洗涤后，加入无水硫酸钠干燥，过滤并浓缩，用正己烷/乙酸乙酯(5/1)打浆，过滤后干燥，得4-(6-(4-氯-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-甲酸叔丁酯(17.5g，收率：80.3％)
实施例10：(S)-2-((4-((6-((4-氯-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸的制备
将溶有(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸(7.5g，26.7mmol)、2-(4-氯-2-氟苯氧基)甲基)-6-(哌啶-4-氧基)吡啶盐酸盐(10.0g，26.8mmol)和碳酸氢钠(5.6g，66.7mmol)的N,N-二甲基甲酰胺(150mL)混合溶液在40℃下搅拌6小时，然后用水(250mL)稀释，滴加甲酸调pH＝5，室温搅拌2小时后，过滤，真空干燥，得(S)-2-((4-((6-((4-氯-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸(14.4g，收率：90.0％)。1HNMR(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).
实施例11：(S)-2-((4-((6-((4-氰基-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸的制备
将含有(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸(7.5g，26.7mmol)、2-(4-氰基-2-氟苯氧基)甲基)-6-(哌啶-4-氧基)吡啶盐酸盐(9.7g，26.7mmol)和碳酸氢钠(5.6g，66.7mmol)的N,N-二甲基甲酰胺(100mL)混合溶液在45℃下搅拌16小时，然后加水(250mL)稀释，滴加甲酸调pH＝5，室温搅拌2小时后，过滤，真空干燥，得(S)-2-((4-((6-((4-氰基-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基 甲基)-1H-苯并[d]咪唑-6-甲酸(13.9g，收率：90.8％)。1HNMR(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).
实施例12：(S)-2-((4-((6-((4-氯-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸的制备：
1)(S)-2-((4-((6-((4-氯-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯的制备：
将含有(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(7.9g，26.8mmol)、2-(4-氯-2-氟苯氧基)甲基)-6-(哌啶-4-氧基)吡啶盐酸盐(10.0g，26.8mmol)和碳酸氢钠(5.6g，66.7mmol)的N,N-二甲基甲酰胺(100mL)混合溶液在40℃下搅拌16小时，然后用水(250mL)，室温搅拌2小时后，过滤，真空干燥，得(S)-2-((4-((6-((4-氯-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(14.8g，收率：93.1％)。1H 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).
2)(S)-2-((4-((6-((4-氯-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸的合成：
向溶有(S)-2-((4-((6-((4-氯-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(10.0g，16.8mmol)的四氢呋喃：水(1：1)的混合溶液(200mL)中加入氢氧化钠(2.0g，50.0mmol)，并在室温下搅拌混合物12小时，加入水(100mL)，用甲酸将反应液调节至pH＝4～5，过滤，滤饼用水洗涤后，真空干燥，得到(S)-2-((4-((6-((4-氯-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸(9.2g，收率：94.3％)。
实施例13：(S)-2-((4-((6-((4-氰基-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸的制备：
1)(S)-2-((4-((6-((4-氰基-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯的制备：
将含有(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(8.1g，27.5mmol)、2-(4-氰基-2-氟苯氧基)甲基)-6-(哌啶-4-氧基)吡啶盐酸盐(10.0g，27.5mmol)和碳酸氢钠(5.8g，68.8mmol)的N,N-二甲基甲酰胺(100mL)混合溶液在40℃下搅拌16小时，然后加水(250mL)，室温搅拌2小时后，过滤，真空干燥，得(S)-2-((4-((6-((4-氰基-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(14.6g，收率：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),5.11-4.94(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,1H),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).
2)(S)-2-((4-((6-((4-氰基-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸的合成：
向溶有(S)-2-((4-((6-((4-氰基-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(10.0g，17.1mmol)的四氢呋喃：水(1：1)的混合溶液(200mL)中加入氢氧化钠(2.0g，50.0mmol)，并在室温下搅拌12小时，加入水(100mL)，用甲酸将反应液调节至pH＝4～5，过滤，滤饼用水洗涤后，真空干燥，得到(S)-2-((4-((6-((4-氰基-2-氟苯氧基)甲基)吡啶-2-基)氧基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸(9.0g，收率：92.1％)。
在本发明提及的所有文献都在本发明中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本发明所附权利要求书所限定的范围。

Claims (13)

  1. 式III所示的化合物或其酸式盐：
    其中，R1选自氯或氰基；
    R2选自氢原子或氨基保护基；
    所述酸式盐为所述化合物与酸形成的盐，例如氢溴酸盐、盐酸盐、硫酸盐、硫酸氢盐、亚硫酸盐、磷酸盐、硼酸盐、乙酸盐、三氟乙酸盐、草酸盐、戊酸盐、苯甲酸盐、乳酸盐、甲苯甲酸盐、柠檬酸盐、苹果酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐。
  2. 权利要求1所述化合物或其酸式盐，其中所述的氨基保护基选自苄氧羰基、叔丁氧羰基、烯丙基羰基、笏甲氧羰基、甲氧羰基、乙氧羰基、三甲基硅乙氧羰基、邻苯二甲酰基、对甲苯磺酰基、三氟乙酰基、邻硝基苯磺酰基、对硝基苯磺酰基、特戊酰基、苯甲酰基、三苯甲基、2,4‐二甲氧基苄基、对甲氧基苄基或苄基；
    优选地，式III所示化合物具有如下结构：
    优选地，式III所示化合物的酸式盐具有如下结构：
  3. 式II所示的化合物或其酸式盐：
    其中，R1和其酸式盐的定义如权利要求1所述；
    其中，R3选自C1-20烷基、C6-14芳基或C6-14芳基C1-10烷基，其中所述的C1-20烷基、C6-14芳基或C6-14芳基C1-10烷基各自独立地任选被选自卤素、C1-20烷基、卤代C1-20烷基、C1-20烷氧基、卤代C1-20烷氧基、氰基、氨基、硝基、羟基、氧代(＝O)、羧基和羟基-C1-20烷基中的一个或多个取代基所取代；
    优选地，R3选自C1-10烷基或C6-14芳基C1-10烷基，所述C1-10烷基或C6-14芳基C1-10烷基各自独立地任选被卤素、C1-10烷基、卤代C1-10烷基、C1-10烷氧基、卤代C1-10烷氧基、羧基和羟基-C1-10烷基中的一个或多个取代基所取代。优选地，R3选自C1-6烷基，例如甲基、乙基、异丙基、叔丁基；
    根据本发明的实施方案，R3选C6-14芳基C1-6烷基，例如苄基。
    优选地，式II所示化合物具有如下结构：
  4. 一种式I所示化合物或其可药用盐的制备方法，其特征在于，包括以下步骤：权利要求3所述式II所示化合物或其酸式盐与合适的碱发生水解反应，得到式I所示化合物或其可药用盐；
    其中，R1和其酸式盐的定义如权利要求1所述；R3的定义如权利要求3所述；
    所述合适的碱选自无机碱，如：氢氧化锂、氢氧化钠、碳酸钠、碳酸钾、碳酸铯或氢氧化钾、磷酸钾、磷酸钠。
  5. 一种式I所示化合物或其可药用盐的制备方法，其特征在于，包括以下步骤：式IIIa所示化合物或其酸式盐与式IV所示化合物发生亲核取代反应制备得到式I所示化合物或其可药用盐，
    其中，R1的定义如权利要求1所述；
    其中，X代表合适的离去基团，例如选自氯、溴、碘、甲磺酸酯、三氟甲磺酸酯或对甲苯 磺酸酯。
  6. 权利要求3所述的式II化合物或其酸式盐的制备方法，其特征在于，所述方法包括式IIIa所示化合物或其酸式盐与式V所示化合物发生亲核取代反应生成式II所示化合物或其酸式盐的步骤，
    其中，R1的定义如权利要求1所述；
    其中，R3的定义如权利要求3所述；X的定义如权利要求5所述。
  7. 根据权利要求5或6所述的制备方法，其中所述的亲核取代反应在碱存在下进行，所述的碱选自磷酸钾、碳酸钾、碳酸钠、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、三乙胺、N,N-二异丙基乙胺、4-二甲氨基吡啶、吗啉、N-甲基吗啉或吡啶中的一种或几种，优选自碳酸钾、碳酸氢钠或三乙胺。
  8. 根据权利要求5所述的制备方法，其特征在于，所述方法还包括式IIIb所示化合物或其酸式盐经脱保护生成式IIIa所示化合物的步骤，
    其中，R1、R2的定义如权利要求1所述。
  9. 权利要求1所述式III所示化合物或其酸式盐的制备方法，包括以下步骤：式VI所示化合物与式VII所示化合物经Mitsunobu反应得到式III所示化合物或其酸式盐，
    其中，R1和R2的定义如权利要求1所述。
  10. 权利要求1所述式III所示化合物或其酸式盐的制备方法，其由式VIII所示化合物与式IX所示化合物经取代反应得到式III所示化合物或其酸式盐，
    其中，R1和R2的定义如权利要求1所述，X代表合适的离去基团，例如选自氯、溴、碘、甲磺酸酯、三氟甲磺酸酯或对甲苯磺酸酯。
  11. 权利要求1所述式III所示化合物或其酸式盐的制备方法，其由式VI所示化合物与式X所示化合物经取代反应得到式III所示化合物或其酸式盐，
    其中，R1和R2的定义如权利要求1所述；
    其中，R0代表合适的离去基团，特别是氯、溴、碘、甲磺酸酯、三氟甲磺酸酯或对甲苯磺酸酯。
  12. 一种药物组合物，其包括权利要求4所述的式I所示化合物或其可药用盐及可药用的载体。
  13. 权利要求4所述的式I所示化合物或其可药用盐，在制备预防或治疗GLP1R靶点及其相应信号通路相关的疾病的药物中的应用，所述疾病选自T2DM、糖尿病前期、特发性T1D、LADA、EOD、YOAD、MODY、营养不良相关性糖尿病、妊娠糖尿病、高血糖症、胰岛素抗性、肝脏胰岛素抗性、葡萄糖耐受不良、糖尿病神经病变、糖尿病肾病变、肾疾病、糖尿病视网膜病变、脂肪细胞功能障碍、内脏脂肪细胞囤积、睡眠窒息症、肥胖症、进食障碍、使用其它药剂导致的体重增加、过度嗜糖、血脂异常症、高胰岛素血症、NAFLD、NAS、纤维变性、硬化、肝细胞癌、心血管疾病、动脉粥样硬化、冠状动脉疾病、外周血管疾病、高血压、内皮功能障碍、受损的血管顺应性、充血心力衰竭、心肌梗塞、中风、出血性中风、缺血性中风、创伤性脑损伤、肺性高血压、血管成形术后再狭窄、间歇性跛行、餐后脂血症、代谢性酸中毒、酮体症、关节炎、骨质疏松症、帕金森病、左心室肥大、外周动脉疾病、黄斑变性、白内障、肾小球硬化、慢性肾衰竭、代谢综合征、综合征Ⅺ、经前综合征、心绞痛、血栓症、动脉粥样硬化、短暂性脑缺血发作、血管再狭窄、葡萄糖代谢不良、受损的空腹血糖病况、高尿酸血症、痛风、勃起功能障碍、皮肤和结缔组织异常、牛皮癣、足部溃疡、溃疡性结肠炎、阿尔茨海默病、精神分裂症、认知功能受损、炎性肠病、短肠征、克隆病、结肠炎、肠易激综合征、多囊性卵巢综合征。
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