WO2019154047A1 - 烷氧基苯并五元(六元)杂环胺类化合物及其药物用途 - Google Patents

烷氧基苯并五元(六元)杂环胺类化合物及其药物用途 Download PDF

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WO2019154047A1
WO2019154047A1 PCT/CN2019/072468 CN2019072468W WO2019154047A1 WO 2019154047 A1 WO2019154047 A1 WO 2019154047A1 CN 2019072468 W CN2019072468 W CN 2019072468W WO 2019154047 A1 WO2019154047 A1 WO 2019154047A1
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formula
membered
compound
amine compound
heterocyclic amine
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叶德泳
莫明广
杨金童
周璐
楚勇
费金钰
齐翔宇
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复旦大学
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Priority to US16/967,118 priority Critical patent/US11396504B2/en
Priority to JP2020542775A priority patent/JP7475049B2/ja
Priority to EP19751009.2A priority patent/EP3750890A4/en
Publication of WO2019154047A1 publication Critical patent/WO2019154047A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the field of medicinal chemistry, and relates to an alkoxybenzopentagon (hexagonal) heterocyclic amine compound and a pharmaceutical use thereof, in particular to an alkoxybenzopentagon (hexagonal) heterocyclic amine compound or a pharmaceutical thereof Acceptable salts and their use in the preparation of sphingomyelin synthase inhibitors and in the preparation of prophylactic or therapeutic atherosclerosis, type II diabetes, fatty liver and obesity and their metabolic syndrome, and inflammatory diseases including enteritis Use in medicine.
  • Atherosclerosis is one of the main pathological basis of many cardiovascular and cerebrovascular diseases. Therefore, research on anti-atherosclerotic drugs has become a hot spot in the field of drug research and development. Studies have also shown that atherosclerosis is characterized by the appearance of yellow matter containing cholesterol, fat, etc. in the intima of the large and middle arteries, leading to thrombosis, blood supply disorders, etc.; although its molecular pathology has not yet been fully elucidated, it is recognized in the industry.
  • dyslipidemia is the most important inducer of atherosclerosis, and the formation of atheroma and arteriosclerosis is closely related to the abnormal expression of lipid components.
  • dyslipidemia refers to abnormal lipid metabolism or transport, resulting in higher than normal plasma lipids and increased blood viscosity.
  • the main manifestations are low-density lipoprotein (LDL) and very low-density lipoprotein (very low).
  • Low-density lipoprotein (VLDL) levels and high-density lipoprotein (HDL) levels decrease. Therefore, lowering LDL and/or raising HDL can play a role in regulating blood lipids, and blood lipid regulating drugs have become clinically the main drugs for anti-atherosclerosis.
  • statins can reduce the level of LDL cholesterol in plasma by inhibiting the key enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG Co-A reductase) in the process of cholesterol biosynthesis.
  • HMG Co-A reductase 3-hydroxy-3-methylglutaryl coenzyme A reductase
  • sphingomyelin synthase inhibitors PPAR agonists
  • infusion of apolipoproteins liver X receptor activators and phospholipid transfer proteins.
  • PLTP phospholipid transfer proteins
  • SM sphingomyelin
  • its metabolic enzymes mediate a series of cellular processes while causing lipoprotein changes, suggesting that it plays an important role in the development of atherosclerosis .
  • sphingomyelin can induce atherosclerosis through a variety of pathways: (1) inhibition of triglyceride (TG) lipolysis (Park TS, Panek RL, et al. Atherosclerosis. 2006, 189 (2): 264- 72.); (2) delaying the clearance of lipoprotein residues that cause AS (Schlitt A, Hojjati MR, et al. J Lipid Res. 2005, 46(2): 196-200.); (3) affecting HDL mediation Guided reverse cholesterol transport, causing cholesterol clearance disorder (Sano O, Kobayashi A, et al. J Lipid Res. 2007, 48 (11): 2377-84; Marmillot P, Patel S, et al. Metabolism.
  • TG triglyceride
  • ceramide and SM synthesis or decomposition related products are regulators of cell proliferation, activation, and apoptosis, affecting the growth and stability of atherosclerotic plaque (Park, T .-S.; Panek, RL; et al. Circulation. 2004, 110, 3465-3471.).
  • SM-rich LDL has strong cohesion and adhesion, which makes it easier for macrophages to accumulate in the arterial wall to form foam cells and promote AS (Fan Y, Shi S, et al. Arterioscler Thromb Vasc Biol, 2010 , 30:2114-20.).
  • SMS sphingomyelin synthase
  • PC ceramide and lecithin
  • Sr sphingomyelin synthase-associated protein
  • SMS1 and SMS2 regulate the related functions, in which SMS1 is mainly distributed in the Golgi and is responsible for 60%-80% of SM synthesis, while SMS2 is mainly distributed on the cell membrane and responsible for 20%-40% of SM synthesis in vivo.
  • SMSr has no enzyme catalytic function.
  • Yano et al. found that SMS1 knockout in mice dysregulated mitochondrial function, thereby increasing active oxides and impairing insulin secretion (M. Yano, K., et al. J Biol Chem.
  • SMS1 white adipose tissue
  • WAT white adipose tissue
  • knockout of SMS1 Will affect reproduction etc.
  • Complete knockout of SMS1 can cause adverse reactions such as hearing loss (Lu MH, et al. J Physiol. 2012; 590: 4029–4044). Therefore, SMS1 may not be a very ideal target for drug action.
  • the knockout of SMS2 is different from the SMS1 knockout. Not only is there no serious physiological damage, but it is also beneficial for prevention of atherosclerosis, improvement of insulin resistance, etc. (Li Z, Zhang H, et al. Mol. Cell. Biol. 2011, 31(20): 4205-4218).
  • SMS directly regulates SM levels
  • overexpression of SMS is a common phenomenon in atherosclerotic lesions and one of the key indicators of atherosclerotic lesions (Xian-cheng Jiang; Furcy Paultre; et al Arterioscler. Thromb. Vasc Biol. 2000, 20, 2614-2618; Zhiqiang Li; Tiruneh K. et al. Biochimica et Biophysica Acta, 2007, 1771, 1186-1194.).
  • SMS2 deficiency can prevent obesity and insulin resistance induced by high-fat diet, while in the liver of SMS2 knockout mice, it is difficult to observe large mature fat plaques, indicating that SMS2 is involved in the liver.
  • the formation of fatty plaques can induce the development of obesity and type 2 diabetes (Susumu Mitsutake, Kota Zama, et al. Journal of Biological Chemistry. 2011, 286 (32), 28544-28555).
  • a decrease in SM in plasma caused by SMS2 deficiency can improve insulin sensitivity in animal tissues and throughout the body (Li Z, Zhang H, et al. Mol. Cell. Biol. 2011, 31(20): 4205-4218).
  • Gene knockout SMS2 can increase glucose uptake by insulin-targeted tissues such as bones and muscles in mice, thereby lowering blood glucose levels (Sugimoto, Masayuki, et al. Biochimica et Biophysica Acta 1861 2016, 688-702).
  • Sphingomyelin (d18:1/16) was found to accumulate in diabetic patients and glomeruli, and was also confirmed in mice on a high-fat diet compared to the blank group; in vitro, in the cell experiment, additional SM (d18) : 1 / 16) can mention ATP levels and reduce AMPK; inhibitor sphingomyelin synthase activity can reverse this phenomenon, which means SM (d18: 1 / 16) as a regulatory factor, can regulate diabetic nephropathy and obesity The ratio of ATP to AMP in the medium; inhibition of sphingomyelin synthase can reduce the high ratio of ATP to AMP in diabetic nephropathy and obesity (S. Miyamoto et al. EBio Medicine 2016, (7) 121-134). Sphingomyelinase small molecule inhibitors may be used to prevent and treat metabolic syndromes such as type 2 diabetes, obesity and fatty liver.
  • SMS2 knockout can significantly improve inflammation and insulin resistance in other high-fat-fed mice and other metabolic syndromes (Susumu Mitsutake, Kota Zama, et al. Journal of Biological Chemistry. 2011, 286 (32), 28544-28555).
  • SMS2 dextran sulfate sodium
  • DSS dextran sulfate sodium
  • Sphingomyelinase 2 small molecule inhibitors may be used to prevent and treat inflammation-related diseases such as enteritis and intestinal cancer.
  • the sphingomyelin synthase small molecule inhibitor compound D2 was discovered (Xiaodong Deng, Fu Lin, et al. European Journal of Medicinal Chemistry, 2014, 73, 1). -7), although its inhibitory activity against SMS2 in vitro is enhanced compared with D609, it still has the following defects: the inhibitory activity against SMS2 needs to be improved, it contains a cyano group with a high potential toxicity risk, and water solubility and stability, etc. Physical and chemical properties are not good.
  • the cell homogenate supernatant was used as the enzyme source, the measured 2- quinolone derivative of the inhibitory activity of IC 50 value of 6.5nM (R.Adachi et al .European Journal of Medicinal Chemistry, 2017, 136, 283-293); its activity and selectivity are higher, but due to its relatively large molecular weight and high cLogP (MW 625.57; cLogP 6.47), it may have certain drug-forming problems.
  • the inventors of the present application intend to provide novel alkoxybenzopenta(6-membered) heterocyclic amine compounds and their pharmaceutical use.
  • the object of the present invention is to overcome the defects and deficiencies of the prior art, and to provide alkoxybenzo-5-e (heterocyclic) heterocyclic amine compounds and their pharmaceutical uses, in particular to alkoxybenzoquinone (six-membered) a cyclic amine compound or a pharmaceutically acceptable salt thereof and use thereof in the preparation of a sphingomyelin synthase inhibitor, and in the preparation of a prophylactic or therapeutic atherosclerosis, type II diabetes, fatty liver and obesity and metabolic syndrome thereof Use in medicines including inflammatory diseases such as enteritis.
  • a first object of the present invention is to provide an alkoxybenzopenta(6-membered) heterocyclic amine compound or a pharmaceutically acceptable salt thereof; said alkoxybenzo-5-element (hexagonal) heterocyclic ring
  • the amine compound is a free base or a salt having a structure represented by the formula (I).
  • X is selected from any one or two of O, N, S, and C.
  • Y is selected from any one or two of O, N, S, and C.
  • R 4 may be methyl or hydrogen, ethyl
  • R 1 is selected from benzene, heterocyclic ring or acyl group.
  • heterocyclic structure is, but not limited to, the following structure:
  • the acyl structure is, but not limited to, the following structure:
  • R 2 is selected from any one of hydrogen, methyl, ethyl, and propyl
  • R 3 is selected from the group consisting of alkoxy, phenylcyclomethylene and heterocyclic methylene including, but not limited to, benzyloxy, pyridylmethylene, alkane of 1-8 carbons or alkaneamine of 1-8 carbons;
  • the R 3 structure is but not limited to the following structure:
  • R is selected from the group consisting of oF, mF, pF, o-Cl, m-Cl, p-Cl, o-Me, m-Me, p-Me, o-CF 3 , m-CF 3 , p-CF 3 , o- Any one or two of OCF 3 , m-OCF 3 , p-OCF 3 , o-OMe, m-OMe, p-OMe, o-CN, m-CN, p-CN, o-Et or phenyl Substituent
  • m 0-5.
  • the compound of the present invention contains a basic group which can form a salt with an acid, and can form a salt of a derivative by an ordinary means, including an organic acid salt such as acetate, citrate, fumarate, maleate or oxalic acid.
  • Salt malate, citrate, succinate, tartrate, lactate, camphorsulfonate, besylate, p-toluenesulfonate, methanesulfonate, trifluoroacetate, trifluoro Methanesulfonate and the like; inorganic acid salts such as hydrohalic acid (hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid) salts, sulfates, phosphates, nitrates and the like. Or may form glutamate or aspartate with an amino acid such as glutamic acid or aspartic acid.
  • Preferred salts are the hydrochloride salt, the hydrobromide salt.
  • the alkoxybenzopenta(6-membered) heterocyclic amine compound of the present invention further includes a solvate thereof, and the solvent thereof is preferably water, ethanol or methanol.
  • a second object of the present invention is to provide the use of the alkoxybenzopenta(6-membered) heterocyclic amine compound represented by the formula (I) for the preparation of a sphingomyelin synthase 2 small molecule inhibitor.
  • the present invention uses a high performance liquid chromatography (HPLC) fluorescence quantitative detection method reported in the literature to determine the inhibitory activity of the alkoxybenzoquinone (hexa) heterocyclic amine compound represented by the formula (I) on sphingomyelin synthase ( Xiaodong Deng; Hong Sun; et al.
  • a further object of the present invention is to provide an alkoxybenzopentagon (hexagonal) heterocyclic amine compound represented by the formula (I) and a salt or solvate thereof for the preparation and use thereof for the prevention and treatment of abnormal levels of sphingomyelin Increased use in diseases including atherosclerosis, type 2 diabetes, fatty liver and obesity and its metabolic syndrome, and inflammatory diseases including enteritis.
  • an alkoxybenzopentagon (hexagonal) heterocyclic amine compound represented by the formula (I) and a salt or solvate thereof for the preparation and use thereof for the prevention and treatment of abnormal levels of sphingomyelin Increased use in diseases including atherosclerosis, type 2 diabetes, fatty liver and obesity and its metabolic syndrome, and inflammatory diseases including enteritis.
  • the present invention proves by experiments that the disclosed compound has remarkable inhibitory activity against SMS2; ideal physicochemical properties such as stability and water solubility; and it does not contain potential toxic groups, and has potential toxic and side effects, and can be used as a therapeutic level by sphingomyelin. Drugs caused by abnormally increased diseases such as atherosclerosis, type 2 diabetes, fatty liver and obesity and inflammation.
  • the above medicament may further comprise one or more pharmaceutically acceptable carriers, including conventional diluents, excipients, fillers, binders, humectants, disintegrants, absorption promotion in the pharmaceutical field.
  • a surfactant, a surfactant, an adsorption carrier, a lubricant, etc., if necessary, a flavoring agent, a sweetener or the like may be added.
  • the invention has the beneficial effects that the provided alkoxybenzo five-membered (hexa-membered) heterocyclic amine compound is a novel structure of a sphingomyelin synthase inhibitor having a submicromolar level of molecular level inhibitory activity and
  • the selectivity of subtype SMS2 can be further developed into drugs for the treatment of inflammatory diseases including atherosclerosis, type II diabetes, fatty liver and obesity and its metabolic syndrome, and including enteritis.
  • the target compounds are of the formulae I-2 and I-4 to I-27, specifically: 4-(2-chloro-5-fluorobenzyloxy)-3-(pyridin-3-ylamino)benzo[d]isoxine Azole (Formula I-2); 4-(2-Fluorobenzyloxy)-3-(pyridin-3-ylamino)benzo[d]isoxazole (Formula I-4); 4-(3-Fluorine Benzyloxy)-3-(pyridin-3-ylamino)benzo[d]isoxazole (Formula I-5); 4-(4-Fluorobenzyloxy)-3-(pyridin-3-ylamino)-3-(pyridin-3-ylamino)
  • the corresponding target compound 25 was obtained by reacting the corresponding hydroxy compound 24 with benzyl bromide.
  • the corresponding alkylamine is reacted with the intermediate 31 to obtain the corresponding target compound of the formula I-35 to I-38, specifically: 4-(2- Chloro-5-fluorobenzyloxy)-3-(2-(N,N-diethyl)acetamido)benzo[d]isoxazole (Formula I-35); 4-(2-Chlor-5 -fluorobenzyloxy)-3-(2-(1-pyrrolidinyl)acetamido)benzo[d]isoxazole (Formula I-36); 4-(2-Chloro-5-fluorobenzyloxy) 3-(2-(1-piperidinyl)acetamido)benzo[d]isoxazole (Formula I-37); 4-(2-Chloro-5-fluorobenzyloxy)-3-(2- (4-morpholine)acetamido)benzo[d]
  • Example 12 Synthesis of 3-(pyridin-3-ylamino)-4-((2-phenylpyridin-4-yl)methoxy)-benzo[d]isoxazole (Formula I-39) .
  • the substituted benzyl bromide was prepared with the corresponding substituted benzyl alcohol, and then with 3-(pyridin-3-ylamino)-4-hydroxybenzo[d].
  • the isoxazole reaction gave the corresponding target compound I-39.
  • the compound 38 was used instead of the substituted benzyl bromide to react with 3-(pyridin-3-ylamino)-4-hydroxybenzo[d]isoxazole.
  • Target compound I-40 was used instead of the substituted benzyl bromide to react with 3-(pyridin-3-ylamino)-4-hydroxybenzo[d]isoxazole.
  • Example 15 Inhibition of sphingomyelin synthase 2 in vitro by alkoxybenzopentagon (hexagonal) heterocyclic amine compounds
  • Vortex mixer (Shanghai Jingke Industrial Co., Ltd. model XW-80A).
  • HPLC column COSMOSIL 5C18-MS-II (4.6 mm I.D. x 250 mm).
  • DMPC Purchased from Santa Cruz (USA), dissolved in ethanol at a concentration of 40 mmol/L.
  • the organic solvents used were purchased from Shanghai Sinopharm Co., Ltd., methanol was chromatographically pure, water was Milli-Q pump filtered, deionized, ultra-pure water ultrafiltration through 0.22 ⁇ m membrane, and other bio-consumable materials were purchased from domestic companies.
  • test compound solution accurately weigh 1 to 2 mg of each test compound, firstly add an appropriate amount of DMSO to prepare a 3 mmol/L stock solution. Take a volume of the DMSO stock solution of the test compound, and then add an appropriate amount of DMSO to dilute the test compound to the desired concentration of the solution.
  • SMS1 SMS2 pure enzyme DDM solution and buffer were provided by the National Protein Science Center (Shanghai) Cao Yu Group.
  • SMS2 pure enzyme DDM solution (total protein content 1.5 ⁇ g/ ⁇ L), 1 ⁇ L of test compound in DMSO or blank DMSO solution, 79.7 ⁇ L DDM buffer to 1.5 mL eppendorf tube, vortex 30 In seconds, it was allowed to stand at room temperature for 5 min. Then, 20 ⁇ L of DDM buffer containing 1 ⁇ L of DMPC in ethanol (40 mmol/L) and 1 ⁇ L of C6-NBD-Ceramide in DMSO (1.16 mmol/L) was added, vortexed for 30 seconds, and then incubated at 37 ° C in a water bath. h. Take out, add 200 ⁇ L of absolute ethanol, and vortex for 30 seconds. 200 ⁇ L of the mixture was taken and stored at 4 ° C for high performance liquid chromatography analysis.
  • the corresponding operation can be carried out by using SMS1 pure enzyme instead of SMS2 pure enzyme.
  • the 6 mM DMSO stock solution of the test compound was subjected to gradient dilution to prepare 5 concentration gradient solutions, and 1 ⁇ L of each was added to the test system of the first step of Example 15, and the sample was prepared according to the method of the first step of Example 15.
  • Alkoxybenzopenta-penta-membered (hexa-membered) heterocyclic amine compounds I-1 to I-38 were determined for inhibition rate and half-inhibitory concentration (IC 50 ) of sphingomyelin synthase 1 at 50 ⁇ M.
  • the experiment can be carried out by the operation of measuring the concentration corresponding to the half inhibitory concentration (IC 50 ) of sphingomyelin synthase 2 with the corresponding concentration.

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Abstract

属药物化学领域，涉及式I所示的烷氧基苯并五元(六元)杂环胺类化合物或其药学上可接受的盐及其药物用途，其中所述R1，R2，R3与发明内容中的详细描述一致。该类化合物能选择性抑制鞘磷脂合酶2活性，可用于治疗由于鞘磷脂水平异常增加所引起的疾病。进一步包括所述的化合物、其药学上可接受的盐、或以其为有效活性成分的药物组合物在制备预防和治疗由于鞘磷脂水平异常增加所引起的疾病药物中的应用，所述由于鞘磷脂水平异常增加所引起的疾病包括动脉粥样硬化、II型糖尿病、脂肪肝和肥胖及其代谢综合症以及包括肠炎等炎症性疾病。

Description

烷氧基苯并五元(六元)杂环胺类化合物及其药物用途 技术领域
本发明属药物化学领域，涉及烷氧基苯并五元(六元)杂环胺类化合物及其药物用途，具体涉及烷氧基苯并五元(六元)杂环胺类化合物或其药学上可接受的盐及其在制备鞘磷脂合酶抑制剂中的用途以及在制备预防或治疗动脉粥样硬化、II型糖尿病、脂肪肝和肥胖及其代谢综合症以及包括肠炎等炎症性疾病的药物中的用途。
背景技术
据报道，在我国，心脑血管病发病率与死亡率近年显著增加至除肿瘤外总死因的第2位，已经成为危害人类健康的主要疾病之一。研究显示，动脉粥样硬化(atherosclerosis，AS)是许多心脑血管疾病的主要病理基础之一，因此，抗动脉粥样硬化药物的研究成为当前药物研发领域的热点。研究还显示，动脉粥样硬化表现为大、中动脉内膜出现含胆固醇、类脂肪等的黄色物质，从而导致血栓形成、供血障碍等；虽然其分子病理尚未完全阐明，但业内公认在已知的诸多因素中血脂异常是动脉粥样硬化形成的最重要的诱导因素，并且粥瘤和动脉硬化的形成与脂质成分的异常表达密切相关。通常，血脂异常是指脂肪代谢或转运异常导致血浆中脂质高于正常，血液粘稠度增高，其主要表现为低密度脂蛋白(low-density lipoprotein,LDL)和极低密度脂蛋白(very low-density lipoprotein,VLDL)水平升高以及高密度脂蛋白(high-density lipoprotein,HDL)水平下降。因此，降低LDL和(或)升高HDL可以起到调节血脂的作用，并且调血脂药亦成为临床上用于抗动脉粥样硬化的主要药物。
临床上常用的调血脂药主要有他汀类、贝特类、胆酸结合树脂类、烟酸等。其中，他汀类药物通过抑制胆固醇生物合成过程中的关键酶-3-羟基-3-甲基戊二酰辅酶A还原酶(HMG Co-A还原酶)，降低血浆中LDL胆固醇的水平，能减少冠 心病的发病率(Linsel-Nitschke P,Tall AR.Nat.Rev.Drug.Discov,2005,4,193-206)。然而，有研究表明使用普伐他汀(pravastatin)或阿托伐他汀(atorvastatin)强化治疗冠心患者后，LDL胆固醇水平虽有不同程度降低，但仍然存在心血管病的高发病率(Cannon CP,Braunwald E,et a1.N Engl J Med,2004,350:l495-l504)，因此，通过单独降低LDL胆固醇水平带来的治疗效果存在一定的限度；还有研究显示他汀类药物存在着横纹肌溶解等严重的不良反应。
随着研究的深入，有研究提出了多种抗动脉粥样硬化的潜在药物靶标如：鞘磷脂合酶抑制剂、PPAR激动剂、输注载脂蛋白、肝脏X受体激活剂和磷脂转移蛋白(PLTP)抑制剂等；尤其是鞘磷脂(sphingomyelin,SM)及其代谢酶在引起脂蛋白改变的同时介导一系列细胞过程，表明其在动脉粥样硬化发生发展进程中扮演着重要的角色。
研究表明，鞘磷脂能通过多种途径诱发动脉粥样硬化：(1)抑制甘油三酯(TG)的脂解(Park TS,Panek RL,et al.Atherosclerosis.2006,189(2):264-72.)；(2)延缓致AS的脂蛋白残粒的清除(Schlitt A,Hojjati MR,et al.J Lipid Res.2005,46(2):196-200.)；(3)影响HDL介导的胆固醇逆向转运，造成胆固醇清除障碍(Sano O,Kobayashi A,et al.J Lipid Res.2007,48(11):2377-84；Marmillot P,Patel S,et al.Metabolism.2007,56(2):251-9.)；(4)神经酰胺及SM合成或分解的相关产物是细胞增殖、激活、凋亡的调节因子，影响着动脉粥样硬化斑块的生长与稳定(Park,T.-S.；Panek,R.L.；et al.Circulation.2004,110,3465-3471.)。(5)富含SM的LDL具有很强的凝聚和黏附，导致巨噬细胞更易于在动脉壁滞留聚集而形成泡沫细胞从而促进AS(Fan Y,Shi S,et al.Arterioscler Thromb Vasc Biol,2010,30:2114-20.)。
流行病学调查也显示，人类SM水平与动脉粥样硬化(AS)存在独立的相关性，血浆SM浓度是动脉粥样硬化的独立危险因子，在评价动脉粥样硬化发展过程中具有指标性的意义(Jiang,X.-C.；Paultre,F.；et al.Arterioscler.Thromb.Vasc.Biol.2000,20,2614-2618；Zhiqiang Li；Maria J.Basterr；et al.Biochimica et Biophysica Acta.2005,1735,130–134.)；动物实验研究已经显示对SM从头生物合成的抑制确实能有效降低apoE-KO小鼠的血浆胆固醇及甘油三脂水平，升高HDL-胆固醇含量，从而阻止AS病变的发展(Park,T.-S.；Panek,R.L.；et  al.Circulation.2004,110,3465-3471.)；因此，业内认为降低血浆中鞘磷脂水平或抑制SM的合成可达到减缓或阻止动脉粥样硬化发生发展的目的。
此外，研究人员发现鞘磷脂合酶(Sphingomyelin synthase,SMS)可调节神经酰胺(ceramide)与卵磷脂(PC)合成SM，是鞘磷脂从头合成途径最后一步的关键酶。鞘磷脂合酶主要有三个亚型，鞘磷脂合酶1(SMS1)、鞘磷脂合酶2(SMS2)和鞘磷脂合酶相关蛋白(SMSr)。在体内主要是SMS1和SMS2对相关功能进行调节，其中SMS1主要分布在高尔基体内并负责了60％-80％的SM合成，而SMS2主要分布在细胞膜上同时负责20％-40％的体内SM合成(Tafesse FG,et al.J Biol Chem.2007；282(24):1753-1747)。而SMSr无酶催化功能。Yano等研究人员发现，对小鼠进行SMS1敲除使线粒体的功能出现失调，从而提高活性氧化物，导致胰岛素分泌功能的受损(M.Yano,K.,et al.J Biol Chem.2011；286(5):3992-4002)，同时氧化应激也会严重损害白色脂肪组织(WAT)(M.Yano,et al.PLoS One.2013；8(4):e61380)；而且SMS1的敲除会影响到生殖等(Wittmann A,et al.PLoS One.2016；11(10):e0164298)。彻底敲除SMS1则会造成听力下降(Lu MH,et al.J Physiol.2012；590:4029–4044)等不良反应。因此SMS1可能不是一个十分理想的药物作用靶点。但是，SMS2的敲除不同于SMS1敲除，不但没有发现有严重的生理受损现象而且还能有利于如动脉粥样硬化的预防，胰岛素抵抗的改善等(Li Z,Zhang H,et al.Mol.Cell.Biol.2011,31(20):4205-4218)。
进一步的研究发现，SMS直接调控SM水平，SMS的过度表达是动脉粥样硬化病变组织中的普遍现象，也是动脉粥样硬化病变发生的关键指标之一(Xian-cheng Jiang；Furcy Paultre；et al.Arterioscler.Thromb.Vasc Biol.2000,20,2614-2618；Zhiqiang Li；Tiruneh K.et al.Biochimica et Biophysica Acta,2007,1771,1186–1194.)。动物实验显示SMS2和apoE双基因敲除小鼠模型的主动脉弓动脉粥样硬化斑块显著减小，头臂动脉中SM等脂质水平显著降低，同时对小鼠的正常生理未见影响(Fan Y,Shi S,et al.Arterioscler.Thromb.Vasc Biol,2010,30:2114-20.)，表明SMS催化合成SM的反应处于鞘磷脂生物合成循环的最后环节，抑制其活性引起潜在的毒副反应较小；综上研究结果，业内展望，通过抑制鞘磷脂合酶2降低鞘磷脂水平可成为治疗动脉粥样硬化的新方法，鞘磷脂合酶2作为抗动脉粥样硬化的新靶标具有潜在优越性，鞘磷脂合酶2选择性抑制剂将有 可能成为新型的抗动脉粥样硬化的治疗药物。
除此之外，有研究发现SMS2缺乏可以防止高脂饮食诱导的肥胖和胰岛素抵抗，同时在SMS2基因敲除小鼠的肝脏中，很难观察到大的成熟的脂肪斑块，表明SMS2参与肝脏脂肪斑块的形成且可诱导肥胖和Ⅱ型糖尿病的发生(Susumu Mitsutake,Kota Zama,et al.Journal of Biological Chemistry.2011,286(32),28544-28555)。SMS2缺乏导致的血浆中SM的降低可以改善动物组织和整个身体中胰岛素的敏感性(Li Z,Zhang H,et al.Mol.Cell.Biol.2011,31(20):4205-4218)。基因敲除SMS2，可以使小鼠的胰岛素靶向的组织如骨骼、肌肉提高葡萄糖的吸收，从而降低血糖水平(Sugimoto,Masayuki,et al.Biochimica et Biophysica Acta 1861 2016，688–702)。鞘磷脂(d18:1/16)被发现在糖尿病患者和的肾小球里累积，同时在高脂饮食的小鼠相比空白组也得到证实；在体外的细胞实验中,额外添加SM(d18:1/16)可以提到ATP水平和减低AMPK；抑制剂鞘磷脂合酶的活性能逆转这一现象，这意味着SM(d18:1/16)作为调节因子，可以调节糖尿病肾病和肥胖症中ATP与AMP的比例；抑制鞘磷脂合酶可以降低糖尿病肾病和肥胖症中ATP与AMP的高比例(S.Miyamoto et al.EBioMedicine 2016,(7)121–134)。鞘磷脂合酶小分子抑制剂将可能用于预防和治疗Ⅱ型糖尿病、肥胖和脂肪肝等代谢综合症。
文献报道SMS2基因敲除能明显改善由高脂喂养的小鼠发生炎症和胰岛素耐受以及其他代谢性综合症(Susumu Mitsutake,Kota Zama,et al.Journal of Biological Chemistry.2011,286(32),28544-28555)。在研究鞘磷脂的种类对炎症的影响时，发现在体外添加非常长的链的鞘磷脂(d18:1/24:0)可以在直接激活巨噬细胞；而对比SMS2基因敲除和野生型小鼠发现SMS2基因敲除的小鼠中常长的链的鞘磷脂(d18:1/24:0)减低明显，因此从分子机制的表型也可以得出抑制SMS2的活性具有抗炎的作用(Hideaki Sakamoto.et al.Biochemical and Biophysical Research Communications,2016,1-6)。最新文献报道，SMS2基因的缺失能明显改善葡聚糖硫酸钠(DSS)诱导的鼠结肠炎，同时也能减少由氧化重氮甲烷/葡聚糖硫酸钠(DSS)诱导的肠癌的发生(Ohnishi,T et al,FASEB J,2017,31(9),3816-3830)。鞘磷脂合酶2小分子抑制剂将可能用于预防和治疗肠炎、肠癌等炎症相关疾病。
目前有文献报道的鞘磷脂合酶抑制剂之一是D609(Aimin Meng；Chiara  Luberto；et al.Experimental Cell Research,2004,292,385–392.)，该化合物对鞘磷脂合酶的抑制作用较弱(IC 50＝375μM)，且其化学结构上含有原磺酸酯而使得结构高度不稳定(Bai,A.et al.J.Pharmacol.Exp.Ther.2004,309,1051-1059)，半衰期短；基于同源模建的鞘磷脂合酶三维结构模型的虚拟筛选，发现了鞘磷脂合酶小分子抑制剂化合物D2(Xiaodong Deng,Fu Lin,et al.European Journal of Medicinal Chemistry,2014,73,1-7)，其体外对SMS2的抑制活性虽较D609增强，但仍存在如下缺陷：对SMS2的抑制活性有待提高，其含有潜在毒性风险较大的氰基基团，并且水溶性和稳定性等理化性质不佳。公开报道的2-烷氧基苯甲酰芳胺类化合物是一类高活性的鞘磷脂酶的抑制剂，然而其活性处于微摩尔级别，且对SMS1和SMS2亚型选择性未见报道(WO2016029767A1)。日本武田制药公司公布了一类2-喹啉酮类衍生物具有高选择性的鞘磷脂酶2抑制作用。利用293细胞系进行高表达人源SMS2，再用其细胞匀浆的上清液作为酶源，测得2-喹啉酮类衍生物的抑制活性IC 50值为6.5nM(R.Adachi et al.European Journal of Medicinal Chemistry,2017,136,283-293)；其活性与选择性较高，但是由于其分子量比较大以及高的cLogP(MW 625.57；cLogP 6.47)，使其可能存在一定的成药性问题。文献报道了2-苄氧苯基噁唑并吡啶类化合物具备微摩尔级别的SMS2活性和好的选择性，并且首次报道了抑制剂对纯的SMS1和SMS2的抑制剂活性(Qi et al.Bioorg Med Chem Lett,2017,27(15),3511-3515),但是其活性有待进一步提高。日本北海道大学公布了对人源蛋白高表达细胞匀浆抑制活性IC 50值为130nM的SMS2抑制剂，然而其人源的SMS1活性未见报道(JP2017128518A)。
基于现有技术的现状，本申请的发明人拟提供新的烷氧基苯并五元(六元)杂环胺类化合物及其药物用途。
发明内容
本发明的目的在于克服现有技术的缺陷和不足，提供烷氧基苯并五元(六元)杂环胺类化合物及其药物用途，具体涉及烷氧基苯并五元(六元)杂环胺类化合物或其药学上可接受的盐及其在制备鞘磷脂合酶抑制剂中的用途以及在制备预防或治疗动脉粥样硬化、II型糖尿病、脂肪肝和肥胖及其代谢综合症以及包括肠炎等炎症性疾病的药物中的用途。
本发明的第一个目的是提供烷氧基苯并五元(六元)杂环胺类化合物或其药学上可接受的盐；所述的烷氧基苯并五元(六元)杂环胺类化合物是具有如式(I)所示结构的游离碱或盐，
Figure PCTCN2019072468-appb-000001
式中，
X选自O,N,S,C中的任意一个或两个。
Y选自O,N,S,C中的任意一个或两个。
X,Y的组合得到的结构为但不限于以下结构：
Figure PCTCN2019072468-appb-000002
其中R 4可以为甲基或者氢，乙基；
R 1选自苯、杂环或者酰基。
杂环结构为但不限于以下结构：
Figure PCTCN2019072468-appb-000003
酰基结构为但不限于以下结构：
Figure PCTCN2019072468-appb-000004
R 2选自氢，甲基，乙基，丙基中的任意一个；
R 3选自烷氧基，苯环亚甲基和杂环亚甲基，其中包括但不限于苄氧，吡啶亚 甲基，1-8个碳的烷烃或者1-8个碳的烷烃氨；
R 3结构为但不限于以下结构：
Figure PCTCN2019072468-appb-000005
R选自o-F，m-F，p-F，o-Cl，m-Cl，p-Cl，o-Me，m-Me，p-Me，o-CF 3，m-CF 3，p-CF 3，o-OCF 3，m-OCF 3，p-OCF 3，o-OMe，m-OMe，p-OMe，o-CN，m-CN，p-CN，o-Et或者苯基中的任意一个或两个取代基；
m为0-5。
可以进一步地描述为式Ⅰ-1～式Ⅰ-40的化合物：
Figure PCTCN2019072468-appb-000006
Figure PCTCN2019072468-appb-000007
Figure PCTCN2019072468-appb-000008
Figure PCTCN2019072468-appb-000009
本发明化合物含有碱性基团可与酸成盐，采用普通手段可以形成衍生物的盐，包括有机酸盐如乙酸盐、枸橼酸盐、富马酸盐、马来酸盐、草酸盐、苹果酸盐、柠檬酸盐、琥珀酸盐、酒石酸盐、乳酸盐、樟脑磺酸盐、苯磺酸盐、对甲苯磺酸盐、甲磺酸盐、三氟醋酸盐、三氟甲磺酸盐等；无机酸盐如氢卤酸(氢氟酸、氢氯酸、氢溴酸、氢碘酸)盐、硫酸盐、磷酸盐、硝酸盐等。或与氨基酸，如谷氨酸或天冬氨酸可形成谷氨酸盐或天冬氨酸盐。优选的盐为盐酸盐、溴氢酸盐。
本发明烷氧基苯并五元(六元)杂环胺类化合物还包括其溶剂合物，其溶剂优选为水、乙醇或甲醇。
本发明的第二个目的是提供式(I)所示的烷氧基苯并五元(六元)杂环胺类化合物在制备鞘磷脂合酶2小分子抑制剂中的用途。本发明采用文献报道的高 效液相色谱(HPLC)荧光定量检测方法测定式(I)所示的烷氧基苯并五元(六元)杂环胺类化合物对鞘磷脂合酶的抑制活性(Xiaodong Deng；Hong Sun；et al.Analytical Letters,2012,45:12,1581-1589)，通过其中的NBD-ceramide和NBD-sphingomyelin的含量变化计算出抑制剂对鞘磷脂合酶催化神经酰胺转化为鞘磷脂的活性的改变。
基于高效液相色谱(HPLC)荧光定量法的活性测试实验表明，式(I)所示的烷氧基苯并五元(六元)杂环胺类化合物具有亚微摩尔级的鞘磷脂合酶抑制活性，而且具有优越的亚型选择性，能选择性地抑制SMS2亚型，对SMS1和SMS2的有效浓度差达几百倍，是抑制鞘磷脂合酶2的有效化合物；高效液相色谱(HPLC)荧光定量方法检测所述化合物对鞘磷脂合酶2(SMS2)的抑制活性。
本发明的进一步目的是提供式(I)所示的烷氧基苯并五元(六元)杂环胺类化合物及其盐类或溶剂合物在制备用于预防和治疗由鞘磷脂水平异常增加引起疾病包括动脉粥样硬化、II型糖尿病、脂肪肝和肥胖及其代谢综合症以及包括肠炎等炎症性疾病药物中的用途。
本发明通过实验证实，所公开的化合物对SMS2的抑制活性显著；稳定性和水溶性等理化性质理想；且其不含有潜在的毒性基团，潜在的毒副作用小，可以作为治疗由鞘磷脂水平异常增加所引起的疾病如动脉粥样硬化、Ⅱ型糖尿病、脂肪肝和肥胖和炎症的药物。
在上述药物中还可以含有一种或多种药学上可接受的载体，所述载体包括药学领域的常规稀释剂，赋形剂，填充剂，粘合剂，湿润剂，崩解剂，吸收促进剂，表面活性剂，吸附载体，润滑剂等，必要时还可以加入香味剂，甜味剂等。
本发明的有益效果在于所提供的烷氧基苯并五元(六元)杂环胺类化合物是一类结构新颖的鞘磷脂合酶抑制剂，具有亚微摩尔级的分子水平抑制活性以及对亚型SMS2的选择性，具有良好的潜力和应用前景，可进一步制成为治疗包括动脉粥样硬化、II型糖尿病、脂肪肝和肥胖及其代谢综合症以及包括肠炎等炎症性疾病的药物。
具体实施方式
实施例1：制备4-(2-乙基苄氧基)-3-(吡啶-3-基氨基)苯并[d]异恶唑(式Ⅰ-1)一)、2-苄氧基-6-氟苯氰(化合物1)的合成
Figure PCTCN2019072468-appb-000010
将5.0g(36.5mmol,1.0eq)2-氰基-3-氟苯酚，10.0g(73mmol,2.0eq)碳酸钾和200mg碘化钾溶解于100mL乙腈中，再加入6.55g(38.3mmol,1.05eq)苄溴，加毕，在室温反应12h，之后减压蒸出大部分溶剂，加水，用乙酸乙酯萃取，用饱和食盐水洗涤有机相，无水Na 2SO 4干燥，浓缩，用硅胶伴样，色谱层析柱分离(石油醚：乙酸乙酯＝15：1)得化合物4，8.0g白色固体，收率96％。
经检测，结构正确，检测结果如下：MS(ESI)(m/z):228.0(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ7.73–7.62(m,1H),7.43(d,J＝7.0Hz,2H),7.38(t,J＝7.4Hz,2H),7.32(d,J＝7.1Hz,1H),7.16(d,J＝8.7Hz,1H),7.03(t,J＝8.8Hz,1H),5.27(s,2H).
二)、3-氨基-4-苄氧基苯并[d]异恶唑(化合物6)的合成
Figure PCTCN2019072468-appb-000011
将4.0g(53.3mmol,1.5eq)乙酰氧肟酸溶于150mL干燥DMF中，加入6.0g(53.3mmol,1.5eq)叔丁醇钾，氮气保护下，室温反应30分钟，分批加入8.0g(35.2mmol,1.0eq)2-苄氧基-6-氟苯氰，加毕室温反应6h。之后减压蒸出大部分溶剂，加水，用乙酸乙酯萃取，用饱和食盐水洗涤有机相，无水Na 2SO 4干燥，浓缩，用二氯甲烷和石油醚进行重结晶得2.0g化合物6，收率24％。
经检测，结构正确，检测结果如下：MS(ESI)(m/z):241.0(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ7.50(d,J＝6.8Hz,2H),7.42–7.34(m,3H),7.34–7.28(m,1H),6.96(d,J＝8.4Hz,1H),6.76(d,J＝8.0Hz,1H),5.86(s,2H),5.29(s,2H).
三)、3-(吡啶-3-基氨基)-4-苄氧基苯并[d]异恶唑(化合物8)的合成
Figure PCTCN2019072468-appb-000012
将3.0g(12.5mmol,1.0eq)3-氨基-4-苄氧基苯并[d]异恶唑，3.0g(18.75mmol,1.5eq)3-溴吡啶，1.14g(1.25mmol,0.1eq)Pd 2(dba) 3,1.44g(2.50mmol,0.2eq)Xantphos和3.45g(25.0mmol,2.0eq)无水碳酸钾混合加入50mL二氧六环，氮气置换三次后，在氮气保护下，加热到125℃回流12h，之后减压蒸出大部分溶剂，加水，用乙酸乙酯萃取，用饱和食盐水洗涤有机相，无水Na 2SO 4干燥，浓缩，用硅胶伴样，色谱层析柱分离(石油醚：乙酸乙酯＝3：2)得化合物8，3.1g米黄色固体，收率78％。
经检测，结构正确，检测结果如下：MS(ESI)(m/z):318.0(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ8.73(d,J＝2.8Hz,1H),8.28(s,1H),8.18(dd,J＝4.7,1.4Hz,1H),8.09–8.01(m,1H),7.54(d,J＝7.5Hz,2H),7.47(t,J＝8.2Hz,1H),7.43–7.34(m,3H),7.31(t,J＝7.2Hz,1H),7.11(d,J＝8.4Hz,1H),6.85(d,J＝8.0Hz,1H),5.41(s,2H).
四)、3-(吡啶-3-基氨基)-4-羟基苯并[d]异恶唑(化合物9)的合成
Figure PCTCN2019072468-appb-000013
将3.1g(9.8mmol,1.0eq)3-(吡啶-3-基氨基)-4-苄氧基苯并[d]异恶唑溶于20mL40％的氢溴酸和20mL冰乙酸中，加热到65℃反应12h,反应完全后，减压蒸出大部分溶剂，加水，用饱和碳酸钠水溶液中和到pH＝8,加入适量乙酸乙酯萃取，得一混悬物，过滤得部分灰色固体产物，母液继续用乙酸乙酯萃取，用饱和食盐水洗涤有机相，无水Na 2SO 4干燥，浓缩，用硅胶伴样，色谱层析柱分离(二氯甲烷：甲醇＝20：1)得化合物9，共得1.4g灰色固体，收率63％。
经检测，结构正确，检测结果如下：MS(ESI)(m/z):228.0(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ11.20(s,1H),8.90(d,J＝2.7Hz,1H),8.35(s,1H),8.20– 8.13(m,2H),7.40–7.32(m,2H),6.97(d,J＝8.3Hz,1H),6.65(d,J＝7.8Hz,1H).
五)、2-乙基苄溴(化合物11)的合成
Figure PCTCN2019072468-appb-000014
将250mg(1.84mmol,1.0eq)2-乙基苄醇溶于10mL无水乙醚中，用冰水浴冷却到0℃，加入191mg(0.72mmol,0.5eq)三溴化磷，加毕，在0℃反应15min,后撤去冰水浴，自然升温到室温反应2h，用冰水浴冷却到0℃，加水，乙酸乙酯萃取，饱和食盐水洗涤有机相，无水Na 2SO 4干燥，浓缩，得到250mg油状物11，产率89％，该粗产物可不经纯化进行下步反应。
六)、4-(2-乙基苄氧基)-3-(吡啶-3-基氨基)苯并[d]异恶唑(式Ⅰ-1)的合成
Figure PCTCN2019072468-appb-000015
将50mg(0.22mmol,1.0eq)3-(吡啶-3-基氨基)-4-羟基苯并[d]异恶唑，44mg g(0.22mmol,1.0eq)2-乙基苄溴和61mg(0.44mmol,2.0eq)无水碳酸钾混合，加入5mL丙酮，加毕，在室温反应3h，加水，乙酸乙酯萃取，饱和食盐水洗涤有机相，无水Na 2SO 4干燥，浓缩，硅胶伴样，色谱层析柱分离(石油醚：乙酸乙酯＝2：1)得化合物Ⅰ-1，得30mg白色固体，收率39％。
经检测，结构正确，检测结果如下：MS(ESI)(m/z):346.0(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ8.64(d,J＝2.7Hz,1H),8.22(s,1H),8.15(d,J＝4.6Hz,1H),8.00(dt,J＝8.6,2.0Hz,1H),7.48(t,J＝7.8Hz,2H),7.35(dd,J＝8.4,4.7Hz,1H),7.28–7.21(m,2H),7.22–7.15(m,1H),7.11(d,J＝8.4Hz,1H),6.89(d,J＝8.0Hz,1H),5.44(s,2H),2.73(t,J＝7.5Hz,2H),1.11(t,J＝7.5Hz,3H).。
实施例2：化合物式Ⅰ-2，Ⅰ-4～Ⅰ-27的合成
Figure PCTCN2019072468-appb-000016
Figure PCTCN2019072468-appb-000017
参照实施实例1中第六步合成化合物式Ⅰ-1的条件，用相应的取代苄溴与 3-(吡啶-3-基氨基)-4-羟基苯并[d]异恶唑反应得到相应的目标化合物式Ⅰ-2和Ⅰ-4至Ⅰ-27，具体为：4-(2-氯-5-氟苄氧基)-3-(吡啶-3-基氨基)苯并[d]异恶唑(式Ⅰ-2)；4-(2-氟苄氧基)-3-(吡啶-3-基氨基)苯并[d]异恶唑(式Ⅰ-4)；4-(3-氟苄氧基)-3-(吡啶-3-基氨基)苯并[d]异恶唑(式Ⅰ-5)；4-(4-氟苄氧基)-3-(吡啶-3-基氨基)苯并[d]异恶唑(式Ⅰ-6)；4-(2-氯苄氧基)3-(吡啶-3-基氨基)苯并[d]异恶唑(式Ⅰ-7)；4-(3-氯苄氧基)-3-(吡啶-3-基氨基)苯并[d]异恶唑(式Ⅰ-8)；4-(4-氯苄氧基)-3-(吡啶-3-基氨基)苯并[d]异恶唑(式Ⅰ-9)；4-(2-甲基苄氧基)-3-(吡啶-3-基氨基)苯并[d]异恶唑(式Ⅰ-10)；4-(3-甲基苄氧基)-3-(吡啶-3-基氨基)苯并[d]异恶唑(式Ⅰ-11)；4-(4-甲基苄氧基)-3-(吡啶-3-基氨基)苯并[d]异恶唑(式Ⅰ-12)；4-(2-三氟甲基苄氧基)-3-(吡啶-3-基氨基)苯并[d]异恶唑(式Ⅰ-13)；4-(3-三氟甲基苄氧基)-3-(吡啶-3-基氨基)苯并[d]异恶唑(式Ⅰ-14)；4-(4-三氟甲基苄氧基)-3-(吡啶-3-基氨基)苯并[d]异恶唑(式Ⅰ-15)；4-(2-甲氧基苄氧基)-3-(吡啶-3-基氨基)苯并[d]异恶唑(式Ⅰ-16)；4-(3-甲氧基苄氧基)-3-(吡啶-3-基氨基)苯并[d]异恶唑(式Ⅰ-17)；4-(4-甲氧基苄氧基)-3-(吡啶-3-基氨基)苯并[d]异恶唑(式Ⅰ-18)；4-(2-三氟甲氧基苄氧基)-3-(吡啶-3-基氨基)苯并[d]异恶唑(式Ⅰ-19)；4-(3-三氟甲氧基苄氧基)-3-(吡啶-3-基氨基)苯并[d]异恶唑(式Ⅰ-20)；4-(4-三氟甲氧基苄氧基)-3-(吡啶-3-基氨基)苯并[d]异恶唑(式Ⅰ-21)；4-(2-氰基苄氧基)-3-(吡啶-3-基氨基)苯并[d]异恶唑(式Ⅰ-22)；4-(3-氰基苄氧基)-3-(吡啶-3-基氨基)苯并[d]异恶唑(式Ⅰ-23)；4-(4-氰基苄氧基)-3-(吡啶-3-基氨基)苯并[d]异恶唑(式Ⅰ-24)；4-(2，6-二甲基苄氧基)-3-(吡啶-3-基氨基)苯并[d]异恶唑(式Ⅰ-25)；4-(2，6-二氯苄氧基)-3-(吡啶-3-基氨基)苯并[d]异恶唑(式Ⅰ-26)；4-(2，6-二氟苄氧基)-3-(吡啶-3-基氨基)苯并[d]异恶唑(式Ⅰ-27)。
经检测，结构正确，检测结果如下：
式Ⅰ-2 MS(ESI)(m/z):370.1(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ8.72(d,J＝2.7Hz,1H),8.32(s,1H),8.18(dd,J＝4.7,1.5Hz,1H),8.05(d,J＝8.4Hz,1H),7.64–7.51(m,3H),7.38(dd,J＝8.4,4.7Hz,1H),7.29(dt,J＝8.7,4.3Hz,1H),7.20(d,J＝8.4Hz,1H),6.90(d,J＝8.0Hz,1H),5.46(s,2H).
式Ⅰ-4 MS(ESI)(m/z):336.1(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ8.67(d,J＝2.7Hz,1H),8.20(s,1H),8.15(d,J＝4.6Hz,1H),8.00(d,J＝8.5Hz,1H), 7.60(t,J＝7.6Hz,1H),7.48(t,J＝8.2Hz,1H),7.35(td,J＝9.2,8.7,5.6Hz,2H),7.21(dt,J＝15.3,8.6Hz,2H),7.12(d,J＝8.6Hz,1H),6.89(d,J＝8.1Hz,1H),5.44(s,2H).
式Ⅰ-5 MS(ESI)(m/z):336.1(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ8.75(d,J＝2.7Hz,1H),8.34(s,1H),8.16(dd,J＝4.7,1.5Hz,1H),8.06(ddd,J＝8.4,3.0,1.5Hz,1H),7.48(d,J＝8.2Hz,1H),7.46–7.39(m,2H),7.36(dd,J＝8.7,3.9Hz,2H),7.12(d,J＝8.4Hz,2H),6.82(d,J＝8.0Hz,1H),5.41(s,2H).
式Ⅰ-6 MS(ESI)(m/z):336.1(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ8.71(s,1H),8.25(s,1H),8.14(d,J＝4.6Hz,1H),8.02(d,J＝8.4Hz,1H),7.65–7.51(m,2H),7.43(t,J＝8.2Hz,1H),7.33(dd,J＝8.3,4.7Hz,1H),7.18(t,J＝8.7Hz,2H),7.08(d,J＝8.4Hz,1H),6.81(d,J＝8.1Hz,1H),5.35(s,2H).
式Ⅰ-7 MS(ESI)(m/z):336.1(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ8.67(s,1H),8.23(s,1H),8.15(s,1H),8.01(d,J＝8.4Hz,1H),7.60(s,1H),7.49(q,J＝8.9,7.5Hz,2H),7.34(s,3H),7.14(d,J＝8.4Hz,1H),6.85(d,J＝7.9Hz,1H),5.46(s,2H).
式Ⅰ-8 MS(ESI)(m/z):352.1(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ8.77(d,J＝2.6Hz,1H),8.33(s,1H),8.21–8.14(m,1H),8.11–8.03(m,1H),7.67(s,1H),7.48(dd,J＝9.4,7.2Hz,2H),7.37(td,J＝10.2,8.7,5.8Hz,3H),7.13(d,J＝8.4Hz,1H),6.83(d,J＝8.0Hz,1H),5.41(s,2H).
式Ⅰ-9 MS(ESI)(m/z):352.1(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ8.77(d,J＝2.7Hz,1H),8.30(s,1H),8.19(d,J＝4.6Hz,1H),8.11–8.02(m,1H),7.58(d,J＝8.1Hz,2H),7.45(dd,J＝8.1,6.2Hz,3H),7.37(dd,J＝8.4,4.7Hz,1H),7.12(d,J＝8.4Hz,1H),6.83(d,J＝8.0Hz,1H),5.41(s,2H).
式Ⅰ-10 MS(ESI)(m/z):332.1(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ8.54(s,1H),8.17–7.98(m,2H),7.89(d,J＝8.4Hz,1H),7.34(d,J＝8.0Hz,2H),7.29–7.17(m,1H),7.09(s,3H),6.99(d,J＝8.4Hz,1H),6.75(d,J＝8.0Hz,1H),5.28(s,2H),2.24(s,3H).
式Ⅰ-11 MS(ESI)(m/z):332.1(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ8.71(d,J＝2.7Hz,1H),8.28(s,1H),8.16(d,J＝4.6Hz,1H),8.03(d,J＝8.4Hz,1H),7.46(t,J＝8.2Hz,1H),7.35(q,J＝5.3Hz,2H),7.30(d,J＝7.7Hz,1H),7.25(t,J＝ 7.5Hz,1H),7.10(d,J＝8.1Hz,2H),6.82(d,J＝8.0Hz,1H),5.35(s,2H),2.26(s,3H).
式Ⅰ-12 MS(ESI)(m/z):332.1(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ8.73(s,1H),8.27(s,1H),8.17(s,1H),8.05(d,J＝8.3Hz,1H),7.44(t,J＝8.2Hz,3H),7.37(d,J＝7.5Hz,1H),7.17(d,J＝7.6Hz,2H),7.10(d,J＝8.4Hz,1H),6.83(d,J＝7.9Hz,1H),5.36(s,2H),2.25(s,3H).
式Ⅰ-13 MS(ESI)(m/z):386.1(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ8.66(d,J＝2.8Hz,1H),8.19(s,1H),8.15(d,J＝4.6Hz,1H),8.08–7.95(m,1H),7.79(d,J＝7.9Hz,2H),7.69(t,J＝7.7Hz,1H),7.52(dt,J＝29.6,7.9Hz,2H),7.34(dd,J＝8.5,4.7Hz,1H),7.15(d,J＝8.4Hz,1H),6.76(d,J＝8.0Hz,1H),5.55(s,2H).
式Ⅰ-14 MS(ESI)(m/z):386.1(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ8.73(d,J＝2.7Hz,1H),8.37(s,1H),8.19–8.12(m,1H),8.08–8.01(m,1H),7.97(s,1H),7.82(d,J＝7.6Hz,1H),7.66(d,J＝7.9Hz,1H),7.60(t,J＝7.7Hz,1H),7.48(t,J＝8.3Hz,1H),7.34(dd,J＝8.4,4.7Hz,1H),7.12(d,J＝8.5Hz,1H),6.85(d,J＝8.1Hz,1H),5.48(s,2H).
式Ⅰ-15 MS(ESI)(m/z):386.1(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ8.79(d,J＝2.7Hz,1H),8.40(s,1H),8.17(d,J＝4.7Hz,1H),8.08(d,J＝8.5Hz,1H),7.74(s,4H),7.46(t,J＝8.2Hz,1H),7.36(dd,J＝8.4,4.8Hz,1H),7.12(d,J＝8.5Hz,1H),6.79(d,J＝8.1Hz,1H),5.52(s,2H).
式Ⅰ-16 MS(ESI)(m/z):348.0(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ8.66(d,J＝2.7Hz,1H),8.18(d,J＝7.1Hz,2H),8.01(d,J＝8.0Hz,1H),7.53–7.43(m,2H),7.39–7.30(m,2H),7.10(dd,J＝19.3,8.3Hz,2H),6.94(t,J＝7.3Hz,1H),6.85(d,J＝8.0Hz,1H),5.38(s,2H),3.81(s,3H).
式Ⅰ-17 MS(ESI)(m/z):348.0(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ8.74(d,J＝2.7Hz,1H),8.31(s,1H),8.17(d,J＝4.7Hz,1H),8.06(d,J＝8.1Hz,1H),7.46(t,J＝8.2Hz,1H),7.40–7.32(m,1H),7.28(t,J＝7.9Hz,1H),7.11(dd,J＝14.6,6.4Hz,3H),6.85(t,J＝8.9Hz,2H),5.37(s,2H),3.69(s,3H).
式Ⅰ-18 MS(ESI)(m/z):348.0(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ8.71(d,J＝2.7Hz,1H),8.22(s,1H),8.17(d,J＝4.7Hz,1H),8.07–8.01(m,1H),7.47(dd,J＝12.7,8.1Hz,3H),7.36(dd,J＝8.4,4.7Hz,1H),7.09(d,J＝8.4Hz,1H), 6.92(d,J＝8.3Hz,2H),6.87(d,J＝8.0Hz,1H),5.32(s,2H),3.70(s,3H).
式Ⅰ-19 MS(ESI)(m/z):402.1(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ8.68(d,J＝2.7Hz,1H),8.21(s,1H),8.17(d,J＝4.7Hz,1H),8.02(d,J＝7.9Hz,1H),7.73(d,J＝7.6Hz,1H),7.55–7.47(m,2H),7.44(d,J＝7.6Hz,2H),7.36(dd,J＝8.4,4.8Hz,1H),7.16(d,J＝8.4Hz,1H),6.85(d,J＝8.0Hz,1H),5.48(s,2H).
式Ⅰ-20 MS(ESI)(m/z):402.0(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ8.75(d,J＝2.8Hz,1H),8.33(s,1H),8.17(d,J＝4.6Hz,1H),8.09–8.01(m,1H),7.57(d,J＝10.4Hz,2H),7.50(dt,J＝12.3,8.1Hz,2H),7.39–7.27(m,2H),7.13(d,J＝8.4Hz,1H),6.86(d,J＝8.0Hz,1H),5.45(s,2H).
式Ⅰ-21 MS(ESI)(m/z):402.0(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ8.76(d,J＝2.7Hz,1H),8.31(s,1H),8.18(d,J＝4.6Hz,1H),8.05(d,J＝8.5Hz,1H),7.67(d,J＝8.3Hz,2H),7.48(t,J＝8.2Hz,1H),7.38(d,J＝8.1Hz,3H),7.12(d,J＝8.4Hz,1H),6.84(d,J＝7.9Hz,1H),5.44(s,2H).
式Ⅰ-22 MS(ESI)(m/z):343.1(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ8.71(d,J＝2.6Hz,1H),8.17(d,J＝4.7Hz,2H),8.04(ddd,J＝8.3,2.8,1.4Hz,1H),7.96–7.88(m,1H),7.83(d,J＝7.8Hz,1H),7.79–7.71(m,1H),7.61–7.47(m,2H),7.36(dd,J＝8.4,4.7Hz,1H),7.17(d,J＝8.4Hz,1H),6.95(d,J＝8.0Hz,1H),5.60(s,2H).
式Ⅰ-23 MS(ESI)(m/z):343.1(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ8.74(s,1H),8.33(s,1H),8.14(d,J＝4.6Hz,1H),8.04(d,J＝5.3Hz,2H),7.85(d,J＝7.9Hz,1H),7.76(d,J＝7.6Hz,1H),7.58(d,J＝7.7Hz,1H),7.45(t,J＝8.2Hz,1H),7.39–7.29(m,1H),7.11(d,J＝8.4Hz,1H),6.80(d,J＝8.0Hz,1H),5.42(s,2H).
式Ⅰ-24 MS(ESI)(m/z):343.1(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ8.78(s,1H),8.37(s,1H),8.21–8.10(m,1H),8.06(d,J＝8.4Hz,1H),7.83(d,J＝7.8Hz,2H),7.69(d,J＝7.9Hz,2H),7.44(t,J＝8.2Hz,1H),7.35(t,J＝6.7Hz,1H),7.11(d,J＝8.4Hz,1H),6.76(d,J＝8.0Hz,1H),5.49(s,2H).
式Ⅰ-25 MS(ESI)(m/z):346.1(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ8.27(d,J＝2.7Hz,1H),8.11(d,J＝4.6Hz,1H),7.79(d,J＝5.5Hz,2H),7.56(t,J＝8.2Hz,1H),7.29(dd,J＝8.5,4.7Hz,1H),7.16(dd,J＝7.8,5.8Hz,2H),7.08(d,J＝7.5 Hz,2H),7.01(d,J＝8.0Hz,1H),5.34(s,2H),2.36(s,6H).
式Ⅰ-26 MS(ESI)(m/z):386.0(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ8.46(d,J＝2.7Hz,1H),8.15(d,J＝4.7Hz,1H),7.94(s,1H),7.89(d,J＝9.5Hz,1H),7.60(d,J＝7.6Hz,3H),7.50(dd,J＝8.9,7.2Hz,1H),7.34(dd,J＝8.4,4.6Hz,1H),7.23(d,J＝8.4Hz,1H),7.13(d,J＝8.0Hz,1H),5.54(s,2H).
式Ⅰ-27 MS(ESI)(m/z):354.1(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ8.60(s,1H),8.19(d,J＝4.3Hz,1H),8.11(s,1H),7.97(d,J＝8.2Hz,1H),7.66–7.48(m,2H),7.37(dd,J＝8.3,4.4Hz,1H),7.26–7.14(m,3H),7.07(d,J＝7.9Hz,1H),5.49(s,2H).。
实施例3：制备3-(吡啶-3-基氨基)-4-(2-三氟甲氧基-5-氯苄氧基)-苯并[d]异恶唑(式Ⅰ-3)
一)、2-三氟甲氧基-5-氯苯甲醛(化合物13)的合成
Figure PCTCN2019072468-appb-000018
将1.0g(5.1mmol,1.0eq)4-三氟甲氧基氯苯溶于20mL无水四氢呋喃中，氮气保护，冷却到-80℃，滴加3.1mL(6.1mmol,1.2eq)2M LDA,15min滴完，保持-80℃反应20min，加入0.47mL DMF，缓慢升温到-50℃反应40min，加入1.22g(20.4mmol,4.0eq)乙酸淬灭反应，加水，乙酸乙酯萃取，饱和食盐水洗涤有机相，无水Na 2SO 4干燥，浓缩，硅胶伴样，色谱层析柱分离(石油醚：乙酸乙酯＝20：1)得化合物13，800mg浅黄色油状物，收率70％。
经检测，结构正确，检测结果如下：MS(ESI)(m/z):225.0(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ10.14(s,1H),7.91(d,J＝2.7Hz,1H),7.88(dd,J＝8.8,2.6Hz,1H),7.60(dd,J＝8.8,1.7Hz,1H).
二)、2-三氟甲氧基-5-氯苄醇(化合物14)的合成
Figure PCTCN2019072468-appb-000019
向反应瓶中加入800mg(3.57mmol,1.0eq)2-三氟甲氧基-5-氯苯甲醛和10mL乙醇，在冰浴下向上述体系中加160mg(4.21mmol,1.2eq)硼氢化钠。之后在冰浴下搅拌反应30min，后升到室温反应3h，之后减压蒸出大部分溶剂，加水，用乙酸乙酯萃取，用饱和食盐水洗涤有机相，无水Na 2SO 4干燥，浓缩，用硅胶伴样，色谱层析柱分离(石油醚：乙酸乙酯＝15：1)得600mg化合物14，为白色固体，收率75％。
经检测，结构正确，检测结果如下：MS(ESI)(m/z):225.0(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ7.56(d,J＝2.6Hz,1H),7.42(dd,J＝8.8,2.6Hz,1H),7.33(dd,J＝8.7,1.6Hz,1H),5.49(t,J＝5.8Hz,1H),4.52(d,J＝5.9Hz,2H).
三)、3-(吡啶-3-基氨基)-4-(2-三氟甲氧基-5-氯苄氧基)-苯并[d]异恶唑-4-(2-三氟甲氧基-5-氯苄氧基)(式Ⅰ-3)的合成
Figure PCTCN2019072468-appb-000020
参照实施实例1中第五，六步合成化合物式Ⅰ-1的条件，用相应的取代苄醇制备取代苄溴，取代苄溴与3-(吡啶-3-基氨基)-4-羟基苯并[d]异恶唑反应得到相应的目标化合物。
经检测，结构正确，检测结果如下：式Ⅰ-3 MS(ESI)(m/z):436.1(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ8.68(s,1H),8.29(s,1H),8.12(d,J＝4.5Hz,1H),8.00(d,J＝8.3Hz,1H),7.84(s,1H),7.53–7.44(m,3H),7.35–7.30(m,1H),7.14(d,J＝8.4Hz,1H),6.84(d,J＝8.0Hz,1H),5.39(s,2H).。
实施例4：3-(甲基(吡啶-3-基)氨基)-4-(2,6-二氟苄氧基)苯并[d]异恶唑(式Ⅰ-28)的合成
Figure PCTCN2019072468-appb-000021
向反应瓶中加入40mg(0.10mmol,1.0eq)I-26和5mLDMF，在冰浴下向上述体系中加5mg(0.14mmol,1.3eq)氢化钠，之后加入15mg(0.104mmol,1.0eq)碘甲烷。之后在冰浴下搅拌反应15min，后升到室温反应1h，加水，用乙酸乙酯萃取，用饱和食盐水洗涤有机相，无水Na 2SO 4干燥，浓缩，用硅胶伴样，色谱层析柱分离(石油醚：乙酸乙酯＝3：1)得化合物I-28，20mg白色固体，收率50％。
经检测，结构正确，检测结果如下：MS(ESI)(m/z):401.0(M+H) +. 1H NMR(400MHz,DMSO-d6)δ7.92(d,J＝2.7Hz,1H),7.86–7.78(m,1H),7.55(t,J＝8.2Hz,1H),7.44(d,J＝3.3Hz,3H),7.24(d,J＝8.5Hz,1H),7.07(ddd,J＝8.2,3.0,1.4Hz,1H),6.91(d,J＝8.0Hz,1H),6.69(dd,J＝8.3,4.7Hz,1H),4.95(s,2H),3.26(s,3H).。
实施例5：3-(吡啶-3-基氨基)-4-苄氧基-1H-吲唑(式Ⅰ-29)的合成
一)、4-苄氧基-1H-吲唑-3-胺(16)的合成
Figure PCTCN2019072468-appb-000022
向反应瓶中加入1.0g(4.4mmol,1.0eq)4和4mL85％水合肼，乙醇10mL，升到100℃反应过夜，反应完全后，蒸干溶剂，加5mL水搅拌得一混悬液，过滤得化合物16，840mg白色固体，收率80％。
经检测，结构正确，检测结果如下：MS(ESI)(m/z):240.0(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ11.39(s,1H),7.47(d,J＝7.5Hz,2H),7.37(t,J＝7.5Hz,2H),7.29(t,J＝7.3Hz,1H),7.04(t,J＝8.0Hz,1H),6.73(d,J＝8.3Hz,1H),6.35(d,J＝7.7Hz,1H),5.17(s,2H),4.90(s,2H).
二)、2-(4-苄氧基-1H-3-吲唑基)-异吲哚啉-1,3-二酮(17)的合成
Figure PCTCN2019072468-appb-000023
向反应瓶中加入240mg(1.0mmol,1.0eq)15和148mg(1.0mmol,1.0eq)邻苯二甲酸酐，升到170℃反应30分钟，反应完全后，降到室温，加5mL乙酸乙酯搅拌得一混悬液，过滤得化合物17，185mg白色固体，收率50％。
经检测，结构正确，检测结果如下：MS(ESI)(m/z):370.0(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ13.46(s,1H),7.93–7.83(m,4H),7.32(t,J＝8.0Hz,1H),7.15(d,J＝8.4Hz,1H),7.08–6.97(m,3H),6.92(t,J＝7.6Hz,2H),6.65(d,J＝7.7Hz,1H),4.96(s,2H).
二)、2-(1-叔丁氧羰基-4-苄氧基-1H-3-吲唑基)-异吲哚啉-1,3-二酮(18)的合成
Figure PCTCN2019072468-appb-000024
向反应瓶中加入200mg(0.54mmol,1.0eq)17和198mg(1.63mmol,3.0eq)DMAP，溶于5mL DCM中，再加入142mg(0.65mmol,1.2eq)(Boc) 2O，在室温反应过夜，加水，用DCM萃取，用饱和食盐水洗涤有机相，无水Na 2SO 4干燥，浓缩，用硅胶伴样，色谱层析柱分离(石油醚：乙酸乙酯＝6：1)得化合物18，80mg白色固体，收率31％。
经检测，结构正确，检测结果如下：MS(ESI)(m/z):470.0(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ7.85(s,4H),7.71(d,J＝8.5Hz,1H),7.61(t,J＝8.2Hz,1H),7.04(t,J＝7.2Hz,1H),7.02–6.96(m,3H),6.94(t,J＝7.5Hz,2H),4.99(s,2H),1.63(s,9H).
三)、1-叔丁氧羰基-4-苄氧基-1H-吲唑-3-胺(19)的合成
Figure PCTCN2019072468-appb-000025
向反应瓶中加入50mg(0.11mmol,1.0eq)18和6.9mg(0.14mmol,1.4eq)85％水合肼，乙醇3mL，室温反应5h，反应完全后，蒸干溶剂，加水，用DCM萃取，用饱和食盐水洗涤有机相，无水Na 2SO 4干燥，浓缩，用硅胶伴样，色谱层析柱分离(石油醚：乙酸乙酯＝4：1)得化合物19，20mg白色固体，收率56％。
经检测，结构正确，检测结果如下：MS(ESI):m/z 340[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ7.51–7.42(m,3H),7.40–7.32(m,3H),7.33–7.27(m,1H),6.78(d,J＝7.9Hz,1H),5.81(s,2H),5.26(s,2H),1.52(s,9H).
四)、1-叔丁氧羰基-3-(吡啶-3-基氨基)-4-苄氧基-1H-吲唑(20)的合成
Figure PCTCN2019072468-appb-000026
参照实施实例1中第三步合成化合物8的条件，用相应的氨基化合物19与3-溴基吡啶(化合物7)反应得到相应的目标化合物20。
经检测，结构正确，检测结果如下：MS(ESI):m/z 417[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ8.74(s,1H),8.18(s,1H),8.15(d,J＝2.4Hz,1H),8.14–8.10(m,1H),7.55(d,J＝7.5Hz,2H),7.52–7.43(m,2H),7.40(t,J＝7.5Hz,2H),7.37–7.29(m,2H),6.89(d,J＝7.5Hz,1H),5.40(s,2H),1.59(s,9H).
五)、3-(吡啶-3-基氨基)-4-苄氧基-1H-吲唑(式Ⅰ-29)的合成
Figure PCTCN2019072468-appb-000027
向反应瓶中加入50mg(0.12mmol,1.0eq)20，溶于5mL的二氯甲烷中，加 入0.3mL三氟乙酸，室温反应2h，反应完全后，加水，用DCM萃取，用饱和食盐水洗涤有机相，无水Na 2SO 4干燥，浓缩，用硅胶伴样，色谱层析柱分离(石油醚：乙酸乙酯＝3：1)得化合物Ⅰ-29，20mg白色固体，收率53％。
经检测，结构正确，检测结果如下：MS(ESI):m/z 317[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ12.16(s,1H),8.54(d,J＝2.7Hz,1H),7.98(d,J＝4.6Hz,1H),7.96–7.91(m,1H),7.86(s,1H),7.48(d,J＝7.4Hz,2H),7.36(t,J＝7.4Hz,2H),7.30(d,J＝7.1Hz,1H),7.23(dd,J＝8.4,4.7Hz,1H),7.16(t,J＝8.0Hz,1H),6.89(d,J＝8.3Hz,1H),6.49(d,J＝7.7Hz,1H),5.27(s,2H).。
实施例6：1-甲基-3-(吡啶-3-基氨基)-4-苄氧基-1H-吲唑(式Ⅰ-30)的合成
一)、2-(1-甲基-4-苄氧基-1H-3-吲唑基)-异吲哚啉-1,3-二酮(21)的合成
Figure PCTCN2019072468-appb-000028
向反应瓶中加入150mg(0.41mmol,1.0eq)17和112mg(0.81mmol,2.0eq)K 2CO 3，溶于5mL DMF中，再加入75mg(0.53mmol,1.3eq)碘甲烷，在室温反应过夜，加水，用二氯甲烷萃取，用饱和食盐水洗涤有机相，无水Na 2SO 4干燥，浓缩，用硅胶伴样，色谱层析柱分离(石油醚：乙酸乙酯＝4：1)得化合物21，100mg白色固体，收率64％。
经检测，结构正确，检测结果如下：MS(ESI):m/z 384[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ7.77(t,J＝1.8Hz,4H),7.31–7.23(m,1H),7.16(dd,J＝8.6,1.8Hz,1H),6.95–6.86(m,3H),6.86–6.77(m,2H),6.58(dd,J＝7.6,1.7Hz,1H),4.86(s,2H),3.94(s,3H).
二)、1-甲基-3-(吡啶-3-基氨基)-4-苄氧基--1H-吲唑(式Ⅰ-30)的合成
Figure PCTCN2019072468-appb-000029
参照实施实例5中第三、第四步合成化合物20的条件，用相应的化合物21代替化合物18进行相应的类似反应得到相应的目标化合物Ⅰ-30。
经检测，结构正确，检测结果如下：MS(ESI):m/z 311[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ8.56(d,J＝2.7Hz,1H),8.00(d,J＝4.7Hz,1H),7.95(dt,J＝8.5,2.0Hz,1H),7.90(s,1H),7.47(d,J＝7.4Hz,2H),7.36(t,J＝7.4Hz,2H),7.30(d,J＝7.2Hz,1H),7.27–7.17(m,2H),7.00(d,J＝8.4Hz,1H),6.51(d,J＝7.7Hz,1H),5.29(s,2H),3.84(s,3H).。
实施例7：3-(吡啶-3-基氨基)-4-苄氧基-苯并[d]异噻唑(式Ⅰ-31)的合成
一)、4-苄氧基苯并[d]异噻唑-3-胺(23)的合成
Figure PCTCN2019072468-appb-000030
向反应瓶中加入228mg(1.0mmol,1.0eq)4和78mg(1.0mmol,1.0eq)硫化钠，溶于5mL DMSO氮气保护下，在70℃反应12h。整个反应体系冷却到0℃，滴加1.4mL 25％氨水溶液和1.4mL 15％次氯酸钠溶液。反应慢慢升温到室温反应5h。反应完全后，加水，用乙酸乙酯萃取，用饱和食盐水洗涤有机相，无水Na 2SO 4干燥，浓缩，用硅胶伴样，色谱层析柱分离(石油醚：乙酸乙酯＝4：1)得化合物23，200mg白色固体，收率78％。
经检测，结构正确，检测结果如下：MS(ESI):m/z 257[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ7.50(s,1H),7.48(s,1H),7.42–7.32(m,4H),7.36–7.27(m,1H),6.89(d,J＝7.4Hz,1H),6.45(s,2H),5.28(s,2H).
二)、3-(吡啶-3-基氨基)-4-苄氧基-苯并[d]异噻唑(式Ⅰ-31)的合成
Figure PCTCN2019072468-appb-000031
参照实施实例1中第三步合成化合物8的条件，用相应的氨基化合物23与 3-溴基吡啶(化合物7)反应得到相应的目标化合物Ⅰ-31。
经检测，结构正确，检测结果如下：MS(ESI):m/z 334[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ9.03(s,1H),8.44(d,J＝2.7Hz,1H),8.23(dd,J＝8.6,1.8Hz,1H),8.12(dd,J＝4.7,1.8Hz,1H),7.62(d,J＝7.2Hz,2H),7.58(d,J＝8.1Hz,1H),7.53–7.38(m,4H),7.30(dd,J＝8.6,4.7Hz,1H),7.07(d,J＝7.8Hz,1H),5.42(s,2H).。
实施例8：1-(吡啶-3-基氨基)-8-苄氧基异喹啉(式Ⅰ-32)的合成
一)8-苄氧基异喹啉(25)的合成
Figure PCTCN2019072468-appb-000032
参照实施实例1中第一步合成化合物2的条件，用相应的羟基化合物24与苄溴反应得到相应的目标化合物25。
经检测，结构正确，检测结果如下：MS(ESI):m/z 236[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ10.70(s,1H),7.48(d,J＝7.6Hz,2H),7.39(t,J＝8.0Hz,1H),7.24(t,J＝7.5Hz,2H),7.14(t,J＝7.3Hz,1H),6.99(d,J＝7.9Hz,1H),6.94(t,J＝6.5Hz,1H),6.87(d,J＝8.1Hz,1H),6.25(d,J＝7.0Hz,1H),5.07(s,2H).
二)8-苄氧基异喹啉-2-氮氧化物(26)的合成
Figure PCTCN2019072468-appb-000033
向反应瓶中加入290mg(1.23mmol,1.0eq)26和225mg(1.48mmol,1.2eq)间氯过氧苯甲酸(m-CPBA)，溶于5mL DCM，在室温反应12h。用饱和碳酸钠水溶液淬灭反应，加水，用乙酸乙酯萃取，用饱和食盐水洗涤有机相，无水Na 2SO 4干燥，浓缩，用硅胶伴样，色谱层析柱分离(石油醚：乙酸乙酯＝1：1)得化合物26，260mg白色固体，收率84％。
经检测，结构正确，检测结果如下：MS(ESI):m/z 252[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ8.61(t,J＝1.2Hz,1H),8.02(dd,J＝7.1,1.8Hz,1H),7.76(d,J＝7.1Hz,1H),7.43–7.34(m,4H),7.28(t,J＝7.4Hz,2H),7.21(t,J＝7.2Hz,1H),7.12–7.06(m,1H),5.18(s,2H).
三)1-氯-8-苄氧基异喹啉(27)的合成
Figure PCTCN2019072468-appb-000034
向反应瓶中加入200mg(0.80mmol,1.0eq)26和1.5mL三氯氧磷(POCl 3)，在90℃反应5h。反应完毕后，减压蒸出大部分溶剂，加水，用饱和碳酸钠水溶液调节pH＝8-9，用二氯甲烷萃取，用饱和食盐水洗涤有机相，无水Na 2SO 4干燥，浓缩得化合物27，不进一步纯化，直接用于下一步反应。
四)1-(吡啶-3-基氨基)-8-苄氧基异喹啉(式Ⅰ-32)的合成
Figure PCTCN2019072468-appb-000035
参照实施实例1中第三步合成化合物8的条件，用相应的化合物27与3-氨基吡啶反应得到相应的目标化合物Ⅰ-32。
经检测，结构正确，检测结果如下：MS(ESI):m/z 328[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ10.01(s,1H),8.19(d,J＝2.6Hz,1H),8.14(dd,J＝8.6,2.4Hz,1H),8.08(d,J＝4.0Hz,1H),7.97(d,J＝5.7Hz,1H),7.72–7.64(m,2H),7.63(t,J＝8.0Hz,1H),7.54–7.45(m,3H),7.40(d,J＝8.0Hz,1H),7.27(d,J＝7.8Hz,1H),7.23(dd,J＝8.3,4.7Hz,1H),7.13(d,J＝5.7Hz,1H),5.40(s,2H).。
实施例9：4-(2-氯-5-氟苄氧基)-3-(嘧啶-5-基氨基)苯并[d]异恶唑(式Ⅰ-33)的合成
一)、2-(2-氯-5-氟苄氧基)-6-氟苯氰(化合物27)的合成
Figure PCTCN2019072468-appb-000036
参照实施实例1中第一步合成化合物4的条件，用相应的化合物2与28反应得到相应的目标化合物29。
经检测，结构正确，检测结果如下：MS(ESI):m/z 280[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ7.77–7.66(m,1H),7.57(dd,J＝8.9,5.1Hz,1H),7.47(dd,J＝9.2,3.1Hz,1H),7.33–7.24(m,1H),7.22(d,J＝8.6Hz,1H),7.08(t,J＝8.8Hz,1H),5.30(s,2H).
二)、3-氨基-4-(2-氯-5-氟苄氧基)苯并[d]异恶唑(30)的合成
Figure PCTCN2019072468-appb-000037
参照实施实例1中第二步合成化合物6的条件，用相应的化合物29与5反应得到相应的目标化合物30。
经检测，结构正确，检测结果如下：MS(ESI):m/z 293[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ7.60–7.52(m,1H),7.53–7.44(m,1H),7.43–7.34(m,1H),7.31–7.21(m,1H),7.03–6.96(m,1H),6.74(d,J＝8.0Hz,1H),5.85(s,2H),5.30(s,2H).
三)、4-(2-氯-5-氟苄氧基)-3-(嘧啶-5-基氨基)苯并[d]异恶唑(式Ⅰ-33)的合成
Figure PCTCN2019072468-appb-000038
参照实施实例1中第三步合成化合物8的条件，用相应的化合物30与31反应得到相应的目标化合物I-33。
实施例10：4-(2-氯-5-氟苄氧基)-3-(2-(N,N-二甲基)乙酰氨基)苯并[d]异恶唑(式 Ⅰ-34)的合成
一)、3-(2-氯乙酰氨基)-4-(2-氯-5-氟苄氧基)苯并[d]异恶唑(化合物33)的合成
Figure PCTCN2019072468-appb-000039
向反应瓶中加入200mg(0.68mmol,1.0eq)30和108mg(1.36mmol,2.0eq)吡啶，溶于10mL DCM，再慢慢加入116mg(1.02mmol,1.5eq)氯乙酰氯，在室温反应2h。加水，用二氯甲烷萃取，用饱和食盐水洗涤有机相，无水Na 2SO 4干燥，浓缩，用硅胶伴样，色谱层析柱分离(石油醚：乙酸乙酯＝2：1)得化合物33，130mg白色固体，收率52％。
经检测，结构正确，检测结果如下：MS(ESI):m/z 370[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),7.62–7.52(m,2H),7.48(dd,J＝9.4,3.0Hz,1H),7.29(d,J＝8.5Hz,1H),7.25(dd,J＝8.5,3.0Hz,1H),6.91(d,J＝8.0Hz,1H),5.28(s,2H),4.22(s,2H).
二)、4-(2-氯-5-氟苄氧基)-3-(2-(N,N-二甲基)乙酰氨基)苯并[d]异恶唑(式Ⅰ-34)的合成
Figure PCTCN2019072468-appb-000040
向反应瓶中加入70mg(0.19mmol,1.0eq)33和2mL(4mmol,20.0eq)2M二甲胺的四氢呋喃溶液，溶于5mL乙腈中，再加入66mg(0.48mmol,2.5eq)碳酸钾和15mg碘化钾，加热到45℃反应2h。加水，用乙酸乙酯萃取，用饱和食盐水洗涤有机相，无水Na 2SO 4干燥，浓缩，用硅胶伴样，色谱层析柱分离(石油醚：乙酸乙酯＝1：1)得化合物I-34，29mg白色固体，收率40％。
经检测，结构正确，检测结果如下：MS(ESI):m/z 378[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ10.10(s,1H),7.67–7.57(m,3H),7.40–7.31(m,1H),7.28(d,J＝8.4Hz,1H),7.03(d,J＝8.0Hz,1H),5.31(s,2H),3.00(s,2H),1.96(s,6H).。
实施例11：Ⅰ-35～Ⅰ-38的合成
Figure PCTCN2019072468-appb-000041
Figure PCTCN2019072468-appb-000042
参照实施实例10中第二步合成化合物式Ⅰ-34的条件，用相应的烷基胺与中间体31反应得到相应的目标化合物式Ⅰ-35至Ⅰ-38，具体为：4-(2-氯-5-氟苄氧基)-3-(2-(N,N-二乙基)乙酰氨基)苯并[d]异恶唑(式Ⅰ-35)；4-(2-氯-5-氟苄氧基)-3-(2-(1-吡咯烷)乙酰氨基)苯并[d]异恶唑(式Ⅰ-36)；4-(2-氯-5-氟苄氧基)-3-(2-(1-哌啶)乙酰氨基)苯并[d]异恶唑(式Ⅰ-37)；4-(2-氯-5-氟苄氧基)-3-(2-(4-吗啉)乙酰氨基)苯并[d]异恶唑(式Ⅰ-38)。
经检测，结构正确，检测结果如下：
式Ⅰ-35 MS(ESI)(m/z):406.1(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ10.18(s,1H),7.71–7.52(m,3H),7.39–7.28(m,1H),7.24(d,J＝8.4Hz,1H),7.02(d,J＝8.1Hz,1H),5.29(s,2H),3.00(s,2H),2.11(q,J＝7.2Hz,4H),0.74(t,J＝7.2Hz,6H).
式Ⅰ-36 MS(ESI)(m/z):404.1(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ10.10(s,1H),7.57-7.51(m,3H),7.25(q,J＝8.6Hz,2H),6.92(d,J＝8.0Hz,1H),5.30(s,2H),3.16(s,2H),2.38(s,4H),1.47(s,4H).
式Ⅰ-37 MS(ESI)(m/z):418(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ10.11(s,1H),7.61–7.53(m,2H),7.53–7.46(m,1H),7.33–7.20(m,2H),6.92(d,J＝8.1Hz,1H),5.37(s,2H),3.02(s,2H),2.29(s,4H),1.37–1.20(m,6H).
式Ⅰ-38 MS(ESI)(m/z):420(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ10.08(s,1H),7.62–7.44(m,3H),7.24(d,J＝8.5Hz,2H),6.88(d,J＝7.8Hz,1H),5.33(s, 2H),3.37(s,4H),3.04(s,2H),2.30(s,4H).。
实施例12：3-(吡啶-3-基氨基)-4-((2-苯基吡啶-4-基)甲氧基)-苯并[d]异恶唑(式Ⅰ-39)的合成.
一)、2-苯基异烟碱醛(化合物34)的合成
Figure PCTCN2019072468-appb-000043
将2-氯异烟碱醛500mg(3.53mmol,1.0eq)和苯硼酸517mg(4.24mmol,1.2eq)溶于甲苯(50mL)中，加入四三苯基磷靶204mg(0.177mmol,0.05eq)和2N碳酸钠(3.53mL)，氮气保护下，加热到90℃反应12h，加水，用乙酸乙酯萃取，用饱和食盐水洗涤有机相，无水Na 2SO 4干燥，浓缩，用硅胶伴样，色谱层析柱分离(石油醚：乙酸乙酯＝15：1)得化合物34，455mg白色固体，收率70％。
经检测，结构正确，检测结果如下：MS(ESI):m/z 184[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ10.14(s,1H),8.93(dd,J＝4.9,0.9Hz,1H),8.39(s,1H),8.17–8.12(m,2H),7.74(dd,J＝4.9,1.4Hz,1H),7.56–7.45(m,3H).
二)、(2-苯基吡啶-4-基)甲醇(化合物35)的合成
Figure PCTCN2019072468-appb-000044
参考化合物14的合成。
经检测，结构正确，检测结果如下：MS(ESI):m/z 186[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ8.57(dd,J＝5.0,0.8Hz,1H),8.08–8.01(m,2H),7.85(dd,J＝1.6,0.8Hz,1H),7.52–7.44(m,2H),7.43–7.38(m,1H),7.30–7.26(m,1H),5.49(t,J＝5.8Hz,1H),4.60(dt,J＝5.8,0.9Hz,2H).
三)、3-(吡啶-3-基氨基)-4-((2-苯基吡啶-4-基)甲氧基)-苯并[d]异恶唑(式Ⅰ-39)的合成
Figure PCTCN2019072468-appb-000045
参照实施实例1中第五，六步合成化合物式Ⅰ-1的条件，用相应的取代苄醇制备取代苄溴，再与3-(吡啶-3-基氨基)-4-羟基苯并[d]异恶唑反应得到相应的目标化合物I-39。
经检测，结构正确，检测结果如下：式Ⅰ-39 MS(ESI)(m/z):395(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ8.85(d,J＝2.8Hz,1H),8.66(d,J＝5.0Hz,1H),8.53(s,1H),8.19(dd,J＝4.7,1.4Hz,1H),8.16(s,1H),8.10(dd,J＝8.4,2.8Hz,1H),8.08–8.03(m,2H),7.52(d,J＝8.2Hz,1H),7.50–7.41(m,4H),7.38–7.33(m,1H),7.17(d,J＝8.4Hz,1H),6.87(d,J＝8.0Hz,1H),5.55(s,2H).。
实施例13：4-(3–((3-(吡啶-3-基氨基)苯并[d]异恶唑-4-基)氧基)丙基)哌啶-1-甲酸叔丁酯(式Ⅰ-40)的合成
一)、4-(3–((甲磺酰基)氧基)丙基)哌啶-1-甲酸叔丁酯(化合物38)的合成
Figure PCTCN2019072468-appb-000046
将250mg(1.03mmol,1.0eq)化合物37和159mg(1.23mmol,1.2eq)DIPEA(二异丙基乙胺)溶于5mL干燥的二氯甲烷中，在冰水浴条件下向上述溶液中滴加甲磺酰氯1.44mg(1.23mmol,1.2eq)，在冰水浴条件下反应15min后，升到室温反应过夜。加水，用二氯甲烷萃取，用饱和食盐水洗涤有机相，无水Na 2SO 4干燥，浓缩。不进一步纯化直接用于下一步反应。
二)、4-(3–((3-(吡啶-3-基氨基)苯并[d]异恶唑-4-基)氧基)丙基)哌啶-1-甲酸叔丁酯(式Ⅰ-40)的合成
Figure PCTCN2019072468-appb-000047
参照实施实例1中第六步合成化合物式Ⅰ-1的条件，用化合物38代替取代苄溴与3-(吡啶-3-基氨基)-4-羟基苯并[d]异恶唑反应得到相应的目标化合物I-40。
经检测，结构正确，检测结果如下：式Ⅰ-40 MS(ESI)(m/z):453(M+H) +. 1H NMR(400MHz,DMSO-d 6)δ8.80(t,J＝3.3Hz,1H),8.22(ddt,J＝6.2,3.3,1.5Hz,2H),8.09(ddt,J＝8.3,3.0,1.7Hz,1H),7.55(t,J＝8.1Hz,1H),7.41(dd,J＝8.3,4.7Hz,1H),7.17(dd,J＝8.3,6.4Hz,1H),6.88(t,J＝7.1Hz,1H),4.23(t,J＝6.4Hz,2H),3.92(s,2H),2.67(s,2H),1.92(d,J＝7.6Hz,2H),1.67(d,J＝12.9Hz,2H),1.44(d,J＝29.6Hz,3H),1.38(s,9H),0.99(dd,J＝15.0,10.4Hz,2H).。
实施例14：化合物式Ⅰ-2的盐酸盐的制备
将0.60g(1.63mmol,1.0eq)化合物Ⅰ-2溶于10mL干燥的乙酸乙酯中，在冰水浴条件下向上述溶液中滴加1.44mL(1.8mmol,1.1eq)HCl(g)的乙酸乙酯溶液(c＝1.25mol/L)，反应10min后抽滤，干燥得到0.53g白色粉末状固体，收率80％。
实施例15：烷氧基苯并五元(六元)杂环胺类化合物体外对鞘磷脂合酶2的抑制作用测定
实验仪器与材料
1.电热恒温水浴锅(上海一恒科技有限公司)。
2.旋涡混合器(上海精科实业有限公司型号XW-80A)。
3.高速离心机(型号Eppendorf 5804R)。
4.高效液相色谱Agilent 1100(Agilent Technologies,Palo Alto,CA,USA)，配四元泵，真空脱气，FLD荧光检测器。
5.HPLC色谱柱COSMOSIL 5C18-MS-Ⅱ(4.6mm I.D.×250mm)。
6.DMPC.购自Santa Cruz(USA)，用乙醇溶解，浓度为40mmol/L。
7.C6-NBD-Ceramide(6-((N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)hexanoyl)-sphingosine).购自Santa Cruz(USA).用DMSO溶解，浓度为1.16mmol/L。
8.所用有机溶剂均购于上海国药试剂公司，甲醇为色谱纯，水为Milli-Q泵过滤，去离子化，经0.22μm膜超滤的超纯水，其他生物耗材购于国产公司。
9.配制待测化合物溶液：精确称取各待测化合物1～2mg，首先加入适量的DMSO精确配制成3mmol/L的储备溶液。取一定体积的待测化合物的DMSO储备溶液，再加入适量体积的DMSO将待测化合物稀释至所需浓度的溶液。
10.SMS1、SMS2纯酶DDM溶液及缓冲液由国家蛋白质科学中心(上海)曹禹课题组提供。
一)、烷氧基苯并五元(六元)杂环胺类化合物对鞘磷脂合酶2的抑制活性检测
将0.03μL SMS2纯酶DDM溶液(总蛋白含量为1.5μg/μL)、1μL待测化合物的DMSO溶液或空白DMSO溶液、79.7μL DDM缓冲液，加至1.5mL的eppendorf管中，涡旋振荡30秒，在室温静置5min。之后加入含有1μL DMPC的乙醇溶液(40mmol/L)和1μL C6-NBD-Ceramide的DMSO溶液(1.16mmol/L)的DDM缓冲液共20μL，涡旋振荡30秒后，在37℃水浴下孵育0.5h。取出，加入200μL的无水乙醇，涡旋振荡30秒。取出200μL混合液于4℃下储存，供高效液相色谱分析备用。
二)、烷氧基苯并五元(六元)杂环胺类化合物对鞘磷脂合酶1的抑制活性检测
参照以上SMS2的抑制活性检测方法，用SMS1纯酶代替SMS2纯酶进行相应的操作即可。
参考文献(Xiaodong Deng；Hong Sun；et al.Analytical Letters,2012,45(12):1581-1589.)，采用与文献相同的高效液相色谱方法进行上述所制备样品的荧光定量分析。分析并记录空白组、阳性对照组(化合物D2)及待测化合物组样品中C6-NBD-SM与C6-NBD-Ceramide在对应HPLC谱图上的峰面积Asm值和Acer值，依据下述公式计算出待测化合物的抑制率，
Figure PCTCN2019072468-appb-000048
依据上述方法，测定化合物式Ⅰ-1～Ⅰ-38体外对鞘磷脂合酶2的抑制活性， 活性结果为：
三)、烷氧基苯并五元(六元)杂环胺类化合物Ⅰ-1～Ⅰ-38对鞘磷脂合酶2的半数抑制浓度(IC 50)测定
将待测化合物6mM的DMSO储备溶液进行梯度稀释，配制5个浓度梯度的溶液并分别取1μL添加至实施例15第一步的测试体系中，按照实施例15第一步的方法制备样品并经高效液相色谱方法测定化合物在5个不同浓度下的Asm值(化合物D2为阳性对照物)，分别计算5个不同浓度下的抑制率并拟合得到半数抑制浓度IC 50，每个化合物平行测定3组。化合物式Ⅰ-1～Ⅰ-38对SMS2的半数抑制浓度(IC 50)和SMS1单一浓度(50μM)抑制率以及部分化合物对SMS1的半数抑制浓度(IC 50)见表1。
四)、烷氧基苯并五元(六元)杂环胺类化合物Ⅰ-1～Ⅰ-38对鞘磷脂合酶1在50μM下抑制率以及半数抑制浓度(IC 50)测定。
用相应的浓度按类似鞘磷脂合酶2的半数抑制浓度(IC 50)测定的操作进行实验即可。
表1.化合物式Ⅰ-1～Ⅰ-38对鞘磷脂合酶2半数抑制浓度(IC 50)和鞘磷脂合酶1的单一浓度(50μM)抑制率
Figure PCTCN2019072468-appb-000049
Figure PCTCN2019072468-appb-000050
a参考文献值. b实验测定值.
“-”表示没有测定。

Claims (8)

  1. 式(I)结构的烷氧基苯并五元(六元)杂环胺类化合物或其药学上可接受的盐；
    Figure PCTCN2019072468-appb-100001
    式中，
    X选自O,N,S,C中的任意一个或两个；
    Y选自O,N,S,C中的任意一个或两个；
    其中，X,Y的组合得到以下结构：
    Figure PCTCN2019072468-appb-100002
    其中R 4为甲基或者氢，乙基；
    R 1选自苯环、杂环或者酰基；
    其中，杂环结构为：
    Figure PCTCN2019072468-appb-100003
    酰基结构为：
    Figure PCTCN2019072468-appb-100004
    R 2选自氢，甲基，乙基，丙基中的任意一个；
    R 3选自烷氧基，苯环亚甲基和杂环亚甲基，其中包括苄氧，吡啶亚甲基，1-8个碳的烷烃或者1-8个碳的烷烃氨；
    R 3结构为：
    Figure PCTCN2019072468-appb-100005
    R选自o-F，m-F，p-F，o-Cl，m-Cl，p-Cl，o-Me，m-Me，p-Me，o-CF 3，m-CF 3，p-CF 3，o-OCF 3，m-OCF 3，p-OCF 3，o-OMe，m-OMe，p-OMe，o-CN，m-CN，p-CN，o-Et或者苯基中的任意一个或两个取代基；
    m为0-5。
  2. 按权利要求1所述的式(I)结构的烷氧基苯并五元(六元)杂环胺类化合物或其药学上可接受的盐，其特征在于，所述的烷氧基苯并五元(六元)杂环胺类化合物结构为：
    Figure PCTCN2019072468-appb-100006
    Figure PCTCN2019072468-appb-100007
    Figure PCTCN2019072468-appb-100008
    Figure PCTCN2019072468-appb-100009
    Figure PCTCN2019072468-appb-100010
  3. 按权利要求1或2所述的式(I)结构的烷氧基苯并五元(六元)杂环胺类化合物或其药学上可接受的盐，其特征在于，所述的药学上可接受的盐为盐酸盐、溴氢酸盐、酒石酸盐、甲磺酸盐。
  4. 权利要求1～3任一所述的式(I)结构的烷氧基苯并五元(六元)杂环胺类化合物或其药学上可接受的盐与医学上可接受的载体组成的药物组合物。
  5. 权利要求1～4任一所述的式(I)结构的烷氧基苯并五元(六元)杂环胺类化合物、其药学上可接受的盐及其与医学上可接受的载体组成的药物组合物在制备鞘磷脂合酶小分子抑制剂中的用途。
  6. 按权利要求1或2所述的式(I)结构的烷氧基苯并五元(六元)杂环胺类化合物或其药学上可接受的盐，其特征在于，所述的烷氧基苯并五元(六元)杂环胺类化合物还包括其溶剂合物，其中的溶剂为水、乙醇或甲醇。
  7. 权利要求1～5任一权项所述的式(I)结构的烷氧基苯并五元(六元)杂环胺类化合物、其药学上可接受的盐及其与医学上可接受的载体组成的药物组合物在制备预防和治疗由鞘磷脂水平异常增加所引起疾病的药物中的用途。
  8. 按权利要求7所述的用途，其特征在于，所述由鞘磷脂水平异常增加所引起的疾病为动脉粥样硬化、II型糖尿病、脂肪肝或肥胖及其代谢综合症以及肠炎炎症性疾病。
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