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CN106674098B - N-(3-cyano-4-alkoxyphenyl) picolinamide compounds and their uses - Google Patents

N-(3-cyano-4-alkoxyphenyl) picolinamide compounds and their uses Download PDF

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CN106674098B
CN106674098B CN201611206701.6A CN201611206701A CN106674098B CN 106674098 B CN106674098 B CN 106674098B CN 201611206701 A CN201611206701 A CN 201611206701A CN 106674098 B CN106674098 B CN 106674098B
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cyano
phenyl
pyridine
pyrazinamide
niacinamide
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CN106674098A (en
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孟繁浩
张廷剑
李松晔
王琳
孙琦
梁经纬
何鑫
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China Medical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The invention belongs to field of medicaments, more particularly to one kindN(3- cyano -4- alkoxyl phenyl) pyridine carboxamides and application thereof.Such compound in vitro xanthine oxidase inhibitory activity test in shown good effect, and can be used for preparing treatment gout drug.Preparation method synthesis material is easy to get, cost is relatively low, and synthetic technological condition is simply controllable, and yield is preferable.

Description

N-(3-氰基-4-烷氧基苯基)吡啶甲酰胺类化合物及其用途N-(3-cyano-4-alkoxyphenyl) picolinamide compounds and their uses

技术领域technical field

本发明属于医药领域，尤其涉及一种N-(3-氰基-4-烷氧基苯基)吡啶甲酰胺类化合物及其用途。The invention belongs to the field of medicine, in particular to an N- (3-cyano-4-alkoxyphenyl) picolinamide compound and use thereof.

背景技术Background technique

痛风是由于长期高尿酸血症导致尿酸盐沉积于关节和软组织而形成的一组异质性、代谢类疾病。其临床特点为：高尿酸血症，急、慢性关节炎，关节畸形，慢性间质性肾炎或肾结石等，严重者还会并发肾衰竭或心脑血管病而危及生命。据统计数据显示，痛风已成为仅次于糖尿病的第二大代谢性疾病。近年来随着人民生活水平的提高和饮食结构的改变，我国的痛风发病率呈逐年上升的趋势，给社会和家庭均带来了巨大的压力和沉重的经济负担。Gout is a group of heterogeneous and metabolic diseases caused by the deposition of urate in joints and soft tissues due to long-term hyperuricemia. Its clinical characteristics are: hyperuricemia, acute and chronic arthritis, joint deformity, chronic interstitial nephritis or kidney stones, etc. In severe cases, renal failure or cardiovascular and cerebrovascular diseases can be life-threatening. According to statistics, gout has become the second largest metabolic disease after diabetes. In recent years, with the improvement of people's living standards and the change of diet structure, the incidence of gout in my country has been increasing year by year, which has brought huge pressure and heavy economic burden to society and families.

痛风的发病机制为：当体内尿酸生成增多或排泄减少时，可导致体内尿酸水平升高，当超过其溶解限度时，尿酸会沉积于关节和软组织，引起炎症反应。尿酸是人体嘌呤代谢的最终产物，黄嘌呤氧化酶是嘌呤代谢中的一个关键酶，在嘌呤代谢的最后阶段，黄嘌呤氧化酶催化黄嘌呤和次黄嘌呤氧化生成尿酸，因此抑制黄嘌呤氧化酶的活性可以有效的减少尿酸的生成。所以，在高尿酸血症和痛风的治疗中，黄嘌呤氧化酶抑制剂占有非常重要的地位。The pathogenesis of gout is: when the production of uric acid in the body is increased or the excretion of uric acid is decreased, the level of uric acid in the body can increase. Uric acid is the final product of human purine metabolism, and xanthine oxidase is a key enzyme in purine metabolism. In the final stage of purine metabolism, xanthine oxidase catalyzes the oxidation of xanthine and hypoxanthine to uric acid, thus inhibiting xanthine oxidase The activity can effectively reduce the production of uric acid. Therefore, in the treatment of hyperuricemia and gout, xanthine oxidase inhibitors occupy a very important position.

目前，已上市的黄嘌呤氧化酶抑制剂有别嘌醇(Allopurinol)，非布司他(Febuxostat)和托匹司他（Topiroxostat），种类十分有限且有一定的毒副作用，因此，研制高效低毒的黄嘌呤氧化酶抑制剂具有良好的市场前景。At present, the listed xanthine oxidase inhibitors include Allopurinol, Febuxostat and Topiroxostat. The types are very limited and have certain toxic and side effects. Therefore, the development of high-efficiency and low-efficiency Toxic xanthine oxidase inhibitors have good market prospects.

发明内容SUMMARY OF THE INVENTION

针对上述问题，本发明提供一种N-(3-氰基-4-烷氧基苯基)吡啶甲酰胺类化合物，此类化合物在体外黄嘌呤氧化酶抑制活性测试中显现出了良好的效果，并且可用于制备治疗痛风的药物。In view of the above problems, the present invention provides an N- (3-cyano-4-alkoxyphenyl) picolinamide compound, which shows a good effect in the in vitro xanthine oxidase inhibitory activity test , and can be used to prepare medicines for the treatment of gout.

为了实现上述目的，本发明提供的N-(3-氰基-4-烷氧基苯基)吡啶甲酰胺类化合物通式如下。In order to achieve the above purpose, the general formula of N- (3-cyano-4-alkoxyphenyl)picolinamide compounds provided by the present invention is as follows.

其中： R1独立为1-10个碳的烷基、3-10个碳原子环烷基、甲氧乙基、苄基或取代苄基；取代苄基可以是卤代苄基、氰基苄基或烷氧基苄基；R2独立为氢、羟基或氨基，R2可分别位于吡啶环的邻位、间位或对位；Ar片段独立为4-吡啶甲酸（异烟酸）、3-吡啶甲酸（烟酸）或2-吡啶甲酸。Wherein: R1 is independently alkyl of 1-10 carbon atoms, cycloalkyl of 3-10 carbon atoms, methoxyethyl, benzyl or substituted benzyl; substituted benzyl can be halobenzyl, cyanobenzyl Or alkoxybenzyl; R2 is independently hydrogen, hydroxyl or amino, and R2 can be located in the ortho, meta or para position of the pyridine ring; the Ar fragment is independently 4-picolinic acid (isonicotinic acid), 3-picolinic acid (niacin) or 2-picolinic acid.

所述通式Ⅰ的N-(3-氰基-4-烷氧基苯基)吡啶甲酰胺类化合物，选自下述任意一种：但不仅限于以下化合物，只要化合物结构式满足通式，均为本发明的限定范围。The N- (3-cyano-4-alkoxyphenyl) picolinamide compounds of the general formula I are selected from any one of the following: but not limited to the following compounds, as long as the compound structural formula satisfies the general formula, all It is the limited scope of the present invention.

N-(3-氰基-4-正丙氧基苯基)异烟酰胺。 N- (3-cyano-4-n-propoxyphenyl)isonicotinamide.

N-(3-氰基-4-异丙氧基苯基)异烟酰胺。 N- (3-cyano-4-isopropoxyphenyl)isonicotinamide.

N-(3-氰基-4-正丁氧基苯基)异烟酰胺。 N- (3-cyano-4-n-butoxyphenyl)isonicotinamide.

N-(3-氰基-4-仲丁氧基苯基)异烟酰胺。 N- (3-cyano-4-sec-butoxyphenyl)isonicotinamide.

N-(3-氰基-4-异丁氧基苯基)异烟酰胺。 N- (3-cyano-4-isobutoxyphenyl)isonicotinamide.

N-(3-氰基-4-甲氧乙氧基苯基)异烟酰胺。 N- (3-cyano-4-methoxyethoxyphenyl)isonicotinamide.

N-(3-氰基-4-正戊氧基苯基)异烟酰胺。 N- (3-cyano-4-n-pentyloxyphenyl)isonicotinamide.

N-(3-氰基-4-异戊氧基苯基)异烟酰胺。 N- (3-cyano-4-isoamyloxyphenyl)isonicotinamide.

N-(3-氰基-4-环戊氧基苯基)异烟酰胺。 N- (3-cyano-4-cyclopentyloxyphenyl)isonicotinamide.

N-(3-氰基-4-正已氧基苯基)异烟酰胺。 N- (3-cyano-4-n-hexyloxyphenyl)isonicotinamide.

N-(3-氰基-4-正庚氧基苯基)异烟酰胺。 N- (3-cyano-4-n-heptyloxyphenyl)isonicotinamide.

N-(3-氰基-4-正辛氧基苯基)异烟酰胺。 N- (3-cyano-4-n-octyloxyphenyl)isonicotinamide.

N-(3-氰基-4-苄氧基苯基)异烟酰胺。 N- (3-cyano-4-benzyloxyphenyl)isonicotinamide.

N-(3-氰基-4-（4-氯）苄氧基苯基)异烟酰胺。 N- (3-cyano-4-(4-chloro)benzyloxyphenyl)isonicotinamide.

N-(3-氰基-4-（4-氰基）苄氧基苯基)异烟酰胺。 N- (3-cyano-4-(4-cyano)benzyloxyphenyl)isonicotinamide.

N-(3-氰基-4-正丙氧基苯基)烟酰胺。 N- (3-cyano-4-n-propoxyphenyl)nicotinamide.

N-(3-氰基-4-异丙氧基苯基)烟酰胺。 N- (3-cyano-4-isopropoxyphenyl)nicotinamide.

N-(3-氰基-4-正丁氧基苯基)烟酰胺。 N- (3-cyano-4-n-butoxyphenyl)nicotinamide.

N-(3-氰基-4-仲丁氧基苯基)烟酰胺。 N- (3-cyano-4-sec-butoxyphenyl)nicotinamide.

N-(3-氰基-4-异丁氧基苯基)烟酰胺。 N- (3-cyano-4-isobutoxyphenyl)nicotinamide.

N-(3-氰基-4-甲氧乙氧基苯基)烟酰胺。 N- (3-cyano-4-methoxyethoxyphenyl)nicotinamide.

N-(3-氰基-4-正戊氧基苯基)烟酰胺。 N- (3-cyano-4-n-pentoxyphenyl)nicotinamide.

N-(3-氰基-4-异戊氧基苯基)烟酰胺。 N- (3-cyano-4-isoamyloxyphenyl)nicotinamide.

N-(3-氰基-4-环戊氧基苯基)烟酰胺。 N- (3-cyano-4-cyclopentyloxyphenyl)nicotinamide.

N-(3-氰基-4-正已氧基苯基)烟酰胺。 N- (3-cyano-4-n-hexyloxyphenyl)nicotinamide.

N-(3-氰基-4-正庚氧基苯基)烟酰胺。 N- (3-cyano-4-n-heptyloxyphenyl)nicotinamide.

N-(3-氰基-4-正辛氧基苯基)烟酰胺。 N- (3-cyano-4-n-octyloxyphenyl)nicotinamide.

N-(3-氰基-4-苄氧基苯基)烟酰胺。 N- (3-cyano-4-benzyloxyphenyl)nicotinamide.

N-(3-氰基-4-（4-氯）苄氧基苯基)烟酰胺。 N- (3-cyano-4-(4-chloro)benzyloxyphenyl)nicotinamide.

N-(3-氰基-4-（4-氰基）苄氧基苯基)烟酰胺。 N- (3-cyano-4-(4-cyano)benzyloxyphenyl)nicotinamide.

N-(3-氰基-4-正丙氧基苯基)-2-吡啶甲酰胺。 N- (3-cyano-4-n-propoxyphenyl)-2-pyridinecarboxamide.

N-(3-氰基-4-异丙氧基苯基)-2-吡啶甲酰胺。 N- (3-cyano-4-isopropoxyphenyl)-2-pyridinecarboxamide.

N-(3-氰基-4-正丁氧基苯基)-2-吡啶甲酰胺。 N- (3-cyano-4-n-butoxyphenyl)-2-pyridinecarboxamide.

N-(3-氰基-4-仲丁氧基苯基)-2-吡啶甲酰胺。 N- (3-cyano-4-sec-butoxyphenyl)-2-pyridinecarboxamide.

N-(3-氰基-4-异丁氧基苯基)-2-吡啶甲酰胺。 N- (3-cyano-4-isobutoxyphenyl)-2-pyridinecarboxamide.

N-(3-氰基-4-甲氧乙氧基苯基)-2-吡啶甲酰胺。 N- (3-cyano-4-methoxyethoxyphenyl)-2-pyridinecarboxamide.

N-(3-氰基-4-正戊氧基苯基)-2-吡啶甲酰胺。 N- (3-cyano-4-n-pentyloxyphenyl)-2-pyridinecarboxamide.

N-(3-氰基-4-异戊氧基苯基)-2-吡啶甲酰胺。 N- (3-cyano-4-isoamyloxyphenyl)-2-pyridinecarboxamide.

N-(3-氰基-4-环戊氧基苯基)-2-吡啶甲酰胺。 N- (3-cyano-4-cyclopentyloxyphenyl)-2-pyridinecarboxamide.

N-(3-氰基-4-正已氧基苯基)-2-吡啶甲酰胺。 N- (3-cyano-4-n-hexyloxyphenyl)-2-pyridinecarboxamide.

N-(3-氰基-4-正庚氧基苯基)-2-吡啶甲酰胺。 N- (3-cyano-4-n-heptyloxyphenyl)-2-pyridinecarboxamide.

N-(3-氰基-4-正辛氧基苯基)-2-吡啶甲酰胺。 N- (3-cyano-4-n-octyloxyphenyl)-2-pyridinecarboxamide.

N-(3-氰基-4-苄氧基苯基)-2-吡啶甲酰胺。 N- (3-cyano-4-benzyloxyphenyl)-2-pyridinecarboxamide.

N-(3-氰基-4-（4-氯）苄氧基苯基)-2-吡啶甲酰胺。 N- (3-cyano-4-(4-chloro)benzyloxyphenyl)-2-pyridinecarboxamide.

N-(3-氰基-4-（4-氰基）苄氧基苯基)-2-吡啶甲酰胺。 N- (3-cyano-4-(4-cyano)benzyloxyphenyl)-2-pyridinecarboxamide.

N-(3-氰基-4-正丙氧基苯基)-5-氨基烟酰胺。 N- (3-cyano-4-n-propoxyphenyl)-5-aminonicotinamide.

N-(3-氰基-4-异丙氧基苯基) -5-氨基烟酰胺。 N- (3-cyano-4-isopropoxyphenyl)-5-aminonicotinamide.

N-(3-氰基-4-正丁氧基苯基) -5-氨基烟酰胺。 N- (3-cyano-4-n-butoxyphenyl)-5-aminonicotinamide.

N-(3-氰基-4-仲丁氧基苯基) -5-氨基烟酰胺。 N- (3-cyano-4-sec-butoxyphenyl)-5-aminonicotinamide.

N-(3-氰基-4-正戊氧基苯基) -5-氨基烟酰胺。 N- (3-cyano-4-n-pentyloxyphenyl)-5-aminonicotinamide.

N-(3-氰基-4-异戊氧基苯基) -5-氨基烟酰胺。 N- (3-cyano-4-isoamyloxyphenyl)-5-aminonicotinamide.

N-(3-氰基-4-正已氧基苯基) -5-氨基烟酰胺。 N- (3-cyano-4-n-hexyloxyphenyl)-5-aminonicotinamide.

N-(3-氰基-4-苄氧基苯基) -5-氨基烟酰胺。 N- (3-cyano-4-benzyloxyphenyl)-5-aminonicotinamide.

N-(3-氰基-4-（4-氯）苄氧基苯基) -5-氨基烟酰胺。 N- (3-cyano-4-(4-chloro)benzyloxyphenyl)-5-aminonicotinamide.

所述的通式Ⅰ所示化合物的制备，具体步骤为。The specific steps for the preparation of the compound represented by the general formula I are as follows.

（1）以邻羟基苯甲腈为起始原料，经硝化，烷基化，还原制得重要中间体5-氨基-2-烷氧基苯甲腈。(1) Using o-hydroxybenzonitrile as the starting material, the important intermediate 5-amino-2-alkoxybenzonitrile is obtained by nitration, alkylation and reduction.

（2）5-氨基-2-烷氧基苯甲腈在碱存在的条件下，分别被异烟酰氯、烟酰氯或2－吡啶甲酰氯酰化，得到分别得到N-(3-氰基-4-烷氧基苯基)异烟酰胺、N-(3-氰基-4-烷氧基苯基)烟酰胺和N-(3-氰基-4-烷氧基苯基)-2-吡啶甲酰胺。(2) 5-amino-2-alkoxybenzonitrile is acylated by isonicotinyl chloride, nicotinyl chloride or 2-picolinoyl chloride in the presence of a base to obtain N-(3-cyano- 4-Alkoxyphenyl)isonicotinamide, N-(3-cyano-4-alkoxyphenyl)nicotinamide and N-(3-cyano-4-alkoxyphenyl)-2- Picolinamide.

（3）5-氨基-2-烷氧基苯甲腈在EDCI/HOAT条件下，与5-Boc-氨基烟酰氯缩合，再经脱保护得到N-(3-氰基-4-烷氧基苯基)-5-氨基烟酰胺。(3) 5-Amino-2-alkoxybenzonitrile was condensed with 5-Boc-aminonicotinyl chloride under EDCI/HOAT conditions, and then deprotected to obtain N-(3-cyano-4-alkoxyl group) phenyl)-5-aminonicotinamide.

一种药用组合物，它包含前面所述的任一化合物和药学上可接受的载体，作为在制备治疗痛风药物中的应用。A pharmaceutical composition, which comprises any of the aforementioned compounds and a pharmaceutically acceptable carrier, is used in the preparation of a medicine for treating gout.

优选的，一种用于治疗痛风的药物组合物制剂，它包含前面所述的任一化合物、及其药学上可接受的载体淀粉、微晶纤维素、硬质酸镁或甘油。Preferably, a pharmaceutical composition preparation for treating gout, which comprises any of the aforementioned compounds, and pharmaceutically acceptable carriers thereof, starch, microcrystalline cellulose, magnesium stearate or glycerin.

本发明的有益效果。Beneficial effects of the present invention.

本发明所提供的N-(3-氰基-4-烷氧基苯基)吡啶甲酰胺类化合物的制备方法合成原料易得、成本较低，合成工艺条件简单可控，而且收率较好；可以有效的抑制黄嘌呤氧化酶的活性，进而可用于研制治疗痛风的药物组合物制剂。The preparation method of N- (3-cyano-4-alkoxyphenyl)picolinamide compounds provided by the invention has easy-to-obtain raw materials, low cost, simple and controllable synthesis process conditions, and good yield ; Can effectively inhibit the activity of xanthine oxidase, and then can be used to develop a pharmaceutical composition preparation for the treatment of gout.

具体实施方式Detailed ways

下面通过实施例对本发明作进一步的说明。The present invention will be further illustrated by the following examples.

实施例1。Example 1.

步骤1、5-硝基-2-羟基苯甲腈的制备。Step 1. Preparation of 5-nitro-2-hydroxybenzonitrile.

于500 mL反应瓶中加入水杨腈（100 g，0.84 mol）和冰乙酸（200 mL），50℃搅拌下缓慢滴加浓硝酸（74.4 mL，1.1 mol），控制反应温度在50-70℃之间，加毕继续反应4 h，反应完毕后冷却，倒入冰水中，抽滤，滤饼用大量水洗，自然干燥，得淡黄色固体82 g，收率：59.5%。In a 500 mL reaction flask, salicylonitrile (100 g, 0.84 mol) and glacial acetic acid (200 mL) were added, and concentrated nitric acid (74.4 mL, 1.1 mol) was slowly added dropwise with stirring at 50 °C, and the reaction temperature was controlled at 50-70 °C During the addition, the reaction was continued for 4 h. After the reaction was completed, it was cooled, poured into ice water, filtered with suction, the filter cake was washed with a large amount of water, and dried naturally to obtain 82 g of a pale yellow solid, yield: 59.5%.

步骤2、5-氨基-2-烷氧基苯甲腈的制备。Step 2. Preparation of 5-amino-2-alkoxybenzonitrile.

于反应瓶中加入步骤1制备的5-硝基-2-羟基苯甲腈（110 mmol），卤代烷烃（110mmol），无水碳酸钾（165 mmol），碘化钾（11 mmol）和DMF（80 mL）， 60℃下反应过夜，TCL反应完全，反应液冷却后，倒入300 mL水中，乙酸乙酯（100 mL*3）萃取，有机层水洗，饱和食盐水洗，无水硫酸钠干燥过夜，过滤，滤液减压浓缩至干，得淡黄色油状物5-硝基-2-烷氧基苯甲腈。To the reaction flask were added 5-nitro-2-hydroxybenzonitrile (110 mmol) prepared in step 1, haloalkane (110 mmol), anhydrous potassium carbonate (165 mmol), potassium iodide (11 mmol) and DMF (80 mL) ), reacted at 60 °C overnight, the TCL reaction was complete, the reaction solution was cooled, poured into 300 mL of water, extracted with ethyl acetate (100 mL*3), the organic layer was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate overnight, filtered , the filtrate was concentrated to dryness under reduced pressure to obtain 5-nitro-2-alkoxybenzonitrile as a pale yellow oil.

于反应瓶中加入步骤2制备的5-硝基-2-烷氧基苯甲腈（58.2 mol），及还原铁粉（223.8 mmol），氯化铵（29.1 mmol），乙醇（15 mL）和水（45 mL），回流3 h，反应完全，加水稀释，乙酸乙酯萃取3次，每次50 mL，饱和食盐水洗，无水硫酸钠干燥，过滤，减压浓缩至干得精产品，柱层析纯化（乙酸乙酯：石油醚 = 1:5-1:1）得纯品。Into the reaction flask were added 5-nitro-2-alkoxybenzonitrile (58.2 mol) prepared in step 2, and reduced iron powder (223.8 mmol), ammonium chloride (29.1 mmol), ethanol (15 mL) and Water (45 mL), refluxed for 3 h, the reaction was complete, diluted with water, extracted with ethyl acetate 3 times, 50 mL each time, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain a refined product, which was used in a column. Purified by chromatography (ethyl acetate: petroleum ether = 1:5-1:1) to obtain pure product.

实施例2。Example 2.

（1）5-氨基-2-正丙氧基苯甲腈的制备。(1) Preparation of 5-amino-2-n-propoxybenzonitrile.

以溴代正丙烷为原料，制备方法同实施例1中的步骤（2），得到黄色油状物，收率45.2%。1H NMR (600 MHz, DMSO-d6) δ 6.96 (d, J = 9.0 Hz, 1H), 6.83 (dd, J =9.0, 2.8 Hz, 1H), 6.76 (d, J = 2.8 Hz, 1H), 5.10 (s, 2H), 4.08 (t, J = 6.4Hz, 2H), 1.81 – 1.67 (m, 2H), 0.96 (t, J = 7.0 Hz, 3H)。Using bromo-n-propane as raw material, the preparation method is the same as that of step (2) in Example 1, to obtain a yellow oil with a yield of 45.2%. 1 H NMR (600 MHz, DMSO-d6) δ 6.96 (d, J = 9.0 Hz, 1H), 6.83 (dd, J =9.0, 2.8 Hz, 1H), 6.76 (d, J = 2.8 Hz, 1H), 5.10 (s, 2H), 4.08 (t, J = 6.4 Hz, 2H), 1.81 – 1.67 (m, 2H), 0.96 (t, J = 7.0 Hz, 3H).

（2）5-氨基-2-异丙氧基苯甲腈。(2) 5-Amino-2-isopropoxybenzonitrile.

以溴代异丙烷原料，制备方法同实施例1中的步骤（2），得到黄色油状物，收率32.6%。1H NMR (600 MHz, DMSO-d6) δ 6.96 (d, J = 9.0 Hz, 1H), 6.83 (dd, J =8.9, 2.8 Hz, 1H), 6.76 (d, J = 2.8 Hz, 1H), 5.09 (s, 2H), 4.46 (dt, J = 12.1,6.1 Hz, 1H), 1.23 (d, J = 6.1 Hz, 6H) 。Using bromoisopropane as raw material, the preparation method is the same as that of step (2) in Example 1 to obtain a yellow oil with a yield of 32.6%. 1 H NMR (600 MHz, DMSO-d6) δ 6.96 (d, J = 9.0 Hz, 1H), 6.83 (dd, J =8.9, 2.8 Hz, 1H), 6.76 (d, J = 2.8 Hz, 1H), 5.09 (s, 2H), 4.46 (dt, J = 12.1, 6.1 Hz, 1H), 1.23 (d, J = 6.1 Hz, 6H).

（3）5-氨基-2-正丁氧基苯甲腈。(3) 5-amino-2-n-butoxybenzonitrile.

以溴代正丁烷为原料，制备方法同实施例1中的步骤（2），得到黄色固体，收率42.0%。1H NMR (600 MHz, DMSO-d6) δ 6.95 (d, J = 9.0 Hz, 1H), 6.84 (dd, J =8.9, 2.8 Hz, 1H), 6.77 (d, J = 2.8 Hz, 1H), 5.05 (s, 2H), 3.96 (t, J = 6.4Hz, 2H), 1.66 (m, 2H), 1.50 – 1.37 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H) 。Using bromo-n-butane as raw material, the preparation method is the same as that of step (2) in Example 1, to obtain a yellow solid with a yield of 42.0%. 1 H NMR (600 MHz, DMSO-d6) δ 6.95 (d, J = 9.0 Hz, 1H), 6.84 (dd, J =8.9, 2.8 Hz, 1H), 6.77 (d, J = 2.8 Hz, 1H), 5.05 (s, 2H), 3.96 (t, J = 6.4Hz, 2H), 1.66 (m, 2H), 1.50 – 1.37 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H).

（4）5-氨基-2-仲丁氧基苯甲腈。(4) 5-Amino-2-sec-butoxybenzonitrile.

以溴代仲丁烷为原料，制备方法同实施例1中的步骤（2），得到黄色油状物，收率42.3%。1H NMR (600 MHz, DMSO-d6) δ6.95 (d, J = 9.0 Hz, 1H), 6.83 (dd, J = 8.9,2.8 Hz, 1H), 6.76 (d, J = 2.8 Hz, 1H), 5.09 (s, 2H), 4.27 (dd, J = 12.0, 6.0Hz, 1H), 1.59 (m, 2H), 1.19 (d, J = 6.1 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H) 。Using bromo-sec-butane as a raw material, the preparation method is the same as that of step (2) in Example 1, to obtain a yellow oil with a yield of 42.3%. 1 H NMR (600 MHz, DMSO-d6) δ6.95 (d, J = 9.0 Hz, 1H), 6.83 (dd, J = 8.9, 2.8 Hz, 1H), 6.76 (d, J = 2.8 Hz, 1H) , 5.09 (s, 2H), 4.27 (dd, J = 12.0, 6.0Hz, 1H), 1.59 (m, 2H), 1.19 (d, J = 6.1 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H).

（5）5-氨基-2-异丁氧基苯甲腈。(5) 5-Amino-2-isobutoxybenzonitrile.

以溴代异丁烷为原料，制备方法同实施例1中的步骤（2），得到黄色固体，收率23.4%。1H NMR (600 MHz, DMSO-d6) δ 6.93 (d, J = 9.0 Hz, 1H), 6.84 (dd, J =8.9, 2.8 Hz, 1H), 6.80 – 6.76 (m, 1H), 5.05 (s, 2H), 3.73 (d, J = 6.5 Hz,2H), 1.98 (dt, J = 13.3, 6.6 Hz, 1H), 0.97 (d, J = 6.7 Hz, 6H) 。Using bromoisobutane as a raw material, the preparation method is the same as that of step (2) in Example 1, to obtain a yellow solid with a yield of 23.4%. 1 H NMR (600 MHz, DMSO-d6) δ 6.93 (d, J = 9.0 Hz, 1H), 6.84 (dd, J =8.9, 2.8 Hz, 1H), 6.80 – 6.76 (m, 1H), 5.05 (s , 2H), 3.73 (d, J = 6.5 Hz, 2H), 1.98 (dt, J = 13.3, 6.6 Hz, 1H), 0.97 (d, J = 6.7 Hz, 6H).

（6）5-氨基-2-甲氧乙氧基苯甲腈。(6) 5-Amino-2-methoxyethoxybenzonitrile.

以甲基溴乙基醚为原料，制备方法同实施例1中的步骤（2），得到类白色固体，收率22.1%。1H NMR (600 MHz, DMSO- d6) δ 6.97 (d, J = 9.0 Hz, 1H), 6.85 (dd, J =8.9, 2.7 Hz, 1H), 6.79 (d, J = 2.7 Hz, 1H), 5.13 (s, 2H), 4.18 – 4.00 (m,2H), 3.72 – 3.56 (m, 2H), 3.32 (s, 3H) 。Using methyl bromoethyl ether as a raw material, the preparation method was the same as that of step (2) in Example 1, and an off-white solid was obtained in a yield of 22.1%. 1 H NMR (600 MHz, DMSO-d6) δ 6.97 (d, J = 9.0 Hz, 1H), 6.85 (dd, J =8.9, 2.7 Hz, 1H), 6.79 (d, J = 2.7 Hz, 1H), 5.13 (s, 2H), 4.18 – 4.00 (m, 2H), 3.72 – 3.56 (m, 2H), 3.32 (s, 3H).

（7）5-氨基-2-正戊氧基苯甲腈。(7) 5-Amino-2-n-pentyloxybenzonitrile.

以溴代正戊烷为原料，制备方法同实施例1中的步骤（2），黄色油状物，收率36.4%。1HNMR (600 MHz, DMSO- d6) δ 6.94 (d, J = 9.0 Hz, 1H), 6.84 (dd, J = 9.0, 2.8Hz, 1H), 6.78 (d, J = 2.5 Hz, 1H), 5.05 (s, 2H), 3.95 (t, J = 6.4 Hz, 2H),1.75 – 1.57 (m, 2H), 1.45 – 1.27 (m, 4H), 0.88 (t, J = 7.1 Hz, 3H)。Using bromo-n-pentane as raw material, the preparation method is the same as that of step (2) in Example 1, and the yield is 36.4% as a yellow oil. 1 HNMR (600 MHz, DMSO-d6) δ 6.94 (d, J = 9.0 Hz, 1H), 6.84 (dd, J = 9.0, 2.8Hz, 1H), 6.78 (d, J = 2.5 Hz, 1H), 5.05 (s, 2H), 3.95 (t, J = 6.4 Hz, 2H), 1.75 – 1.57 (m, 2H), 1.45 – 1.27 (m, 4H), 0.88 (t, J = 7.1 Hz, 3H).

（8）5-氨基-2-异戊氧基苯甲腈。(8) 5-Amino-2-isoamyloxybenzonitrile.

以溴代异戊烷为原料，制备方法同实施例1中的步骤（2），得到黄色固体，收率39.1%。1H NMR (600 MHz, DMSO-d6) δ 6.98 – 6.95 (m, 1H), 6.84 (dd, J = 9.0, 2.8Hz, 1H), 6.77 (d, J = 2.8 Hz, 1H), 5.04 (s, 2H), 4.01 – 3.93 (m, 2H), 1.82 –1.73 (m, 1H), 1.58 (q, J = 6.7 Hz, 2H), 0.92 (t, J = 6.3 Hz, 6H)。Using bromoisopentane as a raw material, the preparation method is the same as that of step (2) in Example 1, to obtain a yellow solid with a yield of 39.1%. 1 H NMR (600 MHz, DMSO-d6) δ 6.98 – 6.95 (m, 1H), 6.84 (dd, J = 9.0, 2.8Hz, 1H), 6.77 (d, J = 2.8 Hz, 1H), 5.04 (s , 2H), 4.01 – 3.93 (m, 2H), 1.82 – 1.73 (m, 1H), 1.58 (q, J = 6.7 Hz, 2H), 0.92 (t, J = 6.3 Hz, 6H).

（9）5-氨基-2-环戊氧基苯甲腈。(9) 5-Amino-2-cyclopentyloxybenzonitrile.

以氯代环戊烷原料，制备方法同实施例1中的步骤（2），得到黄色油状物，收率36.1%。1H NMR (600 MHz, DMSO-d6) δ 6.95 (d, J = 9.0 Hz, 1H), 6.84 (dd, J =9.0, 2.8 Hz, 1H), 6.75 (d, J = 2.8 Hz, 1H), 5.06 (s, 2H), 4.77 (td, J = 5.7,3.0 Hz, 1H), 1.88 – 1.77 (m, 2H), 1.77 – 1.64 (m, 4H), 1.62 – 1.51 (m, 2H)。Using chlorocyclopentane as raw material, the preparation method is the same as that of step (2) in Example 1, to obtain a yellow oil with a yield of 36.1%. 1 H NMR (600 MHz, DMSO-d6) δ 6.95 (d, J = 9.0 Hz, 1H), 6.84 (dd, J =9.0, 2.8 Hz, 1H), 6.75 (d, J = 2.8 Hz, 1H), 5.06 (s, 2H), 4.77 (td, J = 5.7, 3.0 Hz, 1H), 1.88 – 1.77 (m, 2H), 1.77 – 1.64 (m, 4H), 1.62 – 1.51 (m, 2H).

（10）5-氨基-2-正已氧基苯甲腈。(10) 5-Amino-2-n-hexyloxybenzonitrile.

以溴代正已烷为原料，制备方法同实施例1中的步骤（2），得到黄色油状物，收率35.7%。1H NMR (600 MHz, DMSO-d6) δ 6.94 (d, J = 9.0 Hz, 1H), 6.84 (dd, J =8.9, 2.8 Hz, 1H), 6.77 (d, J = 2.8 Hz, 1H), 5.05 (s, 2H), 3.95 (t, J = 6.4Hz, 2H), 1.66 (m, 2H), 1.45 – 1.36 (m, 2H), 1.33 – 1.24 (m, 4H), 0.91 – 0.82(m, 3H)。Using bromo-n-hexane as a raw material, the preparation method is the same as that of step (2) in Example 1, to obtain a yellow oil with a yield of 35.7%. 1 H NMR (600 MHz, DMSO-d6) δ 6.94 (d, J = 9.0 Hz, 1H), 6.84 (dd, J =8.9, 2.8 Hz, 1H), 6.77 (d, J = 2.8 Hz, 1H), 5.05 (s, 2H), 3.95 (t, J = 6.4Hz, 2H), 1.66 (m, 2H), 1.45 – 1.36 (m, 2H), 1.33 – 1.24 (m, 4H), 0.91 – 0.82(m, 3H).

（11）5-氨基-2-正庚氧基苯甲腈。(11) 5-Amino-2-n-heptyloxybenzonitrile.

以溴代正庚烷为原料，制备方法同实施例1中的步骤（2），得到黄色油状物，收率42.4%。1H NMR (600 MHz, DMSO-d6) δ 6.95 (d, J = 9.0 Hz, 1H), 6.84 (dd, J =8.9, 2.8 Hz, 1H), 6.76 (d, J = 2.8 Hz, 1H), 5.05 (s, 2H), 4.11 (t, J = 6.4Hz, 2H), 1.77 – 1.66 (m, 2H), 1.46 – 1.37 (m, 2H), 1.37 – 1.21 (m, 6H), 0.85(t, J = 6.9 Hz, 3H)。Using bromo-n-heptane as a raw material, the preparation method is the same as that of step (2) in Example 1 to obtain a yellow oil with a yield of 42.4%. 1 H NMR (600 MHz, DMSO-d6) δ 6.95 (d, J = 9.0 Hz, 1H), 6.84 (dd, J =8.9, 2.8 Hz, 1H), 6.76 (d, J = 2.8 Hz, 1H), 5.05 (s, 2H), 4.11 (t, J = 6.4Hz, 2H), 1.77 – 1.66 (m, 2H), 1.46 – 1.37 (m, 2H), 1.37 – 1.21 (m, 6H), 0.85(t, J = 6.9 Hz, 3H).

（12）5-氨基-2-正辛氧基苯甲腈。(12) 5-Amino-2-n-octyloxybenzonitrile.

以溴代正辛烷为原料，制备方法同实施例1中的步骤（2），得到黄色油状物，收率34.8%。1H NMR (600 MHz, DMSO-d6) δ 6.94 (d, J = 9.0 Hz, 1H), 6.84 (dd, J =9.0, 2.8 Hz, 1H), 6.77 (d, J = 2.8 Hz, 1H), 5.05 (s, 2H), 3.95 (t, J = 6.4Hz, 2H), 1.72 – 1.60 (m, 2H), 1.45 – 1.33 (m, 2H), 1.34 – 1.21 (m, 8H), 0.85(t, J = 7.0 Hz, 3H)。Taking bromo-n-octane as raw material, the preparation method is the same as that of step (2) in Example 1, to obtain a yellow oil with a yield of 34.8%. 1 H NMR (600 MHz, DMSO-d6) δ 6.94 (d, J = 9.0 Hz, 1H), 6.84 (dd, J =9.0, 2.8 Hz, 1H), 6.77 (d, J = 2.8 Hz, 1H), 5.05 (s, 2H), 3.95 (t, J = 6.4Hz, 2H), 1.72 – 1.60 (m, 2H), 1.45 – 1.33 (m, 2H), 1.34 – 1.21 (m, 8H), 0.85(t, J = 7.0 Hz, 3H).

（13）5-氨基-2-苄氧基苯甲腈。(13) 5-Amino-2-benzyloxybenzonitrile.

以氯苄为原料，制备方法同实施例1中的步骤（2），得到粉色粉末，收率42.7%。1HNMR (600 MHz, DMSO-d6) δ 7.44 (d, J = 7.3 Hz, 2H), 7.40 (d, J = 7.3 Hz, 2H),7.33 (t, J = 7.2 Hz, 1H), 7.05 (d, J = 9.0 Hz, 1H), 6.84 (dd, J = 8.9, 2.8Hz, 1H), 6.80 (d, J = 2.8 Hz, 1H), 5.10 (m, 4H)。Using benzyl chloride as a raw material, the preparation method is the same as that of step (2) in Example 1, and a pink powder is obtained with a yield of 42.7%. 1 HNMR (600 MHz, DMSO-d6) δ 7.44 (d, J = 7.3 Hz, 2H), 7.40 (d, J = 7.3 Hz, 2H), 7.33 (t, J = 7.2 Hz, 1H), 7.05 (d , J = 9.0 Hz, 1H), 6.84 (dd, J = 8.9, 2.8Hz, 1H), 6.80 (d, J = 2.8 Hz, 1H), 5.10 (m, 4H).

（14）5-氨基-2-(4-氯)苄氧基苯甲腈。(14) 5-Amino-2-(4-chloro)benzyloxybenzonitrile.

以对氯溴苄为原料，制备方法同实施例1中的步骤（2），得到类白色固体，收率29.9%。1H NMR (600 MHz, DMSO-d6) δ 7.50 – 7.43 (m, 4H), 7.03 (d, J = 9.0 Hz,1H), 6.84 (dd, J = 9.0, 2.8 Hz, 1H), 6.79 (d, J = 2.8 Hz, 1H), 5.11 (s, 4H)。Using p-chlorobenzyl bromide as a raw material, the preparation method is the same as that of step (2) in Example 1 to obtain an off-white solid with a yield of 29.9%. 1 H NMR (600 MHz, DMSO-d6) δ 7.50 – 7.43 (m, 4H), 7.03 (d, J = 9.0 Hz, 1H), 6.84 (dd, J = 9.0, 2.8 Hz, 1H), 6.79 (d , J = 2.8 Hz, 1H), 5.11 (s, 4H).

（15）5-氨基-2-(4-氰基)苄氧基苯甲腈。(15) 5-Amino-2-(4-cyano)benzyloxybenzonitrile.

以对腈基溴苄为原料，制备方法同实施例1中的步骤（2），得到类白色固体，收率30.6%。1H NMR (600 MHz, DMSO-d6) δ 7.89 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4Hz, 2H), 7.02 (d, J = 9.0 Hz, 1H), 6.84 (dd, J = 8.9, 2.8 Hz, 1H), 6.81 (d, J= 2.8 Hz, 1H), 5.18 (m, 4H)。Using p-nitrile benzyl bromide as a raw material, the preparation method is the same as that of step (2) in Example 1, to obtain an off-white solid with a yield of 30.6%. 1 H NMR (600 MHz, DMSO-d6) δ 7.89 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 9.0 Hz, 1H), 6.84 ( dd, J = 8.9, 2.8 Hz, 1H), 6.81 (d, J = 2.8 Hz, 1H), 5.18 (m, 4H).

实施例3。Example 3.

N-(4-烷氧基-3-氰基苯基)异烟酰胺的合成方法。Synthesis of N- (4-alkoxy-3-cyanophenyl)isonicotinamide.

于反应瓶中加入步骤2纯化的2-烷氧基-5-氨基苯甲腈（0.6 mmol），三乙胺（1.5mmol）和二氯甲烷（15 mL），-5°C搅拌下滴加二氯甲烷（15 mL）的异烟酰氯 (0.72 mmol)，维持温度反应1 h后，加水，分出有机层，水层用二氯甲烷萃取，合并有机层，饱和食盐水洗，无水硫酸钠干燥，减压浓缩至干；粗产品经柱层析纯化，得目标产物。2-alkoxy-5-aminobenzonitrile (0.6 mmol) purified in step 2, triethylamine (1.5 mmol) and dichloromethane (15 mL) were added to the reaction flask, and added dropwise with stirring at -5°C Isonicotinyl chloride (0.72 mmol) in dichloromethane (15 mL), maintained at temperature for 1 h, added water, separated the organic layer, extracted the aqueous layer with dichloromethane, combined the organic layers, washed with saturated brine, anhydrous sodium sulfate Dry and concentrate to dryness under reduced pressure; the crude product is purified by column chromatography to obtain the target product.

（1）N-(3-氰基-4-正丙氧基苯基)异烟酰胺（样品编号ANP01）。(1) N- (3-cyano-4-n-propoxyphenyl)isonicotinamide (Sample No. ANP01).

以实施例2中的2-正丙氧基-5-氨基苯甲腈为原料，经过本实施例中的合成方法，制备得到目标产物。Using 2-n-propoxy-5-aminobenzonitrile in Example 2 as a raw material, through the synthesis method in this example, the target product was prepared.

1H NMR (600 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.80 (dd, J = 4.4, 1.6 Hz,2H), 8.10 (d, J = 2.6 Hz, 1H), 7.95 (dd, J = 9.2, 2.6 Hz, 1H), 7.85 (dd, J =4.4, 1.6 Hz, 2H), 7.29 (d, J = 9.2 Hz, 1H), 4.09 (t, J = 6.4 Hz, 2H), 1.87 –1.69 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.80 (dd, J = 4.4, 1.6 Hz, 2H), 8.10 (d, J = 2.6 Hz, 1H), 7.95 (dd, J = 9.2, 2.6 Hz, 1H), 7.85 (dd, J =4.4, 1.6 Hz, 2H), 7.29 (d, J = 9.2 Hz, 1H), 4.09 (t, J = 6.4 Hz, 2H), 1.87 –1.69 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H).

（2）N -(3-氰基-4-异丙氧基苯基)异烟酰胺（样品编号ANP02）。(2) N- (3-cyano-4-isopropoxyphenyl)isonicotinamide (Sample No. ANP02).

以实施例2中的5-氨基-2-异丙氧基苯甲腈为原料，经过本实施例中的合成方法，制备得到目标产物。Using the 5-amino-2-isopropoxybenzonitrile in Example 2 as a raw material, through the synthesis method in this example, the target product was prepared.

1H NMR (600 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.80 (d, J = 5.9 Hz, 2H),8.09 (d, J = 2.6 Hz, 1H), 7.94 (dd, J = 9.2, 2.6 Hz, 1H), 7.85 (dd, J = 4.5,1.4 Hz, 2H), 7.33 (d, J = 9.3 Hz, 1H), 4.76 (dt, J = 12.1, 6.0 Hz, 1H), 1.32(d, J = 6.0 Hz, 6H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.80 (d, J = 5.9 Hz, 2H), 8.09 (d, J = 2.6 Hz, 1H), 7.94 (dd, J = 9.2 , 2.6 Hz, 1H), 7.85 (dd, J = 4.5, 1.4 Hz, 2H), 7.33 (d, J = 9.3 Hz, 1H), 4.76 (dt, J = 12.1, 6.0 Hz, 1H), 1.32(d , J = 6.0 Hz, 6H).

（3）N -(3-氰基-4-正丁氧基苯基)异烟酰胺（样品编号ANP03）。(3) N- (3-cyano-4-n-butoxyphenyl)isonicotinamide (Sample No. ANP03).

以实施例2中的5-氨基-2-正丁氧基苯甲腈为原料，在经过本实施例中的合成方法，制备得到目标产物。Using the 5-amino-2-n-butoxybenzonitrile in Example 2 as a raw material, the target product was prepared through the synthesis method in this example.

1H NMR (600 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.80 (d, J = 5.9 Hz, 2H),8.09 (d, J = 2.6 Hz, 1H), 7.95 (dd, J = 9.2, 2.6 Hz, 1H), 7.85 (dd, J = 4.4,1.6 Hz, 2H), 7.30 (d, J = 9.2 Hz, 1H), 4.14 (t, J = 6.4 Hz, 2H), 1.74 (tt, J= 12.6, 6.4 Hz, 2H), 1.57 – 1.38 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.80 (d, J = 5.9 Hz, 2H), 8.09 (d, J = 2.6 Hz, 1H), 7.95 (dd, J = 9.2 , 2.6 Hz, 1H), 7.85 (dd, J = 4.4, 1.6 Hz, 2H), 7.30 (d, J = 9.2 Hz, 1H), 4.14 (t, J = 6.4 Hz, 2H), 1.74 (tt, J = 12.6, 6.4 Hz, 2H), 1.57 – 1.38 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H).

（4）N -(3-氰基-4-仲丁氧基苯基)异烟酰胺（样品编号ANP04）。(4) N- (3-cyano-4-sec-butoxyphenyl)isonicotinamide (Sample No. ANP04).

以实施例2中的5-氨基-2-仲丁氧基苯甲腈为原料，在经过本实施例中的合成方法，制备得到目标产物。Using the 5-amino-2-sec-butoxybenzonitrile in Example 2 as a raw material, the target product was prepared through the synthesis method in this example.

1H NMR (600 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.80 (dd, J = 4.4, 1.6 Hz,2H), 8.09 (d, J = 2.6 Hz, 1H), 7.94 (dd, J = 9.2, 2.7 Hz, 1H), 7.85 (dd, J =4.4, 1.6 Hz, 2H), 7.32 (d, J = 9.3 Hz, 1H), 4.56 (h, J = 6.0 Hz, 1H), 1.70 –1.63 (m, 2H), 1.28 (d, J = 6.1 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.80 (dd, J = 4.4, 1.6 Hz, 2H), 8.09 (d, J = 2.6 Hz, 1H), 7.94 (dd, J = 9.2, 2.7 Hz, 1H), 7.85 (dd, J =4.4, 1.6 Hz, 2H), 7.32 (d, J = 9.3 Hz, 1H), 4.56 (h, J = 6.0 Hz, 1H), 1.70 –1.63 (m, 2H), 1.28 (d, J = 6.1 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H).

（5）N -(3-氰基-4-异丁氧基苯基)异烟酰胺（样品编号ANP05）。(5) N- (3-cyano-4-isobutoxyphenyl)isonicotinamide (Sample No. ANP05).

以实施例2中的5-氨基-2-异丁氧基苯甲腈为原料，在经过本实施例中的合成方法，制备得到目标产物。Using the 5-amino-2-isobutoxybenzonitrile in Example 2 as a raw material, the target product was prepared through the synthesis method in this example.

1H NMR (600 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.80 (d, J = 5.5 Hz, 2H),8.09 (d, J = 2.3 Hz, 1H), 7.95 (dd, J = 9.1, 2.3 Hz, 1H), 7.85 (d, J = 5.5Hz, 2H), 7.30 (d, J = 9.2 Hz, 1H), 3.92 (d, J = 6.4 Hz, 2H), 2.06 (dt, J =13.3, 6.7 Hz, 1H), 1.01 (d, J = 6.7 Hz, 6H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.80 (d, J = 5.5 Hz, 2H), 8.09 (d, J = 2.3 Hz, 1H), 7.95 (dd, J = 9.1 , 2.3 Hz, 1H), 7.85 (d, J = 5.5Hz, 2H), 7.30 (d, J = 9.2 Hz, 1H), 3.92 (d, J = 6.4 Hz, 2H), 2.06 (dt, J =13.3 , 6.7 Hz, 1H), 1.01 (d, J = 6.7 Hz, 6H).

（6）N -(3-氰基-4-正戊氧基苯基)异烟酰胺（样品编号ANP06）。(6) N- (3-cyano-4-n-pentyloxyphenyl)isonicotinamide (Sample No. ANP06).

以实施例2中的5-氨基-2-正戊氧基苯甲腈为原料，经过本实施例中的合成方法，制备得到目标产物。Using 5-amino-2-n-pentyloxybenzonitrile in Example 2 as a raw material, through the synthesis method in this example, the target product was prepared.

1H NMR (600 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.80 (dd, J = 4.4, 1.6 Hz,2H), 8.09 (d, J = 2.6 Hz, 1H), 7.95 (dd, J = 9.2, 2.6 Hz, 1H), 7.85 (dd, J =4.4, 1.6 Hz, 2H), 7.29 (d, J = 9.2 Hz, 1H), 4.12 (t, J = 6.5 Hz, 2H), 1.82 –1.68 (m, 2H), 1.50 – 1.29 (m, 4H), 0.90 (t, J = 7.2 Hz, 3H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.80 (dd, J = 4.4, 1.6 Hz, 2H), 8.09 (d, J = 2.6 Hz, 1H), 7.95 (dd, J = 9.2, 2.6 Hz, 1H), 7.85 (dd, J =4.4, 1.6 Hz, 2H), 7.29 (d, J = 9.2 Hz, 1H), 4.12 (t, J = 6.5 Hz, 2H), 1.82 –1.68 (m, 2H), 1.50 – 1.29 (m, 4H), 0.90 (t, J = 7.2 Hz, 3H).

（7）N -(3-氰基-4-异戊氧基苯基)异烟酰胺（样品编号ANP07）。(7) N- (3-cyano-4-isoamyloxyphenyl)isonicotinamide (Sample No. ANP07).

以实施例2中的5-氨基-2-异戊氧基苯甲腈为原料，经过本实施例中的合成方法，制备得到目标产物。Using 5-amino-2-isoamyloxybenzonitrile in Example 2 as a raw material, through the synthesis method in this example, the target product was prepared.

1H NMR (600 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.80 (dd, J = 4.4, 1.6 Hz,2H), 8.09 (d, J = 2.6 Hz, 1H), 7.95 (dd, J = 9.2, 2.6 Hz, 1H), 7.85 (dd, J =4.4, 1.6 Hz, 2H), 7.32 (d, J = 9.2 Hz, 1H), 4.16 (t, J = 6.6 Hz, 2H), 1.81(dq, J = 13.4, 6.7 Hz, 1H), 1.66 (q, J = 6.6 Hz, 2H), 0.95 (d, J = 6.7 Hz,6H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.80 (dd, J = 4.4, 1.6 Hz, 2H), 8.09 (d, J = 2.6 Hz, 1H), 7.95 (dd, J = 9.2, 2.6 Hz, 1H), 7.85 (dd, J =4.4, 1.6 Hz, 2H), 7.32 (d, J = 9.2 Hz, 1H), 4.16 (t, J = 6.6 Hz, 2H), 1.81(dq , J = 13.4, 6.7 Hz, 1H), 1.66 (q, J = 6.6 Hz, 2H), 0.95 (d, J = 6.7 Hz, 6H).

（8）N -(3-氰基-4-正庚氧基苯基)异烟酰胺（样品编号ANP08）。(8) N- (3-cyano-4-n-heptyloxyphenyl)isonicotinamide (Sample No. ANP08).

以实施例2中的5-氨基-2-正庚氧基苯甲腈为原料，经过本实施例中的合成方法，制备得到目标产物。Using 5-amino-2-n-heptyloxybenzonitrile in Example 2 as a raw material, through the synthesis method in this example, the target product was prepared.

1H NMR (600 MHz, DMSO-d6) δ10.61 (s, 1H), 8.80 (d, J = 5.8 Hz, 2H),8.09 (d, J = 2.6 Hz, 1H), 7.95 (dd, J = 9.2, 2.6 Hz, 1H), 7.88 – 7.81 (m,2H), 7.29 (d, J = 9.2 Hz, 1H), 4.13 (t, J = 6.4 Hz, 2H), 1.83 – 1.65 (m, 2H),1.51 – 1.38 (m, 2H), 1.38 – 1.19 (m, 6H), 0.87 (t, J = 6.9 Hz, 3H)。 1 H NMR (600 MHz, DMSO-d6) δ10.61 (s, 1H), 8.80 (d, J = 5.8 Hz, 2H), 8.09 (d, J = 2.6 Hz, 1H), 7.95 (dd, J = 9.2, 2.6 Hz, 1H), 7.88 – 7.81 (m, 2H), 7.29 (d, J = 9.2 Hz, 1H), 4.13 (t, J = 6.4 Hz, 2H), 1.83 – 1.65 (m, 2H), 1.51 – 1.38 (m, 2H), 1.38 – 1.19 (m, 6H), 0.87 (t, J = 6.9 Hz, 3H).

（9）N -(3-氰基-4-正辛氧基苯基)异烟酰胺（样品编号ANP09）。(9) N- (3-cyano-4-n-octyloxyphenyl)isonicotinamide (Sample No. ANP09).

以实施例2中的5-氨基-2-正辛氧基苯甲腈为原料，经过本实施例中的合成方法，制备得到目标产物。Using 5-amino-2-n-octyloxybenzonitrile in Example 2 as a raw material, through the synthesis method in this example, the target product was prepared.

1H NMR (600 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.80 (dd, J = 4.5, 1.5 Hz,2H), 8.09 (d, J = 2.6 Hz, 1H), 7.95 (dd, J = 9.2, 2.6 Hz, 1H), 7.85 (dd, J =4.4, 1.6 Hz, 2H), 7.29 (d, J = 9.2 Hz, 1H), 4.12 (t, J = 6.4 Hz, 2H), 1.83 –1.66 (m, 2H), 1.48 – 1.40 (m, 2H), 1.36 – 1.21 (m, 8H), 0.86 (t, J = 7.0 Hz,3H). 1 H NMR (600 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.80 (dd, J = 4.5, 1.5 Hz, 2H), 8.09 (d, J = 2.6 Hz, 1H), 7.95 (dd, J = 9.2, 2.6 Hz, 1H), 7.85 (dd, J =4.4, 1.6 Hz, 2H), 7.29 (d, J = 9.2 Hz, 1H), 4.12 (t, J = 6.4 Hz, 2H), 1.83 –1.66 (m, 2H), 1.48 – 1.40 (m, 2H), 1.36 – 1.21 (m, 8H), 0.86 (t, J = 7.0 Hz, 3H).

（10）N -(3-氰基-4-苄氧基苯基)异烟酰胺（样品编号ANP10）。(10) N- (3-cyano-4-benzyloxyphenyl)isonicotinamide (Sample No. ANP10).

以实施例2中的5-氨基-2-苄氧基苯甲腈为原料经过本实施例中的合成方法，制备得到目标产物。Using the 5-amino-2-benzyloxybenzonitrile in Example 2 as a raw material, the target product was prepared through the synthesis method in this example.

1H NMR (600 MHz, DMSO-d6) δ 10.63 (s, 1H), 8.80 (d, J = 5.4 Hz, 2H),8.12 (d, J = 2.6 Hz, 1H), 7.96 (dd, J = 9.2, 2.6 Hz, 1H), 7.85 (dd, J = 4.5,1.6 Hz, 2H), 7.49 (d, J = 7.4 Hz, 2H), 7.45 – 7.31 (m, 4H), 5.29 (s, 2H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.63 (s, 1H), 8.80 (d, J = 5.4 Hz, 2H), 8.12 (d, J = 2.6 Hz, 1H), 7.96 (dd, J = 9.2 , 2.6 Hz, 1H), 7.85 (dd, J = 4.5, 1.6 Hz, 2H), 7.49 (d, J = 7.4 Hz, 2H), 7.45 – 7.31 (m, 4H), 5.29 (s, 2H).

（11）N -(3-氰基-4（4-氯）苄氧基苯基)异烟酰胺（样品编号ANP11）。(11) N- (3-cyano-4(4-chloro)benzyloxyphenyl)isonicotinamide (Sample No. ANP11).

以实施例2中的2-（4-氯）苄氧基-5-氨基苯甲腈为原料，经过本实施例中的合成方法，制备得到目标产物。Using 2-(4-chloro)benzyloxy-5-aminobenzonitrile in Example 2 as a raw material, through the synthesis method in this example, the target product was prepared.

1H NMR (600 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.80 (d, J = 5.7 Hz, 2H),8.12 (d, J = 2.5 Hz, 1H), 7.96 (dd, J = 9.2, 2.5 Hz, 1H), 7.85 (d, J = 5.9Hz, 2H), 7.51 (s, 4H), 7.38 (d, J = 9.2 Hz, 1H), 5.29 (s, 2H)。5-氨基-2-(4-氰基)苄氧基苯甲腈 1 H NMR (600 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.80 (d, J = 5.7 Hz, 2H), 8.12 (d, J = 2.5 Hz, 1H), 7.96 (dd, J = 9.2 , 2.5 Hz, 1H), 7.85 (d, J = 5.9Hz, 2H), 7.51 (s, 4H), 7.38 (d, J = 9.2 Hz, 1H), 5.29 (s, 2H). 5-Amino-2-(4-cyano)benzyloxybenzonitrile

（12）N -(3-氰基-4（4-氰基）苄氧基苯基)异烟酰胺（样品编号ANP12）。(12) N- (3-cyano-4(4-cyano)benzyloxyphenyl)isonicotinamide (Sample No. ANP12).

以实施例2中的2-（4-氰基）苄氧基-5-氨基苯甲腈为原料，经过本实施例中的合成方法，制备得到目标产物。Using 2-(4-cyano)benzyloxy-5-aminobenzonitrile in Example 2 as a raw material, through the synthesis method in this example, the target product was prepared.

1H NMR (600 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.80 (d, J = 5.8 Hz, 2H),8.14 (d, J = 2.4 Hz, 1H), 7.96 (dd, J = 9.2, 2.5 Hz, 1H), 7.92 (d, J = 8.2Hz, 2H), 7.85 (d, J = 5.8 Hz, 2H), 7.67 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 9.2Hz, 1H), 5.41 (s, 2H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.80 (d, J = 5.8 Hz, 2H), 8.14 (d, J = 2.4 Hz, 1H), 7.96 (dd, J = 9.2 , 2.5 Hz, 1H), 7.92 (d, J = 8.2 Hz, 2H), 7.85 (d, J = 5.8 Hz, 2H), 7.67 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 9.2 Hz, 1H), 5.41 (s, 2H).

（13）N-(3-氰基-4-甲氧乙氧基苯基)异烟酰胺（样品编号ANP13）。(13) N- (3-cyano-4-methoxyethoxyphenyl)isonicotinamide (Sample No. ANP13).

以实施例2中的2-甲氧乙氧基-5-氨基苯甲腈为原料，经过本实施例中的合成方法，制备得到目标产物。Using 2-methoxyethoxy-5-aminobenzonitrile in Example 2 as a raw material, through the synthesis method in this example, the target product was prepared.

1H NMR (600 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.80 (dd, J = 4.5, 1.5 Hz,2H), 8.10 (d, J = 2.6 Hz, 1H), 7.95 (dd, J = 9.2, 2.6 Hz, 1H), 7.85 (dd, J =4.5, 1.6 Hz, 2H), 7.32 (d, J = 9.2 Hz, 1H), 4.34 – 4.21 (m, 2H), 3.77 – 3.63(m, 2H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.80 (dd, J = 4.5, 1.5 Hz, 2H), 8.10 (d, J = 2.6 Hz, 1H), 7.95 (dd, J = 9.2, 2.6 Hz, 1H), 7.85 (dd, J =4.5, 1.6 Hz, 2H), 7.32 (d, J = 9.2 Hz, 1H), 4.34 – 4.21 (m, 2H), 3.77 – 3.63(m, 2H).

（14）N-(3-氰基-4-环戊氧基苯基)异烟酰胺（样品编号ANP14）。(14) N- (3-cyano-4-cyclopentyloxyphenyl)isonicotinamide (Sample No. ANP14).

以实施例2中的5-氨基-2-环戊氧基苯甲腈为原料，经过本实施例中的合成方法，制备得到目标产物。Using the 5-amino-2-cyclopentyloxybenzonitrile in Example 2 as a raw material, through the synthesis method in this example, the target product was prepared.

1H NMR (600 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.80 (dd, J = 4.5, 1.5 Hz,2H), 8.09 (d, J = 2.6 Hz, 1H), 7.94 (dd, J = 9.2, 2.6 Hz, 1H), 7.85 (dd, J =4.4, 1.6 Hz, 2H), 7.30 (d, J = 9.2 Hz, 1H), 4.99 (t, J = 5.7 Hz, 1H), 1.95(m, 2H), 1.80 – 1.65 (m, 4H), 1.67 – 1.51 (m, 2H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.80 (dd, J = 4.5, 1.5 Hz, 2H), 8.09 (d, J = 2.6 Hz, 1H), 7.94 (dd, J = 9.2, 2.6 Hz, 1H), 7.85 (dd, J =4.4, 1.6 Hz, 2H), 7.30 (d, J = 9.2 Hz, 1H), 4.99 (t, J = 5.7 Hz, 1H), 1.95(m , 2H), 1.80 – 1.65 (m, 4H), 1.67 – 1.51 (m, 2H).

（15）N-(3-氰基-4-正已氧基苯基)异烟酰胺（样品编号ANP15）。(15) N- (3-cyano-4-n-hexyloxyphenyl)isonicotinamide (Sample No. ANP15).

以实施例2中的5-氨基-2-正已氧基苯甲腈为原料，经过本实施例中的合成方法，制备得到目标产物。Using 5-amino-2-n-hexyloxybenzonitrile in Example 2 as a raw material, through the synthesis method in this example, the target product was prepared.

1H NMR (600 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.79 (dd, J = 4.4, 1.6 Hz,2H), 8.09 (d, J = 2.6 Hz, 1H), 7.95 (dd, J = 9.2, 2.6 Hz, 1H), 7.85 (dd, J =4.4, 1.6 Hz, 2H), 7.28 (d, J = 9.2 Hz, 1H), 4.12 (t, J = 6.5 Hz, 2H), 1.81 –1.68 (m, 2H), 1.50 – 1.37 (m, 2H), 1.36 – 1.27 (m, 4H), 0.88 (t, J = 7.1 Hz,3H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.79 (dd, J = 4.4, 1.6 Hz, 2H), 8.09 (d, J = 2.6 Hz, 1H), 7.95 (dd, J = 9.2, 2.6 Hz, 1H), 7.85 (dd, J =4.4, 1.6 Hz, 2H), 7.28 (d, J = 9.2 Hz, 1H), 4.12 (t, J = 6.5 Hz, 2H), 1.81 –1.68 (m, 2H), 1.50 – 1.37 (m, 2H), 1.36 – 1.27 (m, 4H), 0.88 (t, J = 7.1 Hz, 3H).

实施例4。Example 4.

N-(3-氰基-4-烷氧基苯基)烟酰胺的合成。Synthesis of N- (3-cyano-4-alkoxyphenyl)nicotinamide.

于反应瓶中加入2-烷氧基-5-氨基苯甲腈（0.6 mmol），三乙胺（1.5 mmol）和二氯甲烷（15 mL），-5°C搅拌下滴加二氯甲烷（15 mL）的烟酰氯 (0.72 mmol)，维持温度反应1 h后，加水，分出有机层，水层用二氯甲烷萃取，合并有机层，饱和食盐水洗，无水硫酸钠干燥，减压浓缩至干。粗产品经柱层析纯化，得目标产物。2-alkoxy-5-aminobenzonitrile (0.6 mmol), triethylamine (1.5 mmol) and dichloromethane (15 mL) were added to the reaction flask, and dichloromethane ( 15 mL) of nicotinyl chloride (0.72 mmol), maintain the temperature for 1 h, add water, separate the organic layer, extract the aqueous layer with dichloromethane, combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. to dry. The crude product was purified by column chromatography to obtain the target product.

下面化合物（1）至（15）分别以实施例2中制备的对应化合物为原料，采用上述的合成方法制备得到的目标化合物。The following compounds (1) to (15) use the corresponding compounds prepared in Example 2 as raw materials, respectively, and are the target compounds prepared by the above-mentioned synthetic method.

（1）N-(3-氰基-4-正丙氧基)烟酰胺（样品编号ANM01）。(1) N- (3-cyano-4-n-propoxy)nicotinamide (Sample No. ANM01).

1H NMR (600 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.10 (d, J = 1.7 Hz, 1H),8.77 (dd, J = 4.8, 1.6 Hz, 1H), 8.36 – 8.24 (m, 1H), 8.10 (d, J = 2.6 Hz,1H), 7.95 (dd, J = 9.2, 2.6 Hz, 1H), 7.58 (ddd, J = 8.0, 4.8, 0.7 Hz, 1H),7.29 (d, J = 9.2 Hz, 1H), 4.10 (t, J = 6.4 Hz, 2H), 1.85 – 1.71 (m, 2H), 1.01(t, J = 7.4 Hz, 3H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.10 (d, J = 1.7 Hz, 1H), 8.77 (dd, J = 4.8, 1.6 Hz, 1H), 8.36 – 8.24 (m , 1H), 8.10 (d, J = 2.6 Hz, 1H), 7.95 (dd, J = 9.2, 2.6 Hz, 1H), 7.58 (ddd, J = 8.0, 4.8, 0.7 Hz, 1H), 7.29 (d, J = 9.2 Hz, 1H), 4.10 (t, J = 6.4 Hz, 2H), 1.85 – 1.71 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H).

（2）N-(3-氰基-4-异丙氧基苯基)烟酰胺（样品编号ANM02）。(2) N- (3-cyano-4-isopropoxyphenyl)nicotinamide (Sample No. ANM02).

1H NMR (600 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.10 (s, 1H), 8.77 (d, J =3.7 Hz, 1H), 8.33 – 8.22 (m, 1H), 8.09 (d, J = 2.6 Hz, 1H), 7.93 (dd, J =9.2, 2.7 Hz, 1H), 7.58 (dd, J = 7.6, 4.8 Hz, 1H), 7.32 (d, J = 9.3 Hz, 1H),4.76 (m, 1H), 1.32 (d, J = 6.0 Hz, 6H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.10 (s, 1H), 8.77 (d, J =3.7 Hz, 1H), 8.33 – 8.22 (m, 1H), 8.09 (d , J = 2.6 Hz, 1H), 7.93 (dd, J =9.2, 2.7 Hz, 1H), 7.58 (dd, J = 7.6, 4.8 Hz, 1H), 7.32 (d, J = 9.3 Hz, 1H), 4.76 (m, 1H), 1.32 (d, J = 6.0 Hz, 6H).

（3）N -(3-氰基-4-正丁氧基苯基)烟酰胺（样品编号ANM03）。(3) N- (3-cyano-4-n-butoxyphenyl)nicotinamide (Sample No. ANM03).

1H NMR (600 MHz, DMSO-d6) δ 10.27 (s, 1H), 9.14 (d, J = 1.8 Hz, 1H),8.79 (dd, J = 4.8, 1.6 Hz, 1H), 8.37 – 8.28 (m, 1H), 7.93 (dd, J = 8.0, 1.4Hz, 1H), 7.70 (dd, J = 7.8, 1.6 Hz, 1H), 7.64 – 7.54 (m, 1H), 7.33 (t, J =7.9 Hz, 1H), 4.10 (t, J = 6.3 Hz, 2H), 1.67 (tt, J = 12.5, 6.3 Hz, 2H), 1.40(dd, J = 15.0, 7.5 Hz, 2H), 0.82 (t, J = 7.4 Hz, 3H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.27 (s, 1H), 9.14 (d, J = 1.8 Hz, 1H), 8.79 (dd, J = 4.8, 1.6 Hz, 1H), 8.37 – 8.28 (m , 1H), 7.93 (dd, J = 8.0, 1.4Hz, 1H), 7.70 (dd, J = 7.8, 1.6 Hz, 1H), 7.64 – 7.54 (m, 1H), 7.33 (t, J =7.9 Hz, 1H), 4.10 (t, J = 6.3 Hz, 2H), 1.67 (tt, J = 12.5, 6.3 Hz, 2H), 1.40 (dd, J = 15.0, 7.5 Hz, 2H), 0.82 (t, J = 7.4 Hz, 3H).

（4）N -(3-氰基-4-仲丁氧基苯基)烟酰胺（样品编号ANM04）。(4) N- (3-cyano-4-sec-butoxyphenyl)nicotinamide (Sample No. ANM04).

1H NMR (600 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.11 (s, 1H), 8.77 (d, J =3.8 Hz, 1H), 8.37 – 8.22 (m, 1H), 8.09 (d, J = 2.6 Hz, 1H), 7.93 (dd, J =9.2, 2.7 Hz, 1H), 7.65 –7.54 (m, 1H), 7.31 (d, J = 9.3 Hz, 1H), 4.55 (h, J =6.0 Hz, 1H), 1.75 – 1.54 (m, 2H), 1.28 (d, J = 6.1 Hz, 3H), 0.95 (t, J = 7.4Hz, 3H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.11 (s, 1H), 8.77 (d, J =3.8 Hz, 1H), 8.37 – 8.22 (m, 1H), 8.09 (d , J = 2.6 Hz, 1H), 7.93 (dd, J =9.2, 2.7 Hz, 1H), 7.65 –7.54 (m, 1H), 7.31 (d, J = 9.3 Hz, 1H), 4.55 (h, J = 6.0 Hz, 1H), 1.75 – 1.54 (m, 2H), 1.28 (d, J = 6.1 Hz, 3H), 0.95 (t, J = 7.4Hz, 3H).

（5）N -(3-氰基-4-异丁氧基苯基)烟酰胺（样品编号ANM05）。(5) N- (3-cyano-4-isobutoxyphenyl)nicotinamide (Sample No. ANM05).

1H NMR (600 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.11 (s, 1H), 8.77 (d, J =3.8 Hz, 1H), 8.37 – 8.22 (m, 1H), 8.09 (d, J = 2.6 Hz, 1H), 7.93 (dd, J =9.2, 2.7 Hz, 1H), 7.65 – 7.54 (m, 1H), 7.31 (d, J = 9.3 Hz, 1H), 4.55 (h, J =6.0 Hz, 1H), 1.75 – 1.54 (m, 2H), 1.28 (d, J = 6.1 Hz, 3H), 0.95 (t, J = 7.4Hz, 3H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.11 (s, 1H), 8.77 (d, J =3.8 Hz, 1H), 8.37 – 8.22 (m, 1H), 8.09 (d , J = 2.6 Hz, 1H), 7.93 (dd, J =9.2, 2.7 Hz, 1H), 7.65 – 7.54 (m, 1H), 7.31 (d, J = 9.3 Hz, 1H), 4.55 (h, J = 6.0 Hz, 1H), 1.75 – 1.54 (m, 2H), 1.28 (d, J = 6.1 Hz, 3H), 0.95 (t, J = 7.4Hz, 3H).

（6）N -(3-氰基-4-正戊氧基苯基)烟酰胺（样品编号ANM06）。(6) N- (3-cyano-4-n-pentyloxyphenyl)nicotinamide (Sample No. ANM06).

1H NMR (600 MHz, DMSO-d6) δ 10.61 (s, 1H), 9.13 (d, J = 1.7 Hz, 1H),8.79 (dd, J = 4.9, 1.6 Hz, 1H), 8.44 – 8.26 (m, 1H), 8.10 (d, J = 2.6 Hz,1H), 7.95 (dd, J = 9.2, 2.6 Hz, 1H), 7.69 – 7.55 (m, 1H), 7.29 (d, J = 9.2Hz, 1H), 4.12 (t, J = 6.5 Hz, 2H), 1.83 – 1.68 (m, 2H), 1.49 – 1.27 (m, 4H),0.90 (t, J = 7.2 Hz, 3H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.61 (s, 1H), 9.13 (d, J = 1.7 Hz, 1H), 8.79 (dd, J = 4.9, 1.6 Hz, 1H), 8.44 – 8.26 (m , 1H), 8.10 (d, J = 2.6 Hz, 1H), 7.95 (dd, J = 9.2, 2.6 Hz, 1H), 7.69 – 7.55 (m, 1H), 7.29 (d, J = 9.2Hz, 1H) , 4.12 (t, J = 6.5 Hz, 2H), 1.83 – 1.68 (m, 2H), 1.49 – 1.27 (m, 4H), 0.90 (t, J = 7.2 Hz, 3H).

（7）N -(3-氰基-4-异戊氧基苯基)烟酰胺（样品编号ANM07）。(7) N- (3-cyano-4-isoamyloxyphenyl)nicotinamide (Sample No. ANM07).

1H NMR (600 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.10 (d, J = 1.5 Hz, 1H),8.77 (dd, J = 4.7, 1.3 Hz, 1H), 8.40 – 8.20 (m, 1H), 8.09 (d, J = 2.6 Hz,1H), 7.95 (dd, J = 9.2, 2.6 Hz, 1H), 7.58 (dd, J = 7.8, 4.9 Hz, 1H), 7.31 (d,J = 9.2 Hz, 1H), 4.15 (t, J = 6.6 Hz, 2H), 1.82 (dt, J = 13.4, 6.7 Hz, 1H),1.66 (q, J = 6.7 Hz, 2H), 0.95 (d, J = 6.7 Hz, 6H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.10 (d, J = 1.5 Hz, 1H), 8.77 (dd, J = 4.7, 1.3 Hz, 1H), 8.40 – 8.20 (m , 1H), 8.09 (d, J = 2.6 Hz, 1H), 7.95 (dd, J = 9.2, 2.6 Hz, 1H), 7.58 (dd, J = 7.8, 4.9 Hz, 1H), 7.31 (d, J = 9.2 Hz, 1H), 4.15 (t, J = 6.6 Hz, 2H), 1.82 (dt, J = 13.4, 6.7 Hz, 1H), 1.66 (q, J = 6.7 Hz, 2H), 0.95 (d, J = 6.7 Hz, 6H).

（8）N -(3-氰基-4-正庚氧基苯基)烟酰胺（样品编号ANM08）。(8) N- (3-cyano-4-n-heptyloxyphenyl)nicotinamide (Sample No. ANM08).

1H NMR (600 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.10 (d, J = 1.8 Hz, 1H),8.77 (dd, J = 4.8, 1.6 Hz, 1H), 8.34 – 8.23 (m, 1H), 8.09 (d, J = 2.6 Hz,1H), 7.94 (dd, J = 9.2, 2.6 Hz, 1H), 7.62 – 7.53 (m, 1H), 7.29 (d, J = 9.2Hz, 1H), 4.13 (t, J = 6.4 Hz, 2H), 1.82 – 1.68 (m, 2H), 1.47 – 1.38 (m, 2H),1.30 (ddt, J = 10.4, 6.7, 5.8 Hz, 6H), 0.87 (t, J = 6.9 Hz, 3H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.10 (d, J = 1.8 Hz, 1H), 8.77 (dd, J = 4.8, 1.6 Hz, 1H), 8.34 – 8.23 (m , 1H), 8.09 (d, J = 2.6 Hz, 1H), 7.94 (dd, J = 9.2, 2.6 Hz, 1H), 7.62 – 7.53 (m, 1H), 7.29 (d, J = 9.2Hz, 1H) , 4.13 (t, J = 6.4 Hz, 2H), 1.82 – 1.68 (m, 2H), 1.47 – 1.38 (m, 2H), 1.30 (ddt, J = 10.4, 6.7, 5.8 Hz, 6H), 0.87 (t , J = 6.9 Hz, 3H).

（9）N -(3-氰基-4-正辛氧基苯基)烟酰胺（样品编号ANM09）。(9) N- (3-cyano-4-n-octyloxyphenyl)nicotinamide (Sample No. ANM09).

1H NMR (600 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.10 (d, J = 1.9 Hz, 1H),8.77 (dd, J = 4.8, 1.5 Hz, 1H), 8.28 (dt, J = 7.9, 1.9 Hz, 1H), 8.09 (d, J =2.6 Hz, 1H), 7.94 (dd, J = 9.2, 2.6 Hz, 1H), 7.58 (dd, J = 7.8, 4.9 Hz, 1H),7.29 (d, J = 9.2 Hz, 1H), 4.13 (t, J = 6.4 Hz, 2H), 1.81 – 1.69 (m, 2H), 1.50– 1.40 (m, 2H), 1.37 – 1.20 (m, 8H), 0.86 (t, J = 6.9 Hz, 3H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.10 (d, J = 1.9 Hz, 1H), 8.77 (dd, J = 4.8, 1.5 Hz, 1H), 8.28 (dt, J = 7.9, 1.9 Hz, 1H), 8.09 (d, J =2.6 Hz, 1H), 7.94 (dd, J = 9.2, 2.6 Hz, 1H), 7.58 (dd, J = 7.8, 4.9 Hz, 1H), 7.29 (d, J = 9.2 Hz, 1H), 4.13 (t, J = 6.4 Hz, 2H), 1.81 – 1.69 (m, 2H), 1.50 – 1.40 (m, 2H), 1.37 – 1.20 (m, 8H), 0.86 (t, J = 6.9 Hz, 3H).

（10）N -(3-氰基-4-苄氧基苯基)烟酰胺（样品编号ANM10）。(10) N- (3-cyano-4-benzyloxyphenyl)nicotinamide (Sample No. ANM10).

1H NMR (600 MHz, DMSO-d6) δ 10.57 (s, 1H), 9.10 (s, 1H), 8.77 (d, J =3.6 Hz, 1H), 8.33 – 8.22 (m, 1H), 7.95 (dd, J = 9.2, 2.6 Hz, 1H), 7.58 (m,1H), 7.49 (d, J = 7.0 Hz, 2H), 7.46 – 7.34 (m, 4H), 5.29 (s, 2H) 。 1 H NMR (600 MHz, DMSO-d6) δ 10.57 (s, 1H), 9.10 (s, 1H), 8.77 (d, J =3.6 Hz, 1H), 8.33 – 8.22 (m, 1H), 7.95 (dd , J = 9.2, 2.6 Hz, 1H), 7.58 (m, 1H), 7.49 (d, J = 7.0 Hz, 2H), 7.46 – 7.34 (m, 4H), 5.29 (s, 2H).

（11）N -(3-氰基-(4-氯)苄氧基苯基)烟酰胺（样品编号ANM11）。(11) N- (3-cyano-(4-chloro)benzyloxyphenyl)nicotinamide (Sample No. ANM11).

1H NMR (600 MHz, DMSO-d6) δ 10.58 (s, 1H), 9.10 (d, J = 1.6 Hz, 1H),8.77 (dd, J = 4.8, 1.6 Hz, 1H), 8.43 – 8.19 (m, 1H), 8.12 (d, J = 2.6 Hz,1H), 7.95 (dd, J = 9.2, 2.6 Hz, 1H), 7.58 (m, 1H), 7.55 – 7.44 (m, 4H), 7.38(d, J = 9.2 Hz, 1H), 5.29 (s, 2H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.58 (s, 1H), 9.10 (d, J = 1.6 Hz, 1H), 8.77 (dd, J = 4.8, 1.6 Hz, 1H), 8.43 – 8.19 (m , 1H), 8.12 (d, J = 2.6 Hz, 1H), 7.95 (dd, J = 9.2, 2.6 Hz, 1H), 7.58 (m, 1H), 7.55 – 7.44 (m, 4H), 7.38(d, J = 9.2 Hz, 1H), 5.29 (s, 2H).

（12）N -(3-氰基-(4-氰基)苄氧基苯基)烟酰胺（样品编号ANM12）。(12) N- (3-cyano-(4-cyano)benzyloxyphenyl)nicotinamide (Sample No. ANM12).

1H NMR (600 MHz, DMSO-d6) δ 10.59 (s, 1H), 9.10 (s, 1H), 8.78 (d, J =3.8 Hz, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 2.5 Hz, 1H), 7.96 (dd, J= 9.2, 2.5 Hz, 1H), 7.92 (d, J = 8.2 Hz, 2H), 7.67 (d, J = 8.2 Hz, 2H), 7.59(dd, J = 7.8, 4.8 Hz, 1H), 7.37 (d, J = 9.2 Hz, 1H), 5.41 (s, 2H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.59 (s, 1H), 9.10 (s, 1H), 8.78 (d, J =3.8 Hz, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 2.5 Hz, 1H), 7.96 (dd, J = 9.2, 2.5 Hz, 1H), 7.92 (d, J = 8.2 Hz, 2H), 7.67 (d, J = 8.2 Hz, 2H), 7.59 (dd, J = 7.8, 4.8 Hz, 1H), 7.37 (d, J = 9.2 Hz, 1H), 5.41 (s, 2H).

（13）N -(3-氰基-4-甲氧乙氧基苯基)烟酰胺（样品编号ANM13）。(13) N- (3-cyano-4-methoxyethoxyphenyl)nicotinamide (Sample No. ANM13).

1H NMR (600 MHz, DMSO-d6) δ 10.56 (s, 1H), 9.10 (d, J = 1.8 Hz, 1H),8.77 (dd, J = 4.8, 1.6 Hz, 1H), 8.38 – 8.20 (m, 1H), 8.10 (d, J = 2.6 Hz,1H), 7.95 (dd, J = 9.2, 2.6 Hz, 1H), 7.58 (m, 1H), 7.31 (d, J = 9.2 Hz, 1H),4.27 (dd, J = 5.3, 3.7 Hz, 2H), 3.79 – 3.65 (m, 2H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.56 (s, 1H), 9.10 (d, J = 1.8 Hz, 1H), 8.77 (dd, J = 4.8, 1.6 Hz, 1H), 8.38 – 8.20 (m , 1H), 8.10 (d, J = 2.6 Hz, 1H), 7.95 (dd, J = 9.2, 2.6 Hz, 1H), 7.58 (m, 1H), 7.31 (d, J = 9.2 Hz, 1H), 4.27 (dd, J = 5.3, 3.7 Hz, 2H), 3.79 – 3.65 (m, 2H).

（14）N -(3-氰基-4-环戊氧基苯基)烟酰胺（样品编号ANM14）。(14) N- (3-cyano-4-cyclopentyloxyphenyl)nicotinamide (Sample No. ANM14).

1H NMR (600 MHz, DMSO-d6) δ 10.54 (s, 1H), 9.10 (d, J = 1.7 Hz, 1H),8.77 (dd, J = 4.8, 1.6 Hz, 1H), 8.37 – 8.22 (m, 1H), 8.09 (d, J = 2.6 Hz,1H), 7.93 (dd, J = 9.2, 2.7 Hz, 1H), 7.58 (m, 1H), 7.29 (d, J = 9.2 Hz, 1H),4.98 (t, J = 5.7 Hz, 1H), 2.02 – 1.83 (m, 2H), 1.81 – 1.67 (m, 4H), 1.67 –1.54 (m, 2H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.54 (s, 1H), 9.10 (d, J = 1.7 Hz, 1H), 8.77 (dd, J = 4.8, 1.6 Hz, 1H), 8.37 – 8.22 (m , 1H), 8.09 (d, J = 2.6 Hz, 1H), 7.93 (dd, J = 9.2, 2.7 Hz, 1H), 7.58 (m, 1H), 7.29 (d, J = 9.2 Hz, 1H), 4.98 (t, J = 5.7 Hz, 1H), 2.02 – 1.83 (m, 2H), 1.81 – 1.67 (m, 4H), 1.67 – 1.54 (m, 2H).

（15）N -(3-氰基-4-正已氧基苯基)烟酰胺（样品编号ANM15）。(15) N- (3-cyano-4-n-hexyloxyphenyl)nicotinamide (Sample No. ANM15).

1H NMR (600 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.10 (s, 1H), 8.77 (d, J =4.0 Hz, 1H), 8.29 (d, J = 7.9 Hz, 1H), 8.09 (d, J = 1.9 Hz, 1H), 7.94 (d, J =9.1 Hz, 1H), 7.58 (dd, J = 7.7, 4.8 Hz, 1H), 7.29 (d, J = 9.2 Hz, 1H), 4.13(t, J = 6.3 Hz, 2H), 1.85 – 1.64 (m, 2H), 1.44 (m, 2H), 1.32 (m, 4H), 0.89(t, J = 6.6 Hz, 3H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.10 (s, 1H), 8.77 (d, J =4.0 Hz, 1H), 8.29 (d, J = 7.9 Hz, 1H), 8.09 (d, J = 1.9 Hz, 1H), 7.94 (d, J =9.1 Hz, 1H), 7.58 (dd, J = 7.7, 4.8 Hz, 1H), 7.29 (d, J = 9.2 Hz, 1H), 4.13(t, J = 6.3 Hz, 2H), 1.85 – 1.64 (m, 2H), 1.44 (m, 2H), 1.32 (m, 4H), 0.89(t, J = 6.6 Hz, 3H).

实施例5 。Example 5.

N-(3-氰基-4-烷氧基苯基)-2-吡啶甲酰胺的合成方法。Synthesis of N- (3-cyano-4-alkoxyphenyl)-2-pyridinecarboxamide.

于反应瓶中加入2-烷氧基-5-氨基苯甲腈（0.6 mmol），三乙胺（1.5 mmol）和二氯甲烷（15 mL），-5°C搅拌下滴加二氯甲烷（15 mL）的2-吡啶甲酰氯 (0.72 mmol)，维持温度反应1 h后，加水，分出有机层，水层用二氯甲烷萃取，合并有机层，饱和食盐水洗，无水硫酸钠干燥，减压浓缩至干。粗产品经柱层析纯化，得目标产物。2-alkoxy-5-aminobenzonitrile (0.6 mmol), triethylamine (1.5 mmol) and dichloromethane (15 mL) were added to the reaction flask, and dichloromethane ( 15 mL) of 2-picolinoyl chloride (0.72 mmol), maintain the temperature for 1 h, add water, separate the organic layer, extract the aqueous layer with dichloromethane, combine the organic layers, wash with saturated brine, and dry over anhydrous sodium sulfate. Concentrate to dryness under reduced pressure. The crude product was purified by column chromatography to obtain the target product.

下面化合物（1）至（13）分别以实施例2中制备的对应化合物为原料，采用上述的合成方法制备得到的目标化合物。The following compounds (1) to (13) use the corresponding compounds prepared in Example 2 as raw materials, respectively, and are the target compounds prepared by the above-mentioned synthetic method.

（1）N -(3-氰基-4-正丙氧基苯基)-2-吡啶甲酰胺（样品编号ANO01）。(1) N- (3-cyano-4-n-propoxyphenyl)-2-pyridinecarboxamide (Sample No. ANO01).

1H NMR (600 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.74 (d, J = 4.0 Hz, 1H),8.25 (d, J = 2.5 Hz, 1H), 8.17 – 8.04 (m, 3H), 7.74 – 7.65 (m, 1H), 7.26 (d,J = 9.1 Hz, 1H), 4.08 (t, J = 6.3 Hz, 2H), 1.76 (dd, J = 13.9, 6.8 Hz, 2H),1.02 – 0.88 (m, 4H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.74 (d, J = 4.0 Hz, 1H), 8.25 (d, J = 2.5 Hz, 1H), 8.17 – 8.04 (m, 3H) ), 7.74 – 7.65 (m, 1H), 7.26 (d, J = 9.1 Hz, 1H), 4.08 (t, J = 6.3 Hz, 2H), 1.76 (dd, J = 13.9, 6.8 Hz, 2H), 1.02 – 0.88 (m, 4H).

（2）N -(3-氰基-4-异丙氧基苯基)-2-吡啶甲酰胺（样品编号ANO02）。(2) N- (3-cyano-4-isopropoxyphenyl)-2-pyridinecarboxamide (Sample No. ANO02).

1H NMR (600 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.74 (ddd, J = 4.7, 1.5,0.9 Hz, 1H), 8.24 (d, J = 2.7 Hz, 1H), 8.17 – 8.04 (m, 4H), 7.68 (ddd, J =7.5, 4.7, 1.2 Hz, 1H), 7.30 (dd, J = 9.3, 2.4 Hz, 1H), 4.79 – 4.72 (m, 1H),1.31 (d, J = 6.0 Hz, 8H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.74 (ddd, J = 4.7, 1.5, 0.9 Hz, 1H), 8.24 (d, J = 2.7 Hz, 1H), 8.17 – 8.04 (m, 4H), 7.68 (ddd, J =7.5, 4.7, 1.2 Hz, 1H), 7.30 (dd, J = 9.3, 2.4 Hz, 1H), 4.79 – 4.72 (m, 1H), 1.31 (d, J = 6.0 Hz, 8H).

（3）N -(3-氰基-4-正丁氧基苯基)-2-吡啶甲酰胺（样品编号ANO03）。(3) N- (3-cyano-4-n-butoxyphenyl)-2-pyridinecarboxamide (Sample No. ANO03).

1H NMR (600 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.71 (d, J = 4.6 Hz, 1H),8.67 (dd, J = 8.3, 1.4 Hz, 1H), 8.18 (d, J = 7.8 Hz, 1H), 8.10 (td, J = 7.7,1.6 Hz, 1H), 7.72 (ddd, J = 7.5, 4.7, 1.0 Hz, 1H), 7.54 (dd, J = 7.8, 1.3 Hz,1H), 7.33 (t, J = 8.0 Hz, 1H), 4.22 (t, J = 6.2 Hz, 2H), 1.89 – 1.77 (m, 2H),1.65 – 1.54 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.71 (d, J = 4.6 Hz, 1H), 8.67 (dd, J = 8.3, 1.4 Hz, 1H), 8.18 (d, J = 7.8 Hz, 1H), 8.10 (td, J = 7.7, 1.6 Hz, 1H), 7.72 (ddd, J = 7.5, 4.7, 1.0 Hz, 1H), 7.54 (dd, J = 7.8, 1.3 Hz, 1H) , 7.33 (t, J = 8.0 Hz, 1H), 4.22 (t, J = 6.2 Hz, 2H), 1.89 – 1.77 (m, 2H), 1.65 – 1.54 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H).

（4）N -(3-氰基-4-仲丁氧基苯基)-2-吡啶甲酰胺（样品编号ANO04）。(4) N- (3-cyano-4-sec-butoxyphenyl)-2-pyridinecarboxamide (Sample No. ANO04).

1H NMR (600 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.74 (d, J = 4.5 Hz, 1H),8.24 (t, J = 9.2 Hz, 1H), 8.17 – 8.11 (m, 3H), 8.07 (dt, J = 9.1, 4.6 Hz,1H), 7.70 – 7.65 (m, 1H), 7.26 (d, J = 9.2 Hz, 1H), 3.90 (d, J = 6.5 Hz, 3H),2.10 – 2.01 (m, 1H), 1.00 (d, J = 6.7 Hz, 8H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.74 (d, J = 4.5 Hz, 1H), 8.24 (t, J = 9.2 Hz, 1H), 8.17 – 8.11 (m, 3H) ), 8.07 (dt, J = 9.1, 4.6 Hz, 1H), 7.70 – 7.65 (m, 1H), 7.26 (d, J = 9.2 Hz, 1H), 3.90 (d, J = 6.5 Hz, 3H), 2.10 – 2.01 (m, 1H), 1.00 (d, J = 6.7 Hz, 8H).

（5）N -(3-氰基-4-异丁氧基苯基)-2-吡啶甲酰胺（样品编号ANO05）。(5) N- (3-cyano-4-isobutoxyphenyl)-2-pyridinecarboxamide (Sample No. ANO05).

1H NMR (600 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.74 (d, J = 4.5 Hz, 1H),8.23 (dd, J = 15.8, 2.6 Hz, 1H), 8.16 – 8.11 (m, 2H), 8.07 (td, J = 7.7, 1.4Hz, 1H), 7.75 – 7.61 (m, 1H), 7.26 (d, J = 9.2 Hz, 1H), 3.90 (d, J = 6.5 Hz,2H), 2.05 (dp, J = 13.3, 6.6 Hz, 1H), 1.00 (d, J = 6.7 Hz, 6H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.74 (d, J = 4.5 Hz, 1H), 8.23 (dd, J = 15.8, 2.6 Hz, 1H), 8.16 – 8.11 (m , 2H), 8.07 (td, J = 7.7, 1.4Hz, 1H), 7.75 – 7.61 (m, 1H), 7.26 (d, J = 9.2 Hz, 1H), 3.90 (d, J = 6.5 Hz, 2H) , 2.05 (dp, J = 13.3, 6.6 Hz, 1H), 1.00 (d, J = 6.7 Hz, 6H).

（6）N -(3-氰基-4-正戊氧基苯基)-2-吡啶甲酰胺（样品编号ANO06）。(6) N- (3-cyano-4-n-pentyloxyphenyl)-2-pyridinecarboxamide (Sample No. ANO06).

1H NMR (600 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.76 – 8.70 (m, 1H), 8.23(dd, J = 15.8, 2.6 Hz, 1H), 8.17 – 8.11 (m, 3H), 8.07 (td, J = 7.7, 1.7 Hz,1H), 7.68 (ddd, J = 7.5, 4.7, 1.2 Hz, 1H), 7.26 (d, J = 9.2 Hz, 1H), 4.11 (t,J = 6.5 Hz, 3H), 1.78 – 1.71 (m, 3H), 1.45 – 1.30 (m, 5H), 0.94 – 0.86 (m,4H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.76 – 8.70 (m, 1H), 8.23 (dd, J = 15.8, 2.6 Hz, 1H), 8.17 – 8.11 (m, 3H) , 8.07 (td, J = 7.7, 1.7 Hz, 1H), 7.68 (ddd, J = 7.5, 4.7, 1.2 Hz, 1H), 7.26 (d, J = 9.2 Hz, 1H), 4.11 (t, J = 6.5 Hz, 3H), 1.78 – 1.71 (m, 3H), 1.45 – 1.30 (m, 5H), 0.94 – 0.86 (m, 4H).

（7）N -(3-氰基-4-异戊氧基苯基)-2-吡啶甲酰胺（样品编号ANO07）。(7) N- (3-cyano-4-isoamyloxyphenyl)-2-pyridinecarboxamide (Sample No. ANO07).

1H NMR (600 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.74 (d, J = 4.6 Hz, 1H),8.25 (d, J = 2.6 Hz, 1H), 8.17 – 8.13 (m, 2H), 8.07 (td, J = 7.7, 1.4 Hz,1H), 7.68 (dd, J = 7.4, 4.8 Hz, 1H), 7.29 (d, J = 9.2 Hz, 1H), 4.15 (t, J =6.6 Hz, 2H), 1.87 – 1.74 (m, 1H), 1.66 (dq, J = 13.3, 6.8 Hz, 2H), 0.93 (dd,J = 11.2, 6.7 Hz, 6H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.74 (d, J = 4.6 Hz, 1H), 8.25 (d, J = 2.6 Hz, 1H), 8.17 – 8.13 (m, 2H) ), 8.07 (td, J = 7.7, 1.4 Hz, 1H), 7.68 (dd, J = 7.4, 4.8 Hz, 1H), 7.29 (d, J = 9.2 Hz, 1H), 4.15 (t, J =6.6 Hz) , 2H), 1.87 – 1.74 (m, 1H), 1.66 (dq, J = 13.3, 6.8 Hz, 2H), 0.93 (dd, J = 11.2, 6.7 Hz, 6H).

（8）N -(3-氰基-4-苄氧基苯基)-2-吡啶甲酰胺（样品编号ANO08）。(8) N- (3-cyano-4-benzyloxyphenyl)-2-pyridinecarboxamide (Sample No. ANO08).

1H NMR (600 MHz, DMSO-d6) δ 10.57 (s, 1H), 9.10 (d, J = 1.9 Hz, 1H),8.77 (dd, J = 4.8, 1.6 Hz, 1H), 8.33 – 8.24 (m, 1H), 8.12 (d, J = 2.6 Hz,1H), 7.95 (dd, J = 9.2, 2.6 Hz, 1H), 7.58 (dd, J = 7.9, 4.8 Hz, 1H), 7.49 (d,J = 7.2 Hz, 2H), 7.43 (t, J = 7.6 Hz, 2H), 7.41 – 7.33 (m, 2H), 5.29 (s, 2H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.57 (s, 1H), 9.10 (d, J = 1.9 Hz, 1H), 8.77 (dd, J = 4.8, 1.6 Hz, 1H), 8.33 – 8.24 (m , 1H), 8.12 (d, J = 2.6 Hz, 1H), 7.95 (dd, J = 9.2, 2.6 Hz, 1H), 7.58 (dd, J = 7.9, 4.8 Hz, 1H), 7.49 (d, J = 7.2 Hz, 2H), 7.43 (t, J = 7.6 Hz, 2H), 7.41 – 7.33 (m, 2H), 5.29 (s, 2H).

（9）N -(3-氰基-(4-氯)苄氧基苯基)-2-吡啶甲酰胺（样品编号ANO09）。(9) N- (3-cyano-(4-chloro)benzyloxyphenyl)-2-pyridinecarboxamide (Sample No. ANO09).

1H NMR (600 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.74 (d, J = 4.4 Hz, 1H),8.28 (d, J = 2.6 Hz, 1H), 8.20 – 8.11 (m, 2H), 8.07 (td, J = 7.7, 1.6 Hz,1H), 7.69 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.56 – 7.46 (m, 4H), 7.36 (d, J =9.2 Hz, 1H), 5.29 (s, 2H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.74 (d, J = 4.4 Hz, 1H), 8.28 (d, J = 2.6 Hz, 1H), 8.20 – 8.11 (m, 2H) ), 8.07 (td, J = 7.7, 1.6 Hz, 1H), 7.69 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.56 – 7.46 (m, 4H), 7.36 (d, J =9.2 Hz, 1H), 5.29 (s, 2H).

（10）N -(3-氰基-(4-氰基)苄氧基苯基)-2-吡啶甲酰胺（样品编号ANO10）。(10) N- (3-cyano-(4-cyano)benzyloxyphenyl)-2-pyridinecarboxamide (Sample No. ANO10).

1H NMR (600 MHz, DMSO-d6) δ 10.93 (d, J = 39.3 Hz, 1H), 8.73 (dd, J =13.4, 4.7 Hz, 1H), 8.29 (dd, J = 15.0, 2.6 Hz, 1H), 8.19 – 8.03 (m, 3H), 7.95– 7.83 (m, 9H), 7.71 – 7.59 (m, 10H), 7.35 (dd, J = 9.3, 3.1 Hz, 1H), 7.02(d, J = 9.0 Hz, 4H), 6.87 – 6.78 (m, 7H), 5.43 (d, J = 27.9 Hz, 2H), 5.19 (d,J = 47.1 Hz, 14H), 1.19 (dd, J = 22.6, 15.3 Hz, 1H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.93 (d, J = 39.3 Hz, 1H), 8.73 (dd, J =13.4, 4.7 Hz, 1H), 8.29 (dd, J = 15.0, 2.6 Hz, 1H) ), 8.19 – 8.03 (m, 3H), 7.95 – 7.83 (m, 9H), 7.71 – 7.59 (m, 10H), 7.35 (dd, J = 9.3, 3.1 Hz, 1H), 7.02(d, J = 9.0 Hz, 4H), 6.87 – 6.78 (m, 7H), 5.43 (d, J = 27.9 Hz, 2H), 5.19 (d, J = 47.1 Hz, 14H), 1.19 (dd, J = 22.6, 15.3 Hz, 1H ).

（11）N -(3-氰基-4-甲氧乙氧基苯基)-2-吡啶甲酰胺（样品编号ANO11）。(11) N- (3-cyano-4-methoxyethoxyphenyl)-2-pyridinecarboxamide (Sample No. ANO11).

1H NMR (600 MHz, DMSO-d6) δ 10.90 (d, J = 38.0 Hz, 1H), 8.73 (dd, J =14.3, 4.9 Hz, 1H), 8.25 (dd, J = 15.2, 2.6 Hz, 1H), 8.19 – 8.11 (m, 2H), 8.07(td, J = 7.7, 1.6 Hz, 1H), 7.69 (dd, J = 7.2, 4.9 Hz, 1H), 7.29 (d, J = 9.2Hz, 1H), 4.28 – 4.24 (m, 2H), 3.70 (dd, J = 5.2, 3.8 Hz, 2H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.90 (d, J = 38.0 Hz, 1H), 8.73 (dd, J =14.3, 4.9 Hz, 1H), 8.25 (dd, J = 15.2, 2.6 Hz, 1H) ), 8.19 – 8.11 (m, 2H), 8.07(td, J = 7.7, 1.6 Hz, 1H), 7.69 (dd, J = 7.2, 4.9 Hz, 1H), 7.29 (d, J = 9.2Hz, 1H) , 4.28 – 4.24 (m, 2H), 3.70 (dd, J = 5.2, 3.8 Hz, 2H).

（12）N -(3-氰基-4-环戊氧基苯基)-2-吡啶甲酰胺（样品编号ANO12）。(12) N- (3-cyano-4-cyclopentyloxyphenyl)-2-pyridinecarboxamide (Sample No. ANO12).

1H NMR (600 MHz, DMSO-d6) δ 10.88 (d, J = 38.2 Hz, 1H), 8.73 (dd, J =14.3, 4.7 Hz, 1H), 8.23 (dd, J = 15.2, 2.6 Hz, 1H), 8.13 (ddd, J = 10.8, 9.1,5.2 Hz, 2H), 8.07 (td, J = 7.7, 1.7 Hz, 1H), 7.68 (ddd, J = 7.5, 4.8, 1.1 Hz,1H), 7.27 (d, J = 9.2 Hz, 1H), 4.98 (t, J = 5.7 Hz, 1H), 1.94 (ddd, J = 13.3,7.6, 5.8 Hz, 2H), 1.79 – 1.54 (m, 6H)。 1 H NMR (600 MHz, DMSO-d6) δ 10.88 (d, J = 38.2 Hz, 1H), 8.73 (dd, J =14.3, 4.7 Hz, 1H), 8.23 (dd, J = 15.2, 2.6 Hz, 1H) ), 8.13 (ddd, J = 10.8, 9.1, 5.2 Hz, 2H), 8.07 (td, J = 7.7, 1.7 Hz, 1H), 7.68 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H), 7.27 ( d, J = 9.2 Hz, 1H), 4.98 (t, J = 5.7 Hz, 1H), 1.94 (ddd, J = 13.3, 7.6, 5.8 Hz, 2H), 1.79 – 1.54 (m, 6H).

（13）N -(3-氰基-4-正已氧基苯基)-2-吡啶甲酰胺（样品编号ANO13）。(13) N- (3-cyano-4-n-hexyloxyphenyl)-2-pyridinecarboxamide (Sample No. ANO13).

1H NMR (600 MHz, DMSO-d6) δ 10.88 (d, J = 36.6 Hz, 1H), 8.75 –8.70(m, 1H), 8.23 (dd, J = 15.9, 2.6 Hz, 1H), 8.14 (ddd, J = 11.6, 7.8, 3.0 Hz,2H), 8.07 (td, J = 7.7, 1.7 Hz, 1H), 7.68 (ddd, J = 7.6, 4.7, 1.2 Hz, 1H),7.26 (d, J = 9.2 Hz, 1H), 4.11 (t, J = 6.5 Hz, 2H), 1.77 – 1.70 (m, 2H), 1.47– 1.39 (m, 2H), 1.36 – 1.26 (m, 4H), 0.87 (t, J = 7.1 Hz, 3H。 1 H NMR (600 MHz, DMSO-d6) δ 10.88 (d, J = 36.6 Hz, 1H), 8.75 –8.70 (m, 1H), 8.23 (dd, J = 15.9, 2.6 Hz, 1H), 8.14 (ddd , J = 11.6, 7.8, 3.0 Hz, 2H), 8.07 (td, J = 7.7, 1.7 Hz, 1H), 7.68 (ddd, J = 7.6, 4.7, 1.2 Hz, 1H), 7.26 (d, J = 9.2 Hz, 1H), 4.11 (t, J = 6.5 Hz, 2H), 1.77 – 1.70 (m, 2H), 1.47 – 1.39 (m, 2H), 1.36 – 1.26 (m, 4H), 0.87 (t, J = 7.1 Hz, 3H.

实施例6 。Example 6.

N-(3-氰基-4-烷氧基苯基)-5-氨基烟酰胺的合成方法。Synthesis of N- (3-cyano-4-alkoxyphenyl)-5-aminonicotinic acid amide.

于反应瓶中加入5-Boc-氨基烟酸（1.5 mmol），HOAT (1.6 mmol) ，EDCI (3.3mmol)，三乙胺（6 mmol）和二氯甲烷（20 mL），室温下搅拌30 min，然后滴加二氯甲烷（10mL）溶解的2-烷氧基-5-氨基苯甲腈（1.5 mmol），加毕，室温下反应过夜，加水，分出有机层，水层用二氯甲烷萃取，合并有机层，饱和食盐水洗，无水硫酸钠干燥，减压浓缩至干。Add 5-Boc-aminonicotinic acid (1.5 mmol), HOAT (1.6 mmol), EDCI (3.3 mmol), triethylamine (6 mmol) and dichloromethane (20 mL) to the reaction flask, stir at room temperature for 30 min , then 2-alkoxy-5-aminobenzonitrile (1.5 mmol) dissolved in dichloromethane (10 mL) was added dropwise, the addition was completed, the reaction was carried out at room temperature overnight, water was added, the organic layer was separated, and the aqueous layer was washed with dichloromethane After extraction, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure.

向残留物中加二氯甲烷（10 mL）和三氟乙酸（5 mL），室温下反应3h，减压浓缩至干，加10%的碳酸钠溶液，二氯甲烷萃取，合并有机层，饱和食盐水洗，无水硫酸钠干燥，减压浓缩至干得粗产品。粗产品经柱层析纯化得纯品。To the residue were added dichloromethane (10 mL) and trifluoroacetic acid (5 mL), reacted at room temperature for 3 h, concentrated to dryness under reduced pressure, added 10% sodium carbonate solution, extracted with dichloromethane, combined the organic layers, saturated Washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain pure product.

下面化合物（1）至（9）分别以实施例2中制备的对应化合物为原料，采用上述的合成方法制备得到的目标化合物。The following compounds (1) to (9) use the corresponding compounds prepared in Example 2 as raw materials, respectively, and are the target compounds prepared by the above-mentioned synthetic method.

（1）N-(3-氰基-4-正丙氧基苯基)-5-氨基烟酰胺（样品编号ANN01）。(1) N- (3-cyano-4-n-propoxyphenyl)-5-aminonicotinamide (Sample No. ANN01).

1H NMR (600 MHz, DMSO-d 6) δ 10.39 (d, J = 14.2 Hz, 1H), 8.30 (d, J =39.1 Hz, 1H), 8.09 (dd, J = 5.7, 2.5 Hz, 2H), 8.03 – 7.85 (m, 1H), 7.34 (dd,J = 18.6, 16.6 Hz, 1H), 7.26 (d, J = 9.2 Hz, 1H), 5.61 (s, 2H), 4.22 – 3.89(m, 2H), 1.88 – 1.59 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H)。 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.39 (d, J = 14.2 Hz, 1H), 8.30 (d, J =39.1 Hz, 1H), 8.09 (dd, J = 5.7, 2.5 Hz, 2H) , 8.03 – 7.85 (m, 1H), 7.34 (dd, J = 18.6, 16.6 Hz, 1H), 7.26 (d, J = 9.2 Hz, 1H), 5.61 (s, 2H), 4.22 – 3.89(m, 2H) ), 1.88 – 1.59 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H).

（2）N-(3-氰基-4-异丙氧基苯基) -5-氨基烟酰胺（样品编号ANN02）。(2) N- (3-cyano-4-isopropoxyphenyl)-5-aminonicotinamide (Sample No. ANN02).

1H NMR (600 MHz, DMSO-d 6) δ 10.51 (s, 1H), 8.35 (d, J = 23.2 Hz, 1H),8.15 – 8.05 (m, 2H), 7.98 – 7.88 (m, 1H), 7.55 (s, 1H), 7.30 (t, J = 11.0 Hz,1H), 4.74 (dq, J = 12.0, 6.0 Hz, 1H), 1.31 (d, J = 6.0 Hz, 7H)。 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.51 (s, 1H), 8.35 (d, J = 23.2 Hz, 1H), 8.15 – 8.05 (m, 2H), 7.98 – 7.88 (m, 1H), 7.55 (s, 1H), 7.30 (t, J = 11.0 Hz, 1H), 4.74 (dq, J = 12.0, 6.0 Hz, 1H), 1.31 (d, J = 6.0 Hz, 7H).

（3）N-(3-氰基-4-正丁氧基苯基) -5-氨基烟酰胺（样品编号ANN03）。(3) N- (3-cyano-4-n-butoxyphenyl)-5-aminonicotinamide (Sample No. ANN03).

1H NMR (600 MHz, DMSO) δ 10.38 (s, 1H), 8.27 (d, J = 1.6 Hz, 1H),8.13 – 8.05 (m, 2H), 7.98 – 7.89 (m, 1H), 7.37 – 7.31 (m, 1H), 7.27 (d, J =9.2 Hz, 1H), 5.63 (d, J = 23.9 Hz, 2H), 4.12 (t, J = 6.4 Hz, 2H), 1.77 – 1.69(m, 2H), 1.51 – 1.41 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H)。 1 H NMR (600 MHz, DMSO) δ 10.38 (s, 1H), 8.27 (d, J = 1.6 Hz, 1H), 8.13 – 8.05 (m, 2H), 7.98 – 7.89 (m, 1H), 7.37 – 7.31 (m, 1H), 7.27 (d, J =9.2 Hz, 1H), 5.63 (d, J = 23.9 Hz, 2H), 4.12 (t, J = 6.4 Hz, 2H), 1.77 – 1.69(m, 2H) , 1.51 – 1.41 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H).

（4）N-(3-氰基-4-仲丁氧基苯基) -5-氨基烟酰胺（样品编号ANN04）。(4) N- (3-cyano-4-sec-butoxyphenyl)-5-aminonicotinamide (Sample No. ANN04).

1H NMR (600 MHz, DMSO) δ 10.38 (s, 1H), 8.27 (s, 1H), 8.13 – 8.05 (m,2H), 7.98 – 7.90 (m, 1H), 7.35 (t, J = 2.0 Hz, 1H), 7.27 (dd, J = 18.3, 9.2Hz, 1H), 5.63 (d, J = 25.1 Hz, 2H), 3.91 (t, J = 7.7 Hz, 2H), 2.06 (dp, J =13.2, 6.6 Hz, 1H), 1.00 (d, J = 6.7 Hz, 6H)。 1 H NMR (600 MHz, DMSO) δ 10.38 (s, 1H), 8.27 (s, 1H), 8.13 – 8.05 (m, 2H), 7.98 – 7.90 (m, 1H), 7.35 (t, J = 2.0 Hz , 1H), 7.27 (dd, J = 18.3, 9.2Hz, 1H), 5.63 (d, J = 25.1 Hz, 2H), 3.91 (t, J = 7.7 Hz, 2H), 2.06 (dp, J =13.2, 6.6 Hz, 1H), 1.00 (d, J = 6.7 Hz, 6H).

（5）N-(3-氰基-4-正戊氧基苯基) -5-氨基烟酰胺（样品编号ANN05）。(5) N- (3-cyano-4-n-pentyloxyphenyl)-5-aminonicotinamide (Sample No. ANN05).

1H NMR (600 MHz, DMSO) δ 10.38 (s, 1H), 8.27 (d, J = 1.6 Hz, 1H),8.09 (dd, J = 7.9, 2.6 Hz, 2H), 7.93 (dd, J = 9.2, 2.6 Hz, 1H), 7.35 (t, J =2.2 Hz, 1H), 7.26 (d, J = 9.2 Hz, 1H), 5.61 (s, 2H), 4.11 (t, J = 6.5 Hz,2H), 1.79 – 1.69 (m, 2H), 1.46 – 1.29 (m, 4H), 0.90 (t, J = 7.2 Hz, 3H)。 1 H NMR (600 MHz, DMSO) δ 10.38 (s, 1H), 8.27 (d, J = 1.6 Hz, 1H), 8.09 (dd, J = 7.9, 2.6 Hz, 2H), 7.93 (dd, J = 9.2 , 2.6 Hz, 1H), 7.35 (t, J = 2.2 Hz, 1H), 7.26 (d, J = 9.2 Hz, 1H), 5.61 (s, 2H), 4.11 (t, J = 6.5 Hz, 2H), 1.79 – 1.69 (m, 2H), 1.46 – 1.29 (m, 4H), 0.90 (t, J = 7.2 Hz, 3H).

（6）N-(3-氰基-4-异戊氧基苯基) -5-氨基烟酰胺（样品编号ANN06）。(6) N- (3-cyano-4-isoamyloxyphenyl)-5-aminonicotinamide (Sample No. ANN06).

1H NMR (600 MHz, DMSO) δ 10.38 (s, 1H), 8.27 (s, 1H), 8.13 – 8.03 (m,2H), 7.98 – 7.88 (m, 1H), 7.39 – 7.20 (m, 2H), 5.63 (d, J = 25.0 Hz, 2H),4.14 (t, J = 6.5 Hz, 2H), 1.86 – 1.75 (m, 1H), 1.65 (q, J = 6.5 Hz, 2H), 0.94(d, J = 6.6 Hz, 7H)。 1 H NMR (600 MHz, DMSO) δ 10.38 (s, 1H), 8.27 (s, 1H), 8.13 – 8.03 (m, 2H), 7.98 – 7.88 (m, 1H), 7.39 – 7.20 (m, 2H) , 5.63 (d, J = 25.0 Hz, 2H), 4.14 (t, J = 6.5 Hz, 2H), 1.86 – 1.75 (m, 1H), 1.65 (q, J = 6.5 Hz, 2H), 0.94(d, J = 6.6 Hz, 7H).

（7）N-(3-氰基-4-苄氧基苯基) -5-氨基烟酰胺（样品编号ANN07）。(7) N- (3-cyano-4-benzyloxyphenyl)-5-aminonicotinamide (Sample No. ANN07).

1H NMR (600 MHz, DMSO) δ 10.39 (s, 1H), 8.26 (d, J = 1.2 Hz, 1H),8.16 – 8.05 (m, 2H), 7.99 – 7.89 (m, 1H), 7.51 – 7.29 (m, 7H), 5.61 (s, 2H),5.28 (s, 2H)。 1 H NMR (600 MHz, DMSO) δ 10.39 (s, 1H), 8.26 (d, J = 1.2 Hz, 1H), 8.16 – 8.05 (m, 2H), 7.99 – 7.89 (m, 1H), 7.51 – 7.29 (m, 7H), 5.61 (s, 2H), 5.28 (s, 2H).

（8）N-(3-氰基-4-（4-氯）苄氧基苯基) -5-氨基烟酰胺（样品编号ANN08）(8) N- (3-cyano-4-(4-chloro)benzyloxyphenyl)-5-aminonicotinamide (Sample No. ANN08)

1H NMR (600 MHz, DMSO) δ 10.40 (s, 1H), 8.26 (d, J = 1.8 Hz, 1H),8.10 (dd, J = 8.8, 2.6 Hz, 2H), 7.94 (dd, J = 9.2, 2.6 Hz, 1H), 7.54 – 7.47(m, 4H), 7.35 (dd, J = 6.9, 4.7 Hz, 2H), 5.61 (s, 2H), 5.28 (s, 2H)。 1 H NMR (600 MHz, DMSO) δ 10.40 (s, 1H), 8.26 (d, J = 1.8 Hz, 1H), 8.10 (dd, J = 8.8, 2.6 Hz, 2H), 7.94 (dd, J = 9.2 , 2.6 Hz, 1H), 7.54 – 7.47(m, 4H), 7.35 (dd, J = 6.9, 4.7 Hz, 2H), 5.61 (s, 2H), 5.28 (s, 2H).

（9）N-(3-氰基-4-正已氧基苯基) -5-氨基烟酰胺（样品编号ANN09）。(9) N- (3-cyano-4-n-hexyloxyphenyl)-5-aminonicotinamide (Sample No. ANN09).

1H NMR (600 MHz, DMSO) δ 10.38 (s, 1H), 8.27 (s, 1H), 8.09 (dd, J =9.4, 2.1 Hz, 2H), 7.93 (dd, J = 9.1, 2.3 Hz, 1H), 7.41 – 7.19 (m, 2H), 5.67(s, 2H), 4.11 (t, J = 6.4 Hz, 2H), 1.79 – 1.69 (m, 2H), 1.50 – 1.08 (m, 8H),0.90 (dt, J = 13.6, 6.8 Hz, 4H)。 1 H NMR (600 MHz, DMSO) δ 10.38 (s, 1H), 8.27 (s, 1H), 8.09 (dd, J =9.4, 2.1 Hz, 2H), 7.93 (dd, J = 9.1, 2.3 Hz, 1H) ), 7.41 – 7.19 (m, 2H), 5.67(s, 2H), 4.11 (t, J = 6.4 Hz, 2H), 1.79 – 1.69 (m, 2H), 1.50 – 1.08 (m, 8H), 0.90 ( dt, J = 13.6, 6.8 Hz, 4H).

一、目标化合物的黄嘌呤氧化酶抑制活性研究。1. Study on the xanthine oxidase inhibitory activity of the target compounds.

（1）试验材料。(1) Test material.

试剂：黄嘌呤氧化酶（ from bovine, Sigma）、黄嘌呤、焦亚磷酸钠、EDTA-2Na和氢氧化钠。Reagents: xanthine oxidase (from bovine, Sigma), xanthine, sodium pyrophosphite, EDTA-2Na, and sodium hydroxide.

仪器：电子分析天平（AR1140型）、电热恒温水浴锅（DK-98-1型）和UV2100型紫外可见分光光度仪。Instruments: electronic analytical balance (AR1140 type), electrothermal constant temperature water bath (DK-98-1 type) and UV2100 UV-Vis spectrophotometer.

（2）实验方法。(2) Experimental method.

反应稀释液的配制：0.1mol/L焦磷酸钠0.3mmol/L EDTA二钠，pH值8.3。The preparation of the reaction diluent: 0.1 mol/L sodium pyrophosphate, 0.3 mmol/L disodium EDTA, pH 8.3.

样品配制：分别准确称取10 μmmol的实施例3-6制备的化合物，加100 μL的DMSO溶解，然后加900 mL 的稀释液，得到10 mM的母液。Sample preparation: respectively accurately weigh 10 μmmol of the compounds prepared in Examples 3-6, add 100 μL of DMSO to dissolve, and then add 900 mL of diluent to obtain a 10 mM stock solution.

黄嘌呤底物的配制：准确称取9.127mg黄嘌呤，加少量NaOH溶液溶解，再加稀释液稀释至100 mL定容，（现用现配）。Preparation of xanthine substrate: Accurately weigh 9.127 mg of xanthine, add a small amount of NaOH solution to dissolve, and add diluent to dilute to a constant volume of 100 mL (for current use).

酶的配制：精密量取酶母液36µL，加入反应稀释溶液3420µL，得到浓度为75U/L的酶溶液，酶母液的浓度为7200U/L。Preparation of enzyme: Precisely measure 36 µL of the enzyme stock solution, add 3420 µL of the reaction dilution solution to obtain an enzyme solution with a concentration of 75 U/L, and the concentration of the enzyme stock solution is 7200 U/L.

（4）酶活力检测方法。(4) Enzyme activity detection method.

黄嘌呤氧化酶临用时用反应稀释液稀释，反应体系中黄嘌呤氧化酶终浓度15U/L；反应时，依次加入反应稀释液，黄嘌呤氧化酶溶液，样品溶液，25℃孵育10 min后，加入黄嘌呤（终浓度125µM），之后每10s检测一次295nm处检测吸光度(约3分钟)，直到吸光度增加速率出现下降；测试结果，见表1。The xanthine oxidase was diluted with the reaction diluent before use, and the final concentration of xanthine oxidase in the reaction system was 15 U/L; during the reaction, the reaction diluent, xanthine oxidase solution, and sample solution were added in sequence, and after incubation at 25 °C for 10 min, Add xanthine (final concentration 125µM), and then measure the absorbance at 295nm every 10s (about 3 minutes) until the rate of increase in absorbance decreases; the test results are shown in Table 1.

表1 样品在25 μM下的酶抑制活力检测结果。Table 1 Enzyme inhibitory activity test results of samples at 25 μM.

实验证明，该化合物在体外黄嘌呤氧化酶抑制活性测试中显现出了良好的效果。Experiments proved that the compound showed good effect in the test of xanthine oxidase inhibitory activity in vitro.

Claims (5)

1. a kind ofN(3- cyano -4- alkoxyl phenyl) pyridine carboxamides, which is characterized in that describedN(3- cyanogen Base-alkoxyl phenyl) pyridine carboxamides general formula is as follows:
R in general formula I1For the alkyl of 1-10 carbon, 3-10 carbon atom cycloalkyl, methoxyethyl, benzyl and substituted benzyl；Replace Benzyl is halogeno-benzyl or cyanobenzyls；R2Stand alone as hydrogen, hydroxyl or amino, R2It is located at ortho position, the meta position or right of pyridine N Position；Ar stands alone as pyridine -2- formoxyl, pyridine -3- formoxyl or pyridine -4- formoxyl.
2. N- (3- cyano -4- alkoxyl phenyl) pyridine carboxamides as described in claim 1, which is characterized in that The compound of the general formula I are as follows:
N- (3- cyano -4- positive propoxy phenyl) Pyrazinamide；N- (3- cyano -4- isopropyl phenyl) Pyrazinamide；N-(3- Cyano -4- n-butoxyphenyl) Pyrazinamide；N- (3- cyano -4- sec-butoxy phenyl) Pyrazinamide；(3- cyano -4- is different by N- Butoxy phenyl) Pyrazinamide；N- (3- cyano -4- methoxyethoxy phenyl) Pyrazinamide；N- (3- cyano -4- n-pentyloxy Phenyl) Pyrazinamide；N- (3- cyano -4- isoamoxy phenyl) Pyrazinamide；N- (3- cyano -4- cyclopentyloxy phenyl) different cigarette Amide；N- (3- cyano -4- just phenyl) Pyrazinamide；N- (the positive heptyloxybenzene base of 3- cyano -4-) Pyrazinamide；N- (3- cyano -4- n-octyl phenyl) Pyrazinamide；N- (3- cyano -4- benzyloxy-phenyl) Pyrazinamide；N- (3- cyano -4- (4- chlorine) benzyloxy-phenyl) Pyrazinamide；N- (3- cyano -4-(4- cyano) benzyloxy-phenyl) Pyrazinamide；N- (3- cyano- 4- positive propoxy phenyl) niacinamide；
N- (3- cyano -4- isopropyl phenyl) niacinamide；N- (3- cyano -4- n-butoxyphenyl) niacinamide；N- (3- cyanogen Base -4- sec-butoxy phenyl) niacinamide；N- (3- cyano-4-isobutoxy phenyl) niacinamide；N- (3- cyano -4- methoxy (ethoxy) Base phenyl) niacinamide；N- (3- cyano -4- n-pentyloxy phenyl) niacinamide；N- (3- cyano -4- isoamoxy phenyl) nicotinoyl Amine；N- (3- cyano -4- cyclopentyloxy phenyl) niacinamide；N- (3- cyano -4- just phenyl) niacinamide；N- (3- cyano- The positive heptyloxybenzene base of 4-) niacinamide；N- (3- cyano -4- n-octyl phenyl) niacinamide；N- (3- cyano -4- benzyloxy-phenyl) Niacinamide；N- (3- cyano -4-(4- chlorine) benzyloxy-phenyl) niacinamide；N- (3- cyano -4-(4- cyano) benzyloxy-phenyl) cigarette Amide；N- (3- cyano -4- positive propoxy phenyl) -2- pyridine carboxamide；
N- (3- cyano -4- isopropyl phenyl) -2- pyridine carboxamide；N- (3- cyano -4- n-butoxyphenyl) -2- pyridine first Amide；N- (3- cyano -4- sec-butoxy phenyl) -2- pyridine carboxamide；N- (3- cyano-4-isobutoxy phenyl) -2- pyridine Formamide；N- (3- cyano -4- methoxyethoxy phenyl) -2- pyridine carboxamide；N- (3- cyano -4- n-pentyloxy phenyl) -2- Pyridine carboxamide；N- (3- cyano -4- isoamoxy phenyl) -2- pyridine carboxamide；N- (3- cyano -4- cyclopentyloxy phenyl) - 2- pyridine carboxamide；N- (3- cyano -4- just phenyl) -2- pyridine carboxamide；N- (the positive heptyloxybenzene of 3- cyano -4- Base) -2- pyridine carboxamide；N- (3- cyano -4- n-octyl phenyl) -2- pyridine carboxamide；N- (3- cyano -4- benzyloxy benzene Base) -2- pyridine carboxamide；N- (3- cyano -4-(4- chlorine) benzyloxy-phenyl) -2- pyridine carboxamide；N- (3- cyano -4-(4- cyanogen Base) benzyloxy-phenyl) -2- pyridine carboxamide；
N- (3- cyano -4- positive propoxy phenyl) -5- aminonicotinamide；N- (3- cyano -4- isopropyl phenyl) -5- amino Niacinamide；N- (3- cyano -4- n-butoxyphenyl) -5- aminonicotinamide；N- (3- cyano -4- sec-butoxy phenyl) -5- Aminonicotinamide；N- (3- cyano -4- n-pentyloxy phenyl) -5- aminonicotinamide；N- (3- cyano -4- isoamoxy phenyl) - 5- aminonicotinamide；N- (3- cyano -4- just phenyl) -5- aminonicotinamide；N- (3- cyano -4- benzyloxy-phenyl) - 5- aminonicotinamide；N- (3- cyano -4-(4- chlorine) benzyloxy-phenyl) -5- aminonicotinamide.
3. the preparation method of N- (3- cyano -4- alkoxyl phenyl) pyridine carboxamides as claimed in claim 2, It is characterized in that, specific steps are as follows:
(1) it using salicylonitrile as starting material, is nitrified, is alkylated, restored and important intermediate 5- amino -2- alcoxyl is made Base benzonitrile；
(2) 5- amino -2- alkoxy benzene formonitrile HCN in the presence of a base, respectively by different nicotinoyl chlorine, nicotinoyl chlorine or 2- pyridine first Acylated with acid chloride respectively obtains N- (3- cyano -4- alkoxyl phenyl) Pyrazinamide, N- (3- cyano -4- alkoxyl phenyl) nicotinoyl Amine and N- (3- cyano -4- alkoxyl phenyl) -2- pyridine carboxamide；
(3) 5- amino -2- alkoxy benzene formonitrile HCN is condensed under the conditions of EDCI/HOAT with 5-Boc- amino nicotinoyl chlorine, then through remove-insurance Shield obtains N- (3- cyano -4- alkoxyl phenyl) -5- aminonicotinamide.
4. the preparation method of N- (3- cyano -4- alkoxyl phenyl) pyridine carboxamides as claimed in claim 3, It is characterized in that, the 5- amino -2- alkoxy benzene formonitrile HCN preparation method specifically: salicylonitrile is added in step 1 in reaction flask And glacial acetic acid, concentrated nitric acid is slowly added dropwise under 50 DEG C of stirrings, controls reaction temperature between 50-70 DEG C, finishes that the reaction was continued, reaction After it is cooling, pour into ice water, filter, filter cake massive laundering, spontaneously dry, obtaining faint yellow solid is 5- nitro -2- hydroxyl Base benzonitrile；5- nitro -2- hydroxy-phenylformonitrile prepared by step 1, halogenated alkane, Carbon Dioxide is added in step 2 in reaction flask Potassium, potassium iodide and DMF react at 60 DEG C overnight, and TLC fully reacting is poured into water after reaction solution is cooling, uses ethyl acetate 100 mL are extracted three times, organic layer washing, saturated common salt washing, and anhydrous sodium sulfate is dried overnight, filters, and filtrate decompression is concentrated into It is dry, obtain light yellow oil 5- nitro -2- alkoxy benzene formonitrile HCN；5- nitro -2- the alkoxy benzene of preparation is added in reaction flask Formonitrile HCN and reduced iron powder, ammonium chloride, 15 mL second alcohol and waters, flow back 3 h, and fully reacting is diluted with water, ethyl acetate extraction 3 Secondary, 50 mL, saturated common salt washing, anhydrous sodium sulfate dry, filter every time, are concentrated to dryness to obtain 5- amino -2- alkoxy benzene Formonitrile HCN obtains the sterling of 5- amino -2- alkoxy benzene formonitrile HCN with ethyl acetate: petroleum ether=1:5-1:1 column chromatographic purifying.
5. N- (3- cyano -4- alkoxyl phenyl) pyridine carboxamides as described in claim 1-2 is any, with pharmacy Upper acceptable carrier is used to prepare treatment gout drug, the pharmaceutically acceptable carrier be starch, microcrystalline cellulose, Hard magnesium or glycerol.
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