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CN110776486B - Benzofuran micromolecule P2Y14Receptor inhibitors, their preparation and use - Google Patents

Benzofuran micromolecule P2Y14Receptor inhibitors, their preparation and use Download PDF

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CN110776486B
CN110776486B CN201911011418.1A CN201911011418A CN110776486B CN 110776486 B CN110776486 B CN 110776486B CN 201911011418 A CN201911011418 A CN 201911011418A CN 110776486 B CN110776486 B CN 110776486B
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benzofuran
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胡庆华
李环球
刘春晓
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    • C07—ORGANIC CHEMISTRY
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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Abstract

The invention discloses a benzofuran derivative shown in a formula (I), and a preparation method and application thereof. Experimental results show that the benzofuran derivative provided by the invention has better P2Y14Inhibiting activity and antiinflammatory activity, and can be used for preparing P2Y14A therapeutic agent for receptor-related inflammatory diseases.

Description

一种苯并呋喃类小分子P2Y14受体抑制剂，及其制备和应用A kind of benzofuran small molecule P2Y14 receptor inhibitor, and preparation and application thereof

技术领域technical field

本发明属于小分子P2Y14受体抑制剂技术领域，具体涉及一种苯并呋喃类小分子P2Y14受体抑制剂，及其制备和应用。The invention belongs to the technical field of small molecule P2Y 14 receptor inhibitors, in particular to a benzofuran-type small molecule P2Y 14 receptor inhibitor, and its preparation and application.

背景技术Background technique

P2Y14受体属于视紫红质样G蛋白偶联受体(GPCR)的δ-分支。它通过Gi蛋白抑制3'，5'-环腺苷一磷酸(cAMP)的产生，并被尿苷-5'-二磷酸葡萄糖(UDPG)和其他内源性UDP-糖激活。P2Y14受体主要存在于心脏、胎盘、脂肪组织、胃肠道以及外周免疫细胞中，参与促炎作用和免疫应答过程，其活化增强中性粒细胞趋化性和促进肥大细胞释放介质。最近的研究表明，在P2Y14受体基因敲除的小鼠中，P2Y14受体的拮抗作用具有潜在的治疗糖尿病的作用。另有报道称UDPG作为配体激活P2Y14受体与免疫炎症相关疾病有很大关系。因此，P2Y14受体被认为是哮喘、无菌性炎症、糖尿病、神经退行性疾病等炎症相关疾病的潜在靶标。The P2Y 14 receptor belongs to the delta-branch of the rhodopsin-like G protein-coupled receptors (GPCRs). It inhibits the production of 3',5'-cyclic adenosine monophosphate (cAMP) by the Gi protein and is activated by uridine-5'-diphosphate glucose (UDPG) and other endogenous UDP-sugars. P2Y 14 receptors mainly exist in the heart, placenta, adipose tissue, gastrointestinal tract, and peripheral immune cells, and are involved in pro-inflammatory and immune response processes, and their activation enhances neutrophil chemotaxis and promotes mast cells to release mediators. Recent studies have shown that P2Y 14 receptor antagonism has a potential therapeutic effect on diabetes in P2Y 14 receptor knockout mice. It has also been reported that the activation of P2Y 14 receptors by UDPG as a ligand has a great relationship with immune inflammation-related diseases. Therefore, the P2Y 14 receptor is considered as a potential target for inflammation-related diseases such as asthma, sterile inflammation, diabetes, neurodegenerative diseases.

目前对P2Y14受体抑制剂的研究仅仅报道了3种结构类型的化合物(嘧啶并哌啶类、2-萘酸类和3-取代苯甲酸类)，都在临床前研究阶段。其中活性和选择性最高的为2- 萘酸类，然而目前报道的2-萘酸类结构的抑制剂存在溶解性差、口服生物利用度低、合成纯化难度大等缺陷，给进一步讨论构效关系及生物学评价带来了较大的困难。因此寻找新结构类型的P2Y14受体拮抗剂，改善2-萘酸类抑制剂存在的成药性差等问题，成为发现活性强、选择性好的P2Y14受体抑制剂的新策略。The current research on P2Y 14 receptor inhibitors has only reported three structural types of compounds (pyrimidopiperidines, 2-naphthoic acids and 3-substituted benzoic acids), all of which are in the preclinical research stage. Among them, 2-naphthoic acids have the highest activity and selectivity. However, the currently reported inhibitors of 2-naphthoic acid structures have defects such as poor solubility, low oral bioavailability, and difficulty in synthesis and purification. The structure-activity relationship is further discussed. and biological evaluation brought greater difficulties. Therefore, finding new structural types of P2Y 14 receptor antagonists to improve the problems of poor drugability of 2-naphthoic acid inhibitors has become a new strategy to discover P2Y 14 receptor inhibitors with strong activity and good selectivity.

发明内容SUMMARY OF THE INVENTION

发明目的：针对上述技术问题，本发明提供了一种苯并呋喃类小分子P2Y14受体抑制剂，及其制备和应用。本发明提供的苯并呋喃衍生物作为P2Y14受体抑制剂具有很好的活性，且成药性好。Purpose of the invention: In view of the above technical problems, the present invention provides a benzofuran-type small molecule P2Y 14 receptor inhibitor, and its preparation and application. The benzofuran derivatives provided by the invention have good activity as P2Y 14 receptor inhibitors, and have good druggability.

技术方案：为了达到上述发明目的，本发明所采用的技术方案如下：Technical scheme: in order to achieve the above-mentioned purpose of the invention, the technical scheme adopted in the present invention is as follows:

一种苯并呋喃衍生物，具有式(I)所示结构：A kind of benzofuran derivative, has the structure shown in formula (I):

Figure BDA0002244312090000011
Figure BDA0002244312090000011

Figure BDA0002244312090000021
Figure BDA0002244312090000021

其中，所述

Figure BDA0002244312090000022
为取代或非取代的C4～C5杂环基，或者为取代或非取代的苯基，或者为
Figure BDA0002244312090000023
n＝1或2。Among them, the
Figure BDA0002244312090000022
is a substituted or unsubstituted C4-C5 heterocyclic group, or a substituted or unsubstituted phenyl group, or
Figure BDA0002244312090000023
n=1 or 2.

优选，所述取代的苯基，是被卤素、C1～C4的烷基或C1～C4的烷氧基取代的苯基，所述C1～C4的烷基或C1～C4的烷氧基，其中的0-3个氢原子被卤素取代。Preferably, the substituted phenyl group is a phenyl group substituted by halogen, a C1-C4 alkyl group or a C1-C4 alkoxy group, the C1-C4 alkyl group or a C1-C4 alkoxy group, wherein 0-3 hydrogen atoms are replaced by halogen.

优选，所述取代的苯基为单取代的苯基。Preferably, the substituted phenyl group is a monosubstituted phenyl group.

优选，所述

Figure BDA0002244312090000024
为非取代的含有杂原子N、S或O的五元或六元杂环基，或者为单取代的苯基，或者为
Figure BDA0002244312090000025
n＝1或2。Preferably, the
Figure BDA0002244312090000024
is an unsubstituted five- or six-membered heterocyclic group containing the heteroatoms N, S or O, or is a monosubstituted phenyl group, or is
Figure BDA0002244312090000025
n=1 or 2.

进一步优选，所述

Figure BDA0002244312090000026
为噻吩基、四氢吡喃基、4-丁氧基苯基、4-叔丁基苯基、3，4-(亚甲基二氧)基苯基、4-溴代苯基、3-溴代苯基、2-溴代苯基、4-氯代苯基、 3-氯代苯基、2-氯代苯基、4-甲基苯基、3-甲基苯基、2-甲基苯基、4-甲氧基苯基、3- 甲氧基苯基、2-甲氧基苯基、4-三氟甲基苯基、3-三氟甲基苯基、2-三氟甲基苯基、4- 三氟甲氧基苯基、3-三氟甲氧基苯基。Further preferably, the
Figure BDA0002244312090000026
is thienyl, tetrahydropyranyl, 4-butoxyphenyl, 4-tert-butylphenyl, 3,4-(methylenedioxy)phenyl, 4-bromophenyl, 3- bromophenyl, 2-bromophenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-trifluoro Methylphenyl, 4-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl.

更优选地，所述苯并呋喃衍生物选自如下化合物：More preferably, the benzofuran derivatives are selected from the following compounds:

Figure BDA0002244312090000027
Figure BDA0002244312090000027

Figure BDA0002244312090000031
Figure BDA0002244312090000031

所述的苯并呋喃衍生物的制备方法，包括式(II)结构的化合物和式(III)结构的化合物反应，得到式(I)结构的化合物；The preparation method of the benzofuran derivative comprises the reaction of the compound of the structure of formula (II) and the compound of the structure of formula (III) to obtain the compound of the structure of formula (I);

Figure BDA0002244312090000032
Figure BDA0002244312090000032

其中，所述

Figure BDA0002244312090000033
同上所述。Among them, the
Figure BDA0002244312090000033
Same as above.

所述的苯并呋喃衍生物在制备P2Y14抑制剂中的应用。The application of the benzofuran derivatives in the preparation of P2Y 14 inhibitors.

或者，所述的苯并呋喃衍生物在制备P2Y14受体相关炎症性疾病药物中的应用。Or, the use of the benzofuran derivatives in the preparation of medicines for P2Y 14 receptor-related inflammatory diseases.

技术效果：相对于现有技术，本发明提供了一种苯并呋喃衍生物及其制备方法和应用，实验结果表明，本发明提供的苯并呋喃衍生物具有较好的P2Y14抑制活性和抗炎活性，可以作为制备P2Y14受体相关炎症性疾病治疗药物。Technical effect: Compared with the prior art, the present invention provides a benzofuran derivative and a preparation method and application thereof. The experimental results show that the benzofuran derivative provided by the present invention has better P2Y 14 inhibitory activity and anti-oxidative effect. It has inflammatory activity and can be used as a drug for the preparation of P2Y 14 receptor-related inflammatory diseases.

具体实施方式Detailed ways

下面将结合本发明实施例的技术方案进行清楚、完整地描述，制备反应过程如下所示：The following will be clearly and completely described in conjunction with the technical solutions of the embodiments of the present invention, and the preparation reaction process is as follows:

Figure BDA0002244312090000041
Figure BDA0002244312090000041

实施例1Example 1

(1)2-(4-硝基苯基)苯并呋喃的合成:(1) Synthesis of 2-(4-nitrophenyl)benzofuran:

Figure BDA0002244312090000042
Figure BDA0002244312090000042

将水杨醛(1.92mL),对硝基苄溴(3.888g),碳酸钾(2.484g),20mL N,N-二甲基甲酰胺(DMF)加入到50mL圆底烧瓶中，80℃加热回流过夜，TLC点板监测，反应结束后，加水淬灭，加入400ml水，用乙酸乙酯萃取，用无水硫酸钠干燥后旋蒸。对该产物用石油醚：乙酸乙酯(PE:EA)＝10:1过柱，得到黄色固体即为产物。Add salicylaldehyde (1.92mL), p-nitrobenzyl bromide (3.888g), potassium carbonate (2.484g), 20mL N,N-dimethylformamide (DMF) into a 50mL round-bottom flask, heat at 80°C Reflux overnight, monitored by TLC, after the reaction is completed, add water to quench, add 400 ml of water, extract with ethyl acetate, dry with anhydrous sodium sulfate, and then spin-evaporate. The product was passed through a column with petroleum ether:ethyl acetate (PE:EA)=10:1, and a yellow solid was obtained as the product.

1H NMR(600MHz,DMSO)δ8.33(d,J＝8.7Hz,2H),8.16(d,J＝8.8Hz,2H),7.77(s,1H),7.72(d,J＝7.8Hz,1H),7.67(d,J＝8.3Hz,1H),7.39(t,J＝7.5Hz,1H),7.30(t,J＝7.5Hz,1H). 1 H NMR(600MHz, DMSO)δ8.33(d,J=8.7Hz,2H),8.16(d,J=8.8Hz,2H),7.77(s,1H),7.72(d,J=7.8Hz, 1H), 7.67(d, J＝8.3Hz, 1H), 7.39(t, J＝7.5Hz, 1H), 7.30(t, J＝7.5Hz, 1H).

(2)N-(4-(苯并呋喃-2-基)苯基)-2-(4-甲氧基苯基)乙酰胺的合成:(2) Synthesis of N-(4-(benzofuran-2-yl)phenyl)-2-(4-methoxyphenyl)acetamide:

Figure BDA0002244312090000043
Figure BDA0002244312090000043

将2-(4-硝基苯基)苯并呋喃，铁粉，氯化铵，以摩尔比1:10:3的量投到20mL体积比为乙醇:水＝3:1中，80℃加热回流，TLC监测反应，1h后反应完全。过滤，萃取，干燥，PE:EA＝20:1过柱，得到淡黄色固体4-(苯并呋喃-2-基)苯胺。将所得产物，4- 甲氧基苯乙酸，EDCI,HOBt,DIPEA,以摩尔比1:1:1.5:1.5:3的量投到10mL DMF中， TLC监测反应，反应结束后，加水淬灭，萃取，干燥，旋干。加少量乙酸乙酯，使产物析出，过滤，烘干。Put 2-(4-nitrophenyl)benzofuran, iron powder, and ammonium chloride into 20 mL in a molar ratio of 1:10:3 in a volume ratio of ethanol:water=3:1, and heat at 80°C Reflux, TLC monitoring the reaction, the reaction was complete after 1 h. Filter, extract, dry, pass through column with PE:EA=20:1 to obtain 4-(benzofuran-2-yl)aniline as a pale yellow solid. The product therefrom, 4-methoxyphenylacetic acid, EDCI, HOBt, DIPEA, are thrown into 10mL DMF with the amount of mol ratio 1:1:1.5:1.5:3, TLC monitoring reaction, after the reaction finishes, add water to quench, Extract, dry, spin dry. A small amount of ethyl acetate was added to precipitate the product, which was filtered and dried.

1H NMR(400MHz,DMSO)δ7.86(d,J＝8.7Hz,2H),7.74(d,J＝8.8Hz,2H),7.65–7.58(m,2H),7.32–7.24(m,5H),6.90(d,J＝8.7Hz,2H),3.74(s,3H),3.60(s,2H). 1 H NMR(400MHz, DMSO)δ7.86(d,J=8.7Hz,2H),7.74(d,J=8.8Hz,2H),7.65-7.58(m,2H),7.32-7.24(m,5H) ), 6.90(d, J=8.7Hz, 2H), 3.74(s, 3H), 3.60(s, 2H).

13C NMR(101MHz,DMSO)δ169.69,158.07,155.23,154.07,139.85,130.13,129.00,127.73,125.33,124.53,124.25,123.18,120.92,119.29,113.77,110.97,100.82,55.04,42.49, 39.52. 13 C NMR(101MHz,DMSO)δ169.69,158.07,155.23,154.07,139.85,130.13,129.00,127.73,125.33,124.53,124.25,123.18,120.92,119.29,113.77,110.97,100.82,55.04,42.49, 39.52.

实施例2Example 2

Figure BDA0002244312090000051
Figure BDA0002244312090000051

N-(4-(苯并呋喃-2-基)苯基)-2-(4-氯苯基)乙酰胺的合成:Synthesis of N-(4-(benzofuran-2-yl)phenyl)-2-(4-chlorophenyl)acetamide:

以4-氯苯乙酸为原料，合成方法参见实施例1。Using 4-chlorophenylacetic acid as raw material, see Example 1 for the synthesis method.

1H NMR(600MHz,DMSO)δ7.84(d,J＝8.7Hz,2H),7.71(d,J＝8.7Hz,2H),7.60(d, J＝7.4Hz,1H),7.57(d,J＝8.0Hz,1H),7.36(dt,J＝18.3,5.3Hz,4H),7.29–7.25(m,2H),7.24–7.20(m,1H),3.66(s,2H). 1 H NMR (600MHz, DMSO) δ 7.84(d, J=8.7Hz, 2H), 7.71(d, J=8.7Hz, 2H), 7.60(d, J=7.4Hz, 1H), 7.57(d, J=8.0Hz, 1H), 7.36 (dt, J=18.3, 5.3Hz, 4H), 7.29–7.25 (m, 2H), 7.24–7.20 (m, 1H), 3.66 (s, 2H).

13C NMR(101MHz,DMSO)δ168.94,155.18,154.07,139.68,134.80,131.33,131.08,128.98,128.24,125.34,124.65,124.26,123.18,120.92,119.34,110.96,100.87,42.46,39.52. 13 C NMR (101MHz, DMSO)δ168.94,155.18,154.07,139.68,134.80,131.33,131.08,128.98,128.24,125.34,124.65,124.26,123.18,120.92,119.34.12.469

实施例3Example 3

Figure BDA0002244312090000052
Figure BDA0002244312090000052

N-(4-(苯并呋喃-2-基)苯基)-2-(4-溴苯基)乙酰胺的合成:Synthesis of N-(4-(benzofuran-2-yl)phenyl)-2-(4-bromophenyl)acetamide:

以4-溴苯乙酸为原料，合成方法参见实施例1。Using 4-bromophenylacetic acid as raw material, see Example 1 for the synthesis method.

1H NMR(400MHz,DMSO)δ7.88–7.85(m,2H),7.74(d,J＝8.8Hz,2H),7.62(ddd, J＝14.5,4.9,0.8Hz,2H),7.55–7.52(m,2H),7.30(ddd,J＝10.7,5.7,2.0Hz,4H),7.25(td, J＝7.4,1.2Hz,1H),3.68(s,2H). 1 H NMR (400MHz, DMSO) δ 7.88–7.85 (m, 2H), 7.74 (d, J=8.8Hz, 2H), 7.62 (ddd, J=14.5, 4.9, 0.8Hz, 2H), 7.55–7.52 (m, 2H), 7.30 (ddd, J=10.7, 5.7, 2.0Hz, 4H), 7.25 (td, J=7.4, 1.2Hz, 1H), 3.68 (s, 2H).

13C NMR(101MHz,DMSO)δ168.87,155.19,154.08,139.67,135.23,131.46,131.17,128.98,125.35,124.66,124.26,123.18,120.92,119.81,119.34,110.96,100.87,42.53,40.15, 39.94,39.73,39.52,39.31,39.10,38.89. 13 C NMR(101MHz,DMSO)δ168.87,155.19,154.08,139.67,135.23,131.46,131.17,128.98,125.35,124.66,124.26,123.18,120.92,119.81,119.34,110.96,100.87,42.53,40.15, 39.94,39.73, 39.52, 39.31, 39.10, 38.89.

实施例4Example 4

Figure BDA0002244312090000061
Figure BDA0002244312090000061

N-(4-(苯并呋喃-2-基)苯基)-2-(对甲苯基)乙酰胺的合成:Synthesis of N-(4-(benzofuran-2-yl)phenyl)-2-(p-tolyl)acetamide:

以4-甲基苯乙酸为原料，合成方法参见实施例1。Using 4-methylphenylacetic acid as raw material, see Example 1 for the synthesis method.

1H NMR(400MHz,DMSO)δ7.88–7.85(m,2H),7.74(d,J＝8.8Hz,2H),7.62(ddd, J＝14.1,5.0,0.8Hz,2H),7.32–7.28(m,2H),7.25(dd,J＝11.0,4.7Hz,3H),7.14(d,J＝7.9Hz,2H),3.62(s,2H),2.28(s,3H). 1 H NMR (400MHz, DMSO) δ 7.88–7.85 (m, 2H), 7.74 (d, J=8.8Hz, 2H), 7.62 (ddd, J=14.1, 5.0, 0.8Hz, 2H), 7.32–7.28 (m, 2H), 7.25 (dd, J=11.0, 4.7Hz, 3H), 7.14 (d, J=7.9Hz, 2H), 3.62 (s, 2H), 2.28 (s, 3H).

13C NMR(101MHz,DMSO)δ169.49,155.22,154.07,139.82,135.60,132.76,128.97,128.89,125.32,124.55,124.24,123.17,120.91,119.30,110.96,100.82,42.99,40.15,39.94, 39.73,39.52,39.31,39.10,38.89,20.65. 13 C NMR(101MHz,DMSO)δ169.49,155.22,154.07,139.82,135.60,132.76,128.97,128.89,125.32,124.55,124.24,123.17,120.91,119.30,110.96,100.82,42.99,40.15,39.94, 39.73,39.52, 39.31, 39.10, 38.89, 20.65.

实施例5Example 5

Figure BDA0002244312090000062
Figure BDA0002244312090000062

N-(4-(苯并呋喃-2-基)苯基)-2-(噻吩-2-基)乙酰胺的合成:Synthesis of N-(4-(benzofuran-2-yl)phenyl)-2-(thiophen-2-yl)acetamide:

以2-噻吩乙酸为原料，合成方法参见实施例1。Using 2-thiopheneacetic acid as raw material, see Example 1 for the synthesis method.

1H NMR(400MHz,DMSO)δ7.89–7.86(m,2H),7.75(d,J＝8.8Hz,2H),7.63(ddd, J＝13.4,4.9,0.7Hz,2H),7.41(dd,J＝5.0,1.4Hz,1H),7.32(t,J＝1.2Hz,1H),7.31–7.23 (m,2H),7.03–6.98(m,2H),3.92(s,2H). 1 H NMR (400MHz, DMSO) δ 7.89-7.86 (m, 2H), 7.75 (d, J=8.8Hz, 2H), 7.63 (ddd, J=13.4, 4.9, 0.7Hz, 2H), 7.41 (dd , J=5.0, 1.4Hz, 1H), 7.32 (t, J=1.2Hz, 1H), 7.31–7.23 (m, 2H), 7.03–6.98 (m, 2H), 3.92 (s, 2H).

13C NMR(101MHz,DMSO)δ168.23,155.17,154.08,139.60,136.91,128.98,126.69,126.43,125.37,125.13,124.73,124.28,123.18,120.93,119.37,110.98,100.92,39.52,37.58. 13 C NMR (101MHz, DMSO) δ168.23, 155.17, 154.08, 139.60, 136.91, 128.98, 126.69, 126.43, 125.37, 125.13, 124.73, 124.28, 123.18, 120.93, 119.37.

实施例6Example 6

Figure BDA0002244312090000063
Figure BDA0002244312090000063

N-(4-(苯并呋喃-2-基)苯基)-2-(4-丁氧基苯基)乙酰胺的合成:Synthesis of N-(4-(benzofuran-2-yl)phenyl)-2-(4-butoxyphenyl)acetamide:

以4-丁氧基苯乙酸为原料，合成方法参见实施例1。Using 4-butoxyphenylacetic acid as raw material, see Example 1 for the synthesis method.

1H NMR(400MHz,DMSO)δ7.86(d,J＝8.7Hz,2H),7.75(d,J＝8.8Hz,2H),7.65–7.58(m,2H),7.31–7.27(m,2H),7.25(d,J＝8.5Hz,3H),6.89(d,J＝8.6Hz,2H),3.93(t,J＝6.5Hz,2H),3.59(s,2H),1.68(dd,J＝9.5,5.3Hz,2H),1.42(dd,J＝15.0,7.4Hz,2H),0.92(t,J＝7.4Hz,3H). 1 H NMR(400MHz, DMSO)δ7.86(d,J=8.7Hz,2H),7.75(d,J=8.8Hz,2H),7.65-7.58(m,2H),7.31-7.27(m,2H) ),7.25(d,J＝8.5Hz,3H),6.89(d,J＝8.6Hz,2H),3.93(t,J＝6.5Hz,2H),3.59(s,2H),1.68(dd,J =9.5,5.3Hz,2H),1.42(dd,J=15.0,7.4Hz,2H),0.92(t,J=7.4Hz,3H).

13C NMR(151MHz,DMSO)δ169.67,157.48,155.21,154.05,139.83,130.08,128.98,127.58,125.30,124.52,124.22,123.15,120.89,119.28,114.29,110.94,100.80,67.06,42.50, 39.94,39.80,39.66,39.52,39.38,39.24,39.10,30.75,18.73,13.68. 13 C NMR(151MHz,DMSO)δ169.67,157.48,155.21,154.05,139.83,130.08,128.98,127.58,125.30,124.52,124.22,123.15,120.89,119.28,114.29,110.94,100.80,67.06,42.50, 39.94,39.80, 39.66, 39.52, 39.38, 39.24, 39.10, 30.75, 18.73, 13.68.

实施例7Example 7

Figure BDA0002244312090000071
Figure BDA0002244312090000071

N-(4-(苯并呋喃-2-基)苯基)-2-(四氢-2H-吡喃-4-基)乙酰胺的合成:Synthesis of N-(4-(benzofuran-2-yl)phenyl)-2-(tetrahydro-2H-pyran-4-yl)acetamide:

以四氢吡喃4-乙酸为原料，合成方法参见实施例1。Using tetrahydropyran 4-acetic acid as raw material, see Example 1 for the synthesis method.

1H NMR(600MHz,DMSO)δ7.82(d,J＝8.7Hz,2H),7.71(d,J＝8.7Hz,2H),7.58 (dd,J＝19.8,7.7Hz,2H),7.28–7.24(m,2H),7.23–7.20(m,1H),3.80(dd,J＝11.4,2.6Hz, 2H),3.28(d,J＝1.6Hz,1H),3.26(d,J＝1.7Hz,1H),2.25(d,J＝7.1Hz,2H),1.57(dd,J＝ 12.8,1.6Hz,2H),1.23(ddd,J＝24.6,11.9,4.2Hz,2H). 1 H NMR (600MHz, DMSO) δ 7.82 (d, J=8.7Hz, 2H), 7.71 (d, J=8.7Hz, 2H), 7.58 (dd, J=19.8, 7.7Hz, 2H), 7.28– 7.24(m, 2H), 7.23–7.20(m, 1H), 3.80(dd, J=11.4, 2.6Hz, 2H), 3.28(d, J=1.6Hz, 1H), 3.26(d, J=1.7Hz ,1H),2.25(d,J＝7.1Hz,2H),1.57(dd,J＝12.8,1.6Hz,2H),1.23(ddd,J＝24.6,11.9,4.2Hz,2H).

13C NMR(101MHz,DMSO)δ170.21,155.26,154.05,139.76,128.99,125.27,124.42,124.19,123.14,120.87,119.26,110.93,100.73,66.85,43.64,40.15,39.94,39.73,39.52, 39.31,39.10,38.89,32.39,32.07. 13 C NMR(101MHz,DMSO)δ170.21,155.26,154.05,139.76,128.99,125.27,124.42,124.19,123.14,120.87,119.26,110.93,100.73,66.85,43.64,40.15,39.94,39.73,39.52, 39.31,39.10, 38.89, 32.39, 32.07.

实施例8Example 8

Figure BDA0002244312090000072
Figure BDA0002244312090000072

N-(4-(苯并呋喃-2-基)苯基)-2-(4-(叔丁基)苯基)乙酰胺的合成:Synthesis of N-(4-(benzofuran-2-yl)phenyl)-2-(4-(tert-butyl)phenyl)acetamide:

以4-叔丁基苯乙酸为原料，合成方法参见实施例1。Using 4-tert-butylphenylacetic acid as raw material, see Example 1 for the synthesis method.

1H NMR(400MHz,DMSO)δ7.86(d,J＝8.7Hz,2H),7.74(d,J＝8.7Hz,2H),7.61 (dd,J＝14.4,7.6Hz,2H),7.35(d,J＝8.3Hz,2H),7.31(s,1H),7.29–7.22(m,4H),3.63(s, 2H),1.27(s,9H). 1 H NMR (400MHz, DMSO) δ 7.86 (d, J=8.7Hz, 2H), 7.74 (d, J=8.7Hz, 2H), 7.61 (dd, J=14.4, 7.6Hz, 2H), 7.35 ( d, J=8.3Hz, 2H), 7.31(s, 1H), 7.29–7.22(m, 4H), 3.63(s, 2H), 1.27(s, 9H).

13C NMR(101MHz,DMSO)δ169.48,155.21,154.06,148.90,139.82,132.79,128.99,128.76,125.32,125.09,124.55,124.24,123.17,120.91,119.28,110.96,100.82,42.94,39.52, 34.14,31.16. 13 C NMR(101MHz,DMSO)δ169.48,155.21,154.06,148.90,139.82,132.79,128.99,128.76,125.32,125.09,124.55,124.24,123.17,120.91,119.28,110.96,100.82,42.94,39.52, 34.14,31.16.

实施例9Example 9

Figure BDA0002244312090000081
Figure BDA0002244312090000081

N-(4-(苯并呋喃-2-基)苯基)-2-(苯并[d][1,3]二氧杂环戊烯-5-基)乙酰胺的合成:Synthesis of N-(4-(benzofuran-2-yl)phenyl)-2-(benzo[d][1,3]dioxol-5-yl)acetamide:

以3，4-(亚甲基二氧)苯乙酸为原料，合成方法参见实施例1。Using 3,4-(methylenedioxy)phenylacetic acid as raw material, see Example 1 for the synthesis method.

1H NMR(400MHz,DMSO)δ7.86(d,J＝8.8Hz,2H),7.74(d,J＝8.8Hz,2H),7.65–7.58(m,2H),7.32–7.27(m,2H),7.25(td,J＝7.4,1.1Hz,1H),6.92(d,J＝1.5Hz,1H), 6.87(d,J＝7.9Hz,1H),6.80(dd,J＝8.0,1.6Hz,1H),5.99(s,2H),3.58(s,2H). 1 H NMR(400MHz, DMSO)δ7.86(d,J=8.8Hz,2H),7.74(d,J=8.8Hz,2H),7.65-7.58(m,2H),7.32-7.27(m,2H) ), 7.25(td, J＝7.4, 1.1Hz, 1H), 6.92(d, J＝1.5Hz, 1H), 6.87(d, J＝7.9Hz, 1H), 6.80(dd, J＝8.0, 1.6Hz ,1H),5.99(s,2H),3.58(s,2H).

13C NMR(101MHz,DMSO)δ169.44,155.22,154.08,147.17,145.96,139.79,129.41,128.99,125.33,124.57,124.25,123.17,122.16,120.91,119.32,110.96,109.56,108.10,100.81,42.93,40.15,39.94,39.73,39.52,39.31,39.10,38.89. 13 C NMR(101MHz,DMSO)δ169.44,155.22,154.08,147.17,145.96,139.79,129.41,128.99,125.33,124.57,124.25,123.17,122.16,120.91,119.32,110.96,109.56,108.10,100.81,42.93,40.15, 39.94, 39.73, 39.52, 39.31, 39.10, 38.89.

实施例10Example 10

Figure BDA0002244312090000082
Figure BDA0002244312090000082

N-(4-(苯并呋喃-2-基)苯基)-2-(4-(三氟甲基)苯基)乙酰胺的合成:Synthesis of N-(4-(benzofuran-2-yl)phenyl)-2-(4-(trifluoromethyl)phenyl)acetamide:

以4-三氟甲基苯乙酸为原料，合成方法参见实施例1。Using 4-trifluoromethylphenylacetic acid as raw material, see Example 1 for the synthesis method.

1H NMR(400MHz,DMSO)δ7.88(d,J＝8.8Hz,2H),7.73(dd,J＝12.8, 8.5Hz,4H),7.64(dd,J＝7.5,0.9Hz,1H),7.59(t,J＝7.6Hz,3H),7.33–7.28 (m,2H),7.25(td,J＝7.4,1.1Hz,1H),3.82(s,2H). 1 H NMR (400MHz, DMSO) δ 7.88 (d, J=8.8Hz, 2H), 7.73 (dd, J=12.8, 8.5Hz, 4H), 7.64 (dd, J=7.5, 0.9Hz, 1H), 7.59(t,J=7.6Hz,3H),7.33–7.28(m,2H),7.25(td,J=7.4,1.1Hz,1H),3.82(s,2H).

13C NMR(151MHz,DMSO)δ168.57,155.16,154.07,140.62,139.60,130.09,128.97,127.46,127.25,125.35,125.13,124.72,124.26,123.16,120.91,119.37,110.95,100.89,42.91,39.94,39.80,39.66,39.52,39.38,39.24,39.10. 13 C NMR(151MHz,DMSO)δ168.57,155.16,154.07,140.62,139.60,130.09,128.97,127.46,127.25,125.35,125.13,124.72,124.26,123.16,120.91,119.37,110.95,100.89,42.91,39.94,39.80, 39.66, 39.52, 39.38, 39.24, 39.10.

实施例11Example 11

Figure BDA0002244312090000083
Figure BDA0002244312090000083

N-(4-(苯并呋喃-2-基)苯基)-2-(4-(三氟甲氧基)苯基)乙酰胺的合成:Synthesis of N-(4-(benzofuran-2-yl)phenyl)-2-(4-(trifluoromethoxy)phenyl)acetamide:

以4-三氟甲氧基苯乙酸为原料，合成方法参见实施例1。Using 4-trifluoromethoxyphenylacetic acid as raw material, see Example 1 for the synthesis method.

1H NMR(400MHz,DMSO)δ7.87(d,J＝8.8Hz,2H),7.74(d,J＝8.8Hz,2H),7.65–7.58(m,2H),7.47(d,J＝8.7Hz,2H),7.35–7.27(m,4H),7.25(td,J＝7.4,1.1Hz,1H), 3.74(s,2H). 1 H NMR (400 MHz, DMSO) δ 7.87 (d, J=8.8 Hz, 2H), 7.74 (d, J=8.8 Hz, 2H), 7.65-7.58 (m, 2H), 7.47 (d, J=8.7 Hz, 2H), 7.35–7.27(m, 4H), 7.25(td, J=7.4, 1.1Hz, 1H), 3.74(s, 2H).

13C NMR(101MHz,DMSO)δ168.93,155.19,154.09,147.17,139.67,135.33,131.08,128.99,125.35,124.69,124.27,123.18,121.39,120.93,119.36,118.84,110.97,100.89,42.39,40.15,39.94,39.73,39.52,39.31,39.10,38.89. 13 C NMR(101MHz,DMSO)δ168.93,155.19,154.09,147.17,139.67,135.33,131.08,128.99,125.35,124.69,124.27,123.18,121.39,120.93,119.36,118.84,110.97,100.89,42.39,40.15,39.94, 39.73, 39.52, 39.31, 39.10, 38.89.

实施例12Example 12

Figure BDA0002244312090000091
Figure BDA0002244312090000091

N-(4-(苯并呋喃-2-基)苯基)-2-(2-溴苯基)乙酰胺的合成:Synthesis of N-(4-(benzofuran-2-yl)phenyl)-2-(2-bromophenyl)acetamide:

以2-溴苯乙酸为原料，合成方法参见实施例1。Using 2-bromophenylacetic acid as raw material, see Example 1 for the synthesis method.

1H NMR(400MHz,DMSO)δ7.88(d,J＝8.7Hz,2H),7.75(d,J＝8.8Hz,2H),7.65–7.59(m,3H),7.44(dd,J＝7.6,1.7Hz,1H),7.38(td,J＝7.5,1.1Hz,1H),7.32(s,1H),7.31–7.27(m,1H),7.24(dt,J＝7.9,1.7Hz,2H),3.90(s,2H). 1 H NMR (400 MHz, DMSO) δ 7.88 (d, J=8.7 Hz, 2H), 7.75 (d, J=8.8 Hz, 2H), 7.65-7.59 (m, 3H), 7.44 (dd, J=7.6 ,1.7Hz,1H),7.38(td,J=7.5,1.1Hz,1H),7.32(s,1H),7.31–7.27(m,1H),7.24(dt,J=7.9,1.7Hz,2H) ,3.90(s,2H).

13C NMR(101MHz,DMSO)δ168.07,155.23,154.07,139.78,135.58,132.27,129.00,128.84,127.62,125.37,124.60,124.56,124.25,123.18,120.91,119.27,110.97,100.83,43.30,40.15,39.94,39.73,39.52,39.31,39.10,38.89. 13 C NMR(101MHz,DMSO)δ168.07,155.23,154.07,139.78,135.58,132.27,129.00,128.84,127.62,125.37,124.60,124.56,124.25,123.18,120.91,119.27,110.97,100.83,43.30,40.15,39.94, 39.73, 39.52, 39.31, 39.10, 38.89.

实施例13Example 13

Figure BDA0002244312090000092
Figure BDA0002244312090000092

N-(4-(苯并呋喃-2-基)苯基)-2-(邻甲苯基)乙酰胺的合成:Synthesis of N-(4-(benzofuran-2-yl)phenyl)-2-(o-tolyl)acetamide:

以2-甲基苯乙酸为原料，合成方法参见实施例1。Using 2-methylphenylacetic acid as raw material, see Example 1 for the synthesis method.

1H NMR(400MHz,DMSO)δ7.87(d,J＝8.7Hz,2H),7.76(d,J＝8.7Hz,2H),7.65–7.59(m,2H),7.33–7.29(m,2H),7.28–7.25(m,2H),7.19–7.15(m,3H),3.73(s,2H), 2.32(s,3H). 1 H NMR(400MHz, DMSO)δ7.87(d,J=8.7Hz,2H),7.76(d,J=8.7Hz,2H),7.65-7.59(m,2H),7.33-7.29(m,2H) ), 7.28–7.25(m, 2H), 7.19–7.15(m, 3H), 3.73(s, 2H), 2.32(s, 3H).

13C NMR(101MHz,DMSO)δ169.27,155.24,154.08,139.82,136.69,134.52,129.99,129.90,129.00,126.73,125.78,125.35,124.56,124.25,123.18,120.92,119.33,110.97,100.82,41.00,40.15,39.94,39.73,39.52,39.31,39.10,38.89,19.40. 13 C NMR(101MHz,DMSO)δ169.27,155.24,154.08,139.82,136.69,134.52,129.99,129.90,129.00,126.73,125.78,125.35,124.56,124.25,123.18,120.92,119.33,110.97,100.82,41.00,40.15, 39.94, 39.73, 39.52, 39.31, 39.10, 38.89, 19.40.

实施例14Example 14

Figure BDA0002244312090000101
Figure BDA0002244312090000101

N-(4-(苯并呋喃-2-基)苯基)-2-(2-氯苯基)乙酰胺的合成:Synthesis of N-(4-(benzofuran-2-yl)phenyl)-2-(2-chlorophenyl)acetamide:

以2-氯苯乙酸为原料，合成方法参见实施例1。Using 2-chlorophenylacetic acid as raw material, see Example 1 for the synthesis method.

1H NMR(400MHz,DMSO)δ7.88(d,J＝8.7Hz,2H),7.75(d,J＝8.7Hz,2H),7.62 (dd,J＝14.3,7.6Hz,2H),7.46(td,J＝5.9,2.1Hz,2H),7.34–7.28(m,4H),7.26(dd,J＝ 10.9,4.0Hz,1H),3.89(s,2H). 1 H NMR (400MHz, DMSO) δ 7.88 (d, J=8.7Hz, 2H), 7.75 (d, J=8.7Hz, 2H), 7.62 (dd, J=14.3, 7.6Hz, 2H), 7.46 ( td, J＝5.9, 2.1Hz, 2H), 7.34–7.28(m, 4H), 7.26(dd, J＝10.9, 4.0Hz, 1H), 3.89(s, 2H).

13C NMR(101MHz,DMSO)δ168.13,155.23,154.08,139.77,133.81,133.71,132.24,129.01,128.64,127.07,125.37,124.58,124.25,123.17,120.91,119.28,110.97,100.83,40.86,40.15,39.94,39.73,39.52,39.31,39.10,38.89. 13 C NMR(101MHz,DMSO)δ168.13,155.23,154.08,139.77,133.81,133.71,132.24,129.01,128.64,127.07,125.37,124.58,124.25,123.17,120.91,119.28,110.97,100.83,40.86,40.15,39.94, 39.73, 39.52, 39.31, 39.10, 38.89.

实施例15Example 15

Figure BDA0002244312090000102
Figure BDA0002244312090000102

N-(4-(苯并呋喃-2-基)苯基)-2-(2-(三氟甲基)苯基)乙酰胺的合成:Synthesis of N-(4-(benzofuran-2-yl)phenyl)-2-(2-(trifluoromethyl)phenyl)acetamide:

以2-三氟甲基苯乙酸为原料，合成方法参见实施例1。Using 2-trifluoromethylphenylacetic acid as raw material, see Example 1 for the synthesis method.

1H NMR(400MHz,DMSO)δ7.88(d,J＝8.8Hz,2H),7.75–7.72(m,3H),7.68–7.59 (m,3H),7.57–7.49(m,2H),7.32(d,J＝0.6Hz,1H),7.31–7.23(m,2H),3.97(s,2H). 1 H NMR(400MHz, DMSO)δ7.88(d,J=8.8Hz,2H),7.75-7.72(m,3H),7.68-7.59(m,3H),7.57-7.49(m,2H),7.32 (d, J=0.6Hz, 1H), 7.31–7.23 (m, 2H), 3.97 (s, 2H).

13C NMR(101MHz,DMSO)δ168.21,155.22,154.08,139.71,133.77,133.48,132.25,129.00,127.73,127.44,127.35,125.66,125.61,125.38,124.60,124.25,123.18,120.92,119.29,110.97,100.85,40.15,39.94,39.73,39.52,39.31,39.10,38.89. 13 C NMR(101MHz,DMSO)δ168.21,155.22,154.08,139.71,133.77,133.48,132.25,129.00,127.73,127.44,127.35,125.66,125.61,125.38,124.60,124.25,123.18,120.92,119.29,110.97,100.85, 40.15,39.94,39.73,39.52,39.31,39.10,38.89.

实施例16Example 16

Figure BDA0002244312090000103
Figure BDA0002244312090000103

N-(4-(苯并呋喃-2-基)苯基)-2-(3-甲氧基苯基)乙酰胺的合成:Synthesis of N-(4-(benzofuran-2-yl)phenyl)-2-(3-methoxyphenyl)acetamide:

以3-甲氧基苯乙酸为原料，合成方法参见实施例1。Using 3-methoxyphenylacetic acid as raw material, see Example 1 for the synthesis method.

1H NMR(400MHz,DMSO)δ7.89–7.85(m,2H),7.75(d,J＝8.8Hz,2H),7.65–7.62 (m,1H),7.62–7.59(m,1H),7.31(dd,J＝7.2,1.1Hz,2H),7.28–7.26(m,1H),7.26–7.23 (m,1H),6.93(t,J＝4.2Hz,2H),6.85–6.82(m,1H),3.76(s,3H),3.65(s,2H). 1 H NMR(400MHz,DMSO)δ7.89-7.85(m,2H),7.75(d,J=8.8Hz,2H),7.65-7.62(m,1H),7.62-7.59(m,1H),7.31 (dd, J=7.2, 1.1Hz, 2H), 7.28–7.26 (m, 1H), 7.26–7.23 (m, 1H), 6.93 (t, J=4.2Hz, 2H), 6.85–6.82 (m, 1H) ),3.76(s,3H),3.65(s,2H).

13C NMR(151MHz,DMSO)δ169.15,159.21,155.20,154.06,139.75,137.23,129.33,128.97,125.32,124.59,124.24,123.16,121.32,120.90,119.32,114.93,111.95,110.95,100.83,54.98,43.41,39.94,39.80,39.66,39.52,39.38,39.24,39.10. 13 C NMR(151MHz,DMSO)δ169.15,159.21,155.20,154.06,139.75,137.23,129.33,128.97,125.32,124.59,124.24,123.16,121.32,120.90,119.32,114.93,111.95,110.95,100.83,54.98,43.41, 39.94,39.80,39.66,39.52,39.38,39.24,39.10.

实施例17Example 17

Figure BDA0002244312090000111
Figure BDA0002244312090000111

N-(4-(苯并呋喃-2-基)苯基)-2-(3-(三氟甲氧基)苯基)乙酰胺的合成:Synthesis of N-(4-(benzofuran-2-yl)phenyl)-2-(3-(trifluoromethoxy)phenyl)acetamide:

以3-三氟甲氧基苯乙酸为原料，合成方法参见实施例1。Using 3-trifluoromethoxyphenylacetic acid as raw material, see Example 1 for the synthesis method.

1H NMR(400MHz,DMSO)δ7.90–7.86(m,2H),7.75(d,J＝8.8Hz,2H),7.65–7.62 (m,1H),7.62–7.59(m,1H),7.49(t,J＝7.9Hz,1H),7.40–7.36(m,2H),7.33–7.29(m, 2H),7.29–7.23(m,2H),3.78(s,2H). 1 H NMR(400MHz,DMSO)δ7.90-7.86(m,2H),7.75(d,J=8.8Hz,2H),7.65-7.62(m,1H),7.62-7.59(m,1H),7.49 (t, J=7.9Hz, 1H), 7.40–7.36 (m, 2H), 7.33–7.29 (m, 2H), 7.29–7.23 (m, 2H), 3.78 (s, 2H).

13C NMR(101MHz,DMSO)δ168.63,155.17,154.07,148.29,139.60,138.42,130.12,128.96,128.40,125.34,124.70,124.24,123.15,121.67,120.90,119.37,119.08,110.94,100.88,42.61,40.15,39.94,39.73,39.52,39.31,39.10,38.89. 13 C NMR(101MHz,DMSO)δ168.63,155.17,154.07,148.29,139.60,138.42,130.12,128.96,128.40,125.34,124.70,124.24,123.15,121.67,120.90,119.37,119.08,110.94,100.88,42.61,40.15, 39.94, 39.73, 39.52, 39.31, 39.10, 38.89.

实施例18Example 18

Figure BDA0002244312090000112
Figure BDA0002244312090000112

N-(4-(苯并呋喃-2-基)苯基)-2-(3-氯苯基)乙酰胺的合成:Synthesis of N-(4-(benzofuran-2-yl)phenyl)-2-(3-chlorophenyl)acetamide:

以3-氯苯乙酸为原料，合成方法参见实施例1。Using 3-chlorophenylacetic acid as raw material, see Example 1 for the synthesis method.

1H NMR(400MHz,DMSO)δ7.89–7.86(m,2H),7.75(d,J＝8.8Hz,2H),7.62(ddd, J＝13.8,4.9,0.7Hz,2H),7.44(s,1H),7.40–7.36(m,1H),7.35(t,J＝1.8Hz,1H),7.33– 7.30(m,3H),7.28–7.25(m,1H),3.72(s,2H). 1 H NMR (400MHz, DMSO) δ 7.89-7.86 (m, 2H), 7.75 (d, J=8.8Hz, 2H), 7.62 (ddd, J=13.8, 4.9, 0.7Hz, 2H), 7.44 (s ,1H),7.40–7.36(m,1H),7.35(t,J=1.8Hz,1H),7.33–7.30(m,3H),7.28–7.25(m,1H),3.72(s,2H).

13C NMR(101MHz,DMSO)δ168.74,155.18,154.08,139.64,138.20,132.84,130.13,129.12,128.98,127.98,126.60,125.36,124.70,124.27,123.18,120.93,119.37,110.97,100.89,42.68,40.15,39.94,39.73,39.52,39.31,39.10,38.89. 13 C NMR(101MHz,DMSO)δ168.74,155.18,154.08,139.64,138.20,132.84,130.13,129.12,128.98,127.98,126.60,125.36,124.70,124.27,123.18,120.93,119.37,110.97,100.89,42.68,40.15, 39.94, 39.73, 39.52, 39.31, 39.10, 38.89.

实施例19Example 19

Figure BDA0002244312090000121
Figure BDA0002244312090000121

N-(4-(苯并呋喃-2-基)苯基)-2-(间甲苯基)乙酰胺的合成:Synthesis of N-(4-(benzofuran-2-yl)phenyl)-2-(m-tolyl)acetamide:

以3-甲基苯乙酸为原料，合成方法参见实施例1。Using 3-methylphenylacetic acid as raw material, see Example 1 for the synthesis method.

1H NMR(400MHz,DMSO)δ7.87(d,J＝8.7Hz,2H),7.75(d,J＝8.7Hz,2H),7.62 (dd,J＝13.8,7.6Hz,2H),7.31(d,J＝6.3Hz,2H),7.26(dd,J＝7.6,3.3Hz,2H),7.17(dt,J ＝6.6,4.7Hz,3H),3.72(s,2H),2.31(s,3H). 1 H NMR (400MHz, DMSO) δ 7.87 (d, J=8.7Hz, 2H), 7.75 (d, J=8.7Hz, 2H), 7.62 (dd, J=13.8, 7.6Hz, 2H), 7.31 ( d, J=6.3Hz, 2H), 7.26 (dd, J=7.6, 3.3Hz, 2H), 7.17 (dt, J=6.6, 4.7Hz, 3H), 3.72 (s, 2H), 2.31 (s, 3H) ).

13C NMR(101MHz,DMSO)δ169.26,155.24,154.08,139.81,136.69,134.51,129.99,129.90,129.00,126.73,125.78,125.35,124.56,124.24,123.18,120.91,119.33,110.96,100.82,41.00,40.15,39.94,39.73,39.52,39.31,39.10,38.89,19.40. 13 C NMR(101MHz,DMSO)δ169.26,155.24,154.08,139.81,136.69,134.51,129.99,129.90,129.00,126.73,125.78,125.35,124.56,124.24,123.18,120.91,119.33,110.96,100.82,41.00,40.15, 39.94, 39.73, 39.52, 39.31, 39.10, 38.89, 19.40.

实施例20Example 20

Figure BDA0002244312090000122
Figure BDA0002244312090000122

N-(4-(苯并呋喃-2-基)苯基)-2-(3-溴苯基)乙酰胺的合成:Synthesis of N-(4-(benzofuran-2-yl)phenyl)-2-(3-bromophenyl)acetamide:

以3-溴苯乙酸为原料，合成方法参见实施例1。Using 3-bromophenylacetic acid as raw material, see Example 1 for the synthesis method.

1H NMR(400MHz,DMSO)δ7.87(d,J＝8.6Hz,2H),7.74(d,J＝8.6Hz,2H),7.65–7.57(m,3H),7.47(d,J＝7.7Hz,1H),7.37–7.31(m,3H),7.30–7.23(m,2H),3.71(s,2H). 1 H NMR (400 MHz, DMSO) δ 7.87 (d, J=8.6 Hz, 2H), 7.74 (d, J=8.6 Hz, 2H), 7.65-7.57 (m, 3H), 7.47 (d, J=7.7 Hz, 1H), 7.37–7.31 (m, 3H), 7.30–7.23 (m, 2H), 3.71 (s, 2H).

13C NMR(101MHz,DMSO)δ168.76,155.18,154.08,139.63,138.49,131.98,130.45,129.49,128.98,128.36,125.36,124.70,124.27,123.18,121.48,120.93,119.36,110.97,100.90,42.63,40.15,39.94,39.73,39.52,39.31,39.10,38.89. 13 C NMR(101MHz,DMSO)δ168.76,155.18,154.08,139.63,138.49,131.98,130.45,129.49,128.98,128.36,125.36,124.70,124.27,123.18,121.48,120.93,119.36,110.97,100.90,42.63,40.15, 39.94, 39.73, 39.52, 39.31, 39.10, 38.89.

实施例21Example 21

Figure BDA0002244312090000131
Figure BDA0002244312090000131

N-(4-(苯并呋喃-2-基)苯基)-2-(2-甲氧基苯基)乙酰胺的合成:Synthesis of N-(4-(benzofuran-2-yl)phenyl)-2-(2-methoxyphenyl)acetamide:

以2-甲氧基苯乙酸为原料，合成方法参见实施例1。Using 2-methoxyphenylacetic acid as raw material, see Example 1 for the synthesis method.

1H NMR(400MHz,DMSO)δ7.87(d,J＝8.6Hz,2H),7.76(d,J＝8.6Hz,2H),7.62 (dd,J＝13.3,7.6Hz,2H),7.32–7.28(m,2H),7.27–7.22(m,3H),6.99(d,J＝8.1Hz,1H), 6.92(t,J＝7.4Hz,1H),3.78(s,3H),3.67(s,2H). 1 H NMR (400MHz, DMSO) δ 7.87 (d, J=8.6Hz, 2H), 7.76 (d, J=8.6Hz, 2H), 7.62 (dd, J=13.3, 7.6Hz, 2H), 7.32– 7.28(m, 2H), 7.27–7.22(m, 3H), 6.99(d, J=8.1Hz, 1H), 6.92(t, J=7.4Hz, 1H), 3.78(s, 3H), 3.67(s , 2H).

13C NMR(101MHz,DMSO)δ169.31,157.24,155.28,154.05,139.96,130.81,128.99,128.05,125.30,124.37,124.18,124.02,123.13,120.86,120.15,119.21,110.92,110.71,100.70,55.41,39.52,37.76. 13 C NMR(101MHz,DMSO)δ169.31,157.24,155.28,154.05,139.96,130.81,128.99,128.05,125.30,124.37,124.18,124.02,123.13,120.86,120.15,119.21,110.92,110.71,100.70,55.41,39.52, 37.76.

实施例22Example 22

Figure BDA0002244312090000132
Figure BDA0002244312090000132

N-(4-(苯并呋喃-2-基)苯基)-2-(3-(三氟甲基)苯基)乙酰胺的合成:Synthesis of N-(4-(benzofuran-2-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide:

以3-三氟甲基苯乙酸为原料，合成方法参见实施例1。Using 3-trifluoromethylphenylacetic acid as raw material, see Example 1 for the synthesis method.

1H NMR(400MHz,DMSO)δ7.88(d,J＝8.7Hz,2H),7.77–7.72(m,3H),7.66(d,J＝9.7Hz,2H),7.63–7.59(m,3H),7.33–7.29(m,2H),7.28–7.23(m,1H),3.84(s,2H). 1 H NMR(400MHz, DMSO)δ7.88(d,J=8.7Hz,2H),7.77-7.72(m,3H),7.66(d,J=9.7Hz,2H),7.63-7.59(m,3H) ), 7.33–7.29(m, 2H), 7.28–7.23(m, 1H), 3.84(s, 2H).

13C NMR(101MHz,DMSO)δ168.68,155.15,154.07,139.58,137.12,133.45,129.28,128.95,125.85,125.81,125.33,124.70,124.23,123.36,123.33,123.14,120.89,119.37,110.92,100.86,42.61,39.52. 13 C NMR(101MHz,DMSO)δ168.68,155.15,154.07,139.58,137.12,133.45,129.28,128.95,125.85,125.81,125.33,124.70,124.23,123.36,123.33,123.14,120.89,119.37,110.92,100.86,42.61, 39.52.

实施例23Example 23

式I化合物作为P2Y14受体抑制剂的抑制活性评价实验方法：Experimental method for evaluating the inhibitory activity of the compound of formula I as a P2Y 14 receptor inhibitor:

稳转P2Y14受体的HEK293细胞株培养于DMEM培养基中(含10％胎牛血清、100 U/ml青霉素和100μg/ml链霉素)，实验前一天接种至384培养板，接种密度为1×104个细胞/孔，细胞于37℃、95％O2、5％CO2湿度条件下培养。实验前弃去培养基，改用无血清培养基，加入IBMX(500μM)和Ro 20-1724(100μM)抑制PDEs活性，以保证cAMP在一个较高的水平上。采用AC激动剂Forskolin(30μM)刺激细胞cAMP的产生，预先加入不同浓度的受试化合物(0.01、0.1、1、10、100nM)，以PPTN作为阳性对照。同时加入10μM的P2Y14受体激动剂UDPG，30min后根据cAMP GloTM Assay 试剂盒(PROMEGA Co.Ltd，美国)说明书步骤检测细胞内cAMP的含量。根据对cAMP 含量的抑制率计算IC50值，结果见表1，表1为本发明实施例1～22得到的化合物对cAMP 的抑制率(100nM)和IC50值。The HEK293 cell line stably transfected with P2Y 14 receptors was cultured in DMEM medium (containing 10% fetal bovine serum, 100 U/ml penicillin and 100 μg/ml streptomycin), and inoculated into 384 culture plates one day before the experiment at a density of 1×10 4 cells/well, cells were cultured at 37° C., 95% O 2 , 5% CO 2 humidity. Before the experiment, the medium was discarded and replaced with serum-free medium. IBMX (500 μM) and Ro 20-1724 (100 μM) were added to inhibit the activity of PDEs to ensure that cAMP was at a higher level. The AC agonist Forskolin (30 μM) was used to stimulate the production of cAMP in cells, and different concentrations of test compounds (0.01, 0.1, 1, 10, 100 nM) were added in advance, and PPTN was used as a positive control. At the same time, 10 μM of P2Y 14 receptor agonist UDPG was added, and after 30 minutes, the content of intracellular cAMP was detected according to the instructions of the cAMP Glo ™ Assay Kit (PROMEGA Co. Ltd, USA). The IC 50 value was calculated according to the inhibition rate of cAMP content, and the results are shown in Table 1. Table 1 shows the inhibition rate (100 nM) and IC 50 value of the compounds obtained in Examples 1-22 of the present invention to cAMP.

表1Table 1

Figure BDA0002244312090000141
Figure BDA0002244312090000141

Claims (3)

1. Benzofuran derivative, characterized in that it is chosen from the following compounds:
Figure FDA0003562803100000011
2. use of benzofuran derivatives according to claim 1 in the preparation of P2Y14The use of inhibitors.
3. Use of benzofuran derivatives according to claim 1 in the preparation of P2Y14The application of the medicine in treating the inflammatory diseases related to the receptor.
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