Huperzine A C12-site arylated series derivatives as well as preparation method and application of huperzine A C12-site arylated series derivatives

Abstract

The invention relates to the technical field of natural medicines, and discloses huperzine A C12 site arylation series derivatives and a preparation method thereof, and application of the derivatives in preparation of medicines for treating central nervous system degenerative diseases. The derivative has a structure as shown in a general formula I. According to the preparation method, a natural product huperzine A is taken as a raw material, aryl bromide is taken as a substrate, one-step synthesis is carried out through palladium-catalyzed heck coupling reaction, and the compound has the advantages of high chemical selectivity, no need of functional group protection, rapidness and the like. In-vitro enzyme activity and cell experiments prove that the derivative not only shows potential acetylcholin esterase inhibitory activity, but also has high efficiency, low toxicity and better neuroprotective activity, and has a prospect in clinical treatment of Alzheimer's disease. The preparation of the derivatives also provides a design thought for the development of novel central nervous system disease treatment drugs.

Description

Technical Field

[0001] The present invention relates to the field of natural medicinal chemistry, and in particular to a series of huperzine A C12 aryl-substituted derivatives and preparation methods and applications thereof. Background Art

[0002] Alzheimer's disease (AD) is a degenerative disease of the central nervous system primarily associated with aging. It is characterized by a series of cognitive impairments, including difficulty in identifying time and space, decreased intelligence and cognitive abilities, loss of communication skills, and abnormal behavioral patterns. The disease primarily affects people aged 65 and over, with a high prevalence. Factors contributing to the onset of AD include aging, genetic factors, systemic inflammation, and environmental influences. To date, the exact pathogenesis of AD remains unclear. The cholinergic hypothesis is one of the widely accepted pathogenic mechanisms. According to this hypothesis, inhibiting acetylcholinesterase activity in AD patients is one of the main directions for developing anti-AD drugs.

[0003] (-)-Huperzine A is an alkaloid monomer isolated from the Chinese herbal medicine Psoralea corylifolia. Its molecular skeleton is composed of three carbon rings, forming a [3.3.1]nonane bridged ring structure. (-)-Huperzine A exhibits selective and highly effective reversible binding affinity for acetylcholinesterase, and its action lasts longer. However, long-term use of (-)-Huperzine A may cause dizziness, nausea, and digestive disorders. Therefore, the development of novel drugs with strong activity, high selectivity, and minimal side effects, using (-)-Huperzine A as a lead compound, is of great significance. Furthermore, the development of rapid, efficient, highly chemoselective chemical methods that can prepare derivatives in a single reaction without redundant steps such as functional group protection, could greatly improve the efficiency of structural modification of these drugs.

[0004] Based on the above analysis, a C12 aryl-substituted derivative of huperzine A and a preparation method thereof are urgently needed in the art. Summary of the Invention

[0005] In view of the above-mentioned deficiencies, the purpose of the present invention is to prepare a series of C12-arylated derivatives of huperzine A using the natural small molecule drug huperzine A as a lead compound, and to provide a highly chemically selective preparation method and medical use of the derivatives.

[0006] To achieve the above objectives, the specific technical solutions of the present invention are as follows:

[0007] The present invention first discloses a series of huperzine A C12 arylated derivatives, which have a structure shown in general formula I:

[0008] in:

[0009] The R substituents in general formula I include, but are not limited to, 4-chlorobenzene, 4-tert-butylbenzene, 4-fluorobenzene, 4-methoxybenzene, 3-chloro-5-fluorobenzene, 4-isopropylbenzene, 3,5-dimethylbenzene, 4-n-butylbenzene, 4-ethoxybenzene, 4-methylbenzene, 4-naphthylbenzene, 4-pyrrolobenzene, 4-(2-pyridine)benzene, 2-ethoxypyridine, 4-bromobenzene, N,N-dimethylaniline, and 4-trimethylsilylbenzene.

[0010] The present invention also discloses a method for preparing a series of C12-arylated derivatives of huperzine A, comprising the following steps:

[0011] Under an inert atmosphere, Huperzine A and aryl bromide as raw materials undergo a Heck coupling reaction in the presence of a catalytic system consisting of tetrakis(triphenylphosphine)palladium, tri(2-thienyl)phosphine, a solvent, and a base to obtain a series of Huperzine A C12 arylated derivatives; the reaction formula is as follows:

[0012]

[0013] Furthermore, the reaction temperature of the Heck coupling reaction is 90° C. to 110° C., and the reaction time is 24 to 48 hours.

[0014] Furthermore, the reaction temperature is 100° C. and the reaction time is 24 h.

[0015] Furthermore, the molar ratio of huperzine A, aryl bromide, tetrakis(triphenylphosphine)palladium, tri(2-thienyl)phosphine and base is 1:2:0.1:0.7:5.

[0016] Furthermore, the solvent is toluene; and the base is sodium tert-butoxide.

[0017] The present invention also discloses a series of huperzine A C12 arylation derivatives prepared according to any of the above preparation methods.

[0018] The present invention also discloses an application of the above-mentioned series of huperzine A C12 arylated derivatives in the preparation of drugs for treating degenerative diseases of the central nervous system.

[0019] Furthermore, the central nervous system degenerative diseases include:

[0020] Alzheimer's disease; and amyotrophic lateral sclerosis.

[0021] The beneficial effects of the present invention are as follows:

[0022] The method for preparing the aryl fuspinene derivatives provided by the present invention is simple, rapid, and highly chemoselective, requiring no primary amine group protection. It also represents a novel method for preparing C12 arylated derivatives. The aryl bromides used are all commercially available.

[0023] 2. The present invention discovered a new structural modification site of huperzine A, providing useful data for improving the structure-activity relationship of huperzine A.

[0024] 3. In vitro experiments preliminarily confirmed that the synthesized series of derivatives have acetylcholinesterase inhibitory activity, are highly effective and low toxic, and have potential neuroprotective activity, providing candidate compounds for screening of anti-Alzheimer's disease activity. DETAILED DESCRIPTION

[0025] The present invention is described in detail below by way of examples, which are only used to further illustrate the present invention and are not to be construed as limiting the scope of protection of the present invention. The compounds of the present invention are not limited to the representative structures used in the examples, and different substituents may be replaced.

[0026] Example 1

[0027] Compound 1a was prepared from 4-chlorobromobenzene and huperzine A, and the reaction formula is as follows:

[0028]

[0029] In a glove box, a 10ml pressure-resistant reaction tube was added with (14.3mg, 0.01238mmol) tetrakis(triphenylphosphine)palladium, (24mg, 0.0856mmol) tri(2-thienyl)phosphine, and 1ml of anhydrous toluene and stirred for 30-45min. A toluene solution of (30mg, 0.1238mmol) huperzine A, (59mg, 0.6190mmol) sodium tert-butoxide, and (47mg, 0.2478mmol) p-chlorobromobenzene was then added. The reaction tube was sealed and allowed to react at 100°C for 24 hours. After the reaction was completed, the reaction tube was cooled to room temperature, ethyl acetate was added to the reaction system, and the mixture was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated. Purification by column chromatography yielded 35mg of a white solid in an 82% yield. The experimental data are as follows: 1H NMR(601MHz,Chloroform-d)δ13.10(s,1H),7.82(d,J=9.5Hz,1H),7.33–7.27(m,2H), 7.07(dd,J=8.0,2.2Hz,1H),7.02(dd,J=8.1,2.2Hz,1H),6.38(d,J=9.5Hz,1H),5.42( d,J=5.3Hz,1H),3.74(t,J=5.0Hz,1H),3.06(dd,J=16.9,5.1Hz,1H),2.78(dd,J=16.9 ,1.9Hz,1H),2.23(d,J=16.8Hz,1H),2.06(d,J=16.9Hz,1H),1.96(s,3H),1.57(s,3H). 13 C NMR(151MHz,Chloroform-d)δ165.5,144.9,143.0,140.9,138.0,134.6,132.3,129.2,129.0,129.0, 128.7,125.9,124.7,123.5,117.1,56.7,50.6,36.6,35.0,23.9,22.6.HR-ESI-MSm / z353.1409[M+H] + (calcdfor C 21 H 22 ClN2O,353.1421).

[0030] Example 2

[0031] Compound 1b was prepared from 4-tert-butyl bromobenzene and huperzine A, and the reaction formula is as follows:

[0032]

[0033] In a glove box, a 10ml pressure-resistant reaction tube was added with (14.3mg, 0.01238mmol) tetrakis(triphenylphosphine)palladium, (24mg, 0.0856mmol) tri(2-thienyl)phosphine, and 1ml of anhydrous toluene and stirred for 30-45min. A toluene solution of (30mg, 0.1238mmol) huperzine A, (59mg, 0.6190mmol) sodium tert-butoxide, and (52mg, 0.2476mmol) p-tert-butyl bromobenzene was then added. The reaction tube was sealed and allowed to react at 100°C for 24 hours. After the reaction was completed, the reaction tube was cooled to room temperature, ethyl acetate was added to the reaction system, and the mixture was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated. Purification by column chromatography yielded 37mg of a white solid, with a yield of 80%. The experimental data are as follows: 1H NMR(601MHz,Chloroform-d)δ13.34(s,1H),7.81(d,J=9.5Hz,1H),7.32–7.27(m,2H), 7.04(dd,J=7.8,2.0Hz,1H),6.99(dd,J=7.8,2.1Hz,1H),6.37(d,J=9.5Hz,1H),5.42(d ,J=5.2Hz,1H),3.74(t,J=5.4Hz,1H),3.08(dd,J=16.9,5.1Hz,1H),2.82–2.76(m,1H), 2.25(d,J=16.6Hz,1H),2.04(d,J=16.7Hz,1H),1.97(s,3H),1.57(s,3H),1.29(s,6H). 13 C NMR(151MHz,Chloroform-d)δ165.6,149.4,143.3,143.1,140.9,136.9,134.6,127.4,127.2,127 .2,125.7,125.2,124.9,123.7,116.9,56.6,50.6,36.5,34.9,34.6,31.5,23.9,22.6.HR-ESI-MS m / z375.2420[M+H] + (calcd for C 25 H 31 N2O,375.2436).

[0034] Example 3

[0035] Compound 1c was prepared from 4-fluorobromobenzene and huperzine A, and the reaction formula is as follows:

[0036]

[0037] In a glove box, a 10ml pressure-resistant reaction tube was added with (14.3mg, 0.01238mmol) tetrakis(triphenylphosphine)palladium, (24mg, 0.0856mmol) tri(2-thienyl)phosphine, and 1ml of anhydrous toluene and stirred for 30-45min. A toluene solution of (30mg, 0.1238mmol) huperzine A, (59mg, 0.6190mmol) sodium tert-butoxide, and (43mg, 0.2476mmol) p-fluorobromobenzene was then added. The reaction tube was sealed and allowed to react at 100°C for 24 hours. After the reaction was completed, the reaction tube was cooled to room temperature, ethyl acetate was added to the reaction system, and the mixture was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated. Purification by column chromatography yielded 32mg of a white solid, with a yield of 79%. The experimental data are as follows: 1H NMR(601MHz,Chloroform-d)δ13.0(s,1H),7.8(d,J=9.5Hz,1H),7.2–6.8(m,4H),6.4(d,J=9.5Hz,1H),5.6–5.3(m,1H),3.9–3.5(m, 1H),3.1(dd,J=16.9,5.1Hz,1H),2.8(dd,J=17.0,1.9Hz,1H),2.2(d,J=16.8Hz,1H),2.1(d,J=17.2Hz,1H),2.0(s,3H),1.6(s,3H). 13 C NMR(151MHz,Chloroform-d)δ165.5,160.7,143.0,142.2,140.9,137.8,134.6,129.2,129.1,126.1, 124.7,123.5,117.1,115.8,115.3,56.7,50.7,36.6,35.0,24.1,22.6.HR-ESI-MSm / z337.1701[M+H] + (calcdfor C 21 H 21 FN2O,337.1716).

[0038] Example 4

[0039] Compound 1d was prepared from p-bromoanisole and huperzine A, and the reaction formula is as follows:

[0040]

[0041] In a glove box, a 10ml pressure-resistant reaction tube was added with (14.3mg, 0.01238mmol) tetrakis(triphenylphosphine)palladium, (24mg, 0.0856mmol) tri(2-thienyl)phosphine, and 1ml of anhydrous toluene and stirred for 30-45min. A toluene solution of (30mg, 0.1238mmol) huperzine A, (59mg, 0.6190mmol) sodium tert-butoxide, and (46mg, 0.2476mmol) p-bromoanisole was then added. The reaction tube was sealed and allowed to react at 100°C for 24 hours. After the reaction was completed, the reaction tube was cooled to room temperature, ethyl acetate was added to the reaction system, and the mixture was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated. Purification by column chromatography yielded 31mg of a white solid in a 73% yield. The experimental data are as follows: 1H NMR(601MHz,Chloroform-d)δ13.2(s,1H),7.8(d,J=9.5Hz,1H),7.0(dd,J=8.6,2.3Hz ,1H),7.0(dd,J=8.6,2.3Hz,1H),6.8(td,J=5.9,2.9Hz,2H),6.4(d,J=9.5Hz,1H),5.4( dt,J=5.5,1.8Hz,1H),3.8(s,3H),3.7(s,1H),3.1(dd,J=16.9,5.1Hz,1H),2.8(dd,J= 16.9,1.9Hz,1H),2.2(d,J=16.7Hz,1H),2.1(d,J=16.7Hz,1H),2.0(s,3H),1.6(s,3H). 13 C NMR(151MHz,Chloroform-d)δ165.6,158.2,143.2,141.0,138.4,137.2,134.6,128.8,128.6,12 6.8,124.9,123.7,116.9,114.4,113.8,56.6,55.4,50.7,36.6,35.0,24.1,22.6.HR-ESI-MSm / z 349.1901[M+H] + (calcd for C 22 H 24 N2O2,349.1916).

[0042] Example 5

[0043] 1-Bromo-3-chloro-5-fluorobenzene and huperzine A were used to prepare compound 1e. The reaction formula is as follows:

[0044]

[0045] In a glove box, a 10ml pressure-resistant reaction tube was added with (14.3mg, 0.01238mmol) tetrakis(triphenylphosphine)palladium, (24mg, 0.0856mmol) tri(2-thienyl)phosphine, and 1ml of anhydrous toluene and stirred for 30-45min. A toluene solution of (30mg, 0.1238mmol) huperzine A, (59mg, 0.6190mmol) sodium tert-butoxide, and (51mg, 0.2476mmol) 1-bromo-3-chloro-5-fluorobenzene was then added. The reaction tube was sealed and allowed to react at 100°C for 24 hours. After the reaction was completed, the reaction tube was cooled to room temperature, ethyl acetate was added to the reaction system, and the mixture was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated. Purification by column chromatography yielded 35mg of a white solid in a 76% yield. The experimental data are as follows: 1H NMR(601MHz,Chloroform-d)δ13.1(s,1H),7.8(dd,J=9.5,1.3Hz,1H),7.0–6.9( m,2H),6.8–6.7(m,1H),6.4(d,J=8.8Hz,1H),5.4(dt,J=5.4,1.8Hz,1H),3.7(t, J=5.3Hz,1H),3.1(dd,J=17.0,5.1Hz,1H),2.8(dd,J=16.7,1.9Hz,1H),2.4–2.2 (m,1H),2.1(dd,J=16.8,3.3Hz,1H),2.0(d,J=1.5Hz,3H),1.6(t,J=2.1Hz,3H). 13 C NMR(151MHz,Chloroform-d)δ165.5,142.9,140.8,138.8,135.6,134.7,124.6,124.5,123.8 ,123.2,117.2,114.4,114.2,113.5,113.3,56.7,50.5,36.5,34.9,23.6,22.6.HR-ESI-MSm / z 371.1311[M+H] + (calcd for C 21 H 20 ClFN2O,371.1326).

[0046] Example 6

[0047] Compound 1f was prepared from 1-bromo-4-isopropylbenzene and huperzine A, and the reaction formula is as follows:

[0048]

[0049] In a glove box, a 10ml pressure-resistant reaction tube was added with (14.3mg, 0.01238mmol) tetrakis(triphenylphosphine)palladium, (24mg, 0.0856mmol) tri(2-thienyl)phosphine, and 1ml of anhydrous toluene and stirred for 30-45min. A toluene solution of (30mg, 0.1238mmol) huperzine A, (59mg, 0.6190mmol) sodium tert-butoxide, and (49mg, 0.2476mmol) 1-bromo-4-isopropylbenzene was then added. The reaction tube was sealed and allowed to react at 100°C for 24 hours. After the reaction was completed, the reaction tube was cooled to room temperature, ethyl acetate was added to the reaction system, and the mixture was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated. Purification by column chromatography yielded 35mg of a white solid in a 79% yield. The experimental data are as follows: 1H NMR(601MHz,Chloroform-d)δ12.8(s,1H),7.8(d,J=9.5Hz,1H),7.2–7.1(m,2H),7.0(dd,J= 7.6,2.0Hz,1H),7.0(dd,J=7.8,2.0Hz,1H),6.4(d,J=9.5Hz,1H),5.4(d,J=5.3Hz,1H),3.8– 3.7(m,1H),3.1(dd,J=16.9,5.1Hz,1H),2.9(hept,J=6.9Hz,1H),2.8(dd,J=17.0,1.9Hz,1H ),2.2(d,J=16.7Hz,1H),2.0(d,J=16.7Hz,1H),2.0(s,3H),1.6(s,3H),1.2(d,J=6.9Hz,6H). 13 C NMR(151MHz,Chloroform-d)δ165.4,147.1,143.5,143.0,140.9,136.9,134.7,127.7,127.5,127.3,1 26.9,126.4,124.8,123.6,117.0,56.6,50.6,36.6,35.0,33.9,24.2,24.1,24.0,22.6.HR-ESI-MSm / z 361.2276[M+H] + (calcd for C 24 H 29 N2O,361.2280).

[0050] Example 7

[0051] 3,5-Dimethylbromobenzene and Huperzine A were used to prepare compound 1g. The reaction formula is as follows:

[0052]

[0053] In a glove box, a 10ml pressure-resistant reaction tube was added with (14.3mg, 0.01238mmol) tetrakis(triphenylphosphine)palladium, (24mg, 0.0856mmol) tri(2-thienyl)phosphine, and 1ml of anhydrous toluene and stirred for 30-45min. A toluene solution of (30mg, 0.1238mmol) huperzine A, (59mg, 0.6190mmol) sodium tert-butoxide, and (45mg, 0.2476mmol) 3,5-dimethylbromobenzene was then added. The reaction tube was sealed and allowed to react at 100°C for 24 hours. After the reaction was completed, the reaction tube was cooled to room temperature, ethyl acetate was added to the reaction system, and the mixture was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated. Purification by column chromatography yielded 31mg of a white solid in a 74% yield. The experimental data are as follows: 1 H NMR(601MHz,Chloroform-d)δ13.1(s,1H),7.8(d,J=9.5Hz,1H),6.8(d,J=1.7H z,1H),6.7(s,1H),6.7(d,J=1.9Hz,1H),6.4(d,J=9.5Hz,1H),5.4(dt,J=5.6,1. 8Hz,1H),3.7(t,J=5.5Hz,1H),3.1(dd,J=16.9,5.1Hz,1H),2.8(dd,J=16.9,1. 9Hz,1H),2.3(s,3H),2.3(s,4H),2.1(d,J=16.7Hz,1H),2.0(s,3H),1.6(s,3H). 13 C NMR(151MHz,Chloroform-d)δ165.5,146.3,143.2,141.0,138.4,138.0,136.4,134.7,128.1,127. 4,125.5,125.3,124.8,123.7,117.0,56.6,50.7,36.5,35.0,23.9,22.7,21.5,21.4.HR-ESI-MSm / z 347.2106[M+H] + (calcd for C 23 H 27 N2O,347.2123).

[0054] Example 8

[0055] Compound 1h was prepared from bromobenzene and huperzine A, and the reaction formula is as follows:

[0056]

[0057] In a glove box, add (14.3 mg, 0.01238 mmol) tetrakis(triphenylphosphine)palladium, (24 mg, 0.0856 mmol) tri(2-thienyl)phosphine, and 1 ml of anhydrous toluene to a 10 ml pressure-resistant reaction tube and stir for 30-45 minutes. Then, add (30 mg, 0.1238 mmol) huperzine A, (59 mg, 0.6190 mmol) sodium tert-butoxide, and (38 mg, 0.2476 mmol) bromobenzene in toluene. Seal the reaction tube and react at 100°C for 24 hours. After the reaction is complete, cool the reaction tube to room temperature, add ethyl acetate, wash sequentially with water and saturated brine, dry over anhydrous sodium sulfate, and concentrate. Purify by column chromatography to obtain 25 mg of a white solid in a 65% yield. The experimental data are as follows: 1 H NMR(601MHz,Chloroform-d)δ12.9(s,1H),7.8(d,J=9.5Hz,1H),7.3(dtd,J=11.6,7.4,1.4 Hz,2H),7.2(tt,J=7.5,1.3Hz,1H),7.1(dt,J=7.6,1.8Hz,1H),7.1(dt,J=7.5,1.7Hz,1H), 6.4(d,J=9.5Hz,1H),5.4(dd,J=3.7,1.8Hz,1H),3.8(s,1H),3.1(dd,J=16.9,5.1Hz,1H),2 .8(dd,J=16.9,1.9Hz,1H),2.3–2.2(m,1H),2.1(d,J=16.8Hz,1H),2.0(s,3H),1.6(s,3H). 13 CNMR(151MHz,Chloroform-d)δ165.4,146.4,143.0,140.9,137.0,134.7,128.8,128.5,127 .8,127.6,127.2,126.5,124.8,123.6,117.1,56.6,50.6,36.5,35.0,24.0,22.6.HR-ESI-MS m / z319.1801[M+H] + (calcd for C 21 H 23 N2O,319.1810).

[0058] Example 9

[0059] Compound 1i was prepared from 4-butylbromobenzene and huperzine A, and the reaction formula is as follows:

[0060]

[0061] In a glove box, a 10ml pressure-resistant reaction tube was added with (14.3mg, 0.01238mmol) tetrakis(triphenylphosphine)palladium, (24mg, 0.0856mmol) tri(2-thienyl)phosphine, and 1ml of anhydrous toluene. The mixture was stirred for 30-45min. A toluene solution of (30mg, 0.1238mmol) huperzine A, (59mg, 0.6190mmol) sodium tert-butoxide, and (52mg, 0.2476mmol) p-butylbromobenzene was then added. The reaction tube was sealed and allowed to react at 100°C for 24 hours. After the reaction was completed, the reaction tube was cooled to room temperature, ethyl acetate was added, and the mixture was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. Purification by column chromatography yielded 37mg of a white solid, with a yield of 80%. The experimental data are as follows: 1 H NMR(601MHz,Chloroform-d)δ13.1(s,1H),7.8(d,J=9.5Hz,1H),7.1–7.1(m,2H),7.0(dd,J=7.8 ,1.8Hz,1H),7.0–6.9(m,1H),6.4(d,J=9.5Hz,1H),5.4(dt,J=5.7,1.9Hz,1H),3.7(s,1H),3.1( dd,J=16.9,5.1Hz,1H),2.8(dd,J=17.0,1.9Hz,1H),2.6–2.5(m,2H),2.2(d,J=16.7Hz,1H),2.0 (d,J=16.7Hz,1H),2.0(s,3H),1.6(d,J=1.8Hz,5H),1.3(h,J=7.4Hz,2H),0.9(t,J=7.4Hz,3H). 13 C NMR(151MHz,Chloroform-d)δ165.5,143.4,143.2,141.1,140.9,136.9,134.6,128.8,128.4,127.6,127 .4,127.2,124.8,123.7,117.0,56.6,50.6,36.6,35.4,35.0,33.8,24.0,22.6,22.5,14.1.HR-ESI-MSm / z 375.2421[M+H] + (calcd for C 25 H 31 N2O,375.2436).

[0062] Example 10

[0063] Compound 1j was prepared from 4-bromophenethyl ether and huperzine A, and the reaction formula is as follows:

[0064]

[0065] In a glove box, a 10ml pressure-resistant reaction tube was added with (14.3mg, 0.01238mmol) tetrakis(triphenylphosphine)palladium, (24mg, 0.0856mmol) tri(2-thienyl)phosphine, and 1ml of anhydrous toluene and stirred for 30-45min. A toluene solution of (30mg, 0.1238mmol) huperzine A, (59mg, 0.6190mmol) sodium tert-butoxide, and (49mg, 0.2476mmol) 4-bromophenethyl ether was then added. The reaction tube was sealed and reacted at 100°C for 24 hours. After the reaction was completed, the reaction tube was cooled to room temperature, ethyl acetate was added to the reaction system, and the mixture was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated. Purification by column chromatography yielded 27mg of a white solid, with a yield of 60%. The experimental data are as follows: 1 H NMR(601MHz,Chloroform-d)δ13.1(s,1H),7.8(d,J=9.5Hz,1H),7.0–7.0(m,1H),7.0–6.9(m ,1H),6.8(ddt,J=7.5,5.0,2.5Hz,2H),6.4(d,J=9.5Hz,1H),5.4(dt,J=3.6,1.8Hz,1H),4.0( q,J=7.0Hz,2H),3.7(d,J=5.5Hz,1H),3.1(dd,J=16.9,5.1Hz,1H),2.8(dd,J=16.9,1.9Hz,1H ),2.2(d,J=16.7Hz,1H),2.1(d,J=16.8Hz,1H),2.0(s,3H),1.6(s,3H),1.4(t,J=7.0Hz,3H). 13 C NMR(151MHz,Chloroform-d)δ165.5,157.6,143.1,141.0,138.2,137.1,134.6,128.8,128.6,126. 9,124.8,123.7,116.9,114.9,114.3,63.6,56.6,50.7,36.6,35.0,24.1,22.6,15.0.HR-ESI-MSm / z 363.2060[M+H] + (calcd for C 23 H 27 N2O2,363.2073).

[0066] Example 11

[0067] Compound 1k was prepared from p-methylbromobenzene and huperzine A, and the reaction formula is as follows:

[0068]

[0069] In a glove box, a 10ml pressure-resistant reaction tube was added with (14.3mg, 0.01238mmol) tetrakis(triphenylphosphine)palladium, (24mg, 0.0856mmol) tri(2-thienyl)phosphine, and 1ml of anhydrous toluene. The mixture was stirred for 30-45min. A toluene solution of (30mg, 0.1238mmol) huperzine A, (59mg, 0.6190mmol) sodium tert-butoxide, and (42mg, 0.2476mmol) p-methylbromobenzene was then added. The reaction tube was sealed and allowed to react at 100°C for 24 hours. After the reaction was completed, the reaction tube was cooled to room temperature, ethyl acetate was added, and the mixture was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. Purification by column chromatography yielded 27.6mg of a white solid in a 67% yield. The experimental data are as follows: 1 H NMR(601MHz,Chloroform-d)δ13.0(s,1H),7.8(d,J=9.5Hz,1H),7.1–7.1(m,2H),7.0 (dd,J=7.5,1.9Hz,1H),7.0(dd,J=7.7,1.9Hz,1H),6.4(d,J=9.5Hz,1H),5.4(d,J=5. 3Hz,1H),3.7(d,J=5.6Hz,1H),3.1(dd,J=16.9,5.1Hz,1H),2.8(dd,J=16.8,1.9Hz,1 H),2.3(s,3H),2.2(d,J=16.8Hz,1H),2.0(d,J=16.8Hz,1H),2.0(s,3H),1.6(s,3H). 13 C NMR(151MHz,Chloroform-d)δ165.5,143.3,143.1,141.0,136.1,134.6,129.5,129.1,127.6,12 7.5,127.5,127.2,124.8,124.8,117.0,56.6,50.7,36.6,35.0,24.0,22.6,21.2.HR-ESI-MSm / z 333.1950[M+H] + (calcd for C 22 H 25 N2O,333.1967).

[0070] Example 12

[0071] Compound 11 was prepared from 1-(4-bromophenyl)naphthalene and huperzine A, and the reaction formula is as follows:

[0072]

[0073] In a glove box, a 10ml pressure-resistant reaction tube was added with (14.3mg, 0.01238mmol) tetrakis(triphenylphosphine)palladium, (24mg, 0.0856mmol) tri(2-thienyl)phosphine, and 1ml of anhydrous toluene and stirred for 30-45min. A toluene solution of (30mg, 0.1238mmol) huperzine A, (59mg, 0.6190mmol) sodium tert-butoxide, and (69mg, 0.2476mmol) 1-(4-bromophenyl)naphthalene was then added. The reaction tube was sealed and allowed to react at 100°C for 24 hours. After the reaction was completed, the reaction tube was cooled to room temperature, ethyl acetate was added to the reaction system, and the mixture was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated. Purification by column chromatography yielded 38mg of a white solid in a 69% yield. The experimental data are as follows: 1 H NMR(601MHz,Chloroform-d)δ12.9(s,1H),8.0–7.8(m,4H),7.7–7.5(m,2H),7 .5–7.3(m,4H),7.3–7.3(m,1H),7.2(dd,J=7.8,1.9Hz,1H),6.4(d,J=9.5Hz,1H ),5.5(d,J=5.3Hz,1H),3.8(s,1H),3.1(dd,J=16.9,5.1Hz,1H),2.8(d,J=16. 8Hz,1H),2.3(d,J=16.7Hz,1H),2.1(d,J=16.7Hz,1H),2.1(s,3H),1.6(s,3H). 13 C NMR(151MHz,Chloroform-d)δ165.5,145.3,143.1,140.9,139.9,134.6,134.0,131.7,130.5,130.1,128.5,127.9,127.8,127.6 ,127.1,127.1,127.0,126.3,126.3,126.0,126.0,125.5,124.8,123.5,117.2,56.8,50.7,36.7,35.1,24.1,22.7.HR-ESI-MSm / z 445.2267[M+H] + (calcd for C 31 H 29 N2O,445.2280).

[0074] Example 13

[0075] Compound 1m was prepared from 1-(4-bromophenyl)pyrrole and huperzine A, and the reaction formula is as follows:

[0076]

[0077] In a glove box, a 10ml pressure-resistant reaction tube was added with (14.3mg, 0.01238mmol) tetrakis(triphenylphosphine)palladium, (24mg, 0.0856mmol) tri(2-thienyl)phosphine, and 1ml of anhydrous toluene and stirred for 30-45min. A toluene solution of (30mg, 0.1238mmol) huperzine A, (59mg, 0.6190mmol) sodium tert-butoxide, and (54mg, 0.2476mmol) 1-(4-bromophenyl)pyrrole was then added. The reaction tube was sealed and allowed to react at 100°C for 24 hours. After the reaction was completed, the reaction tube was cooled to room temperature, ethyl acetate was added to the reaction system, and the mixture was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated. Purification by column chromatography yielded 28mg of a white solid in a 61% yield. The experimental data are as follows: 1 H NMR (601MHz, Chloroform-d) δ13.1 (s, 1H), 7.8 (d, J = 9.5Hz, 1H), 7.4–7.3 (m, 2H), 7.2–7. 2(m,1H),7.2–7.1(m,1H),7.1(t,J=2.2Hz,2H),6.4(d,J=9.5Hz,1H),6.3(t,J=2.2Hz,2H ),5.4(dt,J=5.4,1.8Hz,1H),3.8(t,J=5.4Hz,1H),3.1(dd,J=16.9,5.1Hz,1H),2.8(dd, J=17.0,1.9Hz,1H),2.3(d,J=16.8Hz,1H),2.1(d,J=16.7Hz,1H),2.0(s,3H),1.6(s,3H). 13 C NMR(151MHz,Chloroform-d)δ165.5,143.7,143.1,140.9,139.3,137.9,134.7,128.9,128.8,126.3,124.7 ,123.5,120.9,120.5,119.4,119.4,117.1,110.7,110.7,56.7,50.7,36.6,35.0,24.0,22.6.HR-ESI-MSm / z 384.2060[M+H] + (calcd for C 25 H 26 N3O,384.2076).

[0078] Example 14

[0079] Compound 1n was prepared from 2-(4-bromophenyl)pyridine and huperzine A, and the reaction formula is as follows:

[0080]

[0081] In a glove box, a 10ml pressure-resistant reaction tube was added with (14.3mg, 0.01238mmol) tetrakis(triphenylphosphine)palladium, (24mg, 0.0856mmol) tri(2-thienyl)phosphine, and 1ml of anhydrous toluene and stirred for 30-45min. A toluene solution of (30mg, 0.1238mmol) huperzine A, (59mg, 0.6190mmol) sodium tert-butoxide, and (54mg, 0.2476mmol) 2-(4-bromophenyl)pyridine was then added. The reaction tube was sealed and allowed to react at 100°C for 24 hours. After the reaction was completed, the reaction tube was cooled to room temperature, ethyl acetate was added to the reaction system, and the mixture was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated. Purification by column chromatography yielded 34mg of a white solid, with a yield of 70%. The experimental data are as follows: 1 H NMR(601MHz,Chloroform-d)δ12.7(s,1H),8.7(ddd,J=4.8,1.8,1.0Hz,1H),7.9(ddd,J=17.9,8 .0,2.0Hz,2H),7.8(d,J=9.5Hz,1H),7.8(td,J=7.6,1.8Hz,1H),7.7(dt,J=8.0,1.1Hz,1H),7.3– 7.2(m,3H),6.4(d,J=9.5Hz,1H),5.4(d,J=5.3Hz,1H),3.8(s,1H),3.1(dd,J=16.9,5.1Hz,1H),2 .8(dd,J=16.8,1.9Hz,1H),2.3(d,J=16.8Hz,1H),2.1(d,J=16.8Hz,1H),2.0(s,3H),1.6(s,3H). 13 C NMR (151MHz, CDCl3) δ165.7,157.1,156.7,149.9,148.4,142.9,141.0,137.7,136.9,134.7,128.3,128.1, 127.3,126.9,126.8,124.7,123.6,122.3,120.5,117.2,56.7,50.7,36.6,35.1,23.9,22.6.HR-ESI-MSm / z 396.2060[M+H] + (calcd for C 26 H 26 N3O,396.2076).

[0082] Example 15

[0083] Compound 1o was prepared from 5-bromo-2-ethoxypyridine and huperzine A according to the following reaction formula:

[0084]

[0085] In a glove box, a 10ml pressure-resistant reaction tube was added with (14.3mg, 0.01238mmol) tetrakis(triphenylphosphine)palladium, (24mg, 0.0856mmol) tri(2-thienyl)phosphine, and 1ml of anhydrous toluene and stirred for 30-45min. A toluene solution of (30mg, 0.1238mmol) huperzine A, (59mg, 0.6190mmol) sodium tert-butoxide, and (49mg, 0.2476mmol) 5-bromo-2-ethoxypyridine was then added. The reaction tube was sealed and allowed to react at 100°C for 24 hours. After the reaction was completed, the reaction tube was cooled to room temperature, ethyl acetate was added to the reaction system, and the mixture was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated. Purification by column chromatography yielded 32mg of a white solid, with a yield of 73%. The experimental data are as follows: 1 H NMR(601MHz,Chloroform-d)δ13.0(s,1H),7.25-7.22(m,1H),7.1(d,J=8.1Hz,1 H),6.4(d,J=9.4Hz,1H),5.9(d,J=8.1Hz,1H),5.5–5.3(m,2H),4.2(dddd,J=17. 1,10.0,7.0,3.0Hz,2H),3.6(d,J=5.7Hz,1H),3.0–2.9(m,2H),2.7(dd,J=16.9, 1.9Hz,1H),2.1(d,J=16.4Hz,1H),1.9(s,3H),1.5(s,3H),1.4(t,J=7.0Hz,3H). 13 C NMR(151MHz,Chloroform-d)δ165.1,163.0,152.5,142.0,138.2,133.8,133.2,125.6,124.6,1 22.9,119.6,118.0,108.7,97.0,62.0,56.6,50.3,34.6,33.7,22.8,14.9,12.5.HR-ESI-MSm / z 364.2006[M+H] + (calcd for C 22 H 26 N3O2,364.2025).

[0086] Example 16

[0087] Compound 1p was prepared from 1,4-dibromobenzene and huperzine A. The reaction formula is as follows:

[0088]

[0089] In a glove box, a 10ml pressure-resistant reaction tube was added with (14.3mg, 0.01238mmol) tetrakis(triphenylphosphine)palladium, (24mg, 0.0856mmol) tri(2-thienyl)phosphine, and 1ml of anhydrous toluene and stirred for 30-45min. A toluene solution of (30mg, 0.1238mmol) huperzine A, (59mg, 0.6190mmol) sodium tert-butoxide, and (58mg, 0.2476mmol) 1,4-dibromobenzene was then added. The reaction tube was sealed and allowed to react at 100°C for 24 hours. After the reaction was completed, the reaction tube was cooled to room temperature, ethyl acetate was added to the reaction system, and the mixture was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated. Purification by column chromatography yielded 26mg of a white solid in a 53% yield. The experimental data are as follows: 1 H NMR(601MHz,Chloroform-d)δ12.9(s,1H),7.8(d,J=9.5Hz,1H),7.4(ddd,J=13.5,8 .0,2.1Hz,2H),7.0(dd,J=8.0,2.2Hz,1H),7.0(dd,J=8.1,2.2Hz,1H),6.4(d,J=9.5 Hz,1H),5.4(d,J=5.3Hz,1H),3.7(s,1H),3.1(dd,J=16.9,5.1Hz,1H),2.8(dd,J=17 .1,1.9Hz,1H),2.2(d,J=16.8Hz,1H),2.1(d,J=16.8Hz,1H),2.0(s,3H),1.6(s,3H). 13 C NMR (151MHz, CDCl3) δ165.5,145.5,145.4,143.0,140.9,137.5,134.7,131.9,131.6,129 .5,129.4,125.9,124.7,120.3,117.2,56.7,50.6,36.6,35.0,23.9,22.6.HR-ESI-MSm / z 397.0901[M+H] + (calcd for C 21 H 22 BrN2O,397.0916).

[0090] Example 17

[0091] 4-Bromo-N,N-dimethylaniline and huperzine A were used to prepare compound 1q, and the reaction formula is as follows:

[0092]

[0093] In a glove box, a 10ml pressure-resistant reaction tube was added with (14.3mg, 0.01238mmol) tetrakis(triphenylphosphine)palladium, (24mg, 0.0856mmol) tri(2-thienyl)phosphine, and 1ml of anhydrous toluene. The mixture was stirred for 30-45min. A toluene solution of (30mg, 0.1238mmol) huperzine A, (59mg, 0.6190mmol) sodium tert-butoxide, and (49mg, 0.2476mmol) 4-bromo-N,N-dimethylaniline was then added. The reaction tube was sealed and allowed to react at 100°C for 24 hours. After the reaction was completed, the reaction tube was cooled to room temperature, ethyl acetate was added, and the mixture was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated. Purification by column chromatography yielded 28mg of a white solid in a 64% yield. The experimental data are as follows: 1 H NMR(601MHz,Chloroform-d)δ13.1(s,1H),7.8(d,J=9.5Hz,1H),7.0–7.0(m,1H) ,6.9–6.9(m,1H),6.7–6.6(m,2H),6.4(d,J=9.5Hz,1H),5.4(dt,J=5.5,1.8Hz,1H ),3.7(t,J=5.4Hz,1H),3.1(dd,J=16.9,5.2Hz,1H),2.9(s,6H),2.8(dd,J=16.9, 1.9Hz,1H),2.3(d,J=16.7Hz,1H),2.1(d,J=16.8Hz,1H),2.0(s,3H),1.6(s,3H). 13 C NMR (151MHz, CDCl3) δ163.6,150.0,142.7,140.4,136.0,134.3,129.1,129.1,128.1,125.2 ,124.3,122.6,112.3,112.3,111.1,54.4,49.2,40.7,35.0,33.0,22.7,12.4.HR-ESI-MSm / z 362.2220[M+H] + (calcd for C 23 H 28 N3O,362.2232).

[0094] Example 18

[0095] Compound 1r was prepared from 1-bromo-4-trimethylsilylbenzene and huperzine A, and the reaction formula is as follows:

[0096]

[0097] In a glove box, a 10ml pressure-resistant reaction tube was added with (14.3mg, 0.01238mmol) tetrakis(triphenylphosphine)palladium, (24mg, 0.0856mmol) tri(2-thienyl)phosphine, and 1ml of anhydrous toluene and stirred for 30-45min. A toluene solution of (30mg, 0.1238mmol) huperzine A, (59mg, 0.6190mmol) sodium tert-butoxide, and (56mg, 0.2476mmol) 1-bromo-4-trimethylsilylbenzene was then added. The reaction tube was sealed and allowed to react at 100°C for 24 hours. After the reaction was completed, the reaction tube was cooled to room temperature, ethyl acetate was added to the reaction system, and the mixture was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated. Purification by column chromatography yielded 33mg of a white solid, with a yield of 70%. The experimental data are as follows: 1 H NMR (601MHz, Chloroform-d) δ12.8 (s, 1H), 7.8 (d, J = 9.5Hz, 1H), 7.4 (dd, J = 12. 7,7.4Hz,2H),7.1(ddd,J=31.3,7.4,1.7Hz,2H),6.4(d,J=9.5Hz,1H),5.4(d,J= 5.3Hz,1H),3.7(d,J=5.7Hz,1H),3.1(dd,J=16.9,5.1Hz,1H),2.8–2.7(m,1H),2 .3(d,J=16.8Hz,1H),2.1(d,J=16.7Hz,1H),2.0(s,3H),1.6(s,3H),0.3(s,9H). 13 C NMR (151MHz, CDCl3) δ165.4,146.8,143.0,140.9,138.4,137.0,134.7,133.8,133.5,127.2,127. 1,127.0,124.8,123.6,117.1,56.6,50.6,36.5,35.0,23.9,22.6,-0.9,-0.9,-0.9.HR-ESI-MSm / z 391.2200[M+H] + (calcd forC 24 H 31 N2OSi,391.2206).

[0098] Test Example 1

[0099] Acetylcholinesterase activity assay of derivatives

[0100] 1. Experimental Materials: Acetylcholinesterase (AChE) from electric eel was purchased from Macklin, and 5,5'-dithiodinitrobenzoic acid (DTNB) and acetylthiocholine (ATC) were purchased from Adamas.

[0101] 2. Experimental procedures: The inhibitory activity of the compounds against AChE was determined using the Ellman method. Huperzine A and the synthesized compounds were dissolved in DMSO to 50 μM / L. All assays were performed in 0.1 M NaH2PO4 / Na2HPO4 buffer (pH 6.7) using a spectraMax absorbance meter. The enzyme solution was prepared by dissolving 2.5 mg (0.5 U / mL) of AChE in pH 8.0 buffer (1 mL). In the experimental group of a 96-well plate, phosphate buffer (pH 6.7, 140 μL), Huperzine A derivatives (I = 100 μM / L or 50 μM / L, 10 μL), and 0.5 U / mL enzyme (10 μL) were added. Blank group A was supplemented with phosphate buffer (pH 6.7, 140 μL) and phosphate buffer (pH 8.0, 20 μL). Blank group B was supplemented with phosphate buffer (pH 6.7, 140 μL), phosphate buffer (pH 8.0, 10 μL) and 10 μL of DMSO. Blank group C was supplemented with phosphate buffer (pH 6.7, 140 μL) and phosphate buffer (pH 8.0, 10 μL). After incubation for 20 minutes, DTNB (0.75 mM / L, 10 μL) and acetylthiocholine chloride (1.5 mM / L, 10 μL) were added and incubated for 20 minutes. The inhibitory activity was calculated by measuring the absorbance at 405 nm. Each concentration was tested in triplicate.

[0102] 3. Experimental results:

[0103] The inhibition rate was calculated according to the following formula:

[0104]

[0105] The specific results are shown in Table 1. Some compounds showed highly effective acetylcholinesterase inhibitory activity, which was better than the positive control huperzine A.

[0106] Table 1. Acetylcholinesterase inhibition rate of compounds 1a-1r

[0107]

[0108]

[0109] a The data are the mean ± standard deviation of at least 5 measurements.

[0110] Test Example 2

[0111] Determination of cytotoxicity and neuroprotective activity of derivatives

[0112] 1. Experimental Materials: Culture medium (DMEM), 10% fetal bovine serum (FBS), and MTT (M2128) were purchased from Sigma-Aldrich (St. Louis, Mo., USA). SH-SY5Y cells were purchased from ATCC, Manassas, VA, USA.

[0113] 2. Experimental steps: Cells were cultured in DMEM medium containing 10% fetal bovine serum and incubated at 37°C and 5% CO2. SH-SY5Y cells were plated at 5×10 3 Cells were seeded at a density of 100 μg / well in a 96-well plate. After a 12-hour pre-incubation, different test compounds (100 μl, 50 μM / L, dissolved in 100% DMSO) were added and treated for 24 hours. The final DMSO concentration was less than 0.1%. Control cells were treated with Huperzine A containing 0.1% DMSO, and DMSO alone served as a negative control.

[0114] Subsequently, 20 μl of MTT solution (5 mg / ml) was added to each well and incubated for another 4 hours. The supernatant was discarded, and 150 μl of DMSO was added to each well to dissolve the formazan crystals. The absorbance was measured at a wavelength of 492 nm using a microplate reader (Thermo MK3, USA).

[0115] The neuroprotective activity was evaluated using a human neuroblastoma SH-SY5Y cell model treated with hydrogen peroxide (H2O2). The cells were cultured in DMEM medium containing 10% fetal bovine serum and incubated at 37°C in 5% CO2. SH-SY5Y cells were plated at 5×10 3 Cells were seeded at a density of 100 μL / well in a 96-well plate. After a 12-hour preincubation, the test compounds (100 μL, 50 μM / L, dissolved in 100% DMSO) were added for 24 hours. 100 μL of 1.2 mM / L H₂O₂ was then added and incubated for an additional 4 hours. Subsequently, 20 μL of MTT solution (5 mg / mL) was added to each well and incubated for another 4 hours. The supernatant was discarded, and 150 μL of DMSO was added to each well to dissolve the formazan crystals. Absorbance was measured at 492 nm using a microplate reader (Thermo MK3, USA).

[0116] 3. Experimental results:

[0117] As shown in Appendix 2 and Table 3, some compounds exhibited low toxicity and were safer than huperzine A. They also showed good neuroprotective activity in the H2O2-induced SH-SY5Y cell injury model and are lead compounds for in-depth activity studies.

[0118] Table 2. Survival rate of SH-SY5Y cells treated with compounds at a concentration of 50 μM / L

[0119]

[0120] a The data are the mean ± standard deviation of at least 5 measurements.

[0121] Table 3. Survival rate of SH-SY5Y cell injury model induced by H2O2 when the compound was administered at a concentration of 50 μM / L

[0122]

[0123] a The data are the mean ± standard deviation of at least 5 measurements.

[0124] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0125] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention.

Claims

1. Huperzine A C12 arylated derivatives, having the structure shown in general formula I: in: In general formula I, the R substituent is selected from: 4-chlorobenzene, 4-tert-butylbenzene, 4-fluorobenzene, 4-methoxybenzene, 3-chloro-5-fluorobenzene, 4-isopropylbenzene, 3,5-dimethyl, phenyl, 4-n-butylbenzene, 4-ethoxybenzene, 4-methylbenzene, 4-naphthylbenzene, 4-pyrrolobenzene, 4-(2-pyridine)benzene, 2-ethoxypyridine, 4-bromobenzene, N,N-dimethylaniline, and 4-trimethylsilylbenzene.

2. A method for preparing the C12-arylated derivatives of huperzine A according to claim 1, comprising: Under an inert atmosphere, a Heck coupling reaction is carried out with huperzine A and an aryl bromide as raw materials in the presence of a catalytic system consisting of tetrakis(triphenylphosphine)palladium, tri(2-thienyl)phosphine, a solvent and a base to obtain a series of huperzine A C12 arylated derivatives.

3. The preparation method according to claim 2, wherein: The reaction temperature of the heck coupling reaction is 90° C. to 110° C., and the reaction time is 24 to 48 hours.

4. The preparation method according to claim 3, wherein: The reaction temperature is 100° C. and the reaction time is 24 h.

5. The preparation method according to claim 2, wherein: The molar ratio of huperzine A, aryl bromide, tetrakis(triphenylphosphine)palladium, tri(2-thienyl)phosphine and base is 1:2:0.1:0.7:

5.

6. The preparation method according to claim 2, wherein: The solvent is toluene; The base is sodium tert-butoxide.

7. A series of huperzine A C12 arylated derivatives prepared according to the preparation method according to any one of claims 2 to 6.

8. Use of the C12-arylated series of huperzine A derivatives according to claim 1 or 7 in the preparation of drugs for treating degenerative diseases of the central nervous system.

9. The use according to claim 8, wherein: The central nervous system degenerative diseases include: Alzheimer's disease; and Amyotrophic lateral sclerosis.

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