Galantamine analogs, processes for their preparation and use thereof

Abstract

This invention relates to a galantamine analogue with cholinesterase-inhibiting activity, its preparation method, and its application. The general structural formula is shown in formula (IA), (IB), or (IC). In formula (IA), R1 is selected from hydrogen, o-fluorine, m-fluorine, p-fluorine, 2,4-difluoro, m-trifluoromethyl, p-methyl, 3,5-dimethoxy, p-chloro, p-nitro, p-cyano, or p-trifluoromethoxy. In formula (IB), R2 is selected from phenyl, o-fluorine, m-fluorine, p-fluorine, 2,4-difluorophenyl, 3,5-difluorophenyl, o-methylphenyl, p-methylphenyl, p-methoxyphenyl, indole, p-cyanophenyl, p-trifluoromethylphenyl, p-trifluoromethoxyphenyl, p-nitrophenyl, or a naphthalene ring. In formula (IC), R3 is selected from hydrogen, o-fluorine, m-fluorine, p-fluorine, m-chloro, p-chloro, p-methyl, o-methoxy, m-methoxy, or p-methoxy. The galantamine analogue of this invention has superior inhibitory activity against cholinesterase compared to galantamine, and is expected to be used to treat cholinergic dysfunction-related diseases.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, specifically relating to a galantamine analog that inhibits cholinesterase activity, its preparation method, and its application. Background Technology

[0002] Alzheimer's disease (AD) is a devastating and progressive neurodegenerative disease that commonly affects the elderly. Clinically, it is characterized by a comprehensive range of dementia symptoms, including learning and memory impairment, executive function decline, and behavioral changes. The FDA has described it as "a devastating disease." A key aspect of the pathogenesis of AD is the depletion of the neurotransmitter acetylcholine (ACh).

[0003] Galanthamine is the most widely distributed and important alkaloid in the Amaryllidaceae family. It was approved by the FDA as an AChEI in 2001. It has a dual mechanism of action on the cholinergic system: it can reversibly inhibit acetylcholinesterase (AChE) and allosterically regulate acetylcholine receptors, thereby enhancing the transmission of the nicotinic neurotransmitter and promoting the release of more ACh.

[0004] Although galantamine exhibits low toxicity, the inventors have discovered that galantamine's inhibitory rate on cholinesterase and its IC50 value... 50 There is still room for improvement. Therefore, from the perspective of medicinal chemistry, the core structure of galantamine is suitable as an ideal lead part for designing highly effective and low-toxicity anti-AD compounds. Providing a more superior AChEI is the technical problem that this invention needs to solve. Summary of the Invention

[0005] To address the problems existing in the prior art, the inventors designed and synthesized a series of novel galantamine analogs, and found that some compounds exhibited superior inhibitory activity against AChE and butyrylcholinesterase (BuChE) compared to galantamine, and their IC50 values ​​were significantly higher. 50 The value is less than the IC50 value of galantamine. 50 Therefore, the galantamine analogues provided by this invention hold promise for development into novel drugs for treating cholinergic dysfunction-related diseases, such as Alzheimer's disease.

[0006] Specifically, the present invention is achieved through the following technical solutions:

[0007] In a first aspect, the present invention provides a galantamine analogue, said galantamine analogue being a compound of formula (IA), (IB) or (IC), or a pharmaceutically acceptable salt thereof:

[0008]

[0009] In the formula (IA), R1 is selected from one of hydrogen, o-fluorine, m-fluorine, p-fluorine, 2,4-difluoro, m-trifluoromethyl, p-methyl, 3,5-dimethoxy, p-chloro, p-nitro, p-cyano, and p-trifluoromethoxy.

[0010] In the formula (ⅠB), R2 is selected from one of phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, o-methylphenyl, p-methylphenyl, p-methoxyphenyl, indole, p-cyanophenyl, p-trifluoromethylphenyl, p-trifluoromethoxyphenyl, p-nitrophenyl, and naphthyl ring.

[0011] In the formula (IC), R3 is selected from one of hydrogen, o-fluorine, m-fluorine, p-fluorine, m-chlorine, p-chlorine, p-methyl, o-methoxy, m-methoxy, and p-methoxy.

[0012] Alternatively, in the above-mentioned galantamine analogues, the structure of the galantamine analogue is shown in the following formula:

[0013]

[0014] Wherein, R1 is selected from one of hydrogen, o-fluorine, m-fluorine, p-fluorine, 2,4-difluoro, m-trifluoromethyl, p-methyl, 3,5-dimethoxy, p-chloro, p-nitro, p-cyano, and p-trifluoromethoxy; R2 is selected from one of phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, o-methylphenyl, p-methylphenyl, p-methoxyphenyl, indole, p-cyanophenyl, p-trifluoromethylphenyl, p-trifluoromethoxyphenyl, p-nitrophenyl, and naphthyl ring; R3 is selected from one of hydrogen, o-fluorine, m-fluorine, p-fluorine, m-chloro, p-chloro, p-methyl, o-methoxy, m-methoxy, and p-methoxy.

[0015] Alternatively, in the above-mentioned galantamine analogues, the structure of the galantamine analogue is as follows:

[0016]

[0017]

[0018] In a second aspect, the present invention provides a method for preparing a galantamine analogue as described in the first aspect above, wherein the galantamine analogue is a compound represented by formula (IA), and the preparation method comprises the following steps:

[0019] (1) Dissolve 4-tert-butoxycarbonylaminopiperidine in an organic solvent, and slowly add benzyl bromide (II) containing the R-substituted group. a Under the action of the alkaline catalyst triethylamine, the reaction at room temperature yields the product with the structural formula (Ⅲ). aIntermediate 1 of ); the R group is selected from one of hydrogen, o-fluorine, m-fluorine, p-fluorine, 2,4-difluoro, m-trifluoromethyl, p-methyl, 3,5-dimethoxy, p-chloro, p-nitro, p-cyano, and p-trifluoromethoxy.

[0020] (2) Intermediate 1 was dissolved in anhydrous DCM, trifluoroacetic acid was added, and the mixture was stirred at room temperature to obtain the structure of formula (Ⅳ). a Intermediate 2 of )

[0021] (3) Galantamine and di(p-nitrobenzene) carbonate were dissolved in anhydrous DCM, stirred for 10-15 min, and then triethylamine was slowly added dropwise. The reaction was carried out at room temperature to obtain the structure of formula (V). a Intermediate 3;

[0022] (4) Dissolve intermediate 2 described in step (2) and intermediate 3 described in step (3) in anhydrous DCM, and react at room temperature under the action of alkaline catalyst DMAP to obtain the compound shown in formula (IA) of galantamine analog.

[0023] The structural formula in the above steps is shown below:

[0024]

[0025] Alternatively, the present invention provides a method for preparing a galantamine analogue as described in the first aspect above, wherein the galantamine analogue is a compound of formula (IB), and the preparation method comprises the following steps:

[0026] (1) Galantamine and di(p-nitrobenzene) carbonate were dissolved in anhydrous DCM, stirred for 10-15 min, and then triethylamine was slowly added dropwise. The reaction was carried out at room temperature to obtain the product with the structural formula (II). b Intermediate 1 of )

[0027] (2) Intermediate 1 and primary amine (III) containing R-substituted groups b Dissolved in anhydrous DCM, the compound was reacted at room temperature with the alkaline catalyst DMAP to give the galantamine analog of formula (IB), wherein the R group is selected from one of phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, o-methylphenyl, p-methylphenyl, p-methoxyphenyl, indole, p-cyanophenyl, p-trifluoromethylphenyl, p-trifluoromethoxyphenyl, p-nitrophenyl, and naphthyl ring;

[0028] The structural formula in the above steps is shown below:

[0029]

[0030] Alternatively, the present invention provides a method for preparing a galantamine analogue as described in the first aspect above, wherein the galantamine analogue is a compound represented by formula (IC), and the preparation method comprises the following steps:

[0031] (1) Galantamine was dissolved in anhydrous DCM. Under ice bath conditions, the mixture was stirred for 20–40 min, and then 5-bromo-2-chloromethylenepyridine was slowly added. The reaction was carried out under the action of an alkaline catalyst to obtain the structure of formula (II). c Intermediate 1 of )

[0032] (2) Intermediate 1 and benzylboronic acid pinacol ester (III) containing R-substituted groups c Dissolved in an organic solvent, under nitrogen protection and with the aid of a catalyst, the mixture is heated to 75–95 °C to carry out a coupling reaction to obtain a galantamine analog (IC), wherein the R group is selected from one of hydrogen, o-fluorine, m-fluorine, p-fluorine, m-chloro, p-chloro, p-methyl, o-methoxy, m-methoxy, and p-methoxy.

[0033] The structural formula in the above steps is shown below:

[0034]

[0035] Alternatively, in the method for preparing the compound represented by the galantamine analog (IA), the organic solvent in step (1) is anhydrous ethanol.

[0036] Alternatively, in the preparation method of the compound represented by the galantamine analog (IC), the alkaline catalyst in step (1) is DIPEA, the organic solvent is a mixed solution of 1,4-dioxane and water with a mixing volume ratio of 4:1, and the catalyst is K2CO3, CsF and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride.

[0037] In a third aspect, the present invention provides the use of the galantamine analogue described in the first aspect above in the preparation of cholinesterase inhibitors.

[0038] In a fourth aspect, the present invention provides the use of the galantamine analogue described in the first aspect above in the preparation of a medicament for treating cholinergic dysfunction-related diseases.

[0039] Alternatively, the cholinergic dysfunction-related disease is Alzheimer's disease.

[0040] The beneficial effects of this invention are as follows: the galantamine analogue provided by this invention has a better inhibition rate against AChE and BuChE than galantamine, and its IC50 is higher. 50 The value is less than the IC50 value of galantamine. 50This value holds promise for development into a new drug for treating diseases related to cholinergic dysfunction. Detailed Implementation

[0041] The present invention will be explained below with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of the invention. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the field or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0042] The instruments and equipment used in the following examples: For parameters not specifically specified in the following examples, conventional techniques can be used. NMR spectroscopy was performed using an AVANCEⅢHD 600MHz NMR spectrometer from Bruker BioSpin GmbH, Switzerland, with deuterated chloroform or deuterated DMSO as the solvent; compound IC 50 The values ​​were determined using a multi-functional microplate reader from Thermo Fisher Scientific, USA.

[0043] Example 1

[0044] The preparation of a galantamine analog (IA) compound and its intermediates in this embodiment are described in the following specific synthetic steps:

[0045] (1) Synthesis of intermediate 1-1: Galantamine (0.6 g, 2.1 mmol) and di(p-nitrobenzene) carbonate (0.95 g, 3.13 mmol) were dissolved in anhydrous DCM. After stirring for 10-15 min, triethylamine (0.21 g, 2.1 mmol) was slowly added dropwise. After reacting at room temperature for 6 h, the solvent was removed, and the mixture was separated by column chromatography to obtain 0.92 g of oily liquid, which is intermediate 1-1, with a yield of 97%.

[0046] (2) Synthesis of intermediate 1-2-1: 4-tert-butoxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of anhydrous ethanol, and benzyl bromide (0.43 g, 2.5 mmol) was slowly added. The reaction was carried out at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed, and the mixture was separated by column chromatography to obtain 0.71 g of an oily liquid, which is intermediate 1-2-1, with a yield of 98%.

[0047] (3) Synthesis of intermediate 1-2-2: Intermediate 1-2-1 (0.71 g, 2.45 mmol) was dissolved in anhydrous DCM, and trifluoroacetic acid (0.84 g, 7.34 mmol) was added. After reacting at room temperature for 4 h, the solvent was removed, the pH was adjusted to weakly alkaline with saturated sodium bicarbonate solution, and then extracted with ethyl acetate. The supernatant was collected, the solvent was removed, and 0.32 g of oily liquid was obtained, which is intermediate 1-2-2 with a yield of 69%.

[0048] (4) Synthesis of intermediate 1-3-1: 4-tert-butoxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of anhydrous ethanol, and 4-fluorobenzyl bromide (0.47 g, 2.5 mmol) was slowly added. The reaction was carried out at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed, and the mixture was separated by column chromatography to obtain 0.67 g of an oily liquid, which is intermediate 1-3-1, with a yield of 87%.

[0049] (5) Synthesis of intermediate 1-3-2: Intermediate 1-3-1 (0.67 g, 2.2 mmol) was dissolved in anhydrous DCM, and trifluoroacetic acid (0.75 g, 6.6 mmol) was added. After reacting at room temperature for 4 h, the solvent was removed, the pH was adjusted to weakly alkaline with saturated sodium bicarbonate solution, and then extracted with ethyl acetate. The supernatant was collected, the solvent was removed, and 0.39 g of oily liquid was obtained, which is intermediate 1-3-2 with a yield of 85%.

[0050] (6) Synthesis of intermediate 1-4-1: 4-tert-butoxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of anhydrous ethanol, and 2-fluorobenzyl bromide (0.47 g, 2.5 mmol) was slowly added. The reaction was carried out at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed, and the mixture was separated by column chromatography to obtain 0.69 g of an oily liquid, which is intermediate 1-4-1, with a yield of 90%.

[0051] (7) Synthesis of intermediate 1-4-2: Intermediate 1-4-1 (0.69 g, 2.2 mmol) was dissolved in anhydrous DCM, and trifluoroacetic acid (0.75 g, 6.6 mmol) was added. After reacting at room temperature for 4 h, the solvent was removed, the pH was adjusted to weakly alkaline with saturated sodium bicarbonate solution, and then extracted with ethyl acetate. The supernatant was collected, the solvent was removed, and 0.25 g of oily liquid was obtained, which is intermediate 1-4-2 with a yield of 55%.

[0052] (8) Synthesis of intermediate 1-5-1: 4-tert-butoxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of anhydrous ethanol, and 3-fluorobenzyl bromide (0.47 g, 2.5 mmol) was slowly added. The reaction was carried out at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed, and the mixture was separated by column chromatography to obtain 0.72 g of an oily liquid, which is intermediate 1-5-1, with a yield of 94%.

[0053] (9) Synthesis of intermediate 1-5-2: Intermediate 1-5-1 (0.72 g, 2.34 mmol) was dissolved in anhydrous DCM, and trifluoroacetic acid (0.8 g, 7.02 mmol) was added. After reacting at room temperature for 4 h, the solvent was removed, the pH was adjusted to weakly alkaline with saturated sodium bicarbonate solution, and then extracted with ethyl acetate. The supernatant was collected, the solvent was removed, and 0.35 g of oily liquid was obtained, which is intermediate 1-5-2 with a yield of 72%.

[0054] (10) Synthesis of intermediate 1-6-1: 4-tert-butoxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of anhydrous ethanol, and 3-trifluoromethylbenzyl bromide (0.60 g, 2.5 mmol) was slowly added. The reaction was carried out at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed, and the mixture was separated by column chromatography to obtain 0.86 g of an oily liquid, which is intermediate 1-6-1, with a yield of 96%.

[0055] (11) Synthesis of intermediate 1-6-2: Intermediate 1-6-1 (0.86 g, 2.4 mmol) was dissolved in anhydrous DCM, and trifluoroacetic acid (0.82 g, 7.2 mmol) was added. After reacting at room temperature for 4 h, the solvent was removed, the pH was adjusted to weakly alkaline with saturated sodium bicarbonate solution, and then extracted with ethyl acetate. The supernatant was collected, the solvent was removed, and 0.47 g of oily liquid was obtained, which is intermediate 1-6-2 with a yield of 76%.

[0056] (12) Synthesis of intermediate 1-7-1: 4-tert-butoxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of anhydrous ethanol, and 4-methylbenzyl bromide (0.46 g, 2.5 mmol) was slowly added. The reaction was carried out at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed, and the mixture was separated by column chromatography to obtain 0.70 g of an oily liquid, which is intermediate 1-7-1, with a yield of 92%.

[0057] (13) Synthesis of intermediate 1-7-2: Intermediate 1-7-1 (0.7 g, 2.3 mmol) was dissolved in anhydrous DCM, and trifluoroacetic acid (0.79 g, 6.9 mmol) was added. After reacting at room temperature for 4 h, the solvent was removed, the pH was adjusted to weakly alkaline with saturated sodium bicarbonate solution, and then extracted with ethyl acetate. The supernatant was collected, the solvent was removed, and 0.36 g of oily liquid was obtained, which is intermediate 1-7-2 with a yield of 77%.

[0058] (14) Synthesis of intermediate 1-8-1: 4-tert-butoxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of anhydrous ethanol, and 3,5-dimethoxybenzyl bromide (0.58 g, 2.5 mmol) was slowly added. The reaction was carried out at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed, and the mixture was separated by column chromatography to obtain 0.86 g of an oily liquid, which is intermediate 1-8-1, with a yield of 98%.

[0059] (15) Synthesis of intermediate 1-8-2: Intermediate 1-8-1 (0.86 g, 2.46 mmol) was dissolved in anhydrous DCM, and trifluoroacetic acid (0.84 g, 7.38 mmol) was added. After reacting at room temperature for 4 h, the solvent was removed, the pH was adjusted to weakly alkaline with saturated sodium bicarbonate solution, and then extracted with ethyl acetate. The supernatant was collected, the solvent was removed, and 0.49 g of oily liquid was obtained, which is intermediate 1-8-2 with a yield of 80%.

[0060] (16) Synthesis of intermediate 1-9-1: 4-tert-butoxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of anhydrous ethanol, and 2,4-difluorobenzyl bromide (0.52 g, 2.5 mmol) was slowly added. The reaction was carried out at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed, and the mixture was separated by column chromatography to obtain 0.78 g of an oily liquid, which is intermediate 1-9-1, with a yield of 96%.

[0061] (17) Synthesis of intermediate 1-9-2: Intermediate 1-9-1 (0.78 g, 2.39 mmol) was dissolved in anhydrous DCM, and trifluoroacetic acid (0.82 g, 7.17 mmol) was added. After reacting at room temperature for 4 h, the solvent was removed, the pH was adjusted to weakly alkaline with saturated sodium bicarbonate solution, and then extracted with ethyl acetate. The supernatant was collected, the solvent was removed, and 0.38 g of oily liquid was obtained, which is intermediate 1-9-2 with a yield of 70%.

[0062] (18) Synthesis of intermediate 1-10-1: 4-tert-butoxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of anhydrous ethanol, and 4-chlorobenzyl bromide (0.51 g, 2.5 mmol) was slowly added. The reaction was carried out at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed, and the mixture was separated by column chromatography to obtain 0.76 g of an oily liquid, which is intermediate 1-10-1, with a yield of 94%.

[0063] (19) Synthesis of intermediate 1-10-2: Intermediate 1-10-1 (0.76 g, 2.35 mmol) was dissolved in anhydrous DCM, and trifluoroacetic acid (0.8 g, 7.04 mmol) was added. After reacting at room temperature for 4 h, the solvent was removed, the pH was adjusted to weakly alkaline with saturated sodium bicarbonate solution, and then extracted with ethyl acetate. The supernatant was collected, the solvent was removed, and 0.18 g of oily liquid was obtained, which is intermediate 1-10-2, with a yield of 34%.

[0064] (20) Synthesis of intermediate 1-11-1: 4-tert-butoxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of anhydrous ethanol, and 4-nitrobenzyl bromide (0.54 g, 2.5 mmol) was slowly added. The reaction was carried out at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed, and the mixture was separated by column chromatography to obtain 0.81 g of an oily liquid, which is intermediate 1-11-1, with a yield of 97%.

[0065] (21) Synthesis of intermediate 1-11-2: Intermediate 1-11-1 (0.81 g, 2.42 mmol) was dissolved in anhydrous DCM, and trifluoroacetic acid (0.83 g, 7.26 mmol) was added. After reacting at room temperature for 4 h, the solvent was removed, the pH was adjusted to weakly alkaline with saturated sodium bicarbonate solution, and then extracted with ethyl acetate. The supernatant was collected, the solvent was removed, and 0.41 g of oily liquid was obtained, which is intermediate 1-11-2 with a yield of 72%.

[0066] (22) Synthesis of intermediate 1-12-1: 4-tert-butoxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of anhydrous ethanol, and 4-cyanobenzyl bromide (0.49 g, 2.5 mmol) was slowly added. The reaction was carried out at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed, and the mixture was separated by column chromatography to obtain 0.75 g of an oily liquid, which is intermediate 1-12-1, with a yield of 95%.

[0067] (23) Synthesis of intermediate 1-12-2: Intermediate 1-12-1 (0.75 g, 2.38 mmol) was dissolved in anhydrous DCM, and trifluoroacetic acid (0.81 g, 7.14 mmol) was added. After reacting at room temperature for 4 h, the solvent was removed, the pH was adjusted to weakly alkaline with saturated sodium bicarbonate solution, and then extracted with ethyl acetate. The supernatant was collected, the solvent was removed, and 0.24 g of oily liquid was obtained, which is intermediate 1-12-2, with a yield of 47%.

[0068] (24) Synthesis of intermediate 1-13-1: 4-tert-butoxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of anhydrous ethanol, and 4-trifluorooxymethylbenzyl bromide (0.64 g, 2.5 mmol) was slowly added. The reaction was carried out at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed, and the mixture was separated by column chromatography to obtain 0.89 g of an oily liquid, which was intermediate 1-13-1, with a yield of 95%.

[0069] (25) Synthesis of intermediate 1-13-2: Intermediate 1-13-1 (0.89 g, 2.38 mmol) was dissolved in anhydrous DCM, and trifluoroacetic acid (0.81 g, 7.14 mmol) was added. After reacting at room temperature for 4 h, the solvent was removed, the pH was adjusted to weakly alkaline with saturated sodium bicarbonate solution, and then extracted with ethyl acetate. The supernatant was collected, the solvent was removed, and 0.47 g of oily liquid was obtained, which is intermediate 1-13-2 with a yield of 72%.

[0070] (26) Synthesis of galantamine analog A1: Intermediate 1-1 (0.6 g, 1.33 mmol) and intermediate 1-2-2 (0.25 g, 1.33 mmol) were dissolved in anhydrous DCM. A basic catalyst, 4-dimethylaminopyridine (0.24 g, 2.1 mmol), was added. After reacting at room temperature for 5 h, the solvent was removed, and the mixture was separated by column chromatography to obtain 233 mg of an oily liquid, which was galantamine analog A1, in 33% yield. NMR data are as follows: 1HNMR(600MHz,DMSO-d6)δ7.33–7.20(m,5H),7.15(d,J=7.8Hz,1H),6.69(d,J=8.2Hz,1H),6.56(d,J=8.1Hz,1H),6.20(d,J=10.4Hz,1H),5.79 –5.76(m,1H),5.07(t,J=5.4Hz,1H),4.42(s,1H),4.07(d,J=15.0Hz,1H),3.72(s,3H),3.56(d,J=15.2Hz,1H),3.41(s,2H),3.35(s,1H),3.27 (dt,J=8.0,4.2Hz,1H),3.18(t,J=13.7Hz,1H),2.90(d,J=14.3Hz,1H),2.77–2.69(m,2H),2.41–2.34(m,1H),2.23(s,3H),2.19(ddd,J=16.5, 6.6,3.7Hz,1H),2.02–1.98(m,1H),1.95–1.91(m,1H),1.68(dd,J=26.1,12.8Hz,2H),1.51–1.47(m,1H),1.40(ddd,J=28.6,11.8,3.6Hz,2H); 13 C NMR(151MHz,DMSO)δ155.84,146.53,143.62,139.11,132.84,129.18,128.59,127.29,123.81,121.49 ,111.89,85.99,63.05,62.61,59.88,55.91,53.45,52.63,48.56,47.80,41.55,33.79,32.22,28.22.

[0071] (27) Synthesis of galantamine analog A2: Intermediate 1-1 (0.6 g, 1.33 mmol) and intermediate 1-3-2 (0.28 g, 1.33 mmol) were dissolved in anhydrous DCM. A basic catalyst, 4-dimethylaminopyridine (0.24 g, 2.1 mmol), was added. After reacting at room temperature for 5 h, the solvent was removed, and the mixture was separated by column chromatography to obtain 168 mg of an oily liquid, which was galantamine analog A2, in 24% yield. NMR data are as follows: 1HNMR (600MHz, DMSO-d6) δ7.30(dd,J=8.4,5.7Hz,2H),7.12(t,J=8.8Hz,3H),6.69(d,J=8.1Hz,1H),6.56(d,J=8.2Hz,1H),6.20(d,J=10.4Hz,1H),5 .78(d,J=4.7Hz,1H),5.07(t,J=5.3Hz,1H),4.43(d,J=3.2Hz,1H),4.08( d,J=14.9Hz,1H),3.72(s,3H),3.56(d,J=15.2Hz,1H),3.40(s,2H),3.33( s,1H),3.26(s,1H),3.19(t,J=13.7Hz,1H),2.93–2.87(m,1H),2.75–2.6 7(m,2H),2.38(dd,J=16.5,3.2Hz,1H),2.24(s,3H),2.19(ddd,J=16.8,6. 5,3.3Hz,1H),1.99(d,J=3.6Hz,1H),1.93(d,J=11.2Hz,1H),1.68(dd,J=2 6.1,12.5Hz,2H),1.52–1.47(m,1H),1.39(ddd,J=28.5,11.8,3.5Hz,2H); 13 CNMR(151MHz,DMSO-d6)δ162.46,160.85,155.84,146.52,143.62,135.26,132.84,130.95,129.92,123.81,1 21.50,115.36,111.89,85.98,63.05,61.64,55.38,53.44,52.47,48.53,47.80,41.55,33.77,32.20,28.21.

[0072] (28) Synthesis of galantamine analog A3: Intermediate 1-1 (0.6 g, 1.33 mmol) and intermediate 1-4-2 (0.28 g, 1.33 mmol) were dissolved in anhydrous DCM. A basic catalyst, 4-dimethylaminopyridine (0.24 g, 2.1 mmol), was added. After reacting at room temperature for 5 h, the solvent was removed, and the mixture was separated by column chromatography to obtain 399 mg of an oily liquid, which was galantamine analog A3, in 58% yield. NMR data are as follows: 1H NMR (600MHz, DMSO-d6) δ7.67(d,J=8.0Hz,2H),7.50(d,J=7.9Hz,2H),7.17(d,J=7.7Hz,1H),6.69(d,J=8.1Hz,1H),6.56(d,J=8.1Hz,1H),6.20( d,J=10.4Hz,1H),5.80–5.76(m,1H),5.07(t,J=5.3Hz,1H),4.42(s,1H) ,4.07(d,J=15.0Hz,1H),3.72(s,3H),3.56(d,J=15.2Hz,1H),3.51(s,2H ),3.43(s,1H),3.31–3.25(m,1H),3.18(t,J=13.7Hz,1H),2.90(d,J=16 .1Hz,1H),2.78–2.67(m,2H),2.41–2.34(m,1H),2.23(s,3H),2.19(ddd, J=15.6,5.8,3.0Hz,1H),2.03–1.98(m,1H),1.97(s,1H),1.69(dd,J=25.5,12.2Hz,2H),1.51–1.46(m,1H),1.41(ddd,J=28.9,11.8,3.6Hz,2H); 13 C NMR (151MHz, DMSO) δ162.01,160.39,155.84,146.54,143.70,133.24,131.91,128.75,124.60,121.37,115.64,1 11.79,87.20,85.98,63.05,60.35,59.87,55.96,55.38,55.03,53.55,48.07,47.79,41.56,34.11,32.17,31.50.

[0073] (29) Synthesis of galantamine analog A4: Intermediate 1-1 (0.6 g, 1.33 mmol) and intermediate 1-5-2 (0.28 g, 1.33 mmol) were dissolved in anhydrous DCM. A basic catalyst, 4-dimethylaminopyridine (0.24 g, 2.1 mmol), was added. After reacting at room temperature for 5 h, the solvent was removed, and the mixture was separated by column chromatography to obtain 456 mg of an oily liquid, which was galantamine analog A4, in 66% yield. NMR data are as follows: 1HNMR (600MHz, DMSO-d6) δ7.35(td,J=7.9,6.1Hz,1H),7.16(d,J=7.8Hz,1H),7.13–7.03(m,3H),6.70(d,J=8.2Hz,1H),6.57(d,J=8.1Hz,1H),6.21( d,J=10.4Hz,1H),5.78(dd,J=10.4,4.6Hz,1H),5.07(t,J=5.3Hz,1H),4.4 3(s,1H),4.11(d,J=14.9Hz,1H),3.72(s,3H),3.61(d,J=4.4Hz,1H),3.59 (s,1H),3.44(s,2H),3.20(td,J=31.9,28.8,15.3Hz,2H),2.93(d,J=14.2 Hz,1H),2.79–2.68(m,2H),2.40–2.35(m,1H),2.26(s,3H),2.20(ddd,J=1 6.6,6.7,3.6Hz,1H),2.04–1.97(m,1H),1.95(s,1H),1.69(dd,J=26.5,12 .5Hz,2H),1.54–1.49(m,1H),1.41(dtd,J=27.7,15.5,13.8,10.2Hz,2H); 13 CNMR(151MHz,DMSO)δ163.50,161.89,155.84,146.54,143.70,142.30,132.84,130.53,125.08,123.88,121.59,115.5 9,114.15,111.93,85.97,63.04,61.81,59.79,55.92,55.39,53.45,52.54,48.46,47.75,41.59,33.72,32.23,28.20.

[0074] (30) Synthesis of galantamine analog A5: Intermediate 1-1 (0.6 g, 1.33 mmol) and intermediate 1-6-2 (0.34 g, 1.33 mmol) were dissolved in anhydrous DCM. A basic catalyst, 4-dimethylaminopyridine (0.24 g, 2.1 mmol), was added. After reacting at room temperature for 5 h, the solvent was removed, and the mixture was separated by column chromatography to obtain 389 mg of an oily liquid, which was galantamine analog A5, in 51% yield. NMR data are as follows: 1H NMR (600MHz, DMSO-d6) δ7.67(d,J=7.9Hz,2H),7.51(d,J=7.9Hz,2H),7.17(d,J=7.7Hz,1H),6.69(d,J=8.1Hz,1H),6.56(d,J=8.1Hz,1H),6.21( d,J=10.4Hz,1H),5.82–5.76(m,1H),5.08(d,J=5.4Hz,1H),4.43(s,1H) ,4.08(d,J=14.9Hz,1H),3.72(s,3H),3.56(d,J=15.2Hz,1H),3.52(s,2H ),3.33(s,1H),3.30–3.24(m,1H),3.19(t,J=13.8Hz,1H),2.90(d,J=14.3Hz,1H),2.78–2.68(m,2H),2.38(dd,J=16.4,2.9Hz,1H),2.24(s,3H) ,2.22–2.17(m,1H),2.01(d,J=11.3Hz,1H),1.97(s,1H),1.69(dd,J=26 .0,12.6Hz,2H),1.52–1.47(m,1H),1.42(ddd,J=28.9,11.7,3.6Hz,2H); 13 CNMR(151MHz,DMSO)δ155.85,146.52,144.28,143.60,132.84,129.72,128.08,125.50,123.79,121.48,1 11.88,85.98,63.06,61.86,59.88,55.91,55.38,53.44,52.59,48.45,47.81,41.55,33.79,32.21,28.21.

[0075] (31) Synthesis of galantamine analog A6: Intermediate 1-1 (0.6 g, 1.33 mmol) and intermediate 1-7-2 (0.27 g, 1.33 mmol) were dissolved in anhydrous DCM. A basic catalyst, 4-dimethylaminopyridine (0.24 g, 2.1 mmol), was added. After reacting at room temperature for 5 h, the solvent was removed, and the mixture was separated by column chromatography to obtain 227 mg of an oily liquid, which was galantamine analog A6, in 33% yield. NMR data are as follows: 1HNMR(600MHz,DMSO-d6)δ7.16–7.08(m,5H),6.68(d,J=8.1Hz,1H),6.56(d,J=8.1Hz,1H),6.20(d,J=10.4Hz,1H),5.79–5.74(m,1H),5.06(t,J =5.3Hz,1H),4.42(s,1H),4.07(d,J=15.0Hz,1H),3.72(s,3H),3.55(d,J=15.2Hz,1H),3.36(s,3H),3.25(dt,J=8.0,4.1Hz,1H),3.17(d,J=13 .5Hz,1H),2.90(d,J=14.2Hz,1H),2.72(t,J=13.8Hz,2H),2.37(ddd,J=15.3,3.2,1.6Hz,1H),2.27(s,3H),2.23(s,3H),2.19(ddd,J=16.1,6. 2,3.1Hz,1H),1.99(td,J=12.4,11.0,6.1Hz,1H),1.90(d,J=11.3Hz,1H),1.67(dd,J=26.1,12.7Hz,2H),1.52–1.46(m,1H),1.43–1.30(m,2H); 13 C NMR (151MHz, DMSO) δ155.84,146.52,143.60,136.28,136.01,132.84,130.03,129.18,123.80,121.48,111.8 9,85.98,63.05,62.35,59.88,55.91,55.39,53.44,52.53,48.58,47.81,41.54,33.78,32.22,28.21,21.16.

[0076] (32) Synthesis of galantamine analog A7: Intermediate 1-1 (0.6 g, 1.33 mmol) and intermediate 1-8-2 (0.33 g, 1.33 mmol) were dissolved in anhydrous DCM. A basic catalyst, 4-dimethylaminopyridine (0.24 g, 2.1 mmol), was added. After reacting at room temperature for 5 h, the solvent was removed, and the mixture was separated by column chromatography to obtain 221 mg of an oily liquid, which was galantamine analog A7, in 30% yield. NMR data are as follows: 1H NMR(600MHz,DMSO-d6)δ7.14(d,J=7.8Hz,1H),6.69(d,J=8.1Hz,1H),6.56( d,J=8.1Hz,1H),6.43(s,2H),6.36(t,J=2.3Hz,1H),6.20(d,J=10.4Hz,1H), 5.79–5.76(m,1H),5.07(t,J=5.4Hz,1H),4.43(d,J=3.3Hz,1H),4.07(d,J=1 5.0Hz,1H),3.72(s,3H),3.71(s,6H),3.56(d,J=15.2Hz,1H),3.34(s,3H),3 .28–3.24(m,1H),3.18(t,J=13.7Hz,1H),2.90(d,J=14.2Hz,1H),2.74(t,J =14.0Hz,2H),2.38(ddt,J=16.4,2.9,1.4Hz,1H),2.23(s,3H),2.19(ddd,J= 16.3,6.2,3.3Hz,1H),2.02–1.95(m,1H),1.92(d,J=11.2Hz,1H),1.68(dd,J =26.4,12.4Hz,2H),1.51–1.46(m,1H),1.39(ddd,J=24.4,12.2,8.6Hz,2H); 13 C NMR (151MHz, DMSO) δ160.79,155.85,146.53,143.60,141.65,132.84,124.72,121.96,112.35,106.91,9 8.99,85.98,63.06,62.65,59.88,55.92,55.52,53.44,52.62,48.56,47.81,41.54,33.78,32.22,28.21.

[0077] (33) Synthesis of galantamine analog A8: Intermediate 1-1 (0.6 g, 1.33 mmol) and intermediate 1-9-2 (0.3 g, 1.33 mmol) were dissolved in anhydrous DCM, and a basic catalyst, 4-dimethylaminopyridine (0.24 g, 2.1 mmol), was added. After reacting at room temperature for 5 h, the solvent was removed, and the mixture was separated by column chromatography to obtain 461 mg of an oily liquid, which was galantamine analog A8, with a yield of 64%. The NMR data are as follows: 1HNMR (600MHz, DMSO-d6) δ7.41(td,J=8.5,6.7Hz,1H),7.21–7.12(m,2H),7.05(td,J=8.4,2.6Hz,1H),6.69(d,J=8.1Hz,1H),6.56(d,J =8.2Hz,1H),6.20(d,J=10.4Hz,1H),5.79–5.76(m,1H),5.08–5.05(m,1H),4.42(s,1H),4.07(d,J=14.9Hz,1H),3.72(s,3H),3.56(d, J=15.2Hz,1H),3.44(s,2H),3.32–3.21(m,2H),3.21–3.15(m,1H),2.90(d,J=14.3Hz,1H),2.76–2.69(m,2H),2.40–2.34(m,1H),2.23 (s,3H),2.20–2.16(m,1H),2.02–1.99(m,1H),1.99–1.95(m,1H),1.68(dd,J=26.2,12.5Hz,2H),1.52–1.47(m,1H),1.43–1.30(m,2H); 13 C NMR (151MHz, DMSO) δ162.59,161.99,161.05,160.27,155.83,146.52,143.61,132.83,123.80,121.49,111.89,1 04.02,85.98,63.59,63.05,59.87,55.91,55.39,54.53,53.44,52.29,48.37,47.80,41.55,33.77,32.19,28.21.

[0078] (34) Synthesis of galantamine analog A9: Intermediate 1-1 (0.6 g, 1.33 mmol) and intermediate 1-10-2 (0.31 g, 1.33 mmol) were dissolved in anhydrous DCM. A basic catalyst, 4-dimethylaminopyridine (0.24 g, 2.1 mmol), was added. After reacting at room temperature for 5 h, the solvent was removed, and the mixture was separated by column chromatography to obtain 469 mg of an oily liquid, which was galantamine analog A9, in 66% yield. NMR data are as follows: 1H NMR(600MHz,DMSO-d6)δ7.36(d,J=8.4Hz,2H),7.29(d,J=8.4Hz,2H),7.15(d, J=7.8Hz,1H),6.69(dd,J=8.2,3.9Hz,1H),6.56(dd,J=8.1,5.3Hz,1H),6.20( d,J=10.4Hz,1H),5.81–5.76(m,1H),5.09–5.05(m,1H),4.42(d,J=3.4Hz,1H) ,4.08(dd,J=15.1,3.7Hz,1H),3.72(s,3H),3.56(dd,J=15.0,2.4Hz,1H),3.40 (s,2H),3.34(s,1H),3.30–3.23(m,1H),3.18(t,J=13.6Hz,1H),2.90(d,J=14 .0Hz,1H),2.75–2.68(m,2H),2.38(ddd,J=15.3,3.2,1.6Hz,1H),2.23(s,3H) ,2.22–2.16(m,1H),2.03–1.96(m,1H),1.96–1.90(m,1H),1.68(dd,J=26.0,1 2.5Hz, 2H), 1.49 (dd, J=13.8, 3.1Hz, 1H), 1.39 (ddd, J=28.8, 11.8, 3.5Hz, 2H); 13 C NMR (151MHz, DMSO) δ155.84,146.52,143.61,138.23,132.83,131.78,130.92,128.57,123.81,121.49,111.8 8,85.98,63.06,61.65,60.35,59.88,55.91,55.39,53.45,52.49,48.50,47.80,41.56,33.79,32.21,28.21.

[0079] (35) Synthesis of galantamine analog A10: Intermediate 1-1 (0.6 g, 1.33 mmol) and intermediate 1-11-2 (0.31 g, 1.33 mmol) were dissolved in anhydrous DCM. A basic catalyst, 4-dimethylaminopyridine (0.24 g, 2.1 mmol), was added. After reacting at room temperature for 5 h, the solvent was removed, and the mixture was separated by column chromatography to obtain 532 mg of an oily liquid, which was galantamine analog A10, with a yield of 73%. NMR data are as follows: 1H NMR (600MHz, DMSO-d6) δ8.19(d,J=8.6Hz,2H),7.57(d,J=8.7Hz,2H),7.18(d,J=7.8Hz,1H),6.70(d,J=8.1Hz,1H),6.57(d,J=8.1Hz,1H),6.2 1(d,J=10.4Hz,1H),5.80–5.76(m,1H),5.07(t,J=5.5Hz,1H),4.43(s,1H),4.08(d,J=15.1Hz,1H),3.72(s,3H),3.56(d,J=9.2Hz,3H),3.29( dd,J=7.6,3.9Hz,2H),3.19(t,J=13.8Hz,1H),2.91(d,J=14.2Hz,1H),2.78–2.68(m,2H),2.38(ddd,J=15.3,3.2,1.6Hz,1H),2.24(s,3H),2. 22–2.17(m,1H),2.06–2.01(m,1H),2.00–1.94(m,1H),1.70(dd,J=25.9,12.5Hz,2H),1.52–1.48(m,1H),1.43(ddd,J=28.6,11.9,3.5Hz,2H); 13 C NMR (151MHz, DMSO) δ155.85,147.67,146.97,146.52,143.61,132.83,130.34,130.04,123.83,121.49,11 1.89,85.98,63.07,61.59,59.87,55.91,55.39,53.44,52.63,48.38,47.80,41.56,33.78,32.20,28.21.

[0080] (36) Synthesis of galantamine analog A11: Intermediate 1-1 (0.6 g, 1.33 mmol) and intermediate 1-12-2 (0.31 g, 1.33 mmol) were dissolved in anhydrous DCM. A basic catalyst, 4-dimethylaminopyridine (0.24 g, 2.1 mmol), was added. After reacting at room temperature for 5 h, the solvent was removed, and the mixture was separated by column chromatography to obtain 127 mg of an oily liquid, which was galantamine analog A11, with a yield of 18%. NMR data are as follows: 1H NMR (600MHz, DMSO-d6) δ7.77(d,J=8.1Hz,2H),7.48(d,J=8.0Hz,2H),7.17(d,J=7.8Hz,1H),6.69(d,J=8.1Hz,1H),6.56(d,J=8.1Hz,1H) ,6.20(d,J=10.4Hz,1H),5.78(d,J=4.9Hz,1H),5.07(t,J=5.3Hz,1H),4.42(s,1H),4.07(d,J=15.0Hz,1H),3.72(s,3H),3.56(d,J=15.2H z,1H),3.51(s,2H),3.31–3.25(m,2H),3.18(t,J=13.6Hz,1H),2.90(d,J=14.3Hz,1H),2.75–2.65(m,2H),2.40–2.33(m,1H),2.23(s,3H ),2.22–2.16(m,1H),2.00(d,J=13.8Hz,1H),1.97(t,J=6.2Hz,1H),1.69(dd,J=26.1,12.5Hz,2H),1.52–1.47(m,1H),1.45–1.36(m,2H); 13 C NMR (151MHz, DMSO) δ155.85,146.52,145.40,143.60,132.84,132.61,129.89,123.79,121.49,119.41,111.8 8,110.06,85.12,63.07,61.89,59.88,55.91,55.39,53.44,52.63,48.40,47.81,41.55,33.78,32.20,28.21.

[0081] (37) Synthesis of galantamine analog A12: Intermediate 1-1 (0.6 g, 1.33 mmol) and intermediate 1-13-2 (0.36 g, 1.33 mmol) were dissolved in anhydrous DCM. A basic catalyst, 4-dimethylaminopyridine (0.24 g, 2.1 mmol), was added. After reacting at room temperature for 5 h, the solvent was removed, and the mixture was separated by column chromatography to obtain 267 mg of an oily liquid, which was galantamine analog A12, in 34% yield. NMR data are as follows: 1H NMR (600MHz, DMSO-d6) δ7.40(d,J=8.3Hz,2H),7.29(d,J=8.1Hz,2H),7.16(d,J=7.8Hz,1H),6.70(d,J=8.2Hz,1H),6.57(d,J=8.0Hz,1H),6.2 1(d,J=10.4Hz,1H),5.85–5.71(m,1H),5.07(t,J=5.4Hz,1H),4.43(s, 1H),4.10(d,J=14.6Hz,1H),3.72(s,3H),3.61–3.56(m,1H),3.45(s,2H) ),3.30–3.15(m,3H),2.93(d,J=14.1Hz,1H),2.76–2.69(m,2H),2.38(dd,J=16.5,3.0Hz,1H),2.26(s,3H),2.20(ddd,J=16.7,6.6,3.5Hz,1H) ,2.01(dt,J=13.2,3.9Hz,1H),1.97(s,1H),1.69(dd,J=26.2,12.6Hz,2H),1.51(dd,J=13.4,3.5Hz,1H),1.39(dtd,J=28.0,12.1,3.5Hz,2H); 13 C NMR (151MHz, DMSO-d6) δ155.84,147.66,146.53,143.68,138.71,132.84,130.83,123.86,121.57,121.42,121. 27,119.73,111.92,85.97,63.05,61.55,59.80,55.91,53.44,52.52,48.47,47.76,41.57,33.73,32.18,28.19.

[0082] The structural formula in the above steps is shown below:

[0083]

[0084]

[0085] The preparation of a galantamine analog (IB) compound and its intermediates in this embodiment are described in the following specific synthetic steps:

[0086] (1) Synthesis of intermediate 2-1: Galantamine (0.6 g, 2.1 mmol) and di(p-nitrobenzene) carbonate (0.95 g, 3.13 mmol) were dissolved in anhydrous DCM. After stirring for 10-15 min, triethylamine (0.21 g, 2.1 mmol) was slowly added dropwise. After reacting at room temperature for 6 h, the solvent was removed, and the mixture was separated by column chromatography to obtain 0.92 g of oily liquid, which is intermediate 2-1, with a yield of 97%.

[0087] (2) Synthesis of galantamine analog B1: Intermediate 2-1 (0.5 g, 1.1 mmol) and benzylamine (0.098 g, 0.92 mmol) were dissolved in anhydrous DCM. A basic catalyst, 4-dimethylaminopyridine (0.017 g, 0.14 mmol), was added. After reacting at room temperature for 5 h, the solvent was removed, and the mixture was separated by column chromatography to obtain 248 mg of an oily liquid, which was galantamine analog B1, with a yield of 64%. NMR data are as follows: 1 H NMR(600MHz,DMSO-d6)δ7.71(t,J=6.2Hz,1H),7.32–7.29(m,2H),7.26–7.20(m,3H),6.69(d,J=8.1Hz,1H),6.56 (d,J=8.1Hz,1H),6.24(d,J=10.4Hz,1H),5.79(dd,J=10.4,4.6Hz,1H),5.10(t,J=5.5Hz,1H),4.44(t,J=3.3Hz, 1H), 4.16 (d, J = 6.2Hz, 2H), 4.08 (d, J = 15.0Hz, 1H), 3.72 (s, 3H), 3.56 (d, J = 15.1Hz, 1H), 3.19 (t, J = 13.6Hz, 1H), 2.90(d,J=14.2Hz,1H),2.44–2.38(m,1H),2.24(s,3H),2.22–2.16(m,1H),2.05–1.96(m,1H),1.53–1.46(m,1H); 13 C NMR(151MHz,DMSO-d6)δ156.84,146.62,143.65,140.41,132.84,130.04,128.68,127.52,127.15 ,123.67,121.46,112.06,85.97,63.42,59.88,56.02,53.44,47.82,44.22,41.56,33.80,28.17.

[0088] (3) Synthesis of galantamine analog B2: Intermediate 2-1 (0.5 g, 1.1 mmol) and 2-fluorobenzylamine (0.12 g, 0.92 mmol) were dissolved in anhydrous DCM. A basic catalyst, 4-dimethylaminopyridine (0.017 g, 0.14 mmol), was added. After reacting at room temperature for 5 h, the solvent was removed, and the mixture was separated by column chromatography to obtain 213 mg of an oily liquid, which was galantamine analog B2, in 53% yield. NMR data are as follows: 1 HNMR(600MHz,DMSO-d6)δ7.73(t,J=6.1Hz,1H),7.39–7.26(m,2H),7.22–7.09(m,2H),6.69(d,J=8.1Hz,1H),6.56(d,J=8 .1Hz,1H),6.24(d,J=10.4Hz,1H),5.79(dd,J=10.4,4.7Hz,1H),5.12–5.09(m,1H),4.44(d,J=3.2Hz,1H),4.22(d,J=6.1H z,2H),4.08(d,J=15.1Hz,1H),3.72(s,3H),3.56(d,J=15.2Hz,1H),3.19(t,J=13.5Hz,1H),2.90(d,J=14.3Hz,1H),2.45– 2.38(m,1H),2.24(s,3H),2.20(ddd,J=16.4,6.3,3.4Hz,1H),2.00(td,J=13.5,3.0Hz,1H),1.50(dd,J=13.7,3.0Hz,1H); 13 C NMR (151MHz, DMSO) δ172.54,161.11,159.49,156.78,146.62,143.65,132.82,130.62,130.05,129.74,129.26,126.87,124 .76,123.58,121.47,115.37,112.04,85.95,63.58,59.87,56.00,55.38,53.43,53.31,47.83,37.90,37.87,33.79,28.13.

[0089] (4) Synthesis of galantamine analog B3: Intermediate 2-1 (0.5 g, 1.1 mmol) and 3-fluorobenzylamine (0.12 g, 0.92 mmol) were dissolved in anhydrous DCM. A basic catalyst, 4-dimethylaminopyridine (0.017 g, 0.14 mmol), was added. After reacting at room temperature for 5 h, the solvent was removed, and the mixture was separated by column chromatography to obtain 197 mg of an oily liquid, which was galantamine analog B3, in 49% yield. NMR data are as follows: 1HNMR (600MHz, DMSO-d6) δ7.76(t,J=6.2Hz,1H),7.38–7.32(m,1H),7.10(d,J=7.7Hz,1H),7.07–7.02(m,2H),6.69( d,J=8.1Hz,1H),6.56(d,J=8.1Hz,1H),6.25(d,J=10.4Hz,1H),5.79(dd,J=10.4,4.6Hz,1H),5.12–5.09(m,1H),4.4 4(s,1H),4.18(d,J=6.2Hz,2H),4.08(d,J=15.1Hz,1H),3.72(s,3H),3.56(d,J=15.2Hz,1H),3.19(t,J=13.5Hz,1H ),2.90(d,J=14.1Hz,1H),2.46–2.37(m,1H),2.24(s,3H),2.22–2.16(m,1H),2.03–1.97(m,1H),1.52–1.47(m,1H); 13 C NMR (151MHz, DMSO) δ163.47,161.86,156.84,146.62,143.64,143.45,132.82,130.63,130.11,123.57, 121.45,114.21,113.99,112.05,85.95,63.56,59.89,55.95,55.38,53.43,47.83,43.75,33.80,28.13.

[0090] (5) Synthesis of galantamine analog B4: Intermediate 2-1 (0.5 g, 1.1 mmol) and 4-fluorobenzylamine (0.12 g, 0.92 mmol) were dissolved in anhydrous DCM. A basic catalyst, 4-dimethylaminopyridine (0.017 g, 0.14 mmol), was added. After reacting at room temperature for 5 h, the solvent was removed, and the mixture was separated by column chromatography to obtain 237 mg of an oily liquid, which was galantamine analog B4, in 59% yield. NMR data are as follows: 1HNMR(600MHz,DMSO-d6)δ7.73(t,J=6.2Hz,1H),7.31–7.26(m,2H),7.13(t,J=8.8Hz,2H),6.69(d,J=8.1Hz,1H), 6.56(d,J=8.1Hz,1H),6.24(d,J=10.4Hz,1H),5.79(dd,J=10.4,4.6Hz,1H),5.12–5.08(m,1H),4.44(d,J=3.3Hz, 1H),4.15(d,J=6.3Hz,2H),4.08(d,J=15.1Hz,1H),3.72(s,3H),3.57(d,J=15.2Hz,1H),3.19(t,J=13.5Hz,1H), 2.91(d,J=14.8Hz,1H),2.44–2.39(m,1H),2.24(s,3H),2.22–2.17(m,1H),2.05–1.95(m,1H),1.52–1.47(m,1H); 13 C NMR (151MHz, DMSO) δ162.41,160.80,156.80,146.61,143.66,136.59,132.82,130.56,129.99,129.55,123 .63,121.47,115.46,112.01,85.96,63.47,59.86,55.98,55.38,53.43,47.82,43.54,41.55,33.79,28.14.

[0091] (6) Synthesis of galantamine analog B5: Intermediate 2-1 (0.5 g, 1.1 mmol) and 3,5-difluorobenzylamine (0.13 g, 0.92 mmol) were dissolved in anhydrous DCM. A basic catalyst, 4-dimethylaminopyridine (0.017 g, 0.14 mmol), was added. After reacting at room temperature for 5 h, the solvent was removed, and the mixture was separated by column chromatography to obtain 156 mg of an oily liquid, which was galantamine analog B5, in 37% yield. NMR data are as follows: 1H NMR (600MHz, DMSO-d6) δ7.79(t,J=6.2Hz,1H),7.08(ddd,J=9.4,6.9,2.4Hz,1H),6.97–6.94(m,2H),6.70(d,J=8.1H z,1H),6.56(d,J=8.1Hz,1H),6.25(d,J=10.3Hz,1H),5.80(dd,J=10.3,4.7Hz,1H),5.12–5.08(m,1H),4.45(t,1H), 4.19(d,J=6.2Hz,2H),4.08(d,J=15.0Hz,1H),3.72(s,3H),3.56(d,J=15.2Hz,1H),3.20(t,J=13.6Hz,1H),2.90(d, J=14.3Hz,1H),2.46–2.41(m,1H),2.24(s,3H),2.22–2.16(m,1H),2.00(td,J=13.4,3.0Hz,1H),1.52–1.47(m,1H); 13 C NMR (151MHz, DMSO) δ163.66,161.95,156.83,146.63,145.31,143.65,132.80,130.72,130.08,123.49, 121.46,112.06,110.32,102.53,85.94,63.70,59.87,56.00,55.38,53.42,47.83,43.56,33.78,28.08.

[0092] (7) Synthesis of galantamine analog B6: Intermediate 2-1 (0.5 g, 1.1 mmol) and 2-methylbenzylamine (0.11 g, 0.92 mmol) were dissolved in anhydrous DCM. A basic catalyst, 4-dimethylaminopyridine (0.017 g, 0.14 mmol), was added. After reacting at room temperature for 5 h, the solvent was removed, and the mixture was separated by column chromatography to obtain 216 mg of an oily liquid, which was galantamine analog B6, in 54% yield. NMR data are as follows: 1H NMR (600MHz, DMSO-d6) δ7.63(t,J=6.1Hz,1H),7.23–7.11(m,4H),6.69(d,J=8.1Hz,1H),6.56(d,J=8.1Hz,1H) ,6.24(d,J=10.4Hz,1H),5.79(dd,J=10.4,4.7Hz,1H),5.10(t,J=5.5Hz,1H),4.44(s,1H),4.16–4.13(m,2H),4 .08(d,J=15.0Hz,1H),3.71(s,3H),3.57(d,J=15.1Hz,1H),3.20(t,J=13.6Hz,1H),2.91(d,J=14.2Hz,1H),2. 45–2.39(m,1H),2.26(s,3H),2.24(s,3H),2.22–2.16(m,1H),2.00(td,J=13.4,3.1Hz,1H),1.53–1.47(m,1H); 13 C NMR (151MHz, DMSO) δ156.76,146.63,143.66,137.99,135.73,132.84,130.26,127.67,127.13,126.15, 123.72,121.48,112.05,85.98,63.42,59.87,56.01,55.39,53.45,47.81,42.10,33.81,28.19,19.08.

[0093] (8) Synthesis of galantamine analog B7: Intermediate 2-1 (0.5 g, 1.1 mmol) and 4-methoxybenzylamine (0.13 g, 0.92 mmol) were dissolved in anhydrous DCM. A basic catalyst, 4-dimethylaminopyridine (0.017 g, 0.14 mmol), was added. After reacting at room temperature for 5 h, the solvent was removed, and the mixture was separated by column chromatography to obtain 192 mg of an oily liquid, which was galantamine analog B7, in 46% yield. NMR data are as follows: 1H NMR (600MHz, DMSO-d6) δ7.64(t,J=6.2Hz,1H),7.17(d,J=8.3Hz,2H),6.86(d,J=8.6Hz,2H),6.69(d,J=8.1Hz,1H),6.56(d, J=8.1Hz,1H),6.23(d,J=10.4Hz,1H),5.78(dd,J=10.4,4.8Hz,1H),5.11–5.08(m,1H),4.43(s,1H),4.09(d,J=6.5Hz,2H),4 .08(d,J=15.0Hz,1H),3.72(s,3H),3.71(s,3H),3.57(d,J=15.1Hz,1H),3.19(t,J=13.5Hz,1H),2.91(d,J=14.3Hz,1H),2.4 4–2.38(m,1H),2.24(s,3H),2.19(ddd,J=16.3,6.3,3.4Hz,1H),2.00(td,J=13.5,3.1Hz,1H),1.50(dd,J=13.9,3.3Hz,1H); 13 C NMR (151MHz, DMSO) δ158.61,156.75,146.61,143.65,132.40,128.90,123.71,121. 47,114.07,112.03,85.97,63.34,59.86,55.48,53.44,47.81,43.68,33.79,28.19.

[0094] (9) Synthesis of galantamine analog B8: Intermediate 2-1 (0.5 g, 1.1 mmol) and 5-(aminomethyl)indole (0.13 g, 0.92 mmol) were dissolved in anhydrous DCM. A basic catalyst, 4-dimethylaminopyridine (0.017 g, 0.14 mmol), was added. After reacting at room temperature for 5 h, the solvent was removed, and the mixture was separated by column chromatography to obtain 127 mg of an oily liquid, which was galantamine analog B8, in 30% yield. NMR data are as follows: 1H NMR (600MHz, DMSO-d6) δ11.01(s,1H),7.64(t,J=6.2Hz,1H),7.40(s,1H),7.33–7.29(m,2H),7.01(dd,J=8.4,1.7Hz,1H),6.69(d,J=8.1H z,1H),6.56(d,J=8.1Hz,1H),6.37(t,J=2.5Hz,1H),6.22(d,J=10.4Hz,1H),5.78(ddd,J=10.4,4.8,1.1Hz,1H),5.14–5.08(m,1H),4.44(d ,J=3.3Hz,1H),4.22(d,J=6.2Hz,2H),4.08(d,J=15.1Hz,1H),3.71(s,3H),3.57(d,J=15.2Hz,1H),3.19(t,J=13.5Hz,1H),2.91(d,J=14. 0Hz,1H),2.41(ddd,J=16.7,3.1,1.6Hz,1H),2.24(s,3H),2.23–2.17(m,1H),2.00(ddt,J=15.9,11.7,3.6Hz,1H),1.50(d,J=13.6Hz,1H); 13 C NMR (151MHz, DMSO) δ156.75,146.62,143.66,135.45,132.85,130.69,130.41,127.94,125.92,123.8 1,121.42,119.10,112.04,111.58,101.36,85.99,63.23,59.86,53.44,47.37,44.84,33.79,28.24.

[0095] (10) Synthesis of galantamine analog B9: Intermediate 2-1 (0.5 g, 1.1 mmol) and 4-cyanobenzylamine (0.12 g, 0.92 mmol) were dissolved in anhydrous DCM. A basic catalyst, 4-dimethylaminopyridine (0.017 g, 0.14 mmol), was added. After reacting at room temperature for 5 h, the solvent was removed, and the mixture was separated by column chromatography to obtain 98 mg of an oily liquid, which was galantamine analog B9, with a yield of 24%. NMR data are as follows: 1H NMR (600MHz, DMSO-d6) δ7.83(t,J=6.2Hz,1H),7.78(d,J=8.0Hz,2H),7.44(d,J=7.9Hz,2H),6.70(d,J=8.1H z,1H),6.57(d,J=8.1Hz,1H),6.26(s,1H),5.79(dd,J=10.4,4.7Hz,1H),5.13–5.07(m,1H),4.44(s,1H),4.2 4(d,J=6.2Hz,2H),4.08(d,J=15.1Hz,1H),3.72(s,3H),3.56(d,J=15.2Hz,1H),3.19(t,J=13.6Hz,1H),2.90 (d,J=14.3Hz,1H),2.44–2.37(m,1H),2.24(s,3H),2.22–2.17(m,1H),2.03–1.96(m,1H),1.52–1.47(m,1H); 13 C NMR (151MHz, DMSO) δ156.88,146.61,146.30,143.64,132.72,130.70,130.10,128.34,123.50,121. 46,119.39,112.02,109.98,85.93,63.66,59.87,56.00,55.39,53.42,47.83,43.45,33.77,28.09.

[0096] (11) Synthesis of galantamine analog B10: Intermediate 2-1 (0.5 g, 1.1 mmol) and 4-trifluoromethylbenzylamine (0.16 g, 0.92 mmol) were dissolved in anhydrous DCM. A basic catalyst, 4-dimethylaminopyridine (0.017 g, 0.14 mmol), was added. After reacting at room temperature for 5 h, the solvent was removed, and the mixture was separated by column chromatography to obtain 67 mg of an oily liquid, which was galantamine analog B10, in 16% yield. NMR data are as follows: 1H NMR (600MHz, DMSO-d6) δ7.83(t,J=6.2Hz,1H),7.68(d,J=8.0Hz,2H),7.47(d,J=8.0Hz,2H),6.70(d,J=8.2Hz,1H),6.57(d, J=8.2Hz,1H),6.25(d,J=10.4Hz,1H),5.79(dd,J=10.4,4.6Hz,1H),5.10(t,J=5.4Hz,1H),4.45(d,J=3.3Hz,1H),4.25(d,J= 6.2Hz,2H),4.08(d,J=15.1Hz,1H),3.72(s,3H),3.57(d,J=15.2Hz,1H),3.20(t,J=13.6Hz,1H),2.91(d,J=14.1Hz,1H),2.4 3(dd,J=16.5,2.9Hz,1H),2.24(s,3H),2.20(ddd,J=16.6,6.4,3.5Hz,1H),2.00(td,J=13.5,3.1Hz,1H),1.52–1.47(m,1H); 13 C NMR (151MHz, DMSO) δ156.88,146.61,145.30,143.65,132.81,130.66,130.06,128.17,125.57, 123.54,121.47,112.01,85.95,63.61,59.87,55.98,55.38,53.43,47.83,43.87,33.78,28.10.

[0097] (12) Synthesis of galantamine analog B11: Intermediate 2-1 (0.5 g, 1.1 mmol) and 4-trifluoromethoxybenzylamine (0.23 g, 0.92 mmol) were dissolved in anhydrous DCM. A basic catalyst, 4-dimethylaminopyridine (0.017 g, 0.14 mmol), was added. After reacting at room temperature for 5 h, the solvent was removed, and the mixture was separated by column chromatography to obtain 167 mg of an oily liquid, which was galantamine analog B11, in 36% yield. NMR data are as follows: 1H NMR (600MHz, DMSO-d6) δ7.77(t,J=6.2Hz,1H),7.37(d,J=8.3Hz,2H),7.31(d,J=8.3Hz,2H),6.70(d,J=8.2Hz,1 H),6.57(d,J=8.2Hz,1H),6.24(d,J=10.4Hz,1H),5.79(dd,J=10.4,4.7Hz,1H),5.10(t,J=5.5Hz,1H),4.45(t,J =3.3Hz,1H),4.19(d,J=6.2Hz,2H),4.09(d,J=15.0Hz,1H),3.72(s,3H),3.57(d,J=15.1Hz,1H),3.25–3.16(m,1 H),2.95–2.88(m,1H),2.46–2.39(m,1H),2.24(s,3H),2.23–2.16(m,1H),2.04–1.97(m,1H),1.53–1.48(m,1H); 13 C NMR(151MHz,DMSO-d6)δ156.83,147.59,146.61,143.66,139.96,132.82,130.61,129.99,129 .33,123.59,121.37,112.02,85.95,63.54,59.85,55.98,53.43,47.81,43.52,33.77,28.11.

[0098] (13) Synthesis of galantamine analog B12: Intermediate 2-1 (0.5 g, 1.1 mmol) and 4-nitrobenzylamine (0.14 g, 0.92 mmol) were dissolved in anhydrous DCM. A basic catalyst, 4-dimethylaminopyridine (0.017 g, 0.14 mmol), was added. After reacting at room temperature for 5 h, the solvent was removed, and the mixture was separated by column chromatography to obtain 298 mg of an oily liquid, which was galantamine analog B12, in 70% yield. NMR data are as follows: 1H NMR (600MHz, DMSO-d6) δ8.19(d,J=8.6Hz,2H),7.89(t,J=6.2Hz,1H),7.52(d,J=8.3Hz,2H),6.71(d,J=8.2Hz,1H),6.57(d, J=8.2Hz,1H),6.25(d,J=10.4Hz,1H),5.80(dd,J=10.4,4.7Hz,1H),5.11(t,J=5.5Hz,1H),4.45(d,J=3.3Hz,1H),4.30(d,J =6.2Hz,2H),4.09(d,J=15.1Hz,1H),3.72(s,3H),3.57(d,J=15.2Hz,1H),3.20(t,J=13.4Hz,1H),2.91(d,J=14.3Hz,1H),2 .46–2.39(m,1H),2.24(s,3H),2.20(ddd,J=16.8,6.4,3.6Hz,1H),2.00(ddd,J=16.5,11.2,2.9Hz,1H),1.54–1.46(m,1H); 13 CNMR(151MHz,DMSO)δ156.89,148.48,146.90,146.61,143.67,132.80,130.70,129.97,128.53,123.95 ,123.50,121.50,112.00,85.94,63.71,59.85,55.99,55.38,53.42,52.98,47.82,43.82,33.76,28.06.

[0099] (14) Synthesis of galantamine analog B13: Intermediate 2-1 (0.5 g, 1.1 mmol) and 2-(aminomethyl)naphthalene (0.14 g, 0.92 mmol) were dissolved in anhydrous DCM. A basic catalyst, 4-dimethylaminopyridine (0.017 g, 0.14 mmol), was added. After reacting at room temperature for 5 h, the solvent was removed, and the mixture was separated by column chromatography to obtain 320 mg of an oily liquid, which was galantamine analog B13, in 74% yield. NMR data are as follows: 1H NMR (600MHz, DMSO-d6) δ7.87(t,J=7.6Hz,3H),7.81(t,J=6.2Hz,1H),7.74(s,1H),7.51–7.41(m,3H),6.70(d,J=8.1Hz, 1H),6.57(d,J=8.1Hz,1H),6.25(d,J=10.4Hz,1H),5.80(dd,J=10.4,4.6Hz,1H),5.13(t,J=5.3Hz,1H),4.45(d,J=3.3Hz ,1H),4.34(d,J=6.2Hz,2H),4.09(d,J=15.2Hz,1H),3.72(s,3H),3.57(d,J=14.9Hz,1H),3.20(t,J=13.5Hz,1H),2.96– 2.85(m,1H),2.47–2.40(m,1H),2.24(s,3H),2.22–2.18(m,1H),2.00(ddd,J=15.5,10.0,3.0Hz,1H),1.53–1.48(m,1H); 13 C NMR (151MHz, DMSO) δ156.90,146.64,143.66,137.99,133.34,132.84,132.55,130.59,130.03,128.32,128.03,126.59, 126.29,126.06,125.61,123.66,121.47,112.04,85.98,63.49,59.87,56.02,55.39,53.44,47.83,44.45,33.79,28.16.

[0100] (15) Synthesis of galantamine analog B14: Intermediate 2-1 (0.5 g, 1.1 mmol) and 2,4-difluorobenzylamine (0.13 g, 0.92 mmol) were dissolved in anhydrous DCM. A basic catalyst, 4-dimethylaminopyridine (0.017 g, 0.14 mmol), was added. After reacting at room temperature for 5 h, the solvent was removed, and the mixture was separated by column chromatography to obtain 167 mg of an oily liquid, which was galantamine analog B14, in 40% yield. NMR data are as follows: 1H NMR (600MHz, DMSO-d6) δ7.73(t,J=6.0Hz,1H),7.37(td,J=8.6,6.6Hz,1H),7.18(td,J=9.9,2.6Hz,1H),7.05(td,J=8.6,2.6Hz, 1H),6.70(d,J=8.1Hz,1H),6.57(d,J=8.1Hz,1H),6.24(d,J=10.3Hz,1H),5.78(dd,J=10.4,4.7Hz,1H),5.09(t,J=5.4Hz,1H),4. 44(s,1H),4.17(d,J=6.0Hz,2H),4.09(d,J=15.1Hz,1H),3.72(s,3H),3.57(d,J=15.1Hz,1H),3.20(t,J=13.5Hz,1H),2.91(d,J =14.2Hz,1H),2.41(dd,J=16.2,2.8Hz,1H),2.25(s,3H),2.21(d,J=3.0Hz,1H),2.00(tt,J=11.9,3.4Hz,1H),1.53–1.48(m,1H); 13 C NMR (151MHz, DMSO) δ162.63,161.01,156.72,146.60,143.67,132.81,131.03,123.56,1 21.50,112.02,104.02,85.92,63.60,59.84,55.99,53.43,47.80,37.52,33.74,28.10.

[0101] (16) Synthesis of galantamine analog B15: Intermediate 2-1 (0.5 g, 1.1 mmol) and 4-methylbenzylamine (0.11 g, 0.92 mmol) were dissolved in anhydrous DCM. A basic catalyst, 4-dimethylaminopyridine (0.017 g, 0.14 mmol), was added. After reacting at room temperature for 5 h, the solvent was removed, and the mixture was separated by column chromatography to obtain 170 mg of an oily liquid, which was galantamine analog B15, in 43% yield. NMR data are as follows: 1H NMR(600MHz,DMSO-d6)δ7.66(t,J=6.2Hz,1H),7.15–7.09(m,4H),6.69(d,J=8.1Hz,1H),6.56(d,J=8.1Hz,1H),6.23 (d,J=10.3Hz,1H),5.78(dd,J=10.3,4.7Hz,1H),5.11–5.08(m,1H),4.43(s,1H),4.11(d,J=6.2Hz,2H),4.08(d,J=1 5.1Hz,1H),3.72(s,3H),3.56(d,J=15.1Hz,1H),3.19(t,J=13.4Hz,1H),2.93–2.86(m,1H),2.44–2.37(m,1H),2.26 (s,3H),2.24(s,3H),2.19(ddd,J=16.4,6.3,3.4Hz,1H),1.99(td,J=13.4,3.0Hz,1H),1.49(dd,J=13.8,3.2Hz,1H); 13 C NMR (151MHz, DMSO) δ156.79,146.62,143.63,137.39,136.15,132.84,130.10,129.22,127.56, 123.68,121.44,112.04,85.97,63.37,59.89,56.01,53.44,47.83,43.98,33.81,28.19,21.14.

[0102] The structural formula in the above steps is shown below:

[0103]

[0104]

[0105] The preparation of a galantamine analog (IC) compound and its intermediates in this embodiment are described in the following specific synthetic steps:

[0106] (1) Synthesis of intermediate 3-1: Galantamine (0.5 g, 1.7 mmol) was stirred in anhydrous DCM for 20-40 min. Under ice bath conditions, 5-bromo-2-chloromethylenepyridine (0.36 g, 1.7 mmol) and the basic catalyst N,N-diisopropylethylamine (0.33 g, 2.55 mmol) were slowly added. After removing the ice bath, the reaction was carried out at room temperature for 12 h. The solvent was removed, and the mixture was separated by column chromatography to obtain 0.69 g of white solid, which was intermediate 3-1, with a yield of 89%.

[0107] (2) Synthesis of galantamine analog C1: 4 mL of 1,4-dioxane and 1 mL of water were mixed and added to a mixture containing intermediate 3-1 (0.46 g, 1.0 mmol), benzylborate pinacol ester (0.28 g, 1.3 mmol), K2CO3 (0.28 g, 2.0 mmol), CsF (0.08 g, 0.5 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.11 g, 0.15 mmol). The mixture was heated to 75–95 °C for 3 h under N2 protection. After removing the solvent, the mixture was separated by column chromatography to obtain 165 mg of an oily liquid, which was galantamine analog C1, with a yield of 34%. NMR data are as follows: 1 HNMR(600MHz, DMSO-d6)δ8.68(d,J=2.2Hz,1H),7.83(dd,J=7.9,2.3Hz,1H),7.68(d,J=8.0Hz,1H),7.34–7.29( m,4H),7.24–7.20(m,1H),6.87(d,J=8.2Hz,1H),6.76(s,1H),6.18(s,1H),5.93–5.89(m,1H),5.15(s,1H),4.89 (t,J=15.0Hz,2H),4.67–4.61(m,2H),4.53(s,1H),4.09(t,J=4.1Hz,1H),4.06(s,2H),3.77(s,3H),3.63(d,J= 13.3Hz,1H),2.81(s,3H),2.27(s,1H),2.20(t,J=16.3Hz,1H),2.06(ddd,J=15.3,5.5,4.0Hz,1H),1.87(s,1H); 13 C NMR (151MHz, DMSO) δ150.70,147.31,146.91,145.91,140.41,138.59,138.01,133.26,131.05,129.27,129.14,128 .69,126.87,125.41,124.31,112.64,86.97,71.38,65.86,59.99,56.10,55.41,46.45,43.61,38.21,32.43,31.75.

[0108] (3) Synthesis of galantamine analog C2: 4 mL of 1,4-dioxane and 1 mL of water were mixed and added to a mixture containing intermediate 3-1 (0.46 g, 1.0 mmol), pinacol ester of 2-fluorobenzylborate (0.31 g, 1.3 mmol), K2CO3 (0.28 g, 2.0 mmol), CsF (0.08 g, 0.5 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.11 g, 0.15 mmol). The mixture was heated to 75–95 °C for 3 h under N2 protection. After removing the solvent, the mixture was separated by column chromatography to obtain 223 mg of an oily liquid, which was galantamine analog C2, with a yield of 46%. NMR data are as follows: 1 HNMR (600MHz, DMSO-d6) δ8.67(d,J=2.3Hz,1H),7.79(dd,J=8.0,2.3Hz,1H),7.66(d,J=8.0Hz,1H),7.40(td,J=7.7 ,1.8Hz,1H),7.32(tdd,J=7.5,5.3,1.8Hz,1H),7.23–7.16(m,2H),6.88(d,J=8.2Hz,1H),6.75(s,1H),6.17(s,1H), 5.92(s,1H),5.13(s,1H),4.89–4.82(m,2H),4.68–4.62(m,2H),4.53(s,1H),4.10(s,3H),3.78(d,J=3.9Hz,3H),3. 63(d,J=18.8Hz,1H),2.80(s,3H),2.25–2.15(m,1H),2.07(td,J=11.2,5.9Hz,1H),2.03–1.96(m,1H),1.88(s,1H); 13 CNMR(151MHz,DMSO-d6)δ163.58,161.96,150.72,147.47,146.67,143.34,138.08,133.28,131.08,129.76,128.73,127.54,1 24.32,116.10,113.78,112.64,112.04,86.97,71.46,65.89,60.63,60.00,56.10,55.40,46.45,43.63,37.75,32.43,31.85.

[0109] (4) Synthesis of galantamine analog C3: 4 mL of 1,4-dioxane and 1 mL of water were mixed and added to a mixture containing intermediate 3-1 (0.46 g, 1.0 mmol), pinacol ester of 3-fluorobenzylborate (0.28 g, 1.3 mmol), K2CO3 (0.28 g, 2.0 mmol), CsF (0.08 g, 0.5 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.11 g, 0.15 mmol). The mixture was heated to 75–95 °C for 3 h under N2 protection. After removing the solvent, the mixture was separated by column chromatography to obtain 184 mg of an oily liquid, which was galantamine analog C3, with a yield of 38%. NMR data are as follows: 1 HNMR(600MHz,DMSO-d6)δ8.70(d,J=2.3Hz,1H),7.88–7.81(m,1H),7.68(d,J=8.0Hz,1H),7.36(td,J=8.0,6.3Hz,1H),7.20–7 .14(m,2H),7.05(td,J=9.1,2.7Hz,1H),6.88(d,J=8.1Hz,1H),6.76(s,1H),6.18(s,1H),5.91(dd,J=9.8,4.5Hz,1H),5.15(d, J=13.4Hz,1H),4.89(t,J=15.5Hz,2H),4.64(t,J=3.5Hz,2H),4.54–4.51(m,1H),4.10(s,1H),4.08(s,2H),3.77(s,3H),3.64( d,J=11.2Hz,1H),2.81(s,3H),2.27(d,J=9.4Hz,1H),2.22(d,J=15.7Hz,1H),2.06(ddd,J=15.3,5.5,4.0Hz,1H),1.88(s,1H); 13 C NMR (151MHz, DMSO) δ163.57,161.96,150.72,147.49,146.92,145.92,143.30,138.07,133.26,131.08,129.76,128.74,127.54,125 .43,124.32,118.61,115.96,113.77,112.63,86.97,71.39,65.87,60.61,59.99,56.09,55.41,46.45,43.63,37.75,32.44,31.74.

[0110] (5) Synthesis of galantamine analog C4: 4 mL of 1,4-dioxane and 1 mL of water were mixed and added to a mixture containing intermediate 3-1 (0.46 g, 1.0 mmol), 4-fluorobenzylborate pinacol ester (0.28 g, 1.3 mmol), K2CO3 (0.28 g, 2.0 mmol), CsF (0.08 g, 0.5 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.11 g, 0.15 mmol). The mixture was heated to 75–95 °C for 3 h under N2 protection. After removing the solvent, the mixture was separated by column chromatography to obtain 187 mg of an oily liquid, which was galantamine analog C4, with a yield of 38%. NMR data are as follows: 1 HNMR(600MHz,DMSO-d6)δ8.68(d,J=2.3Hz,1H),7.83(dd,J=7.9,2.3Hz,1H),7.67(d,J=7.9Hz,1H),7.37–7.32(m, 2H),7.19–7.12(m,2H),6.88(d,J=8.2Hz,1H),6.76(s,1H),6.18(s,1H),5.91(d,J=10.2Hz,1H),5.13(s,1H),4.92 –4.83(m,2H),4.65(q,J=4.2Hz,2H),4.53(s,1H),4.10(td,J=5.3,2.8Hz,1H),4.06(s,2H),3.77(s,3H),3.64(d, J=15.0Hz,1H),2.80(s,3H),2.28(s,1H),2.22(d,J=15.7Hz,1H),2.06(ddd,J=15.3,5.6,4.1Hz,1H),1.88(s,1H); 13 C NMR (151MHz, DMSO) δ162.21,160.61,151.41,150.67,148.23,147.34,146.92,145.92,140.75,138.51,137.97,136.61,133.25,131.09,12 8.71,125.38,124.32,115.91,115.77,112.63,86.96,71.46,65.88,6 0.65,59.99,56.12,55.40,49.06,46.44,43.61,37.26,32.41,31.75.

[0111] (6) Synthesis of galantamine analog C5: 4 mL of 1,4-dioxane and 1 mL of water were mixed and added to a mixture containing intermediate 3-1 (0.46 g, 1.0 mmol), pinacol 4-chlorobenzylborate (0.33 g, 1.3 mmol), K2CO3 (0.28 g, 2.0 mmol), CsF (0.08 g, 0.5 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.11 g, 0.15 mmol). The mixture was heated to 75–95 °C for 3 h under N2 protection. After removing the solvent, the mixture was separated by column chromatography to obtain 67 mg of an oily liquid, which was galantamine analog C5, with a yield of 13%. NMR data are as follows: 1 HNMR (600MHz, DMSO-d6) δ8.68(d,J=2.3Hz,1H),7.83(dd,J=7.9,2.3Hz,1H),7.65(d,J=7.9Hz,1H),7.38(d, J=8.5Hz,2H),7.33(d,J=8.5Hz,2H),6.88(d,J=8.2Hz,1H),6.75(s,1H),6.17(s,1H),5.92(s,1H),5.12(s,1 H),4.85(t,J=12.8Hz,2H),4.67–4.62(m,2H),4.53(s,1H),4.11–4.08(m,1H),4.06(s,2H),3.77(s,3H),3.6 3(d,J=20.4Hz,1H),2.80(s,3H),2.22(d,J=15.6Hz,1H),2.11–2.03(m,1H),2.03–1.95(m,1H),1.88(s,1H); 13 C NMR(151MHz,DMSO)δ150.70,147.40,139.49,138.21,138.03,131.59,131.17,129.06,1 28.72,124.31,112.64,86.96,70.25,63.25,59.99,56.09,46.44,43.62,37.39,31.74.

[0112] (7) Synthesis of galantamine analog C6: 4 mL of 1,4-dioxane and 1 mL of water were mixed and added to a mixture containing intermediate 3-1 (0.46 g, 1.0 mmol), pinacol ester of 3-chlorobenzylborate (0.33 g, 1.3 mmol), K2CO3 (0.28 g, 2.0 mmol), CsF (0.08 g, 0.5 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.11 g, 0.15 mmol). The mixture was heated to 75–95 °C for 3 h under N2 protection. After removing the solvent, the mixture was separated by column chromatography to obtain 106 mg of an oily liquid, which was galantamine analog C6, with a yield of 21%. NMR data are as follows: 1 HNMR (600MHz, DMSO-d6) δ8.71(d,J=2.3Hz,1H),7.87(dd,J=7.9,2.3Hz,1H),7.70(d,J=7.9Hz,1H),7.42(t,J=1.9Hz,1H ),7.35(d,J=7.5Hz,1H),7.29(dd,J=7.8,1.9Hz,2H),6.87(d,J=8.0Hz,1H),6.77(s,1H),6.19(s,1H),5.91(dd,J=10.5 ,4.8Hz,1H),5.17(s,1H),4.96–4.84(m,2H),4.71–4.60(m,2H),4.52(s,1H),4.14(s,1H),4.07(s,2H),3.77(s,3H),3. 66–3.63(m,1H),2.81(s,3H),2.27(d,J=9.5Hz,1H),2.25–2.17(m,1H),2.06(ddd,J=15.3,5.6,4.1Hz,1H),1.88(s,1H); 13 C NMR(151MHz,DMSO-d6)δ150.71,147.52,146.92,145.91,143.03,138.07,133.68,131.00,129.09,128.76 ,128.04,126.91,124.32,112.64,86.97,71.39,65.86,59.99,56.10,55.41,46.45,43.64,37.63,32.43.

[0113] (8) Synthesis of galantamine analog C7: 4 mL of 1,4-dioxane and 1 mL of water were mixed and added to a mixture containing intermediate 3-1 (0.46 g, 1.0 mmol), pinacol ester of 4-methylbenzylborate (0.3 g, 1.3 mmol), K2CO3 (0.28 g, 2.0 mmol), CsF (0.08 g, 0.5 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.11 g, 0.15 mmol). The mixture was heated to 75–95 °C for 3 h under N2 protection. After removing the solvent, the mixture was separated by column chromatography to obtain 267 mg of an oily liquid, which was galantamine analog C7, with a yield of 55%. NMR data are as follows: 1 HNMR (600MHz, DMSO-d6) δ8.66(d,J=2.2Hz,1H),7.81(dd,J=7.9,2.3Hz,1H),7.66(d,J=8.0Hz,1H),7.18(d,J=8. 0Hz,2H),7.12(d,J=7.8Hz,2H),6.88(d,J=8.2Hz,1H),6.76(s,1H),6.18(s,1H),5.94–5.91(m,1H),5.13(d,J=9 .9Hz,1H),4.87(t,J=16.2Hz,2H),4.64(t,J=3.9Hz,2H),4.53(s,1H),4.09(s,1H),4.00(s,2H),3.77(s,3H),3. 62(s,1H),2.80(s,3H),2.26(s,3H),2.21(s,1H),2.06(ddd,J=15.4,5.5,4.0Hz,1H),2.01(s,1H),1.88(s,1H); 13 C NMR (151MHz, DMSO) δ150.65,147.19,145.91,138.85,137.93,137.33,135.89,129.69,129.16,128.66,125.38,124.3 1,118.61,112.64,93.33,86.96,71.45,70.25,65.88,63.26,60.00,56.09,46.45,43.61,37.83,31.74,22.56,21.07.

[0114] (9) Synthesis of galantamine analog C8: 4 mL of 1,4-dioxane and 1 mL of water were mixed and added to a mixture containing intermediate 3-1 (0.46 g, 1.0 mmol), pinacol ester of 4-methoxybenzylborate (0.32 g, 1.3 mmol), K2CO3 (0.28 g, 2.0 mmol), CsF (0.08 g, 0.5 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.11 g, 0.15 mmol). The mixture was heated to 75–95 °C for 3 h under N2 protection. After removing the solvent, the mixture was separated by column chromatography to obtain 222 mg of an oily liquid, which was galantamine analog C8, with a yield of 45%. NMR data are as follows: 1 HNMR(600MHz,DMSO-d6)δ8.66(d,J=2.3Hz,1H),7.80(dd,J=7.9,2.3Hz,1H),7.66(d,J=7.9Hz,1H),7.24–7. 19(m,2H),6.88(dd,J=9.0,2.6Hz,3H),6.76(s,1H),6.18(s,1H),5.92(d,J=10.0Hz,1H),5.14(s,1H),4.88 (q,J=12.7Hz,2H),4.64(t,J=3.8Hz,2H),4.53(s,1H),4.11–4.08(m,1H),3.99(s,2H),3.77(s,3H),3.72(s ,3H),3.65–3.58(m,1H),2.80(s,3H),2.27(s,1H),2.22(d,J=15.8Hz,1H),2.12–1.95(m,1H),1.88(s,1H); 13 C NMR (151MHz, DMSO) δ158.32,150.61,147.16,146.92,145.92,140.75,139.07,137.87,133.25,132.29,130.30, 128.65,125.39,124.31,114.54,112.64,86.96,71.45,65.87,60.62,59.99,55.52,55.40,46.45,37.36,32.42.

[0115] (10) Synthesis of galantamine analog C9: 4 mL of 1,4-dioxane and 1 mL of water were mixed and added to a mixture containing intermediate 3-1 (0.46 g, 1.0 mmol), pinacol ester of 3-methoxybenzylborate (0.32 g, 1.3 mmol), K2CO3 (0.28 g, 2.0 mmol), CsF (0.08 g, 0.5 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.11 g, 0.15 mmol). The mixture was heated to 75–95 °C for 3 h under N2 protection. After removing the solvent, the mixture was separated by column chromatography to obtain 216 mg of an oily liquid, which was galantamine analog C9, with a yield of 43%. NMR data are as follows: 1 H NMR (600MHz, DMSO-d6) δ8.68(d,J=2.2Hz,1H),7.84(dd,J=7.9,2.3Hz,1H),7.67(d,J=8.0Hz,1H),7.23(t,J=7.9Hz ,1H),6.90–6.84(m,3H),6.82–6.77(m,1H),6.76(s,1H),6.17(s,1H),5.93–5.90(m,1H),5.13(d,J=23.1Hz,1H),4 .89(q,J=12.3Hz,2H),4.64(t,J=3.8Hz,2H),4.53(s,1H),4.09(q,J=4.4Hz,1H),4.02(s,2H),3.77(s,3H),3.73(s ,3H),3.63(q,J=9.8,8.5Hz,1H),2.80(s,3H),2.27(s,1H),2.20(t,J=16.3Hz,1H),2.09–2.04(m,1H),1.87(s,1H); 13 C NMR (151MHz, DMSO) δ159.95,150.68,147.28,146.92,145.92,141.92,138.51,137.99,130.20,128.67,125.38,124.30,12 1.46,115.13,112.64,112.11,93.33,86.96,71.44,65.87,63.25,59.99,56.09,55.47,46.45,43.63,38.22,32.42,31.74.

[0116] (11) Synthesis of galantamine analog C10: 4 mL of 1,4-dioxane and 1 mL of water were mixed and added to a mixture containing intermediate 3-1 (0.46 g, 1.0 mmol), pinacol ester of 2-methoxybenzylborate (0.28 g, 1.3 mmol), K2CO3 (0.28 g, 2.0 mmol), CsF (0.08 g, 0.5 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.11 g, 0.15 mmol). The mixture was heated to 75–95 °C for 3 h under N2 protection. After removing the solvent, the mixture was separated by column chromatography to obtain 98 mg of an oily liquid, which was galantamine analog C10, with a yield of 20%. NMR data are as follows: 1 H NMR (600MHz, DMSO-d6) δ8.68(d,J=2.3Hz,1H),7.84(dd,J=7.9,2.3Hz,1H),7.67(d,J=8.0Hz,1H),7.23(t,J=7.9Hz,1H),6 .94–6.84(m,3H),6.79(dd,J=8.2,2.6Hz,1H),6.76(s,1H),6.17(s,1H),5.91(d,J=10.2Hz,1H),5.14(d,J=14.3Hz,1H),4 .87(t,J=14.8Hz,2H),4.64(s,2H),4.52(s,1H),4.09(q,J=4.4,3.9Hz,1H),4.02(s,2H),3.77(s,3H),3.73(s,3H),3.63( q,J=10.5,8.9Hz,1H),2.80(s,3H),2.27(s,1H),2.22(d,J=15.6Hz,1H),2.06(ddd,J=15.3,5.5,3.9Hz,1H),1.88(s,1H); 13 C NMR(151MHz,DMSO-d6)δ159.95,150.68,147.28,141.92,138.51,137.99,130.20,128.67,121.4 6,115.13,112.11,86.97,71.44,65.87,63.26,59.99,56.10,55.47,46.45,43.62,38.22,32.42.

[0117] The structural formula in the above steps is shown below:

[0118]

[0119] Example 2

[0120] Cholinesterase inhibition assays of galantamine analogs A1–A12, B1–B15, and C1–C10:

[0121] Experimental materials and instruments: human serum acetylcholinesterase, human serum butyrylcholinesterase, acetylcholinesterase activity assay kit, DTNB, BTCl, and Tris HCl were purchased from Sigma Aldrich, positive compounds galantamine, donepezil, and rivastigmine were purchased from MedChemExpress, a multi-functional microplate reader was purchased from Thermo Fisher Scientific, and a microplate constant temperature shaker was purchased from Haimen Qilin Bell Instrument Manufacturing Co., Ltd.

[0122] Experimental Method (Acetylcholinesterase): The test compounds (A1-A12, B1-B15, C1-C10) and positive control drugs (galantamine, rivastigmine, donepezil) were dissolved in DMSO and diluted with buffer solution from the assay kit to a final concentration of 10 μM for initial screening. The compound solution (50 μL) was combined with AChE solution (2.005 U / mL, 50 μL) and incubated at 37°C in the dark for 10 min. Then, the working reagent (100 μL) was added, and the absorbance at 405 nm was recorded using a multi-mode microplate reader for data processing.

[0123] Experimental method (butyrylcholinesterase): The compound solution (10 μL), BuChE solution (2.040 U / mL, 50 μL), and DTNB solution (1.5 mM, 160 μL) were mixed and incubated at 37 °C in the dark for 10 min. Then, BTCl solution (15 mM, 30 μL) was added, and the absorbance at 405 nm was recorded using a multi-mode microplate reader. Data processing was then performed.

[0124]

[0125] Where OD represents the absorbance OD value.

[0126] In this experiment, the final concentration of DMSO did not exceed 1%, as this concentration would lead to enzyme inactivation. After three replicate experiments with the 10 μM compound, enzymes exhibiting an inhibition rate of 50% or higher were then subjected to IC50 assay. 50 The inhibition rate of five to seven compounds was determined based on the initial screening results. A linear regression was then performed between the negative logarithm of the compound's molar concentration and the enzyme activity to obtain the molar concentration at which 50% inhibition was achieved; this molar concentration is the IC50 of the compound. 50 Values ​​(using the data processing software GraphPad Prism). See Tables 1 and 2 for specific results.

[0127] Table 1

[0128]

[0129] Table 2

[0130]

[0131]

[0132] As shown in Tables 1 and 2, the galantamine analogues provided by this invention have better overall performance than existing known galantamine and are expected to be developed into new drugs for the treatment of cholinergic dysfunction.

[0133] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. A galantamine analogue, characterized in that, The galantamine analogue is a compound of formula (IC) or a pharmaceutically acceptable salt thereof: In the formula (IC), R3 is selected from one of hydrogen, o-fluorine, m-fluorine, p-fluorine, m-chlorine, p-chlorine, p-methyl, o-methoxy, m-methoxy, and p-methoxy.

2. The galantamine analogue as described in claim 1, characterized in that, The structure of the galantamine analogue is shown below: 、 、 、 、 、 、 、 、 、 。 3. A method for preparing a galantamine analogue as described in claim 1, characterized in that, The galantamine analogue is a compound of formula (IC), and the preparation method includes the following steps: (1) Galantamine was dissolved in anhydrous DCM. Under ice bath conditions, the mixture was stirred for 20-40 min and then 5-bromo-2-chloromethylenepyridine was slowly added. The reaction was carried out under the action of an alkaline catalyst to obtain the structure of formula (II). c Intermediate 1 of ) (2) Intermediate 1 and benzylboronic acid pinacol ester (III) containing R-substituted groups c Dissolved in an organic solvent, under nitrogen protection and with the aid of a catalyst, the mixture is heated to 75-95°C to carry out a coupling reaction to obtain a galantamine analog (IC). The R group is selected from one of hydrogen, o-fluorine, m-fluorine, p-fluorine, m-chloro, p-chloro, p-methyl, o-methoxy, m-methoxy, and p-methoxy. The structural formula in the above steps is shown below: 、 。 4. The preparation method according to claim 3, characterized in that, The alkaline catalyst in step (1) is DIPEA, the organic solvent is a mixed solution of 1,4-dioxane and water with a volume ratio of 4:1, and the catalyst is K2CO3, CsF and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride.

5. The use of the galantamine analogue as described in claim 1 or claim 2 in the preparation of cholinesterase inhibitors.

6. The use of the galantamine analogue as described in claim 1 or claim 2 in the preparation of a medicament for treating cholinergic dysfunction-related diseases.

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