Aromatic amino acid compound, preparation method thereof, pharmaceutical composition and application thereof

Abstract

The application discloses a kind of aromatic amino acid compounds and preparation method, pharmaceutical composition and application thereof.The compound structure is as shown in formula I, which includes isomers, pharmaceutically acceptable salts or mixtures thereof.The aromatic amino acid compound and the pharmaceutical composition thereof can effectively and selectively inhibit butyrylcholinesterase, optimally reach nanomolar concentration level;It also has excellent blood-brain barrier permeability, and in addition, it is almost non-toxic.The prepared drug can effectively treat Alzheimer's disease through neuroprotective effect, memory and cognitive function improvement and various effects.

Description

TECHNICAL FIELD

[0001] The present application relates to a kind of aromatic amino acid compounds and preparation method, pharmaceutical composition and application, especially to a kind of aromatic amino acid compounds and preparation method, pharmaceutical composition and application of selective inhibitor drug of butyrylcholine esterase. BACKGROUND

[0002] Alzheimer's disease (AD) is a progressive fatal neurodegenerative disease. The clinical manifestations are regressive loss of memory and cognitive function, decline of daily life ability and accompanied by various neuropsychiatric symptoms. Therefore, finding drugs and treatment strategies effective for AD has become a key problem to be solved in the medical field of the whole world.

[0003] The pathogenesis of AD is extremely complex. Although scientists have not yet reached a conclusion on the exact cause of AD, a large number of previous studies have shown that AD is mainly induced by the combined action of genetic factors, aging and external environmental factors. Several hypotheses have been proposed, including cholinergic dysfunction, amyloid beta peptide (Aβ) plaque, neurofibrillary tangle and oxidative stress.

[0004] Acetylcholinesterase (ACh) is a cholinergic transmission medium, widely distributed in peripheral and central nervous system. At the neuron level, cholinergic neurotransmission is mainly regulated by two cholinesterases: acetylcholinesterase and butyrylcholinesterase. In healthy adults, AChE plays a major regulatory role in choline activity, and BuChE plays an auxiliary regulatory role. However, the auxiliary regulatory function of BChE changes with the development of AD, and the BuChE / AChE of patients with late AD increases significantly. BChE replaces AChE to hydrolyze choline. Currently, AChE inhibitors are widely used to restore ACh levels, but patients taking AChE inhibitors may experience side effects such as nausea and vomiting. These adverse outcomes are mainly due to the inhibition of peripheral AChE.

[0005] Currently, there are few high-selective butyrylcholinesterase structural types, and only one is in clinical research. The compound is bisnorcymserine, which is a carbamate structure and a covalent inhibitor of BChE. Currently, there is no reversible BChE inhibitor in clinical trials. SUMMARY

[0006] The present application aims to provide a kind of aromatic amino acid compounds and preparation method, pharmaceutical composition and application of selective inhibition of butyrylcholinesterase activity, to solve the problems of poor efficacy, obvious adverse reactions and other deficiencies of existing AChE inhibitor drugs in AD, and the single skeleton type and poor selectivity of existing BChE inhibitor drugs.

[0007] Technical Solution: As the first aspect of the present application, the aromatic amino acid compound of the present application has the structure of Formula I, including its isomers, pharmaceutically acceptable salts or mixtures thereof:

[0008]

[0009] wherein:

[0010] n = 0-4;

[0011] A ring is selected from a 6-10 membered aromatic ring or a 6-10 membered aromatic heterocycle;

[0012] B ring is selected from a 6-10 membered heterocycle or a 6-10 membered aromatic ring, which ring system is substituted with one or more hydrogens, C1-C3 alkyl or C1-C3 alkylamino;

[0013] R1 is selected from one or more hydrogens, C1-C6 alkyl or a 5-6 membered aromatic heterocycle; the chiral atom to which the R1NH group is attached is in the R, S or racemic configuration.

[0014] The compound of the present application designs a class of reversible inhibitors of natural amino acid skeleton. Selective BChE inhibitors can avoid existing cholinergic toxicity, and inhibition of butyrylcholine esterase will be more effective than selective acetylcholine esterase, especially for advanced AD.

[0015] Preferably, in the above structure:

[0016] A ring is selected from a 6-membered or 10-membered aromatic ring or a 9-10 membered nitrogen-containing aromatic heterocycle;

[0017] B ring is selected from a 6-10 membered nitrogen-containing heterocycle or a benzene ring, which ring system is substituted with one or more hydrogens, C1-C3 alkyl or C1-C3 alkylamino;

[0018] R1 is selected from one or more hydrogens, C1-C6 alkyl or a 5-6 membered nitrogen- or oxygen-containing aromatic heterocycle; the chiral atom to which the R1NH group is attached is in the R, S or racemic configuration.

[0019] Further preferably, in the above structure:

[0020] A ring is selected from:

[0021]

[0022] B ring is selected from:

[0023]

[0024] R1 is selected from:

[0025]

[0026] Specifically, the aromatic amino acid compound is selected from any one of the following compounds:

[0027]

[0028]

[0029] The pharmaceutically acceptable salt of the aromatic amino acid compound is a salt of the compound with an acid, which is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid.

[0030] As a second aspect of the present application, the preparation method of the aromatic amino acid compound is:

[0031] (1) when the B ring is selected from ,

[0032] Compound 1 is subjected to substitution, reduction, acylation, deprotection and substitution reactions to obtain compound I;

[0033]

[0034] (2) when the B ring is selected from ,

[0035] Compound 6 is subjected to substitution, protection, acylation and deprotection reactions to obtain compound I;

[0036]

[0037] wherein n, the A ring, R1 and R2 are as defined above;

[0038] The corresponding acid is salted with compound I prepared by the above method to obtain the pharmaceutically acceptable salt of the aromatic amino acid compound.

[0039] As a third aspect of the present application, the pharmaceutical composition of the present application comprises the aromatic amino acid compound and a pharmaceutically acceptable carrier.

[0040] The aromatic amino acid compound can be added with a pharmaceutically acceptable carrier to form common pharmaceutical preparations, such as tablets, capsules, syrups, suspensions or injections, and the preparations can be added with flavorings, sweeteners, liquid / solid fillers, diluents and other common pharmaceutical excipients.

[0041] As a fourth aspect of the present application, the aromatic amino acid compound and the pharmaceutical composition thereof can be prepared as a butyrylcholinesterase inhibitor drug for treating neurodegenerative diseases, particularly Alzheimer's disease.

[0042] Advantages: Compared with the prior art, the present application has the following remarkable advantages:

[0043] (1) The aromatic amino acid compound and the pharmaceutical composition thereof can effectively and selectively inhibit butyrylcholinesterase, with an IC 50 value of less than 50 nM, excellent blood-brain barrier permeability, effective delivery to lesions, and almost no toxicity;

[0044] (2) The aromatic amino acid compound and the pharmaceutical composition thereof have good neuroprotective effects and significantly improve memory and cognitive function, and have multiple mechanisms of anti-Alzheimer's disease activity;

[0045] (3) The compound preparation method is simple and easy to operate. BRIEF DESCRIPTION OF DRAWINGS

[0046] Figure 1 The cytotoxicity of the compound to human neuroblastoma SH-SY5Y cells;

[0047] Figure 2 The neuroprotective efficacy of compounds 18(R) and 22(R) to Aβ 1-42 induced cytotoxicity to human neuroblastoma SH-SY5Y cells;

[0048] Figure 3 The daily body weight of ICR mice in 14 days in the water maze experiment;

[0049] Figure 4 The effect results of the compound on AD-like cognitive impairment of ICR Aβ 1-42 peptide-induced mice in the water maze experiment;

[0050] Figure 5 The average trajectory of the mice in the water maze experiment. DETAILED DESCRIPTION

[0051] The technical solutions of the present application are further described below in combination with examples.

[0052] The structure of the compound is determined by nuclear magnetic resonance (NMR). The instrument is a Bruker AVANCE-300 nuclear magnetic resonance instrument, the determination solvent is CDCl3, the internal standard is TMS, and the chemical shift is 10 -6 ppm.

[0053] Example 1: Synthesis of compound 10

[0054] Step 1: Synthesis of 2-(3,4-dihydroisoquinolin-2(lH)-yl)acetonitrile (2a)

[0055] 1,2,3,4-Tetrahydroisoquinoline (10 mmol) was dissolved in 40 mL of tetrahydrofuran, potassium carbonate (13 mmol) and bromoacetonitrile (12 mmol) were added, stirred at room temperature for 3 hours, after the reaction was completed, filtered, the filtrate was concentrated under vacuum, column chromatography (petroleum ether: ethyl acetate = 5: 1) to get white solid, yield 87.5%.

[0056] 1 H NMR (500 MHz, CDC13) δ 7.21 - 7.18 (m, 1H), 7.18 - 7.14 (m, 2H), 7.09 - 7.05 (m, 1H), 3.82 (s, 1H), 3.74 (s, 1H), 2.99 (t, J = 5.9 Hz, 1H), 2.90 (t, J = 5.9 Hz, 1H).

[0057] Step 2: Synthesis of 2-(3,4-dihydroisoquinolin-2(lH)-yl)ethan-l-amine

[0058] Under ice bath, lithium aluminum hydride (20 mmol) was dispersed in 20 mL of tetrahydrofuran solution, argon protection, 2-(3,4-dihydroisoquinolin-2(lH)-yl)acetonitrile was slowly added, stirred at room temperature for 2-3 hours. Dilute sodium hydroxide to quench the reaction, filter, the filtrate was concentrated under vacuum to get crude yellow oil, yield 91.2%.

[0059] Step 3: Synthesis of tert-butyl (l-((2-(3,4-dihydroisoquinolin-2(lH)-yl)ethyl)amino)-3-(lH-indol-3-yl)- 1-oxopropan-2-yl)carbamate

[0060] (R) N-tert-butoxycarbonyl tryptophan (5 mmol) was dissolved in 20 mL of N,N'-dimethylformamide, under ice bath, N,N'-diisopropyl ethylamine (12 mmol), benzotriazole-1-yl-oxytris-pyrrolidino-phosphonium hexafluorophosphate (6 mmol), 2-(3,4-dihydroisoquinolin-2(lH)-yl)ethan-l-amine (6 mmol) were added, stirred at room temperature for 4-5 hours. Add 20 mL of water to quench, extract with ethyl acetate (30 mL x 3), combine the organic phase, wash with water, saturated brine, dry over anhydrous sodium sulfate. Remove the solvent under vacuum, column chromatography (dichloromethane:methanol = 100:1) to get light yellow solid, yield 67.5%.

[0061] Step 4: Synthesis of 2-amino-N-(2-(3,4-dihydroisoquinolin-2(lH)-yl)ethyl)-3-(lH-indol-3-yl)propan-l-amine

[0062] tert-butyl (l-((2-(3,4-dihydroisoquinolin-2(lH)-yl)ethyl)amino)-3-(lH-indol-3- yl)-l-oxopropan-2-yl)carbamate (3 mmol) was dissolved in 5 mL of trifluoroacetic acid and stirred at room temperature overnight. The solvent was removed in vacuo to give a crude product. Column chromatography (dichloromethane:methanol = 50: 1) gave a colorless oil with a yield of 81.2%.

[0063] (R) 2-amino-N-(2-(3,4-dihydroisoquinolin-2(lH)-yl)ethyl)-3-(lH-indol-3- yl)propan-l-ammonium

[0064] 1 H NMR (300 MHz, CDC13) δ 8.08 (s, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.34 - 7.28 (m, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.19 (s, 2H), 7.12 (dd, J = 7.1, 0.9 Hz, 1H), 6.94 (dd, J = 6.8, 2.5 Hz, 2H), 3.61 (dd, J = 8.0, 4.7 Hz, 1H), 3.52 (d, J = 7.4 Hz, 2H), 3.36 (dd, J = 11.7, 5.0 Hz, 3H), 3.24 (dd, J = 14.5, 4.6 Hz, 1H), 2.89 (dd, J = 14.4, 8.2 Hz, 1H), 2.75 (t, J = 5.6 Hz, 3H), 2.59 (t, J = 5.8 Hz, 3H), 2.49 (t, J = 6.2 Hz, 2H).

[0065] 13 C NMR (126 MHz, CDC13) δ 175.03, 136.35, 134.58, 134.36, 128.68, 127.54, 126.57, 126.23, 125.69, 123.11, 122.14, 119.52, 118.98, 111.69, 111.19, 56.55, 55.75, 55.73, 50.61, 36.18, 31.02, 29.00.

[0066] ESI: m / z [M + H] + , calcd for C 22 H 26 N4O: 363.2107; found: 363.2180

[0067] HPLC: 0 ~ 20 min (A: B = 80: 20), t R = 4.778 min, Purity: 97.708%.

[0068] (S)(R)2-Amino-N-(2-(3,4-dihydroisoquinolin-2(lH)-yl)ethyl)-3-(lH-indol-3- yl)propan-l-amide

[0069] 1 H NMR (300 MHz, CDC13) δ 8.35 (s, 1H), 7.65 (d, J = 7.7 Hz, 2H), 7.32 (d, J = 8.0 Hz, 1H), 7.16 (dd, J = 14.9, 6.1 Hz, 2H), 7.09 (dd, J = 8.8, 5.6 Hz, 4H), 7.01 (d, J = 1.6 Hz, 2H), 6.98 (s, 1H), 3.59 (s, 2H), 3.50 (dd, J = 13.6, 5.9 Hz, 1H), 3.41 (dd, J = 12.8, 6.6 Hz, 1H), 3.32 (dt, J = 6.9, 4.2 Hz, 2H), 2.95 - 2.89 (m, 1H), 2.84 (t, J = 6.4 Hz, 2H), 2.68 (t, J = 5.5 Hz, 2H), 2.58 (t, J = 6.1 Hz, 2H).

[0070] 13 C NMR (75 MHz, CDC13) δ 175.26, 136.47, 134.48, 134.31, 128.73, 127.53, 126.64, 126.32, 125.77, 125.59, 123.41, 122.03, 119.40, 118.93, 111.29, 56.57, 55.76, 50.63, 36.24, 31.08, 30.41, 28.95.

[0071] ESI: m / z [M+H] + , calcd for C 22 H 26 N4O: 363.2107; found: 363.2180

[0072] HPLC: 0~20 min (A:B = 80:20), t R = 4.837 min, Purity: 99.245%.

[0073] Example 2: Synthesis of compound 11

[0074] Reference Example 1.

[0075] Synthesis of (R)-2-amino-3-(lH-indol-3-yl)-N-(2-(l-methyl-3,4-dihydroisoquinolin- 2(lH)-yl)ethyl)propanamide

[0076] 1 H NMR (300 MHz, CDC13) δ 8.08 (s, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.34 - 7.28 (m, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.19 (s, 2H), 7.12 (dd, Ji = 7.1, J2= 0.9 Hz, 1H), 6.94 (dd, Ji = 6.8, J2= 2.5 Hz, 2H), 3.61 (dd, Ji = 8.0, J2= 4.7 Hz, 1H), 3.52 (d, J = 7.4 Hz, 2H), 3.36 (dd, Ji = 11.7, J2= 5.0 Hz, 3H), 3.24 (dd, Ji = 14.5, J2= 4.6 Hz, 1H), 2.89 (dd, Ji = 14.4, J2= 8.2 Hz, 1H), 2.75 (t, J = 5.6 Hz, 3H), 2.59 (t, J = 5.8 Hz, 3H), 2.49 (t, J = 6.2 Hz, 2H).

[0077] 13 C NMR (126 MHz, CDC13) δ 174.96, 140.06, 136.38, 134.12, 128.87, 127.57, 127.34, 125.95, 125.72, 123.10, 122.15, 119.52, 119.00, 111.74, 111.19, 56.65, 55.74, 52.44, 43.48, 36.65, 31.06, 27.41, 19.45.

[0078] ESI: m / z [M+H] + , calcd for C 22 H 26 N4O: 363.2107; found: 363.2180

[0079] HPLC: 0~20 min (A:B = 80:20), t R = 5.687 min, Purity: 95.359%.

[0080] Example 3: Synthesis of compound 12

[0081] Step 1-4 refer to Example 1.

[0082] Step 5: Synthesis of (R)-2-((cyclopropylmethyl)amino)amino-N-(2-(3,4- dihydroisoquinolin-2(lH)-yl)ethyl)-3-(lH-indol-3-yl)propanamide

[0083] (R) 2-Amino-N-(2-(3,4-dihydroisoquinolin-2(lH)-yl)ethyl)-3-(lH-indol-3- yl)propan-l -amine (0.5 mmol) was dissolved in dry dichloromethane, cyclopropylcarboxaldehyde (0.6 mmol) was added, stirred at room temperature for 1 hour, sodium triacetoxyborohydride (0.75 mmol) was added, continued to stir at room temperature for 2 hours. Quenched with 10 mL water, dichloromethane was used to extract, combined organic phase, washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuum, column chromatography (dichloromethane:methanol = 100:1) to get colorless oil, yield 69.5%.

[0084] 1 H NMR (300 MHz, CDC13) δ 8.42 (s, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.81 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.52 (s, 1H), 7.37 (dd, J = 11.6, 5.6 Hz, 2H), 7.28 (d, J = 5.9 Hz, 1H), 3.85 (d, J = 3.9 Hz, 1H), 3.76 (dd, J = 13.3, 6.2 Hz, 1H), 3.68 (dd, J = 10.6, 6.5 Hz, 1H), 3.56 (dd, J = 14.5, 4.5 Hz, 1H), 3.20 (dd, J = 14.4, 8.8 Hz, 1H), 3.10 (t, J = 5.6 Hz, 1H), 2.95 (t, J = 5.7 Hz, 1H), 2.89 - 2.78 (m, 1H), 2.60 (dd, J = 12.0, 6.7 Hz, 1H), 2.47 (dd, J = 12.0, 7.0 Hz, 1H), 0.98 - 0.84 (m, 1H), 0.55 - 0.40 (m, 1H), 0.21 - 0.12 (m, 1H), 0.06 (dt, J = 7.6, 4.1 Hz, 1H).

[0085] 13 C NMR (126 MHz, CDC13) δ 174.60, 136.36, 134.62, 134.35, 128.63, 127.50, 126.52, 126.16, 125.64, 122.82, 122.16, 119.51, 118.98, 111.83, 111.13, 63.09, 56.59, 55.69, 53.75, 50.69, 36.06, 29.40, 29.08, 11.15, 3.28, 2.94.

[0086] ESI: m / z [M+H] + , calcd for C 26 H 33N4O: 417.2576; found: 417.2646.

[0087] HPLC: 0~20 min (A:B=80:20), t R = 5.427 min, Purity: 96.930 %.

[0088] Example 4: Synthesis of compound 13

[0089] Step 1-5 refer to Example 3.

[0090] (R)-2-(Butylamino)-N-(2-(3,4-dihydroisoquinolin-2(lH)-yl)ethyl)-3-(lH-indol-3- yl)propanamide

[0091] 1 H NMR (300 MHz, CDC13) δ 8.13 (s, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.62 (t, J = 4.9 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 7.0 Hz, 1H), 7.22 - 7.19 (m, 1H), 7.18 (dd, J = 3.1, 1.9 Hz, 2H), 7.16 (s, 1H), 7.06 (d, J = 5.1 Hz, 2H), 3.64 (d, J = 3.1 Hz, 2H), 3.55 (dd, J = 13.8, 6.0 Hz, 1H), 3.48 (d, J = 6.2 Hz, 3H), 3.34 (dd, J = 14.4, 4.3 Hz, 1H), 2.96 (dd, J = 14.4, 8.8 Hz, 1H), 2.89 (t, J = 5.7 Hz, 2H), 2.78 - 2.68 (m, 3H), 2.68 - 2.57 (m, 3H), 1.28 - 1.20 (m, 3H), 1.11 (dq, J = 13.7, 7.0 Hz, 3H), 0.72 (t, J = 7.2 Hz, 4H).

[0092] 13 C NMR (126 MHz, CDC13) δ 174.63, 136.36, 134.65, 134.37, 128.64, 127.54, 126.51, 126.15, 125.64, 122.80, 122.17, 119.53, 118.98, 111.88, 111.13, 63.48, 56.65, 55.69, 50.71, 48.64, 36.02, 32.23, 30.34, 29.32, 20.17, 13.80.

[0093] ESI: m / z [M+H] +C 26 H 35 N4O: 419.2733; found:

[0094] HPLC: 0~20min (A:B=80:20), t R = 5.842 min, Purity: 98.365%.

[0095] Example 5: Synthesis of compound 14

[0096] Reference Example 3.

[0097] (R)-N-(2-(3,4-dihydroisoquinolin-2(lH)-yl)ethyl)-3-(lH-indol-3-yl)-2- (methylamino)propanamide

[0098] 1 H NMR (300 MHz, CDC13) δ 8.13 (s, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.61 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.31 (s, 1H), 7.16 (d, J = 5.7 Hz, 5H), 7.05 (d, J = 11.5 Hz, 3H), 3.66 (t, J = 9.6 Hz, 3H), 3.55 (dd, J = 13.3, 6.1 Hz, 1H), 3.48 - 3.40 (m, 2H), 3.34 (dd, J = 14.5, 4.0 Hz, 1H), 2.97 (dd, J = 14.3, 8.9 Hz, 1H), 2.87 (d, J = 5.4 Hz, 2H), 2.74 (d, J = 5.1 Hz, 2H), 2.62 (d, J = 4.2 Hz, 2H), 2.42 (t, J = 7.0 Hz, 2H), 1.30 (s, 3H), 0.69 (t, J = 7.3 Hz, 3H).

[0099] 13 C NMR (126 MHz, CDC13) δ 174.67, 136.35, 134.66, 134.38, 128.63, 127.54, 126.51, 126.15, 125.63, 122.81, 122.16, 119.53, 118.97, 111.86, 111.13, 63.43, 56.64, 55.67, 50.74, 36.05, 29.70, 29.32, 29.13, 23.18, 11.40.

[0100] ESI: m / z [M+H] + , calcd for C 25 H 33N4O: 405.2576; found:

[0101] HPLC: 0~20 min (A:B=80:20), t R = 3.800 min, Purity: 98.592 %.

[0102] Example 6: Synthesis of compound 15

[0103] Reference Example 3

[0104] (R)-N-(2-(3,4-dihydroisoquinolin-2(lH)-yl)ethyl)-3-(lH-indol-3-yl)-2- (isobutylamino)propanamide

[0105] 1 H NMR (300 MHz, CDC13) δ 8.11 (s, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.66 (t, J = 4.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.26 - 7.20 (m, 1H), 7.18 (d, J = 4.1 Hz, 1H), 7.16 (d, J = 1.8 Hz, 1H), 7.15 (s, 1H), 7.09 - 7.02 (m, 2H), 3.79 (t, J = 6.6 Hz, 1H), 3.63 (d, J = 3.9 Hz, 2H), 3.52 (ddd, J = 13.9, 12.6, 5.6 Hz, 2H), 3.41 (d, J = 4.3 Hz, 1H), 2.96 (dd, J = 13.9, 8.4 Hz, 1H), 2.88 (t, J = 5.7 Hz, 2H), 2.73 (t, J = 5.4 Hz, 2H), 2.63 (t, J = 6.1 Hz, 2H), 2.30 - 2.18 (m, 2H), 1.93 - 1.87 (m, 1H), 0.69 (d, J = 1.9 Hz, 3H), 0.67 (d, J = 1.9 Hz, 3H).

[0106] 13 C NMR (126 MHz, CDC13) δ 174.67, 136.36, 134.60, 134.35, 128.62, 127.54, 126.51, 126.14, 125.62, 122.78, 122.16, 119.52, 118.97, 111.86, 111.13, 63.51, 56.85, 56.61, 55.63, 50.74, 36.03, 29.28, 29.08, 28.42, 20.31, 20.18.

[0107] ESI: m / z [M+H] +C 26 H 35 N4O: 419.2733; found:

[0108] HPLC: 0~20min (A:B=80:20), t R = 4.525 min, Purity: 95.332%.

[0109] Example 7: Synthesis of compound 16

[0110] Reference Example 3

[0111] (R)-N-(2-(3,4-dihydroisoquinolin-2(lH)-yl)ethyl)-2-((furan-2- ylmethyl)amino)-3-(lH-indol-3-yl)propanamide

[0112] 1 H NMR (300 MHz, CDC13) δ 8.08 (s, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.57 (s, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.31 (s, 1H), 7.21 - 7.17 (m, 2H), 7.15 (s, 3H), 7.08 (s, 1H), 7.00 (s, 1H), 6.17 (s, 1H), 5.97 (s, 1H), 3.70 (d, J = 14.5 Hz, 1H), 3.65 (s, 2H), 3.58 - 3.50 (m, 2H), 3.48 (d, J = 6.2 Hz, 2H), 3.35 - 3.26 (m, 1H), 3.01 (dd, J = 14.4, 8.8 Hz, 1H), 2.86 (d, J = 5.2 Hz, 2H), 2.73 (t, J = 5.6 Hz, 2H), 2.62 (t, J = 5.8 Hz, 2H).

[0113] 13 C NMR (126 MHz, CDC13) δ 174.05, 153.00, 141.72, 136.35, 134.64, 134.41, 128.67, 127.47, 126.56, 126.18, 125.66, 122.89, 122.16, 119.54, 118.97, 111.38, 111.10, 110.01, 107.07, 62.07, 56.60, 55.74, 50.62, 44.98, 36.13, 29.20, 29.08.

[0114] ESI: m / z [M+H] + , calcd for C 27 H31 N4O: 443.2369; found:

[0115] HPLC: 0~20 min (A:B=80:20), t R = 12.742 min, Purity: 95.898%.

[0116] Example 8: Synthesis of compound 17

[0117] Reference Example 3.

[0118] (R)-N-(2-(3,4-dihydroisoquinolin-2(lH)-yl)ethyl)-3-(lH-indol-3-yl)-2-((pyridin-4-yl- ethyl)amino)propanamide

[0119] 1 H NMR (300 MHz, CDC13) δ 8.24 (s, 1H), 8.13 (dd, J = 4.5, 1.4 Hz, 2H), 7.63 (d, J = 7.5 Hz, 2H), 7.34 (d, J = 8.1 Hz, 1H), 7.21 (d, J = 7.1 Hz, 1H), 7.16 (dd, J = 6.5, 2.0 Hz, 2H), 7.13 (d, J = 4.5 Hz, 1H), 7.09 (d, J = 6.8 Hz, 2H), 7.01 (s, 1H), 3.75 (t, J = 6.5 Hz, 2H), 3.67 (d, J = 14.3 Hz, 1H), 3.58 (s, 2H), 3.48 (dd, J = 12.4, 5.5 Hz, 2H), 3.43 (t, J = 3.8 Hz, 1H), 2.97 (dd, J = 14.4, 9.0 Hz, 1H), 2.77 (d, J = 4.8 Hz, 2H), 2.69 - 2.62 (m, 2H), 2.58 (t, J = 5.9 Hz, 2H).

[0120] 13 C NMR (126 MHz, CDC13) δ 173.76, 149.49, 148.40, 136.41, 134.47, 134.25, 128.73, 127.36, 126.52, 126.37, 125.80, 123.00, 122.68, 122.34, 119.68, 118.83, 111.29, 111.28, 62.80, 56.38, 55.81, 51.31, 50.46, 35.83, 29.31, 29.18.

[0121] ESI: m / z [M+H] + , calcd. for C 28 H32 N5O: 454.2529; found: 454.2605

[0122] HPLC: 0~20 min (A:B=80:20), t R = 5.803 min, Purity: 99.149 %.

[0123] (S)-N-(2-(3,4-dihydroisoquinolin-2(lH)-yl)ethyl)-3-(lH-indol-3-yl)-2-((pyridin-4- yl-ethyl)amino)propanamide

[0124] 1 H NMR (300 MHz, CDC13) δ 8.51 (s, 1H), 7.87 (d, J = 6.4 Hz, 2H), 7.60 (d, J = 7.9 Hz, 2H), 7.41 (d, J = 8.1 Hz, 1H), 7.29 - 7.21 (m, 3H), 7.17 - 7.12 (m, 2H), 7.04 (dd, J = 13.1, 5.0 Hz, 5H), 3.84 - 3.76 (m, 2H), 3.66 - 3.57 (m, 4H), 3.48 - 3.42 (m, 2H), 3.40 (t, J = 4.7 Hz, 1H), 3.04 - 2.93 (m, 1H), 2.79 (t, J = 5.4 Hz, 2H), 2.75 - 2.70 (m, 1H), 2.66 (d, J = 5.7 Hz, 2H).

[0125] ESI: m / z [M+H] + , calcd. for C 28 H 32 N5O: 454.2529; found: 454.2608

[0126] HPLC: 0~20 min (A:B=80:20), t R = 5.913 min, Purity: 99.927 %.

[0127] Example 9: Synthesis of compound 18

[0128] Reference Example 3.

[0129] (R)-N-(2-(3,4-dihydroisoquinolin-2(lH)-yl)ethyl)-2-((2-ethylbutyl)amino)-3-(lH- indol-3-yl)propanamide

[0130] 1H NMR (300 MHz, CDC13) δ 8.10 (s, 1H), 7.72 (t, J = 7.2 Hz, 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.32 (s, 1H), 7.25 (t, J = 7.5 Hz, 1H), 7.18 (dd, J = 4.7, 3.2 Hz, 3H), 7.07 (dd, J = 12.1, 3.8 Hz, 3H), 3.69 (d, J = 15.3 Hz, 2H), 3.56 (dd, J = 14.0, 6.0 Hz, 1H), 3.47 (dd, J = 12.8, 6.6 Hz, 1H), 3.43 - 3.34 (m, 3H), 3.03 - 2.95 (m, 1H), 2.91 (t, J = 6.6 Hz, 3H), 2.75 (t, J = 5.5 Hz, 2H), 2.65 (t, J = 6.1 Hz, 2H), 2.35 (d, J = 8.3 Hz, 3H), 1.18 - 1.07 (m, 6H), 0.70 - 0.59 (m, 7H).

[0131] 13 C NMR (126 MHz, CDC13) δ 174.79, 136.46, 134.66, 134.39, 128.63, 127.53, 126.53, 126.14, 125.64, 122.85, 122.11, 119.45, 118.92, 111.74, 111.21, 63.84, 56.70, 55.72, 51.79, 50.73, 41.00, 36.06, 29.35, 29.16, 23.65, 10.75.

[0132] ESI: m / z [M+H] + , calcd for C 28 H 39 N4O: 447.3046; found: 447.3122

[0133] HPLC: 0 ~ 20 min (A:B = 80:20), t R = 6.318 min, Purity: 96.020 %.

[0134] (S)-N-(2-(3,4-dihydroisoquinolin-2(lH)-yl)ethyl)-2-((2-ethylbutyl)amino)-3-(lH-indol-3- yl)propanamide

[0135] 1H NMR (300 MHz, CDC13) δ 8.13 (s, 1H), 7.73 - 7.62 (m, 2H), 7.35 (d, J = 8.0 Hz, 1H), 7.26 (s, 1H), 7.19 (dd, J = 11.0, 4.1 Hz, 1H), 7.15 - 7.05 (m, 5H), 6.97 (d, J = 2.7 Hz, 3H), 3.57 (s, 2H), 3.42 (tt, J = 11.3, 5.7 Hz, 1H), 3.35 - 3.31 (m, 1H), 3.31 - 3.25 (m, 2H), 2.92 - 2.87 (m, 2H), 2.84 (d, J = 10.2 Hz, 1H), 2.67 (dd, J = 9.1, 3.7 Hz, 2H), 2.51 (td, J = 7.1, 2.1 Hz, 2H), 2.27 (s, 2H), 1.80 - 1.70 (m, 3H), 1.14 - 1.00 (m, 7H), 0.69 - 0.58 (m, 8H).

[0136] 13 C NMR (75 MHz, CDC13) δ 174.95, 136.51, 134.61, 134.37, 128.66, 127.51, 126.56, 126.19, 125.68, 122.98, 122.07, 119.41, 118.89, 111.54, 111.30, 63.86, 56.68, 55.72, 51.78, 50.75, 40.96, 36.08, 30.38, 29.14, 23.84, 10.77.

[0137] ESI: m / z [M + H]+calcd for C + , 447.3046; found: 447.3119 28 H 39 N4O: 447.3046; found: 447.3119

[0138] HPLC: 0 ~ 20 min (A:B = 80:20), t R = 6.388 min, Purity: 96.659%.

[0139] Example 10: Synthesis of compound 19

[0140] Reference Example 3.

[0141] (R)-2-((2-ethylbutyl)amino)-3-(1H-indol-3-yl)-N-(2-(1-methyl-3,4-dihydroisoquinolin- 2(1H)-yl)ethyl)propanamide

[0142] 1H NMR (300 MHz, CDC13) δ 8.03 (d, J = 7.1 Hz, 1H), 7.68 (s, 1H), 7.66 - 7.57 (m, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 7.14 - 7.07 (m, 4H), 7.04 (d, J = 3.0 Hz, 1H), 7.03 (d, J = 3.2 Hz, 1H), 3.77 (p, J = 6.7 Hz, 1H), 3.40 (dd, J = 11.5, 5.6 Hz, 2H), 3.34 (t, J = 3.5 Hz, 1H), 3.30 (dd, J = 7.4, 4.2 Hz, 1H), 3.07 - 2.96 (m, 1H), 2.95 - 2.87 (m, 1H), 2.86 - 2.76 (m, 1H), 2.71 - 2.60 (m, 5H), 2.35 - 2.26 (m, 3H), 1.28 (dd, J = 6.7, 2.3 Hz, 4H), 1.13 - 1.00 (m, 6H), 0.60 (tt, J = 14.2, 7.2 Hz, 7H).

[0143] 13 C NMR (75 MHz, CDC13) δ 174.70, 140.06, 136.43, 134.09, 128.83, 127.55, 127.37, 125.89, 125.68, 122.80, 122.16, 119.49, 118.95, 111.82, 111.18, 63.82, 56.61, 52.45, 51.77, 43.29, 40.96, 36.40, 30.35, 27.37, 23.81, 19.53, 10.68.

[0144] ESI: m / z [M + H]+calcd for C + , 461.3278. 29 H 41 N4O: 461.3202; found: 461.3278

[0145] HPLC: 0 ~ 20 min (A:B = 80:20), t R = 7.800 min, Purity: 97.311%.

[0146] Example 11: Synthesis of compound 20

[0147] Reference Example 3.

[0148] (R)-N-(3-(3,4-dihydroisoquinolin-2(lH)-yl)propyl)-2-((2-ethylbutyl)amino)-3-(lH-indol-3- yl)propanamide

[0149] 1 H NMR (300 MHz, CDC13) δ 8.13 (s, 1H), 7.73 - 7.62 (m, 2H), 7.35 (d, J = 8.0 Hz, 1H), 7.26 (s, 1H), 7.19 (dd, J = 11.0, 4.1 Hz, 1H), 7.15 - 7.05 (m, 5H), 6.97 (d, J = 2.7 Hz, 3H), 3.57 (s, 2H), 3.42 (tt, J = 11.3, 5.7 Hz, 1H), 3.35 - 3.31 (m, 1H), 3.31 - 3.25 (m, 2H), 2.92 - 2.87 (m, 2H), 2.84 (d, J = 10.2 Hz, 1H), 2.67 (dd, J = 9.1, 3.7 Hz, 2H), 2.51 (td, J = 7.1, 2.1 Hz, 2H), 2.27 (s, 2H), 1.80 - 1.70 (m, 3H), 1.14 - 1.00 (m, 7H), 0.69 - 0.58 (m, 8H). 13 C NMR (75 MHz, CDC13) δ 174.77, 136.47, 134.64, 134.31, 128.64, 127.51, 126.57, 126.17, 125.66, 122.87, 122.14, 119.50, 118.91, 111.71, 111.24, 63.83, 56.43, 51.56, 50.99, 40.71, 37.90, 30.36, 29.35, 29.08, 26.73, 23.78, 10.71.

[0150] ESI: m / z [M+H] + , calcd for C 29 H 41 N4O: 461.3202; found: 461.3284

[0151] HPLC: 0 ~ 20 min (A:B = 80:20), t R = 6.512 min, Purity: 95.712%.

[0152] Example 12: Synthesis of compound 21

[0153] Reference Example 3.

[0154] (R)-N-(4-(3,4-dihydroisoquinolin-2(lH)-yl)butyl)-2-((2-ethylbutyl)amino)-3-(lH-indol-3- yl)propanamide

[0155] 1H NMR (300 MHz, CDC13) δ 8.42 (s, 1H), 7.77 - 7.69 (m, 1H), 7.47 (d, J = 4.5 Hz, 1H), 7.41 - 7.32 (m, 3H), 7.28 - 7.15 (m, 6H), 7.06 (dd, J = 12.1, 3.8 Hz, 3H), 3.66 (d, J = 3.7 Hz, 3H), 3.41 - 3.29 (m, 5H), 3.03 - 2.90 (m, 4H), 2.83 - 2.73 (m, 3H), 2.56 (d, J = 4.2 Hz, 3H), 2.36 (dd, J = 15.3, 3.8 Hz, 3H), 1.49 (d, J = 4.9 Hz, 3H), 1.32 (d, J = 4.5 Hz, 3H), 1.18 (s, 6H), 0.73 (dd, J = 13.3, 5.8 Hz, 8H).

[0156] 13 C NMR (75 MHz, CDC13) δ 174.81, 136.59, 134.66, 134.26, 128.71, 127.53, 126.65, 126.24, 125.70, 125.57, 123.08, 122.03, 119.37, 118.77, 111.36, 63.85, 57.88, 56.14, 51.62, 50.93, 40.86, 38.85, 30.38, 29.75, 29.05, 27.67, 24.47, 23.90, 23.69.

[0157] 13 C NMR (75 MHz, CDC13) δ 174.81, 136.59, 134.66, 134.26, 128.71, 127.53, 126.65, 126.24, 125.70, 125.57, 123.08, 122.03, 119.37, 118.77, 111.36, 63.85, 57.88, 56.14, 50.93, 40.86, 38.85, 30.38, 29.75, 29.05, 27.67, 24.47, 23.90, 10.80.

[0158] ESI: m / z [M+H] + , calcd for C 30 H 43 N4O: 475.3315; found: 475.3440

[0159] HPLC: 0 ~ 20 min (A:B = 80:20), t R= 6.867 min, Purity: 98.125 %.

[0160] Example 13: Synthesis of compound 22

[0161] Reference Example 3.

[0162] (R)-N-(4-(3,4-dihydroisoquinolin-2(lH)-yl)butyl)-2-((2-ethylbutyl)amino)-3-(lH-indol-3- yl)propanamide

[0163] 1 H NMR (300 MHz, CDC13) δ 8.53 (s, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 9.0 Hz, 3H), 7.23 (t, J = 7.4 Hz, 1H), 7.15 (s, 6H), 7.08 (s, 3H), 3.67 (s, 3H), 3.39 (d, J = 5.9 Hz, 1H), 3.35 (d, J = 4.2 Hz, 3H), 3.32 (s, 2H), 2.97 (d, J = 7.2 Hz, 3H), 2.95 - 2.90 (m, 2H), 2.78 (t, J = 5.0 Hz, 3H), 2.54 (t, J = 6.3 Hz, 3H), 2.38 (s, 2H), 1.48 (d, J = 2.5 Hz, 8H), 1.43 (dd, J = 6.0, 2.4 Hz, 3H), 1.16 (s, 8H), 0.79 - 0.66 (m, 9H).

[0164] 13 C NMR (75 MHz, CDC13) δ 174.70, 136.66, 134.71, 134.27, 128.67, 127.49, 126.62, 126.15, 125.63, 123.18, 121.82, 119.16, 118.68, 111.43, 111.10, 63.85, 58.34, 56.20, 51.00, 46.32, 40.88, 38.83, 34.25, 30.35, 29.04, 26.51, 24.98, 23.67, 10.73.

[0165] ESI: m / z [M+H] + , calcd for C 31 H 45 N4O: 489.3515; found: 489.3593

[0166] HPLC: 0 ~ 20 min (A:B = 80:20), t R= 7.609 min, Purity: 97.554 %.

[0167] Example 14: Synthesis of compound 23

[0168] Step 1: Synthesis of (2-ethylbutyl)-D-tryptophan

[0169] D-tryptophan (10 mmol) was dissolved in 50 mL of absolute ethanol, sodium hydroxide (10.5 mmol) and 2-ethylbutyraldehyde (1.5 mmol) were added, stirred at room temperature for 2 hours, sodium borohydride (15 mmol) was added, and stirring was continued for 2-3 hours. Most of the solvent was removed in vacuum, the PH was adjusted to 5, a large amount of white solid was precipitated, and the filter cake was dried by suction filtration to obtain the product, with a yield of 96.1%.

[0170] 1 H NMR (300 MHz, DMSO) δ 10.92 (s, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.08 (t, J = 7.4 Hz, 1H), 6.99 (t, J = 7.4 Hz, 1H), 3.50 - 3.44 (m, 1H), 3.26 (dd, J = 14.9, 5.2 Hz, 1H), 3.05 (dd, J = 14.9, 7.8 Hz, 1H), 2.59 (dd, J = 12.0, 6.9 Hz, 1H), 2.50 - 2.43 (m, 1H), 1.45 - 1.32 (m, 1H), 1.32 - 1.15 (m, 4H), 0.73 (t, J = 7.2 Hz, 6H).

[0171] Synthesis of (2-ethylbutyl)-L-tryptophan was the same as the above step, with a yield of 92.5%.

[0172] Step 2: Synthesis of N-(tert-butoxycarbonyl)-N'-(2-ethylbutyl)-D-tryptophan

[0173] 2-(ethylbutyl)-D-tryptophan (8 mmol) was dissolved in tetrahydrofuran: water = 1:1, triethylamine (20 mmol) was added, and di-tert-butyl dicarbonate (20 mmol) was slowly added dropwise, and stirring was continued at room temperature overnight. The PH was adjusted to 5, and ethyl acetate was extracted three times, the solvent was removed in vacuum, and column chromatography (dichloromethane:methanol = 100:1) was used to obtain a colorless foam, with a yield of 81.5%.

[0174] 1H NMR (300 MHz, DMSO) δ 10.90 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 6.98 (t, J = 7.4 Hz, 1H), 3.52 - 3.44 (m, 1H), 3.20 (dd, J = 14.9, 5.2 Hz, 1H), 3.06 (dd, J = 14.9, 7.8 Hz, 1H), 2.58 (dd, J = 12.0, 6.9 Hz, 1H), 2.50 - 2.43 (m, 1H), 1.49 (s, 9H), 1.45 - 1.32 (m, 1H), 1.32 - 1.18 (m, 4H), 0.72 (t, J = 7.2 Hz, 6H).

[0175] The synthesis of N-(tert-butoxycarbonyl)-N'-(2-ethylbutyl)-L-tryptophan was the same as above.

[0176] Step 3: Synthesis of tert-butyl (R)-(1-((2-(aziridin-1-yl)ethyl)amino)-3-(6,7- dihydro-1H-indol-3-yl)-1-oxopropan-2-yl)(2-ethylbutyl)carbamate

[0177] N-(tert-butoxycarbonyl)-N'-(2-ethylbutyl)-D-tryptophan (5 mmol) was dissolved in dry dichloromethane, carbodiimide hydrochloride (7.5 mmol), 1-hydroxybenzotriazole (7.5 mmol), N,N-diisopropylethylamine (15 mmol) were added, stirred for half an hour in ice bath, 2-(aziridin-1-yl)ethan-1-amine (6 mmol) was added, stirred at room temperature overnight. The reaction solution was washed with water, saturated brine respectively, dried with anhydrous sodium sulfate. The solvent was removed in vacuum, column chromatography (dichloromethane:methanol = 80:1) to get color bubble, yield 70.5%.

[0178] 1 H NMR (300 MHz, CDCl3) δ 8.07 (s, 1H), 7.66 (s, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.20 (t, J = 7.1 Hz, 2H), 7.13 (t, J = 7.4 Hz, 1H), 7.04 (s, 1H), 3.47 (s, 1H), 3.33 (s, 3H), 3.06 (s, 1H), 2.63 (s, 8H), 1.60 (s, 11H), 1.48 (s, 12H), 1.19 (s, 2H), 1.13 - 1.02 (m, 2H), 0.77 (t, J = 7.0 Hz, 4H), 0.67 (s, 3H).

[0179] Synthesis of tert-butyl (S)-(l-((2-(azepan-l-yl)ethyl)amino)-3-(6,7-dihydro-lH- indol-3-yl)-l-oxopropan-2-yl)(2-ethylbutyl)carbamate was carried out as above.

[0180] Step 4: Synthesis of (R)N-(2-(aziridin-l-yl)ethyl)-2-(2-ethylbutyl)amino)-3-(lH- indol-3-yl)propanamide

[0181] tert-Butyl (S)-(l-((2-(azepan-l-yl)ethyl)amino)-3-(6,7-dihydro-lH-indol-3-yl)-l- oxopropan-2-yl)(2-ethylbutyl)carbamate (0.5 mmol) was dissolved in ethyl acetate hydrochloric acid solution (4N), stirred at room temperature for 3-4 hours. Adjust the PH > 9, ethyl acetate extraction 2 times, combined organic phase, saturated brine washing, anhydrous sodium sulfate drying. The solvent was removed in vacuum, column chromatography (dichloromethane: methanol = 60: 1) to get colorless oil, yield 70.8%.

[0182] 1 H NMR (300 MHz, CDC13) δ 8.24 (s, 1H), 7.69 (d, J = 7.5 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.22 - 7.16 (m, 1H), 7.15 - 7.08 (m, 1H), 7.06 (d, J = 2.0 Hz, 1H), 3.39 - 3.35 (m, 1H), 3.34 - 3.30 (m, 2H), 3.30 - 3.20 (m, 1H), 2.91 (dd, J = 15.1, 10.1 Hz, 1H), 2.55 (dd, J = 12.3, 5.9 Hz, 6H), 2.42 - 2.26 (m, 2H), 1.57 (s, 8H), 1.20 - 1.06 (m, 5H), 0.67 (q, J = 7.1 Hz, 6H).

[0183] ESI: m / z [M+H] + , calcd for C 25 H 42 N4O: 415.3359; found: 415.3371.

[0184] Synthesis of (S)N-(2-(aziridin-l-yl)ethyl)-2-(2-ethylbutyl)amino)-3-(lH-indol-3- yl)propanamide was carried out as above.

[0185] 1H NMR (300 MHz, CDC13) δ 8.22 (s, 1H), 7.71 (d, J = 7.5 Hz, 2H), 7.38 (d, J = 8.0 Hz, 1H), 7.22 (t, J = 7.0 Hz, 1H), 7.15 (dd, J = 10.9, 4.0 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 3.38 (d, J = 1.5 Hz, 1H), 3.34 (d, J = 6.7 Hz, 2H), 3.32 - 3.23 (m, 1H), 2.93 (dd, J = 15.1, 10.1 Hz, 1H), 2.57 (dd, J = 12.3, 6.0 Hz, 6H), 2.36 (q, J = 10.9 Hz, 2H), 1.59 (s, 8H), 1.22 - 1.09 (m, 5H), 0.69 (q, J = 7.1 Hz, 6H).

[0186] ESI: m / z [M+H] + , calcd for C 25 H 42 N4O: 415.3359; found: 415.3371.

[0187] Example 15: Synthesis of compound 24

[0188] Reference Example 14.

[0189] (R) 2-((2-ethylbutyl)amino)-3-(1H-indol-3-yl)-N-(2-(piperidin-1-yl)ethyl)propan-1- amine

[0190] 1 H NMR (300 MHz, CDC13) δ 8.22 (s, 1H), 7.71 (d, J = 7.5 Hz, 2H), 7.38 (d, J = 8.0 Hz, 1H), 7.22 (t, J = 7.0 Hz, 1H), 7.15 (dd, J = 10.9, 4.0 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 3.38 (d, J = 1.5 Hz, 1H), 3.34 (d, J = 6.7 Hz, 2H), 3.32 - 3.23 (m, 1H), 2.93 (dd, J = 15.1, 10.1 Hz, 1H), 2.57 (dd, J = 12.3, 6.0 Hz, 6H), 2.36 (q, J = 10.9 Hz, 2H), 1.59 (s, 8H), 1.22 - 1.09 (m, 5H), 0.69 (q, J = 7.1 Hz, 6H).

[0191] ESI: m / z [M+H] +C 24 H 38 N4O: 399.3046; found: 399.3055.

[0192] (S) 2-((2-ethylbutyl)amino)-3-(1H-indol-3-yl)-N-(2-(piperidin-1-yl)ethyl)propan-1 -amine

[0193] 1 H NMR (300 MHz, CDC13) δ 8.32 (d, J = 22.6 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.67 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.24 (m, 1H), 7.18 (m, 1H), 7.11 (d, J = 1.7 Hz, 1H), 3.40 - 3.32 (m, 1H), 3.41 - 3.36 (m, 2H), 3.30 (dd, J = 12.1, 6.5 Hz, 1H), 2.98 (dt, J = 15.1, 8.7 Hz, 1H), 2.46 (dd, J = 12.5, 5.7 Hz, 8H), 1.61 - 1.55 (m, 4H), 1.50 (d, J = 5.0 Hz, 2H), 1.25 - 1.14 (m, 5H), 0.71 (dt, J = 10.8, 7.1 Hz, 6H).

[0194] ESI: m / z [M+H] + , calcd for C 24 H 38 N4O: 399.3046; found: 398.3057.

[0195] Example 16: Synthesis of compound 25

[0196] Reference Example 14.

[0197] (R) N-(2-((diethylamino)methyl)benzyl)-2-((2-ethylbutyl)amino)-3-(1H-indol-3-yl)propanamide

[0198] 1H NMR (300MHz, CDCl3) δ8.09(s,1H),7.93(s,1H),7.63(d,J=7.7Hz,1H),7.34(d,J=6.9Hz,1H),7.31(d,J= 8.2Hz,1H),7.23(s,2H),7.16(t,J=7.6Hz,1H),7.08(t,J=7.4Hz,1H),6.91(s,1H),4.50(ddd,J=35.3,14 .2,6.0Hz,2H),3.60(d,J=13.1Hz,1H),3.46(d,J=13.0Hz,1H),3.33–3.21(m,2H),2.90(dd,J=11.1,5.4 Hz,1H),2.37(s,4H),2.34–2.21(m,2H),1.12–1.03(m,5H),0.95(t,J=6.3Hz,6H),0.62(q,J=6.8Hz,6H).

[0199] ESI: m / z [M+H] + ,calcd.for C 29 H 42 N4O:463.3359; found:463.3363.

[0200] (S)N-(2-((diethylamino)methyl)benzyl)-2-((2-ethylbutyl)amino)-3-(1H-indol-3-yl)propionamide

[0201] 1 H NMR (300MHz, CDCl3) δ8.08(s,1H),7.90(s,1H),7.62(d,J=7.7Hz,1H),7.33(d,J=6.9Hz,1H),7.30 (d,J=8.3Hz,1H),7.21(s,2H),7.15(t,J=7.1Hz,1H),7.06(t,J=7.0Hz,1H),6.91(s,1H),4.50(m,2 H),3.62(d,J=13.7Hz,1H),3.44(d,J=13.0Hz,1H),3.30–3.20(m,2H),2.91(dd,J=11.9,5.7Hz,1H ),2.35(s,4H),2.35–2.21(m,2H),1.10–1.01(m,5H),0.93(t,J=6.3Hz,6H),0.64(q,J=6.5Hz,6H).

[0202] ESI: m / z [M+H] + ,calcd.for C 29 H42 N4O: 463.3359; found: 463.3365.

[0203] Example 17: Synthesis of compound 26

[0204] Reference Example 14.

[0205] (R)N-(2-((diethylamino)methyl)phenethyl)-2-((2-ethylbutyl)amino)-3-(1H- indol-3-yl)propanamide

[0206] 1 H NMR (300 MHz, CDC13) δ 8.01 (s, 1H), 7.85 (s, 1H), 7.58 (s, 1H), 7.40 (s, 1H), 7.33 (d, J = 8.2 Hz, 1H), 7.20 (s, 2H), 7.14 (s, 1H), 7.08 (m, 1H), 6.98 (s, 1H), 3.60 (d, J = 13.1 Hz, 1H), 3.50 (m, 2H), 3.46 (d, J = 12.0 Hz, 1H), 3.29 - 3.21 (m, 2H), 2.80 (dd, J = 11.1, 5.4 Hz, 1H), 2.37 (m, 2H), 2.30 (s, 4H), 2.25 - 2.20 (m, 2H), 1.11 - 1.03 (m, 5H), 0.99 (t, J = 6.3 Hz, 6H), 0.69 (q, J = 6.8 Hz, 6H).

[0207] ESI: m / z [M+H] + , calcd for C 30 H 44 N4O: 477.3514; found: 477.3524.

[0208] (S)N-(2-((diethylamino)methyl)phenethyl)-2-((2-ethylbutyl)amino)-3-(1H- indol-3-yl)propanamide

[0209] 1H NMR (300 MHz, CDC13) δ 8.00 (s, 1H), 7.84 (s, 1H), 7.59 (s, 1H), 7.41 (s, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.22 (s, 2H), 7.13 (s, 1H), 7.07 (m, 1H), 6.96 (s, 1H), 3.62 (d, J = 13.1 Hz, 1H), 3.52 (m, 2H), 3.45 (d, J = 12.1 Hz, 1H), 3.29 - 3.20 (m, 2H), 2.82 (dd, J = 11.5, 5.4 Hz, 1H), 2.36 (m, 2H), 2.31 (s, 4H), 2.26 - 2.20 (m, 2H), 1.12 - 1.03 (m, 5H), 0.99 (t, J = 6.3 Hz, 6H), 0.68 (q, J = 6.7 Hz, 6H).

[0210] ESI: m / z [M+H] + , calcd for C 30 H 44 N4O: 477.3514; found: 477.3525.

[0211] Example 18: Synthesis of compound 27

[0212] Reference Example 14.

[0213] (R) N-(2-(aziridin-l-yl)ethyl)-2-(2-ethylbutyl)amino)-3-(naphthalen-2-yl)propanamide

[0214] 1 H NMR (300 MHz, CDC13) δ 8.00 (s, 1H), 7.84 (s, 1H), 7.59 (s, 1H), 7.41 (s, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.22 (s, 2H), 7.13 (s, 1H), 7.07 (m, 1H), 6.96 (s, 1H), 3.62 (d, J = 13.1 Hz, 1H), 3.52 (m, 2H), 3.45 (d, J = 12.1 Hz, 1H), 3.29 - 3.20 (m, 2H), 2.82 (dd, J = 11.5, 5.4 Hz, 1H), 2.36 (m, 2H), 2.31 (s, 4H), 2.26 - 2.20 (m, 2H), 1.12 - 1.03 (m, 5H), 0.99 (t, J = 6.3 Hz, 6H), 0.68 (q, J = 6.7 Hz, 6H).

[0215] ESI: m / z [M+H] + , calcd for C 27 H 41 N3O: 424.3250; found: 424.3261.

[0216] (S) N-(2-(aziridin-1-yl)ethyl)-2-(2-ethylbutylamino)-3-(naphthalen-2-yl)propanamide

[0217] 1 H NMR (300 MHz, CDC13) δ 8.00 (s, 1H), 7.96-7.93 (m, 2H), 7.82 (d, J = 8.3 Hz, 1H), 7.51-7.43 (m, 4H), 3.72 (m, 1H), 3.38-3.35 (m, 1H), 3.34-3.31 (m, 2H), 2.93 (dd, J = 14.1, 10.1 Hz, 1H), 2.57 (dd, J = 12.5, 5.9 Hz, 6H), 2.40-2.28 (m, 2H), 1.56 (s, 8H), 1.21-1.06 (m, 5H), 0.69 (q, J = 7.1 Hz, 6H).

[0218] ESI: m / z [M+H] + , calcd. for C 27 H 41 N3O: 424.3250; found: 424.3260.

[0219] Example 19: Synthesis of compound 28

[0220] Reference Example 14.

[0221] (R) N-(2-(aziridin-1-yl)ethyl)-2-(2-ethylbutylamino)-3-(quinolin-6-yl)propanamide

[0222] 1 H NMR (300 MHz, CDC13) δ 8.00 (s, 1H), 7.96-7.93 (m, 2H), 7.82 (d, J = 8.3 Hz, 1H), 7.51-7.43 (m, 4H), 3.72 (m, 1H), 3.38-3.35 (m, 1H), 3.34-3.31 (m, 2H), 2.93 (dd, J = 14.1, 10.1 Hz, 1H), 2.57 (dd, J = 12.5, 5.9 Hz, 6H), 2.40-2.28 (m, 2H), 1.56 (s, 8H), 1.21-1.06 (m, 5H), 0.69 (q, J = 7.1 Hz, 6H).

[0223] ESI: m / z [M+H] + , calcd. for C 27 H 41 N4O: 425.3202; found: 425.3209.

[0224] (S)N-(2-(aziridin-1-yl)ethyl)-2-(2-ethylbutyl)amino)-3-(quinolin-6-yl)propanamide

[0225] 1 H NMR (300 MHz, CDC13) δ 8.82 (d, J = 8.2 Hz, 1H), 8.00 (s, 1H), 7.97-7.93 (m, 2H), 7.83 (d, J = 8.0 Hz, 1H), 7.50 (m, 2H), 3.73 (m, 1H), 3.39-3.35 (m, 1H), 3.35-3.31 (m, 2H), 2.97 (m, 1H), 2.56 (dd, J = 12.1, 5.8 Hz, 6H), 2.40-2.30 (m, 2H), 1.58 (s, 8H), 1.21-1.07 (m, 5H), 0.68 (q, J = 7.2 Hz, 6H).

[0226] ESI: m / z [M+H] + , calcd. for C 27 H 41 N4O: 425.3202; found: 425.3208.

[0227] Example 20: Synthesis of compound 29

[0228] Reference Example 14.

[0229] (R)N-(2-(aziridin-1-yl)ethyl)-2-(2-ethylbutyl)amino)-3-phenylpropanamide

[0230] 1 H NMR (300 MHz, CDC13) δ 8.82 (d, J = 8.2 Hz, 1H), 8.00 (s, 1H), 7.97-7.93 (m, 2H), 7.83 (d, J = 8.0 Hz, 1H), 7.50 (m, 2H), 3.73 (m, 1H), 3.39-3.35 (m, 1H), 3.35-3.31 (m, 2H), 2.97 (m, 1H), 2.56 (dd, J = 12.1, 5.8 Hz, 6H), 2.40-2.30 (m, 2H), 1.58 (s, 8H), 1.21-1.07 (m, 5H), 0.68 (q, J = 7.2 Hz, 6H).

[0231] ESI: m / z [M+H] + , calcd. for C 23 H 39 N3O: 373.3093; found: 373.3099.

[0232] (S) N-(2-(aziridin-1-yl)ethyl)-2-(2-ethylbutyl)amino)-3-phenylpropanamide

[0233] 1 H NMR (300 MHz, CDC13) δ 8.04 (s, 1H), 7.18-7.14 (m, 5H), 3.75 (m, 1H), 3.41-3.32 (m, 1H), 3.31-3.22 (m, 2H), 2.98 (m, 1H), 2.51 (dd, J = 12.4, 5.5 Hz, 6H), 2.44-2.30 (m, 2H), 1.56 (s, 8H), 1.21-1.06 (m, 5H), 0.71 (q, J = 6.1 Hz, 6H).

[0234] ESI: m / z [M+H] + , calcd. for C 23 H 39 N3O: 373.3093; found: 373.3099.

[0235] Example 21: Cholinesterase inhibitory activity of compounds

[0236] Drugs and reagents: Compounds prepared in Examples 6-18, AChE (E.C. 3.1.1.7, Type VI-S, selected from electric eel), BuChE (E.C. 3.1.1.8, selected from horse serum), 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB), acetylthiocholine (ATC) iodide and butyrylthiocholine (BTC) iodide were purchased from Sigma; tacrine was synthesized in our laboratory (purity > 95%).

[0237] Instrument: THERMO Varioskan Flash full wavelength multifunctional microplate reader.

[0238] Experimental method:

[0239] (1) Preparation of buffer solution: 13.6 g of potassium dihydrogen phosphate was dissolved in 1 L of water, and the pH was adjusted to 8 ± 0.1 with potassium hydroxide. The solution was stored at 4 °C for later use.

[0240] (2) Preparation of 0.01 M DTNB solution: 0.396 g of DTNB and 0.15 g of sodium bicarbonate were dissolved in 100 mL of water to prepare a 0.01 M DTNB solution, which was stored at -20 °C for later use.

[0241] (3) Preparation of 0.075 M ATC, BTC solution: 0.217 g ATC was dissolved in 10 mL water to prepare 0.075 M ATC and BTC solution, which was stored at -20 °C for later use. 0.237 g BTC was dissolved in 10 mL water to prepare 0.075 M BTC solution, which was stored at -20 °C for later use.

[0242] (4) Preparation of AChE, BuChE solution: 5000 units of AChE was dissolved in 1 mL of 1% gel solution, and then diluted with water to 100 mL to prepare AChE solution with a concentration of 5 units / mL, which was stored at -20 °C for later use. 5000 units of BuChE was dissolved in 1 mL of 1% gel solution, and then diluted with water to 100 mL to prepare BuChE solution with a concentration of 5 units / mL, which was stored at -30 °C for later use.

[0243] (5) Preparation of test compound solution: The test compound was dissolved in ethanol to prepare a solution with a concentration of 10 -3 M (ethanol did not affect the test results), and then diluted with water to prepare solutions with concentrations of 10 -4 , 10 -5 , 10 -6 , 10 -7 , 10 -8 , 10 -9 M, respectively.

[0244] Before the experiment, all the solutions were warmed to room temperature, and the AChE and BuChE solutions were diluted with water to prepare enzyme solutions with a concentration of 2.5 units / mL. The background ultraviolet absorption was measured using blank buffer (3 mL). 100 μL of test compound solution, 100 μL of DTNB solution, and 100 μL of enzyme solution were added to 3 mL of buffer, and 20 μL of ATC or BTC solution was added to trigger the reaction. The reaction was timed immediately after the addition of ATC or BTC solution, and the test solution was mixed rapidly at the same time. The ultraviolet absorption was measured at 412 nM after 2 min. The blank control group was measured using the same volume of water instead of the test compound solution. All tests were performed in triplicate. The ultraviolet absorption value of the blank control group was taken as 100%, and the absorbance (OD value) of the test compound at each concentration was recorded. The obtained results were calculated using GraphPad Prism™ (GraphPad Software, San Diego, CA, USA) software to obtain the corresponding IC 50 values using a non-linear regression analysis model, as shown in Table 1.

[0245] Table 1 Cholinesterase inhibitory activity of compounds

[0246]

[0247]

[0248] a μM or inhibitory rate at 100μM or IC 50 (μM).

[0249] Results analysis: The tested compounds and their optical isomers have inhibitory activity on BuChE (eqBChE: 0.04 μM ~ 5.4 μM; hBChE: IC 50 0.033 μM ~ 20.0 μM), and these compounds have no AChE inhibitory activity (IC 50 > 8 μM), indicating that they are very selective BuChE inhibitors.

[0250] Example 22: In vitro blood-brain barrier penetration test of compounds

[0251] Drugs and reagents: 96-well UV plate (#3635, Corning), Multiscreen Permeability Filter Plate (0.4 μm, #MPC4NTR10, Millipore), brain phospholipid (#141101P, Avanti).

[0252] Instrument: Varioskan Flash Multifunctional Microplate Reader (ThermoFisher).

[0253] Experimental method:

[0254] (1) Preparation of compound solution: The tested compound was prepared into a 5 mg / mL stock solution with DMSO, and diluted into a 100 μg / mL compound stock solution with a PBS: anhydrous ethanol = 7:3 solution. The progesterone, verapamil, chlorpromazine, piroxicam, hydrocortisone and β-estradiol standard were prepared into positive compound stock solutions as positive compounds. The blank group without compound was prepared using the same method.

[0255] (2) Preparation of brain phospholipid solution: The brain phospholipid was prepared into a 20 mg / mL solution with n-dodecane.

[0256] Add 200 μL of blank solution to the recipient plate. Carefully add 4 μL of phospholipid solution to the bottom of the donor plate, ensuring it evenly covers the bottom. Then, quickly add 200 μL of drug-treated solution to the donor plate. Place the donor plate on the recipient plate, ensuring the artificial membrane is in contact with the buffer solution. Test each compound in triplicate. Incubate at room temperature for 18 hours. Remove the donor plate and transfer 50 μL of solution from both the donor and recipient plates to a 96-well UV plate. Read the absorbance at wavelengths of 235 nm, 245 nm, 255 nm, 265 nm, and 275 nm. Calculate the P-values ​​of the six positive compounds at each of the five wavelengths. e The values ​​were compared with standard values ​​reported in the literature, and the wavelength with the best fit was selected as the final standard. Data from the drug administration group at this wavelength were used for calculation, and the membrane permeability of the compound was evaluated. e The formula for calculating the value is as follows:

[0257]

[0258]

[0259] Among them, C D and C A The absorbance of the donor plate and the acceptor plate are respectively, C eq To balance the concentration, A refers to 0.337 cm⁻¹ 2 The filter membrane area, V D and V A The reaction liquid volumes in the donor and acceptor plates were 0.2 mL, and t represents the reaction time of 64800 s. The results are shown in Table 2.

[0260] Table 2. In vitro blood-brain barrier permeability of the compounds

[0261]

[0262]

[0263] a Ranges of permeability of PAMPA-BBB assays(Pe×10 -6 (cm / s).

[0264] Compounds of high BBB permeation(CNS+)Pe>5.94

[0265] Compounds of uncertain BBB permeation(CNS+ / -)5.94>Pe>3.07

[0266] Compounds of low BBB permeation (CNS-) Pe < 3.07

[0267] b Values are expressed as the mean ± SD of three independent experiments.

[0268] Result analysis: The Pe values of the test compounds and their optical isomers all reached a high blood-brain barrier penetration level, indicating that they can effectively reach the lesion and exert efficacy.

[0269] Example 23: MTT experiment of compounds

[0270] Drugs and reagents: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (purchased from Aladdin).

[0271] Instrument: THERMO Varioskan Flash full-wavelength multifunctional microplate reader.

[0272] Experimental method: The target cells (5x10 3 , 0.1 mL in volume) were placed in a 96-well flat-bottomed culture plate, and the cells were allowed to adhere to the bottom of the plate at 37°C overnight. The cells were treated with various concentrations of compounds for 24 hours. MTT reagent was added to the wells, and the plate was incubated at 37°C for 4 hours. The cells were destroyed by adding 0.1 mL lysis buffer to the wells. After incubation, they were kept at 37°C for another 24 hours, and the color reaction was measured at 570 nm using a microplate reader. All groups were performed in triplicate. The experimental results are shown in Figure 1

[0273] Result analysis: All compounds showed safety at concentrations of 10, 20 and 40 μM. There was no significant difference in cytotoxicity between compounds 18(R) and 18(S). When the dose reached 80 μM, most of the compounds showed slight cytotoxicity. These results indicate that almost all of these inhibitors we obtained are non-toxic and have the prospect of being developed as drugs.

[0274] Example 24: Neuroprotective effect of compounds on Aβ 1-42 induced damage of SH-SY5Y cells

[0275] Drugs and reagents: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (purchased from Aladdin).

[0276] Instrument: THERMO Varioskan Flash full-wavelength multifunctional microplate reader. ​

[0277] Experimental method: Target cells (5 × 10⁻⁶) 3 Cells (0.1 mL each) were placed in 96-well flat-bottomed culture plates and incubated overnight at 37°C to allow them to adhere to the bottom of the plate. Cells were treated with various concentrations of compounds for 24 hours. MTT reagent was added to the wells, and the plates were incubated at 37°C for 4 hours. Cells were then lysed by adding 0.1 mL of lysis buffer to the wells. After incubation, the cells were kept at 37°C for another 24 hours, and the colorimetric reaction was measured at 570 nm using a microplate reader.

[0278] Results analysis: Given that compounds 18(R) and 22(R) exhibited the best BChE inhibitory activity and effectively inhibited Aβ... 1-42 Self-mediated aggregation; further, the MTT assay was used to analyze Aβ. 1-42 Neuroprotective effect against induced SH-SY5Y cell damage. For example... Figure 2 As shown, when SH-SY5Y cells were exposed to 15 μM Aβ... 1-42 At that time, compared with the untreated group, cell viability decreased sharply to 45.7% (p<0.0001). Treatment with compounds 18(R) and 22(R) increased cell viability. Under the same conditions, 20 μM of compounds 18(R) and 22(R) increased cell viability to 73.4% (p<0.001) and 63.0% (p<0.01), respectively. Therefore, the results indicate that compounds 18(R) and 22(R) have a significant effect on Aβ... 1-42 Induced SH-SY5Y cell damage exhibited good neuroprotective effects.

[0279] Example 25: Water Maze Experiment

[0280] Drugs and reagents: Compound 18, Aβ from Beyotime International Co., Ltd. (Shanghai), and tacrine (purity > 95%).

[0281] Instrument: Panlab SMART 3.0 behavioral video analyzer.

[0282] Animals: Adult male ICR mice (8-10 weeks old, weighing 18-22 grams) were purchased from Yangzhou University Medical Center.

[0283] Experimental methods: Forty mice were randomly divided into five subgroups (n=8 per group): (i) blank control group, (ii) sham operation group, (iii) intracranial injection of Aβ as model group, (iv) donepezil plus Aβ as positive control and (v) compound 18 (10 mg / kg) plus Aβ as experimental group.

[0284] A circular pool (diameter 120 cm, height 60 cm) with a platform (diameter 10 cm) for escape was fixed and filled with 40 cm deep fresh water (maintained at 25 °C) to constitute a water maze. It was placed in a bright room. After 5 days of training and memory, a probe test was performed on the 6thday. To assess cognitive function, each mouse was individually trained on a visible platform (marked with a flag, 5 cm high) for 2 days, and then trained in the water maze with a hidden platform (placed 1 cm below the water surface) from the 3rdto 5thday. All mice were trained twice a day, with each trial lasting 90 seconds. The time for each mouse to find the platform (successful escape) was recorded. If the mouse failed to reach the platform within 90 seconds, the test was terminated and the mouse was carefully placed on the platform by hand. Regardless of success or failure, each mouse was kept on the platform for 30 seconds. On the last day (6thday), the platform was removed from the pool and the mice were tested, allowing each mouse 90 seconds to search for the platform. The time and trajectory of the mice to reach the location of the missing platform were recorded. The results of the experiment are shown in Figures 3-5 .

[0285] Results analysis: As shown in Figure 3 , after the first day of intracerebral microinjection of Aβ, although the model group showed a tendency of weight loss on the third day, the weight gain tended to be stable afterwards, indicating that the surgery did not cause significant physical function damage to the mice. The weight gain of the 18(R) administration group was comparable or even slightly higher than that of the control group, indicating the safety of the administration. As shown in Figure 4 , there was no significant difference in the target escape latency (ELT) between the control group and the sham operation group, indicating that the surgery did not affect the passive avoidance impairment of the mice. The results of the Morris water maze test showed that the ELT of the model group was significantly prolonged Figure 4 (P<0.0001,####) compared with the sham operation animal group, indicating that the learning and memory were impaired and the modeling was successful. The treatment groups of 18(R) and donepezil showed a significant decrease in ELT Figure 4 (P<0.0001 and P<0.01, respectively). The results also showed that 18(R) had a better effect on improving the memory and cognitive function of mice than donepezil at the tested dose, which could be attributed to the multifunctional anti-AD activity. Figure 5 The representative trajectory graphs of the mice in each group showed that the trajectories of the mice in the model group were significantly longer and more chaotic than those in the blank group.

Claims

1. An aromatic amino acid compound, characterized in that, The compound is selected from any of the following compounds: Among them, chiral carbon has an R configuration.

2. The aromatic amino acid compound according to claim 1, characterized in that, The pharmaceutically acceptable salt is a salt formed by the compound and an acid, wherein the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, or mandelic acid.

3. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises the aromatic amino acid compound of claim 1 and a pharmaceutically acceptable carrier.

4. The use of an aromatic amino acid compound according to any one of claims 1 to 2 or a pharmaceutical composition according to claim 3 in the preparation of a butyrylcholinesterase inhibitor drug.

5. The application according to claim 4, characterized in that, The drug is used to treat neurodegenerative diseases.

6. The application according to claim 5, characterized in that, The neurodegenerative disease mentioned is Alzheimer's disease.

Images