Quinine derivative as well as application and preparation method thereof

Abstract

The invention discloses a quinine derivative as well as application and a preparation method thereof. The quinine derivatives are a series of multi-target guiding ligands with MAO-B and acetylcholin esterase inhibition effects at the same time, and can be used for preventing or treating related diseases, especially Alzheimer's disease and Parkinson's disease. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of medicine, and specifically relates to a quinine derivative and an application and a preparation method thereof. Background Art

[0002] Alzheimer's disease (AD) is a primary dementia that affects the health of the elderly and is characterized by progressive memory loss and cognitive impairment. Although the exact pathogenic mechanism of AD is still unclear, many hypotheses have been proposed, providing a basis for the development of drugs to treat AD. The most classic hypothesis is the cholinergic hypothesis, which points out that the lack of acetylcholine (ACh) in the brain is the cause of AD. Therefore, increasing the content of acetylcholine in the brain of AD patients by inhibiting acetylcholinesterase is a feasible strategy.

[0003] On the other hand, monoamine oxidase B (MAO-B) has been found to be overexpressed in the hippocampus and cerebral cortex of AD patients. MAO-B is a flavin adenine dinucleotide (FAD)-containing enzyme that catalyzes the oxidative deamination of a variety of exogenous amines and endogenous neurotransmitters. In this process, hydrogen peroxide is produced as a byproduct. As the main source of ROS, hydrogen peroxide promotes oxidative stress through the iron-catalyzed Fenton reaction, ultimately leading to neuronal damage. This suggests that MAO-B inhibitors may provide beneficial neuroprotective effects for AD treatment by increasing monoamine neurotransmitters and reducing the production of ROS.

[0004] In summary, multi-target anti-AD compounds with simultaneous MAO-B and acetylcholinesterase inhibitory effects provide a new and promising therapeutic approach for the treatment of neurological diseases. Summary of the invention

[0005] In view of the above problems, the present invention proposes a quinine derivative and its application and preparation method. The quinine derivative is a series of multi-target ligands with both MAO-B and acetylcholinesterase inhibitory effects, which can be used to prevent or treat related diseases, especially Alzheimer's disease and Parkinson's disease.

[0006] In a first aspect, the present invention discloses a quinine derivative and a pharmaceutically acceptable salt thereof as shown in formula (I):

[0007]

[0008] In formula (I), R 1 For -C 1 -C 5 Straight chain alkyl or branched chain alkyl;

[0009] R 2 For-(C 1 -C 5) a straight chain or branched alkyl group or a substituent is -(C 1 -C 5 )-substituted aryl;

[0010] or R 1 , R 2 and the nitrogen atom connected to it to form -(C 1 -C 5 ) substituted heterocycloalkyl, -(C 1 -C 5 ) substituted heterocyclic aryl or -(C 1 -C 5 ) substituted heterocyclic aromatic heteroyl.

[0011] Preferably, in formula (I), R 1 is methyl or ethyl, R 2 is ethyl or benzyl, R 1 , R 2 The heterocyclic structure formed by the nitrogen atom connected to it is One of them.

[0012] Preferably, the quinine derivative represented by formula (I) is one of the following compounds:

[0013]

[0014] In a second aspect, the present invention proposes the use of the above-mentioned quinine derivatives and pharmaceutically acceptable salts thereof in the preparation of drugs for treating or preventing diseases caused by acetylcholine deficiency or monoamine oxidase B overexpression.

[0015] Preferably, the disease caused by acetylcholine deficiency or monoamine oxidase B overexpression is Parkinson's disease or Alzheimer's disease.

[0016] In a third aspect, the present invention provides a method for preparing the above-mentioned quinine derivative, the method comprising the following steps:

[0017]

[0018] Step (1): dissolving the raw material McBride's acid shown in Formula 1 in an organic solvent A, stirring at -5°C under nitrogen, and after slowly adding pyridine, dropwise adding the compound shown in Formula 2, reacting at -10 to 10°C for 0.5 to 3 hours, moving to room temperature and continuing stirring for 3 to 8 hours, then filtering the filtrate, washing with hydrochloric acid, extracting the aqueous phase with dichloromethane, combining the organic phases, and then washing with hydrochloric acid and saturated brine in sequence, drying the organic layer with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product A, and then dissolving the crude product A in anhydrous methanol and reacting at 50 to 65°C for 3 to 8 hours, and purifying the mixture A by petroleum ether / ethyl acetate silica gel column chromatography to obtain a compound shown in Formula 3;

[0019] The molar ratio of the McLaughlin acid represented by Formula 1, pyridine, and the compound represented by Formula 2 is 1:1-3:1-3;

[0020] The organic solvent A is selected from one or more of acetonitrile, dichloromethane, methanol, ethanol, and dichloromethane; the volume molar ratio of the organic solvent to the McLaughlin acid shown in Formula 1 is 1 to 3:1 mL / mmol;

[0021]

[0022] Step (2): reacting the compound of formula 3 obtained in step (1), p-toluenesulfonic acid monohydrate, and aniline reactants in an organic solvent B at 55 to 70° C. for 6 to 10 hours, then removing the solvent under reduced pressure to obtain a crude product B, which is dissolved in phenyl ether and refluxed for 40 minutes; cooling the obtained mixture B to room temperature overnight, filtering, taking the filter cake, further purifying it by silica gel column chromatography with petroleum ether / ethyl acetate, and drying it to obtain a compound of formula 4;

[0023] The aniline reactant is one of aniline or p-methoxyaniline;

[0024] The molar ratio of the compound represented by formula 3, p-toluenesulfonic acid monohydrate, and aniline reactants is 9-11:0.15-0.25:10-13;

[0025] The organic solvent B is selected from one or more of acetonitrile, dichloromethane, methanol, ethanol, and hexane;

[0026]

[0027] Step (3): adding the compound of formula 4 obtained in step (2), anhydrous potassium carbonate, methyl iodide and organic solvent C into a first reaction container, reacting at 25-40° C. for 5-8 hours, then filtering, washing with water, and then extracting with ethyl acetate; then, drying the organic layer with sodium sulfate, concentrating under reduced pressure to obtain a crude product C, purifying it with petroleum ether / ethyl acetate through silica gel column chromatography, and drying to obtain a compound of formula 5;

[0028] The ratio of the compound represented by formula 4, anhydrous potassium carbonate and methyl iodide is 1-1.5:3-3.5:3-3.5;

[0029] The organic solvent C is selected from one or more of acetonitrile, dichloromethane, methanol, ethanol, and DMF;

[0030]

[0031] Step (4): Add the compound represented by Formula 5 to a dry second reaction container, dissolve it with an organic solvent D, and slowly drip boron tribromide into the second reaction container; stir the mixture at -30 to -10°C for 0.5 to 5 hours, move it to 25 to 55°C for reaction for 3 to 8 hours, then quench it with a saturated sodium bicarbonate solution, filter the filter cake, and then separate and purify it with petroleum ether / ethyl acetate silica gel column chromatography to obtain the compound represented by Formula 6;

[0032] The ratio of the compound represented by formula 5 to the boron tribromide substance is 2-3:6-8;

[0033] The organic solvent D is selected from any one of ethanol, methanol, dichloromethane and acetonitrile;

[0034]

[0035] Step (5): adding the compound represented by Formula 6, anhydrous potassium carbonate, dibromoalkane and organic solvent E into a third reaction vessel and reacting at 30-56° C. for 4-9 hours; after the reaction, removing the solvent under reduced pressure to obtain a crude product E, and then purifying it with petroleum ether / ethyl acetate through silica gel column chromatography to obtain a compound represented by Formula 7;

[0036] The ratio of the compound represented by formula 6, anhydrous potassium carbonate and dibromoalkane is 0.5:1-2:1-2;

[0037] The organic solvent E is selected from one or more of acetonitrile, dichloromethane, methanol, ethanol, and acetone;

[0038]

[0039] Step (6): adding the compound represented by formula 7, anhydrous potassium carbonate, tetrahydropyrrole and organic solvent F into a fourth reaction vessel and reacting at 60-85° C. until completion; after the reaction, removing the solvent under reduced pressure to obtain a crude product, which is then purified by petroleum ether / ethyl acetate silica gel column chromatography to obtain a compound represented by formula (I);

[0040] The ratio of the compound represented by formula 7, anhydrous potassium carbonate and tetrahydropyrrole is 0.4-0.6:1.5-2:1.5-2;

[0041] The organic solvent F is selected from one or more of acetonitrile, dichloromethane, methanol and ethanol.

[0042] Preferably, in step (6), the compound represented by formula 7, anhydrous potassium carbonate, tetrahydropyrrole and organic solvent F are added and reacted at 60-85° C. for 7-12 hours.

[0043] The beneficial effects of the present invention are as follows: the quinine derivatives provided by the present invention are a new class of compounds, and are the first class of multi-target ligands that can simultaneously target acetylcholinesterase and monoamine oxidase B, and can not only inhibit the activity of acetylcholinesterase, but also inhibit the activity of monoamine oxidase B, thereby protecting neurons and improving the disease state. Therefore, the quinine derivatives of the present invention can be used to prevent or treat the effects of neuromodulatory effects associated with acetylcholine deficiency and monoamine oxidase B overexpression or the risks of various neurological and mental disorders, especially Alzheimer's disease or Parkinson's disease. DETAILED DESCRIPTION

[0044] The present invention is further described below by means of specific embodiments, but the protection scope of the present invention is not limited thereto.

[0045] Example 1

[0046] Preparation method of (14a)

[0047] Step (1): Dissolve McBride's acid (4.468 g, 31 mmol) in anhydrous dichloromethane (13 mL) and stir at -5°C under nitrogen. After slowly adding pyridine (4.8 mL), n-valeryl chloride (3.496 g, 29 mmol) was dripped into the reaction flask. The mixture was reacted at -5°C for 1 hour, moved to room temperature and continued to stir for 6 hours. After the reaction was completed, the mixture was filtered to obtain a filtrate, which was washed with hydrochloric acid (2 mol / L, 2×18 mL). The aqueous phase was extracted with dichloromethane (2×10 mL), and the organic phases were combined, washed with hydrochloric acid (2 mol / L, 2×10 mL) and saturated brine (20 mL), and dried over anhydrous sodium sulfate. After concentration under reduced pressure, it was dissolved in anhydrous CH 3 OH (35 mL), and reacted at 65° C. for 3 h. After the reaction was completed, the crude product was purified by silica gel column chromatography to obtain a colorless oily liquid, namely methyl 3-oxoheptanoate, with a yield of 50.9%.

[0048] Step (2): Dissolve methyl 3-oxoheptanoate (10 mmol), p-toluenesulfonic acid monohydrate (PTSA, 0.18 mmol), p-methoxyaniline (11 mmol) and n-hexane (24 mL) in a round-bottom flask. The mixture is reacted at 70°C for 6 h. After the reaction is completed, the solvent is removed under reduced pressure to obtain a crude product, which is dissolved in phenyl ether and refluxed for 40 minutes. The mixture is cooled to room temperature overnight and filtered to obtain 2-butyl-6-methoxyquinoline-4(1H)-one as a yellow solid with a yield of 23.7%.

[0049] Step (3): 2-butyl-6-methoxyquinoline-4(1H)-one (5 mmol), anhydrous potassium carbonate (2.073 g, 15 mmol), iodomethane (2.129 g, 15 mmol) and anhydrous DMF (15 mL) were added to a dry round-bottom flask. The mixture was stirred at 25°C for 8 h. After the reaction was completed, it was filtered, washed with water, and extracted with ethyl acetate. Subsequently, the organic layer was dried over sodium sulfate, concentrated under reduced pressure to a crude product, and purified by silica gel column chromatography to obtain 2-butyl-4,6-dimethoxyquinoline as a yellow oily liquid with a yield of 44.1%.

[0050] Step (4): Add 2-butyl-4,6-dimethoxyquinoline (0.601 g, 2.45 mmol) to a dry round-bottom flask and dissolve it in anhydrous dichloromethane. Slowly add boron tribromide (1 mol / L, 7.5 mL) dropwise at -30°C under nitrogen protection, stir for 5 h, and move to 25°C and stir for 8 h. After the reaction is completed, quench with saturated sodium bicarbonate solution and filter to obtain 2-butyl-4-methoxyquinoline-6-ol as a white solid with a yield of 83.1%.

[0051] Step (5): 2-butyl-4-methoxyquinolin-6-ol (0.231 g, 1 mmol), anhydrous potassium carbonate (0.207 g, 1.5 mmol), dibromoalkane (1.5 mmol), and acetone (40 mL) were added to a dry round-bottom flask and reacted at 56° C. for 4 hours. After the reaction was completed, the solvent was removed under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography using petroleum ether / ethyl acetate to obtain 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline as a white solid with a yield of 94.8%.

[0052] Step (6): 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline (0.5 mmol), anhydrous potassium carbonate (0.207 g, 1.5 mmol), tetrahydropyrrole (0.107 g, 1.5 mmol), and acetonitrile (15 mL) were added to a dry round-bottom flask and reacted at 85° C. for 7 hours. After the reaction, the solvent was removed under reduced pressure to obtain a crude product, which was then purified by petroleum ether / ethyl acetate silica gel column chromatography to obtain the final product 14a, i.e., 2-butyl-4-methoxy-6-((6-(pethidin-1-yl)hexyl)oxy)quinolone, a yellow oily liquid with a yield of 73.1%.

[0053] 1 H NMR (400 MHz, DMSO-d 6)δ7.76(d,J=9.1Hz,1H),7.34(d,J=2.8Hz,1H),7.30(dd,J=9.0,2.8Hz,1H),6.89(s,1H),4.05(t,J=6.5Hz,2H),4.02(s,3H) ,2.85-2.77(m,2H),2.41(d,J=32.5Hz,5H),1.80-1.69(m,4H),1.55-1.44(m,8H),1.42-1.29(m,7H),0.93(t,J=7.4Hz,3H); 13 C NMR (100 MHz, DMSO-d 6 )δ161.56,161.17,156.17,144.46,130.22,122.10,120.47,101.24,100.70,68.18,58.48(2C) ,56.29,54.12,38.82,31.88,29.08,27.08,26.11,25.90(2C),25.40,24.08,22.60,14.37; HRMS m / z:calc.for C 25 H 38 N 2 O 2 [M+H] + ,399.3006,found,399.3019;HPLC purity:99.5%.

[0054] Example 2

[0055] Preparation method of (14b)

[0056] Step (3): Add 2-butyl-6-methoxyquinoline-4(1H)-one (5 mmol), anhydrous potassium carbonate (2.073 g, 15 mmol), iodomethane (2.129 g, 15 mmol) and anhydrous DMF (15 mL) prepared according to steps (1) and (2) of Example 1 into a dry round-bottom flask. Stir the mixture at 40°C for 5 h. After the reaction is completed, filter, wash with water, and extract with ethyl acetate. Subsequently, the organic layer is dried over sodium sulfate, concentrated under reduced pressure to a crude product, and purified by silica gel column chromatography to obtain 2-butyl-4,6-dimethoxyquinoline as a yellow oily liquid with a yield of 51.9%.

[0057] Step (4): Add 2-butyl-4,6-dimethoxyquinoline (0.601 g, 2.45 mmol) to a dry round-bottom flask and dissolve it in anhydrous dichloromethane. Slowly add boron tribromide (1 mol / L, 7.5 mL) dropwise at -10°C under nitrogen protection, stir for 0.5 h, and move to 55°C and stir for 3 h. After the reaction is completed, quench with saturated sodium bicarbonate solution and filter to obtain 2-butyl-4-methoxyquinoline-6-ol as a white solid with a yield of 85.6%.

[0058] 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline (0.5 mmol) prepared according to step (5) of Example 1, anhydrous potassium carbonate (0.207 g, 1.5 mmol), tetrahydropyrrole (0.107 g, 1.5 mmol), and acetonitrile (15 mL) were added to a dry round-bottom flask and reacted at 78° C. for 10 hours. After the reaction, the solvent was removed under reduced pressure to obtain a crude product, which was then purified by petroleum ether / ethyl acetate silica gel column chromatography to obtain the final product 14b, i.e., 6-((6-(azepan-1-yl)hexyl)oxy)-2-butyl-4-methoxyquinoline, as a yellow solid with a yield of 85.9%.

[0059] mp110.1-111.9℃. 1 H NMR (400 MHz, DMSO-d 6 )δ7.77(d,J=9.1Hz,1H),

[0060] 7.34(d,J=2.8Hz,1H),7.30(dd,J=9.0,2.9Hz,1H),6.90(s,1H),4.07(t,J=6.4Hz,2H),4.02(s,3H),3.04(d,J=59.1Hz,6 H),2.85–2.78(m,2H),1.83-1.71(m,8H),1.69-1.59(m,6H),1.53-1.45(m,2H),1.42-1.33(m,4H),0.93(t,J=7.4Hz,3H); 13 C NMR (100 MHz, DMSO-d 6 )δ161.60,161.17,156.15,144.45,130.24,122.10,120.46,101.29,100.70,68.10,56.97,56.33 ,54.25(2C),38.81,31.86(2C),28.92,26.55(2C),26.44,25.62,24.53,24.19,22.59,14.37; HRMS m / z:calc.for C 26 H40 N 2 O 2 [M+H] + ,413.3163, found, 413.3177; HPLC purity: 98.2%.

[0061] Example 3

[0062] Preparation method of (14c)

[0063] Prepare 2-butyl-6-methoxyquinoline-4(1H)-one according to steps (1) and (2) of Example 1, then prepare 2-butyl-4-methoxyquinoline-6-ol according to steps (3) and (4) of Example 2, and finally prepare 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline according to step (5) of Example 1.

[0064] 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline (0.5 mmol), anhydrous potassium carbonate (0.207 g, 1.5 mmol), tetrahydropyrrole (0.107 g, 1.5 mmol), and acetonitrile (15 mL) were added to a dry round-bottom flask and reacted at 85° C. for 8 hours. After the reaction was completed, the solvent was removed under reduced pressure to obtain a crude product, which was then purified by petroleum ether / ethyl acetate silica gel column chromatography to obtain the final product 14c, i.e., 2-butyl-4-methoxy-6-((6-(3-methylpiperidin-1-yl)hexyl)oxy)quinoline, as a white solid with a yield of 96.4%.

[0065] mp133.7-135.1℃. 1 H NMR (400 MHz, DMSO-d 6 )δ7.80(d,J=9.0Hz,1H),

[0066] 7.36(d,J=2.7Hz,1H),7.33(dd,J=8.9,2.9Hz,1H),6.94(s,1H),4.08(t,J=6.4Hz,2H) ,4.04(s,3H),3.10(q,J=7.3Hz,1H),3.01(t,J=8.6Hz,2H),2.85–2.81(m,2H),2.77-2 .71(m,1H),1.87-1.77(m,4H),1.76-1.70(m,6H),1.53-1.46(m,2H),1.42-1.33(m,4H ),1.23-1.15(m,2H),1.11-1.01(m,1H),0.93(t,J=7.4Hz,3H),0.89(d,J=6.6Hz,3H); 13C NMR (100 MHz, DMSO-d 6 )δ161.52,161.36,156.19,144.16,129.88,122.26,120.43,101.34,100.72,68.09,57.88,56.41,52 .09,46.04,38.56,31.81,30.45,29.23,28.80,26.30,25.51,23.44,22.53,18.95,14.32,8.98; HRMS m / z:calc.for C 26 H 40 N 2 O 2 [M+H] + ,413.3163, found, 413.3184; HPLC purity: 97.9%.

[0067] Example 4

[0068] Preparation method of (14d)

[0069] Prepare 2-butyl-6-methoxyquinoline-4(1H)-one according to steps (1) and (2) of Example 1, then prepare 2-butyl-4-methoxyquinoline-6-ol according to steps (3) and (4) of Example 2, and finally prepare 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline according to step (5) of Example 1.

[0070] 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline (0.5 mmol), anhydrous potassium carbonate (0.207 g, 1.5 mmol), tetrahydropyrrole (0.107 g, 1.5 mmol), and acetonitrile (15 mL) were added to a dry round-bottom flask and reacted at 80° C. for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure to obtain a crude product, which was then purified by petroleum ether / ethyl acetate silica gel column chromatography to obtain the final product 14d, i.e., 2-butyl-4-methoxy-6-((6-(2-methylpiperidin-1-yl)hexyl)oxy)quinoline, a yellow oily liquid with a yield of 75.3%.

[0071] 1 H NMR (400 MHz, DMSO-d 6)δ7.77(d,J=9.1Hz,1H),7.34(d,J=2.8Hz,1H),7.30(dd,J=9.1,2.9Hz,1H),6.90(s,1H),4.08(t,J=6.4Hz,2H),4.02(s,3H),2.99(d,J=57.7Hz, 4H),2.83-2.80(m,2H),1.83-1.76(m,3H),1.75-1.64(m,7H),1.54-1.45 (m,4H),1.42-1.33(m,5H),1.24(d,J=6.3Hz,3H),0.93(t,J=7.4Hz,3H); 13 C NMR (100 MHz, DMSO-d 6 )δ161.57,161.12,156.10,144.39,130.20,122.07,120.41,101.26,100.66,68.06,66.97,62.72,60 .22,56.29,38.76,31.82,28.90,26.45,25.59,24.93,23.44,23.17,22.54,21.21,14.54,14.33; HRMS m / z:calc.for C 26 H 40 N 2 O 2 [M+H] + ,413.3163, found, 413.3175; HPLC purity: 99.5%.

[0072] Example 5

[0073] Preparation method of (14e)

[0074] Step (2): Dissolve 3-oxoheptanoic acid methyl ester (10 mmol) prepared according to step (1) of Example 1, p-toluenesulfonic acid monohydrate (PTSA, 0.18 mmol), p-methoxyaniline (11 mmol) and n-hexane (24 mL) in a round-bottom flask. The mixture is reacted at 55° C. for 10 h. After the reaction is completed, the solvent is removed under reduced pressure to obtain a crude product, which is dissolved in phenyl ether and refluxed for 40 minutes. The mixture is cooled to room temperature overnight and filtered to obtain 2-butyl-6-methoxyquinoline-4(1H)-one as a yellow solid with a yield of 18.6%.

[0075] Then, 2-butyl-4-methoxyquinoline-6-ol was prepared according to steps (3) and (4) of Example 2, and finally 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline was prepared according to step (5) of Example 1.

[0076] 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline (0.5 mmol), anhydrous potassium carbonate (0.207 g, 1.5 mmol), tetrahydropyrrole (0.107 g, 1.5 mmol), and acetonitrile (15 mL) were added to a dry round-bottom flask and reacted at 70° C. for 10 hours. After the reaction was completed, the solvent was removed under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography using petroleum ether / ethyl acetate to obtain the final product 14e, i.e., 2-butyl-4-methoxy-6-((6-(4-(pyrimidin-2-yl)piperazin-1-yl)hexyl)oxy)quinoline, as a yellow solid with a yield of 46.3%.

[0077] 1H NMR (400MHz, DMSO-d6) δ8.38(d,J=4.4Hz,2H),7.81(d,J=9.3Hz,1H),7.47-7.25(m,2H),6.89(s,1H),6.63(s,1H),4.06(t,J=6. 13C NMR(100MHz,DMSO-d6)δ161.68,161.47,161.12,158.30(2C),156.12,144.42,130.17,122.04,120.43,110.46,101.1 4,100.66,68.14,58.31,56.20,53.06(2C),43.73(2C),38.79,31.82,29.09,27.15,26.64,25.92,22.56,14.32; HRMS m / z:calc.forC 28 H 39 N 5 O 2 [M+H]+,478.3177,found,478.3191; HPLC purity:99.1%.

[0078] Example 6

[0079] Preparation method of (14f)

[0080] Prepare 2-butyl-6-methoxyquinoline-4(1H)-one according to steps (1) and (2) of Example 1, then prepare 2-butyl-4-methoxyquinoline-6-ol according to steps (3) and (4) of Example 2, and finally prepare 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline according to step (5) of Example 1.

[0081] 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline (0.5mmol), anhydrous potassium carbonate (0.207g, 1.5mmol), tetrahydropyrrole (0.107g, 1.5mmol), and acetonitrile (15mL) were added to a dry round-bottom flask and reacted at 60°C for 7 hours. After the reaction, the solvent was removed under reduced pressure to obtain a crude product, which was then purified by petroleum ether / ethyl acetate silica gel column chromatography to obtain the final product 14f, i.e., 6-((2-butyl-4-methoxyquinolin-6-yl)oxy)-n,n-diethylhexane-1-amine, as a white solid, 93.9%.

[0082] mp133.8-135.3℃. 1 H NMR (400 MHz, DMSO-d 6 )δ7.79(d,J=9.1Hz,1H),

[0083] 7.35(d,J=2.8Hz,1H),7.31(dd,J=9.1,2.9Hz,1H),6.89(s,1H),4.05(t,J=6.4Hz,2H),4.03(s,3H),2.82(t,J=7.8Hz,6H),2 .73(t,J=7.8Hz,2H),1.81-1.72(m,4H),1.60-1.44(m,4H),1.41-1.34(m,4H),1.10(t,J=7.2Hz,6H),0.94(t,J=7.4Hz,3H); 13 CNMR (100MHz, DMSO-d 6 )δ161.52,161.12,156.11,144.42,130.19,122.03,120.43,101.19,100.67,68.10,56.24, 51.70,46.65(2C),38.77,31.81,28.99,26.65,25.70,24.90,22.55,14.31,10.26(2C); HRMS m / z:calc.for C 24 H 38 N 2 O 2 [M+H] +,387.3006,found,387.3013;HPLCpurity:99.7%.

[0084] Example 7

[0085] Preparation method of (14g)

[0086] Prepare 2-butyl-6-methoxyquinoline-4(1H)-one according to steps (1) and (2) of Example 1, then prepare 2-butyl-4-methoxyquinoline-6-ol according to steps (3) and (4) of Example 2, and finally prepare 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline according to step (5) of Example 1.

[0087] 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline (0.5mmol), anhydrous potassium carbonate (0.207g, 1.5mmol), tetrahydropyrrole (0.107g, 1.5mmol), acetonitrile (15mL) were added to a dry round-bottom flask and reacted at 60°C for 9 hours. After the reaction, the solvent was removed under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography using petroleum ether / ethyl acetate to obtain 14g of the final product, i.e., 2-butyl-6-((6-(4-ethylpiperazin-1-yl)hexyl)oxy)-4-methoxyquinoline, a yellow oily liquid, with a yield of 92.6%.

[0088] 1 H NMR (400 MHz, DMSO-d 6 )δ7.76(d,J=9.0Hz,1H),7.33(d,J=2.8Hz,1H),7.29(dd,J=9.0,2.8Hz,1H),6.88(s,1H),4.04(t,J=6.5Hz,2H),4.01(s,3H) ,2.83-2.79(m,2H),2.35-2.24(m,11H),1.79-1.69(m,4H),1.48-1.23(m,9H),0.97(t,J=7.2Hz,3H),0.93(t,J=7.3Hz,3H); 13 C NMR (100 MHz, DMSO-d 6 )δ161.44,161.11,156.11,144.43,130.15,122.00,120.42,101.11,100.64,68.12,58.20,56.18, 53.10(2C),52.70(2C),52.02,38.79,31.82,29.09,27.12,26.66,25.91,22.56,14.31,12.29; HRMS m / z:calc.forC26 H 41 N 3 O 2 [M+H] + ,428.3272, found, 428.3285; HPLC purity: 99.6%.

[0089] Example 8

[0090] Preparation method of (14h)

[0091] 2-Butyl-6-methoxyquinolin-4(1H)-one was prepared according to steps (1) and (2) of Example 1, and 2-butyl-4-methoxyquinolin-6-ol was then prepared according to steps (3) and (4) of Example 2.

[0092] Step (5): 2-butyl-4-methoxyquinolin-6-ol (0.231 g, 1 mmol), anhydrous potassium carbonate (0.207 g, 1.5 mmol), dibromoalkane (1.5 mmol), and acetone (40 mL) were added to a dry round-bottom flask and reacted at 30° C. for 9 hours. After the reaction was completed, the solvent was removed under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography using petroleum ether / ethyl acetate to obtain 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline as a white solid with a yield of 49.2%.

[0093] 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline (0.5mmol), anhydrous potassium carbonate (0.207g, 1.5mmol), tetrahydropyrrole (0.107g, 1.5mmol), and acetonitrile (15mL) were added to a dry round-bottom flask and reacted at 60°C for 9 hours. After the reaction was completed, the solvent was removed under reduced pressure to obtain a crude product, which was then purified by petroleum ether / ethyl acetate silica gel column chromatography to obtain the final product 14h, i.e., 2-butyl-4-methoxy-6-((6-(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)hexyl)oxy)quinoline, a yellow oily liquid, with a yield of 83.1%.

[0094] 1H NMR (400MHz, DMSO-d6) δ7.76(d,J=9.1Hz,1H),7.33(d,J=2.9Hz,1H),7.28(dd,J=9.1,2.9Hz ,1H),7.11-7.01(m,4H),6.86(s,1H),4.02(t,J=6.5Hz,2H),3.99(s,3H),3.80(q,J=6.5Hz,1 H),2.96-2.89(m,1H),2.82-2.74(m,3H),2.66-2.57(m,2H),2.49-2.44(m,2H),1.77-1.68(m ,4H),1.53-1.42(m,4H),1.40-1.31(m,4H),1.21(d,J=6.6Hz,3H),0.91(t,J=7.3Hz,3H); 13C NMR(100MHz,DMSO-d6)δ161.49,161.14,156.13,144.41,140.52,134.31,130.15,128.93,127.57,126.08,125.93,122.02,120.4 4,101.15,100.74,68.17,56.32,56.21,53.53,43.92,38.76,31.80,29.08,27.49,27.28,27.06,25.90,22.53,19.20,14.30; HRMS m / z:calc.for C30H40N2O2[M+H] + ,461.3163, found, 461.3188; HPLC purity: 100%.

[0095] Example 9

[0096] Preparation method of (14i)

[0097] Step (1): Dissolve McBride's acid (4.468 g, 31 mmol) in anhydrous dichloromethane (13 mL) and stir at -5°C under nitrogen. After slowly adding pyridine (4.8 mL), n-valeryl chloride (3.496 g, 29 mmol) was dripped into the reaction flask. The mixture was reacted at 10°C for 0.5 hours, moved to room temperature and continued to stir for 3 hours. After the reaction was completed, the mixture was filtered to obtain a filtrate, which was washed with hydrochloric acid (2 mol / L, 2×18 mL). The aqueous phase was extracted with dichloromethane (2×10 mL), and the organic phases were combined, washed with hydrochloric acid (2 mol / L, 2×10 mL) and saturated brine (20 mL), and dried over anhydrous sodium sulfate. After concentration under reduced pressure, it was dissolved in anhydrous CH 3OH (35 mL), and reacted at 50° C. for 8 h. After the reaction was completed, the crude product was purified by silica gel column chromatography to obtain a colorless oily liquid, namely methyl 3-oxoheptanoate, with a yield of 53.1%.

[0098] According to step (2) of Example 1, 2-butyl-6-methoxyquinoline-4(1H)-one was prepared, followed by steps (3) and (4) of Example 2 to prepare 2-butyl-4-methoxyquinoline-6-ol, and finally, according to step (5) of Example 1, 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline was prepared.

[0099] 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline (0.5mmol), anhydrous potassium carbonate (0.207g, 1.5mmol), tetrahydropyrrole (0.107g, 1.5mmol), and acetonitrile (15mL) were added to a dry round-bottom flask and reacted at 60°C for 10 hours. After the reaction, the solvent was removed under reduced pressure to obtain a crude product, which was then purified by petroleum ether / ethyl acetate silica gel column chromatography to obtain the final product 14i, i.e., 2-butyl-6-((6-(3,4-dihydroisoquinolin-2(1H)-yl)hexyl)oxy)-4-methoxyquinoline, a yellow oily liquid with a yield of 85.7%.

[0100] 1 H NMR (400 MHz, DMSO-d 6 )δ7.76(d,J=9.0Hz,1H),7.33(d,J=2.9Hz,1H),7.29(dd,J=9.0,2.8Hz,1H),7.1 0-7.00(m,4H),6.87(s,1H),4.03(t,J=6.4Hz,2H),4.00(s,3H),3.51(s,2H),2. 82-2.76(m,4H),2.62(t,J=5.9Hz,2H),2.43(t,J=7.3Hz,2H),1.79-1.68(m,4H) ,1.57-1.50(m,2H),1.48-1.43(m,2H),1.41-1.31(m,4H),0.92(t,J=7.3Hz,3H); 13 C NMR (100 MHz, DMSO-d 6)δ161.52,161.12,156.12,144.36,135.26,134.59,130.14,128.80,126.82,126.35,125.87,122.08,120.41,101 .20,100.62,68.15,58.10,56.24,55.94,50.98,38.76,31.85,29.08,27.15(2C),26.84,25.92,22.55,14.34; HRMS m / z:calc.for C 29 H 38 N 2 O 2 [M+H] + ,447.3006, found, 447.3017; HPLC purity: 99.7%.

[0101] Example 10

[0102] Preparation method of (14j)

[0103] According to step (1) of Example 9, methyl 3-oxoheptanoate was prepared. Then, according to step (2) of Example 1, 2-butyl-6-methoxyquinoline-4(1H)-one was prepared. Then, according to steps (3) and (4) of Example 2, 2-butyl-4-methoxyquinoline-6-ol was prepared. Finally, according to step (5) of Example 1, 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline was prepared.

[0104] 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline (0.5 mmol), anhydrous potassium carbonate (0.207 g, 1.5 mmol), tetrahydropyrrole (0.107 g, 1.5 mmol), and acetonitrile (15 mL) were added to a dry round-bottom flask and reacted at 60° C. for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure to obtain a crude product, which was then purified by petroleum ether / ethyl acetate silica gel column chromatography to obtain the final product 14j, i.e., 2-butyl-4-methoxy-6-((6-(4-phenylpiperidin-1-yl)hexyl)oxy)quinoline, as a yellow solid with a yield of 83.2%.

[0105] mp137.8-139.4℃. 1 H NMR (400 MHz, DMSO-d 6)δ7.77(d,J=9.1Hz,1H),7.34(d,J=2.8Hz,1H),7.32-7.29(m,1H),7.28-7.25(m,2H),7. 22-7.15(m,3H),6.88(s,1H),4.06(t,J=6.4Hz,2H),4.01(s,3H),2.96(d,J=11.0Hz,2H) ,2.83-2.79(m,2H),2.48-2.42(m,1H),2.34-2.30(m,2H),2.01-1.92(m,2H),1.81-1.69 (m,6H),1.67-1.57(m,2H),1.52-1.43(m,4H),1.42-1.32(m,4H),0.93(t,J=7.3Hz,3H); 13 C NMR (100 MHz, DMSO-d 6 )δ161.43,161.12,156.13,146.66,144.46,130.18,128.72(2C),127.06(2C),126.38,122.00,120.45,101.11,100. 67,68.13,58.53,56.16,54.21(2C),42.35,38.81,33.46,31.82(2C),29.10,27.20,26.80,25.93,22.57,14.32; HRMS m / z:calc.for C 31 H 42 N 2 O 2 [M+H] + ,475.3319, found, 475.3337; HPLC purity: 99.4%.

[0106] Embodiment 11

[0107] Preparation method of (14k)

[0108] According to step (1) of Example 9, methyl 3-oxoheptanoate was prepared. Then, according to step (2) of Example 1, 2-butyl-6-methoxyquinoline-4(1H)-one was prepared. Then, according to steps (3) and (4) of Example 2, 2-butyl-4-methoxyquinoline-6-ol was prepared. Finally, according to step (5) of Example 1, 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline was prepared.

[0109] 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline (0.5 mmol), anhydrous potassium carbonate (0.207 g, 1.5 mmol), tetrahydropyrrole (0.107 g, 1.5 mmol), and acetonitrile (15 mL) were added to a dry round-bottom flask and reacted at 60° C. for 12 hours. After the reaction, the solvent was removed under reduced pressure to obtain a crude product, which was then purified by petroleum ether / ethyl acetate silica gel column chromatography to obtain the final product 14k, i.e., N-benzyl-6-((2-butyl-4-methoxyquinolin-6-yl)oxy)-N-ethylhexane-1-amine, a yellow oily liquid with a yield of 68.5%.

[0110] 1 H NMR (400 MHz, DMSO-d 6 )δ7.76(d,J=9.1Hz,1H),7.33(d,J=2.8Hz,1H),7.30-7.26(m,5H),7.22-7.18(m,1H),6.88(s,1H),4.01(t,J=13.2Hz,5H),3.50( s,2H),2.83-2.79(m,2H),2.45-2.35(m,4H),1.77-1.69(m,4H),1.47-1.29(m,8H),0.96(t,J=7.1Hz,3H),0.93(t,J=5.5Hz,3H); 13 C NMR (100 MHz, DMSO-d 6 )δ161.45,161.12,156.12,144.44,140.52,130.16,128.86(2C),128.43(2C),126.97,122.00,120.44,101.11, 100.64,68.11,57.94,56.17,52.88,47.18,38.80,31.83,29.10,27.02,26.92,25.83,22.56,14.31,12.06; HRMS m / z:calc.for C 29 H 40 N 2 O 2 [M+H] + ,449.3163, found, 449.3178; HPLC purity: 99.3%.

[0111] Example 12

[0112] Preparation method of (141)

[0113] According to step (1) of Example 9, methyl 3-oxoheptanoate was prepared. Then, according to step (2) of Example 1, 2-butyl-6-methoxyquinoline-4(1H)-one was prepared. Then, according to steps (3) and (4) of Example 2, 2-butyl-4-methoxyquinoline-6-ol was prepared. Finally, according to step (5) of Example 1, 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline was prepared.

[0114] 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline (0.5 mmol), anhydrous potassium carbonate (0.207 g, 1.5 mmol), tetrahydropyrrole (0.107 g, 1.5 mmol), and acetonitrile (15 mL) were added to a dry round-bottom flask and reacted at 60° C. for 10 hours. After the reaction was completed, the solvent was removed under reduced pressure to obtain a crude product, which was then purified by petroleum ether / ethyl acetate silica gel column chromatography to obtain the final product 141, i.e., 2-butyl-4-methoxy-6-((6-(4-phenylpiperidin-1-yl)hexyl)oxy)quinoline, a yellow oily liquid, 87.6%.

[0115] 1 H NMR (400 MHz, DMSO-d 6 )δ8.11-8.09(m,1H),7.77(d,J=9.0Hz,1H),7.53-7.49(m,1H),7.34(d,J=2.8Hz,1H),7.30(dd ,J=9.0,2.9Hz,1H),6.88(s,1H),6.78(d,J=8.6Hz,1H),6.62(dd,J=7.0,4.9Hz,1H),4.05(t,J =6.5Hz,2H),4.01(s,3H),3.48-3.43(m,4H),2.83-2.79(m,2H),2.43(t,J=5.0Hz,4H),2.31(t ,J=7.2Hz,2H),1.81-1.69(m,4H),1.52-1.43(m,4H),1.41-1.32(m,4H),0.92(t,J=7.3Hz,3H); 13 C NMR (100 MHz, DMSO-d 6)δ161.48,161.13,159.55,156.14,148.01,144.44,137.84,130.18,122.04,120.44,113.35,107.39,101.14,10 0.69,68.16,58.35,56.20,53.07(2C),45.10(2C),38.80,31.82,29.10,27.18,26.68,25.94,22.57,14.32; HRMS m / z:calc.for C 29 H 40 N 4 O 2 [M+H] + ,477.3224, found, 477.3239; HPLC purity: 98.1%.

[0116] Example 13

[0117] Preparation method of (14m)

[0118] According to step (1) of Example 9, methyl 3-oxoheptanoate was prepared. Then, according to step (2) of Example 1, 2-butyl-6-methoxyquinoline-4(1H)-one was prepared. Then, according to steps (3) and (4) of Example 2, 2-butyl-4-methoxyquinoline-6-ol was prepared. Finally, according to step (5) of Example 1, 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline was prepared.

[0119] 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline (0.5mmol), anhydrous potassium carbonate (0.207g, 1.5mmol), tetrahydropyrrole (0.107g, 1.5mmol), and acetonitrile (15mL) were added to a dry round-bottom flask and reacted at 60°C for 9 hours. After the reaction, the solvent was removed under reduced pressure to obtain a crude product, which was then purified by petroleum ether / ethyl acetate silica gel column chromatography to obtain the final product 14m, i.e., 6-((6-(4-benzylpiperidin-1-yl)hexyl)oxy)-2-butyl-4-methoxyquinoline, a yellow oily liquid with a yield of 68.6%.

[0120] 1 H NMR (400 MHz, DMSO-d 6)δ7.76(d,J=9.0Hz,1H),7.33(d,J=2.8Hz,1H),7.29(dd,J=9.0,2.8Hz,1H),7.27- 7.24(m,2H),7.19-7.16(m,1H),7.15-7.12(m,2H),6.88(s,1H),4.04(t,J=6.4Hz,2 H),4.01(s,3H),2.86-2.79(m,4H),2.46(d,J=6.7Hz,2H),2.28(s,2H),1.85(s,2H ),1.79-1.69(m,4H),1.54-1.29(m,11H),1.22-1.12(m,2H),0.92(t,J=7.4Hz,3H); 13 C NMR (100 MHz, DMSO-d 6 )δ161.47,161.12,156.12,144.43,140.70,130.17,129.38(2C),128.54(2C),126.17,122.01,120.43,101.14,100.66, 68.11,58.23,56.19,53.56(2C),42.73,38.79,37.61,31.82(2C),31.75,29.05,27.07,26.47,25.86,22.55,14.32; HRMS m / z:calc.for C 32 H 44 N 2 O 2 [M+H] + ,489.3476, found, 489.3491; HPLC purity: 98.4%.

[0121] Embodiment 14

[0122] Preparation method of (14n)

[0123] Step (1): Dissolve McBride's acid (4.468 g, 31 mmol) in anhydrous dichloromethane (13 mL) and stir at -5°C under nitrogen. After slowly adding pyridine (4.8 mL), n-valeryl chloride (3.496 g, 29 mmol) was dripped into the reaction flask. The mixture was reacted at -10°C for 3 hours, moved to room temperature and continued to stir for 8 hours. After the reaction was completed, the mixture was filtered to obtain a filtrate, which was washed with hydrochloric acid (2 mol / L, 2×18 mL). The aqueous phase was extracted with dichloromethane (2×10 mL), and the organic phases were combined, washed with hydrochloric acid (2 mol / L, 2×10 mL) and saturated brine (20 mL), and dried over anhydrous sodium sulfate. After concentration under reduced pressure, it was dissolved in anhydrous CH 3OH (35 mL), and reacted at 65° C. for 3 h. After the reaction was completed, the crude product was purified by silica gel column chromatography to obtain a colorless oily liquid, namely methyl 3-oxoheptanoate, with a yield of 46.7%.

[0124] According to step (2) of Example 1, 2-butyl-6-methoxyquinoline-4(1H)-one was prepared, followed by steps (3) and (4) of Example 2 to prepare 2-butyl-4-methoxyquinoline-6-ol, and finally, according to step (5) of Example 1, 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline was prepared.

[0125] 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline (0.5mmol), anhydrous potassium carbonate (0.207g, 1.5mmol), tetrahydropyrrole (0.107g, 1.5mmol), and acetonitrile (15mL) were added to a dry round-bottom flask and reacted at 60°C for 8 hours. After the reaction, the solvent was removed under reduced pressure to obtain a crude product, which was then purified by petroleum ether / ethyl acetate silica gel column chromatography to obtain the final product 14n, i.e., 4-(6-(2-butyl-4-methoxyquinoline-6-oxy)hexyl)morpholine, a yellow oily liquid with a yield of 78.9%.

[0126] 1 H NMR (400 MHz, DMSO-d 6 )δ7.76(d,J=9.0Hz,1H),7.33(d,J=2.8Hz,1H),7.30(dd,J=9.0,2.8Hz,1H),6.88(s,1H),4.05(t,J=6.5Hz,2H),4.02(s,3H),3.55(t,J=4.7Hz,4H ),2.83-2.79(m,2H),2.32(t,J=4.6Hz,4H),2.25(t,J=7.2Hz,2H),1.80- 1.69(m,4H),1.49-1.41(m,4H),1.40-1.32(m,4H),0.93(t,J=7.4Hz,3H); 13 C NMR (100 MHz, DMSO-d 6 )δ161.50,161.15,156.16,144.45,130.20,122.05,120.46,101.17,100.68,68.18,66.70( 2C),58.74,56.24,53.89(2C),38.83,31.87,29.13,27.14,26.39,25.96,22.60,14.36; HRMS m / z:calc.for C 24 H 36 N2 O 3 [M+H] + ,401.2799,found,401.2826;HPLCpurity:98.7%.

[0127] Embodiment 15

[0128] Preparation method of (14o)

[0129] According to step (2) of Example 1, 2-butyl-6-methoxyquinoline-4(1H)-one was prepared, followed by steps (3) and (4) of Example 2 to prepare 2-butyl-4-methoxyquinoline-6-ol, and finally, according to step (5) of Example 1, 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline was prepared.

[0130] 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline (0.5mmol), anhydrous potassium carbonate (0.207g, 1.5mmol), tetrahydropyrrole (0.107g, 1.5mmol), and acetonitrile (15mL) were added to a dry round-bottom flask and reacted at 60°C for 8 hours. After the reaction, the solvent was removed under reduced pressure to obtain a crude product, which was then purified by petroleum ether / ethyl acetate silica gel column chromatography to obtain the final product 14o, i.e., 2-butyl-6-((6-(4-isopropylpiperazin-1-yl)hexyl)oxy)-4-methoxyquinoline, a yellow oily liquid with a yield of 78.9%.

[0131] 1 H NMR (400 MHz, DMSO-d 6 )δ7.79(d,J=9.0Hz,1H),7.35(d,J=2.9Hz,1H),7.31(dd,J=9.1,2.8Hz,1H ),6.88(s,1H),4.05(t,J=6.4Hz,2H),4.03(s,3H),2.82(t,J=7.8Hz,2H),2 .77-2.70(m,1H),2.56(s,4H),2.47(s,3H),2.33(t,J=7.4Hz,2H),1.80-1. 70(m,4H),1.49-1.31(m,9H),1.00(d,J=6.6Hz,6H),0.94(t,J=7.4Hz,3H); 13 C NMR (100 MHz, DMSO-d 6)δ161.50,161.13,156.12,144.40,130.16,122.03,120.42,101.16,100.65,68.13,57.87,56.23,54 .63,52.83(2C),48.07(2C),38.77,31.83,29.05,27.01,26.35,25.87,22.55,18.33(2C),14.32; HRMS m / z:calc.for C 27 H 43 N 3 O 2 [M+H] + ,442.3428, found, 442.3443; HPLC purity: 99.8%.

[0132] Example 16

[0133] Preparation method of (14p)

[0134] According to step (2) of Example 1, 2-butyl-6-methoxyquinoline-4(1H)-one was prepared, followed by steps (3) and (4) of Example 2 to prepare 2-butyl-4-methoxyquinoline-6-ol, and finally, according to step (5) of Example 1, 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline was prepared.

[0135] 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline (0.5mmol), anhydrous potassium carbonate (0.207g, 1.5mmol), tetrahydropyrrole (0.107g, 1.5mmol), and acetonitrile (15mL) were added to a dry round-bottom flask and reacted at 60°C for 12 hours. After the reaction, the solvent was removed under reduced pressure to obtain a crude product, which was then purified by petroleum ether / ethyl acetate silica gel column chromatography to obtain the final product 14p, i.e., 6-(6-([1,4'-bipiperidinyl]-1'-yl)hexyl)oxy)-2-butyl-4-methoxyquinoline, a yellow oily liquid with a yield of 98.3%.

[0136] mp69.4-70.7℃. 1 H NMR (400 MHz, DMSO-d 6 )δ7.77(d,J=9.0Hz,1H),

[0137] 7.34(d,J=2.8Hz,1H),7.30(dd,J=9.0,2.9Hz,1H),6.89(s,1H),4.05(t,J=6.4Hz,2H),4.02(s,3H),2.97(t,J=11.1Hz,2H),2.83-2.79(m ,2H),2.64(s,4H),2.36(s,2H),2.00(d,J=12.9Hz,2H),1.80-1.69(m,6H),1.57-1.41(m,12H),1.40-1.31(m,5H),0.93(t,J=7.4Hz,3H); 13 C NMR (100 MHz, DMSO-d 6 )δ161.53,161.12,156.12,144.39,130.17,122.05,120.42,101.20,100.65,68.13,62.25,57.64,56.26,52.6 4(2C),49.91(2C),38.77,31.83(2C),29.01,27.00,26.90(2C),26.43,25.82,25.32,23.96,22.55,14.33; HRMS m / z:calc.for C 30 H 47 N 3 O 2 [M+H] + ,482.3741,found,482.3771; HPLC purity:97.5%.

[0138] Embodiment 17

[0139] Preparation method of (14q)

[0140] According to step (2) of Example 1, 2-butyl-6-methoxyquinoline-4(1H)-one was prepared, followed by steps (3) and (4) of Example 2 to prepare 2-butyl-4-methoxyquinoline-6-ol, and finally, according to step (5) of Example 1, 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline was prepared.

[0141] 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline (0.5mmol), anhydrous potassium carbonate (0.207g, 1.5mmol), tetrahydropyrrole (0.107g, 1.5mmol), and acetonitrile (15mL) were added to a dry round-bottom flask and reacted at 60°C for 7 hours. After the reaction was completed, the solvent was removed under reduced pressure to obtain a crude product, which was then purified by petroleum ether / ethyl acetate silica gel column chromatography to obtain the final product 14q, i.e., 1-(6-(2-butyl-4-methoxyquinolin-6-yl)oxy)hexyl)piperidin-4-ol, a yellow oily liquid with a yield of 76.3%.

[0142] 1 H NMR (400 MHz, DMSO-d 6 )δ7.77(d,J=9.0Hz,1H),7.34(d,J=2.8Hz,1H),7.30(dd,J=9.0,2.9Hz,1H),6.89(s,1H),4.74(s,1H),4.05(t,J=6.4Hz,2H),4.02(s,3H), 3.59(s,2H),2.92(s,2H),2.83-2.79(m,2H),2.67(s,2H),1.81-1.69(m,6H),1.55-1.45(m,6H),1.43-1.30(m,5H),0.93(t,J=7.3Hz,3H); 13 C NMR (100 MHz, DMSO-d 6 )δ161.53,161.13,156.12,144.38,130.15,122.06,120.41,101.19,100.64,68.13,57.57,56. 24,50.80,49.05(2C),38.76,33.72,31.84(2C),29.01,26.95,26.05,25.81,22.55,14.32; HRMS m / z:calc.for C 25 H 38 N 2 O 3 [M+H] + ,415.2955, found, 415.2968; HPLC purity: 97.7%.

[0143] Embodiment 18

[0144] Preparation method of (14r)

[0145] According to step (2) of Example 1, 2-butyl-6-methoxyquinoline-4(1H)-one was prepared, followed by steps (3) and (4) of Example 2 to prepare 2-butyl-4-methoxyquinoline-6-ol, and finally, according to step (5) of Example 1, 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline was prepared.

[0146] 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline (0.5 mmol), anhydrous potassium carbonate (0.207 g, 1.5 mmol), tetrahydropyrrole (0.107 g, 1.5 mmol), and acetonitrile (15 mL) were added to a dry round-bottom flask and refluxed at 60° C. for 8 hours. After the reaction was completed, the solvent was removed under reduced pressure to obtain a crude product, which was then purified by petroleum ether / ethyl acetate silica gel column chromatography to obtain the final product 14r, i.e., (1-(6-((2-butyl-4-methoxyquinolin-6-yl)oxy)hexyl)piperidin-4-yl)methanol, a yellow oily liquid, with a yield of 86.4%.

[0147] 1 H NMR (400 MHz, DMSO-d 6 )δ7.77(d,J=9.0Hz,1H),7.34(d,J=2.8Hz,1H),7.30(dd,J=9.1,2.9Hz,1H),6.89 (s,1H),4.53(s,1H),4.06(t,J=6.4Hz,2H),4.02(s,3H),3.25(t,J=4.8Hz,3H),3 .13(s,2H),2.83-2.79(m,2H),2.62(s,2H),1.81-1.69(m,6H),1.59-1.51(m,2H) ,1.49-1.42(m,3H),1.40-1.33(m,4H),1.31-1.23(m,3H),0.93(t,J=7.4Hz,3H); 13 C NMR (100 MHz, DMSO-d 6 )δ161.52,161.13,156.11,144.37,130.13,122.05,120.42,101.17,100.64,68.11,66.00,57.77, 56.23,53.02(2C),49.05,38.76,38.03,31.84,28.99,28.08(2C),26.92,25.79,22.55,14.31; HRMS m / z:calc.for C 26 H 40 N 2 O 3 [M+H] +,429.3112, found, 429.3127; HPLC purity: 99.5%.

[0148] Embodiment 19

[0149] Preparation method of (14s)

[0150] According to step (2) of Example 1, 2-butyl-6-methoxyquinoline-4(1H)-one was prepared, followed by steps (3) and (4) of Example 2 to prepare 2-butyl-4-methoxyquinoline-6-ol, and finally, according to step (5) of Example 1, 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline was prepared.

[0151] 6-((6-bromohexyl)oxy)-2-butyl-4-methoxyquinoline (0.5mmol), anhydrous potassium carbonate (0.207g, 1.5mmol), tetrahydropyrrole (0.107g, 1.5mmol), and acetonitrile (15mL) were added to a dry round-bottom flask and reacted at 60°C for 8 hours. After the reaction was completed, the solvent was removed under reduced pressure to obtain a crude product, which was then purified by petroleum ether / ethyl acetate silica gel column chromatography to obtain the final product 14s, i.e., N-benzyl-6-((2-butyl-4-methoxyquinolin-6-yl)oxy)-N-methylhexane-1-amine, a yellow oily liquid with a yield of 46.9%.

[0152] 1 H NMR (400 MHz, DMSO-d 6 )δ7.76(d,J=9.0Hz,1H),7.34(d,J=2.8Hz,1H),7.32-7.27(m,5H),7.24-7.20(m,1H),6.88(s,1H),4.04(d,J=6.5Hz,2H),4.01(s,3 H),3.44(s,2H),2.83-2.79(m,2H),2.32(t,J=7.1Hz,2H),2.10(s,3H),1.79-1.69(m,4H),1.52-1.30(m,8H),0.93(t,J=7.3Hz,3H); 13 C NMR (100 MHz, DMSO-d 6)δ161.48,161.13,156.14,144.44,139.74,130.18,129.08(2C),128.51(2C),127.18,122.04,120.44,101. 17,100.67,68.16,62.10,57.09,56.21,42.24,38.79,31.83,29.11,27.17,27.01,25.87,22.56,14.33; HRMS m / z:calc.for C 28 H 38 N 2 O 2 [M+H] + ,435.3006,found,435.3022;HPLCpurity:98.5%.

[0153] Embodiment 20

[0154] Below is the pharmacological experimental data of the sample prepared by the present invention:

[0155] 1. Evaluation of inhibitory activity of acetylcholinesterase and monoamine oxidase B

[0156] (1) In vitro eeAChE and eqBuChE inhibitory activity test

[0157] (a) Test reagents: 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB, D8130), thioacetylcholine iodide (ACTI, 01480), thiobutyrylcholine iodide (BCTI, B3253), eeAChE (electric eel, type VI-S, C3389), eqBuChE (horse serum, C4290) and other reagents were purchased from Sigma-Aldrich; 0.1 M phosphate buffer solution (PBS, pH = 8.0) was prepared in-house.

[0158] Prepare 0.1 M PBS by the following steps: weigh 3.121 g NaH 2 PO 4 ·2H 2 O and 71.640gNa 2 HPO 4 12H 2 O was dissolved in ultrapure water to obtain 0.2M NaH 2 PO 4 and Na 2 HPO 4 Solution. Take 26.5mL of NaH 2 PO 4 and 473.5mLNa 2 HPO 4The solution was mixed thoroughly to obtain 0.1 M PBS.

[0159] (b) Test method: The inhibitory activities of all compounds eeAChE and eqBuChE were determined by the modified Ellman test. The quinine derivatives prepared in Examples 1 to 19 were dissolved in DMSO and diluted with PBS to prepare seven test concentrations (0.02 μM, 0.20 μM, 2 μM, 20 μM, 200 μM, 400 μM, and 2000 μM). The inhibition rate and IC 50 The maximum final concentration of DMSO was 0.025%. The test solution consisted of 110 μL PBS, 10 μL compound and 40 μL eeAChE or eqBuChE (0.02 μ / mL). After incubation of the test solution for 15 minutes, 20 μL DTNB (0.625 mM) and 20 μL ACTI or BCTI (0.625 mM) were added. The OD value was recorded at 405 nm within 30 minutes, and the IC was calculated using GraphPad Prism8 software. 50 All experiments were performed in triplicate at 37 °C.

[0160] (2) hMAO-B inhibitory activity test

[0161] The enzymes and reagents used in the experiment were purchased from Sigma. Before the experiment, the buffer, substrate, color developer and oxygen stabilizer were moved from -20°C to room temperature for thawing. Pargyline and the prepared products of Example 1-Example 19 were respectively prepared into six working solutions with concentrations of 10 μM, 5 μM, 3 μM, 1 μM, 0.5 μM and 0.1 μM, respectively. Experimental group, positive control group and blank control group were set up, with one set of wells in each group, and three times in parallel. First, 10 μL of working solution was added to a 96-well plate. Then 49 μL PBS (pH = 7.4) and 1 μL hMAO-B were added. Subsequently, it was transferred to a 37°C constant temperature incubator and shaken for 10 minutes, and quickly mixed with 37 μL PBS, 1 μL substrate, 1 μL developer and 1 μL stabilizer. The 96-well plate was placed in a 37°C constant temperature microplate reader, and the fluorescence mode (Ex / Em = 535 / 587) was set, and scanned once every minute for 30 minutes. The relative inhibition rate was calculated as follows: % relative inhibition rate = (slope of blank control group - slope of compound group) / (slope of blank control group) x 100%. IC 50 Analyze using GraphPadPrism 8 software.

[0162] Table 1. IC of eeAChE, eqBuChE and hMAO-B inhibitory activities of Examples 14a-s 50 Value, selectivity.

[0163]

[0164]

[0165] The results are shown in Table 1. Quinine derivatives have strong eeAChE inhibition ability, such as 14d, 14f and 14r, IC 50 The values ​​were 1.82, 1.21 and 1.24 μM, respectively. Among them, 14c, 14m, 14n and 14s had selective AChE inhibition (IC 50 Among all eeAChE and hMAO-B dual inhibitors (14f, 14i, 14n and 14o), 14f, 14i, 14n and 14o showed the most balanced hMAO-B and AChE inhibition ability, indicating that 14f, 14i, 14n and 14o are very promising compounds and deserve further study.

[0166] 2. Blood-brain barrier permeability measurement in some examples

[0167] The test compound was dissolved in DMSO at a concentration of 5 mg / mL and diluted to a 25 μg / mL test solution with phosphate buffered saline (PBS, pH = 7.4). An appropriate amount of porcine polar brain lipid (PBL, purchased from AvantiPolar Lipids Co., Ltd.) was directly dissolved in dodecane solution at a concentration of 20 mg / mL. The prepared PBL solution was added to the filter surface of the donor plate (4 μL per well) and the entire filter membrane (area = 0.28 cm) was impregnated with PBL. 2 ), add the test compound solution (Vd) to the donor plate (150 μL), and fill the receptor well with 300 μL PBS (V). Carefully place the donor plate on the receptor plate so that the membrane is in contact with the upper and lower liquid levels. Cover the lid and keep it in the dark at a constant temperature (25°C) for 6 hours. The drug concentration in the receptor plate, donor plate and reference wells is determined by a microplate reader. According to the Pe equation, the concentration and permeability of the test compound in the well can be calculated (the absorbance is substituted into the standard curve to calculate the compound concentration, and each group of samples is tested in parallel 8 times).

[0168]

[0169] Table 2. PAMPA test results of compounds 14f, 14i, 14n, and 14o and their predicted central nervous system permeability.

[0170]

[0171]

[0172] MW: molecular weight; HBA: H-bond acceptor; HBD: H-bond donor.

[0173] ·Category 0:BBB-,Category 1:BBB+.

[0174] Data are presented as mean ± SD from eight independent experiments.

[0175] DCNS+:P e (10-6cm / s)>4.0, BBB permeability is high; CNS±:2.0 <P e (10-6cm / s)<

[0176] 4.0, BBB permeability uncertain; CNS-:P e (10-6cm / s)<2.0, BBB permeability is low.

[0177] Whether the compound can penetrate the blood-brain barrier is a prerequisite for the treatment of neurodegenerative diseases. The online prediction platform (ADMETlab) was used to verify all the compounds represented by formula (I), and the prediction results were BBB+, indicating that the BBB permeability was high. To further confirm this result, a parallel artificial membrane permeation (PAMPA) experiment was performed. According to the definition of the BBB permeability limit, P e Compounds with >4.0 mean high permeability, P e <2.0 indicates low permeability, 2.0 indicates low permeability <P e <4.0 indicates uncertain permeability. The results are shown in Table 2. e The values ​​were all greater than 4.0, indicating that the compounds represented by formula (I) all had a high potential to penetrate the BBB.

Claims

1. A quinine derivative and a pharmaceutically acceptable salt thereof: In formula (I), R1 is a -C1-C5 straight chain alkyl or branched chain alkyl; R2 is -(C1-C5) straight chain or branched alkyl or a substituted aryl group whose substituent is -(C1-C5)-; Or R1, R2 and the nitrogen atom connected thereto form -(C1-C5) substituted heterocycloalkyl, -(C1-C5) substituted heterocyclic aryl or -(C1-C5) substituted heterocyclic aromatic heteroyl.

2. The quinine derivative and the pharmaceutically acceptable salt thereof according to claim 1, characterized in that: In formula (I), R1 is methyl or ethyl, R2 is ethyl or benzyl, and R1, R2 and the nitrogen atom connected thereto form a heterocyclic structure of One of them.

3. The quinine derivative and pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The quinine derivative represented by formula (I) is one of the following compounds:

4. Use of the quinine derivative and the pharmaceutically acceptable salt thereof according to claim 3 in treating or preventing diseases caused by acetylcholine deficiency or monoamine oxidase B overexpression.

5. The use according to claim 5, characterized in that: The disease caused by acetylcholine deficiency or monoamine oxidase B overexpression is Parkinson's disease or Alzheimer's disease.

6. The method for preparing the quinine derivative represented by formula (I) according to claim 1, comprising the following steps: Step (1): dissolving the raw material McBride's acid shown in Formula 1 in an organic solvent A, stirring at -5°C under nitrogen, and after slowly adding pyridine, dropwise adding the compound shown in Formula 2, reacting at -10 to 10°C for 0.5 to 3 hours, moving to room temperature and continuing stirring for 3 to 8 hours, then filtering the filtrate, washing with hydrochloric acid, extracting the aqueous phase with dichloromethane, combining the organic phases, and then washing with hydrochloric acid and saturated brine in sequence, drying the organic layer with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product A, and then dissolving the crude product A in anhydrous methanol and reacting at 50 to 65°C for 3 to 8 hours, and purifying the mixture A by petroleum ether / ethyl acetate silica gel column chromatography to obtain a compound shown in Formula 3; The molar ratio of the McLaughlin acid represented by Formula 1, pyridine, and the compound represented by Formula 2 is 1:1-3:1-3; The organic solvent A is selected from one or more of acetonitrile, dichloromethane, methanol, ethanol, and dichloromethane; the volume molar ratio of the organic solvent to the McLaughlin acid shown in Formula 1 is 1 to 3:1 mL / mmol; Step (2): reacting the compound of formula 3 obtained in step (1), p-toluenesulfonic acid monohydrate, and aniline reactants in an organic solvent B at 55 to 70° C. for 6 to 10 hours, then removing the solvent under reduced pressure to obtain a crude product B, which is dissolved in phenyl ether and refluxed for 40 minutes; cooling the obtained mixture B to room temperature overnight, filtering, taking the filter cake, further purifying it by silica gel column chromatography with petroleum ether / ethyl acetate, and drying it to obtain a compound of formula 4; The aniline reactant is one of aniline or p-methoxyaniline; The molar ratio of the compound represented by formula 3, p-toluenesulfonic acid monohydrate, and aniline reactants is 9-11:0.15-0.25:10-13; The organic solvent B is selected from one or more of acetonitrile, dichloromethane, methanol, ethanol, and hexane; Step (3): adding the compound of formula 4 obtained in step (2), anhydrous potassium carbonate, methyl iodide and organic solvent C into a first reaction container, reacting at 25 to 40° C. for 5 to 8 hours, then filtering, washing with water, and then extracting with ethyl acetate; Subsequently, the organic layer was dried over sodium sulfate, concentrated under reduced pressure to obtain a crude product C, which was purified by silica gel column chromatography using petroleum ether / ethyl acetate and dried to obtain a compound represented by Formula 5; The ratio of the compound represented by formula 4, anhydrous potassium carbonate and methyl iodide is 1-1.5:3-3.5:3-3.5; The organic solvent C is selected from one or more of acetonitrile, dichloromethane, methanol, ethanol, and DMF; Step (4): Add the compound represented by Formula 5 to a dried second reaction container, dissolve it with an organic solvent D, slowly drip boron tribromide into the second reaction container, stir the mixture at -30 to -10°C for 0.5 to 5 hours, move to 25 to 55°C for reaction for 3 to 8 hours, then quench with a saturated sodium bicarbonate solution, filter the filter cake, and separate and purify it with petroleum ether / ethyl acetate silica gel column chromatography to obtain the compound represented by Formula 6; The ratio of the compound represented by formula 5 to the boron tribromide substance is 2-3:6-8; The organic solvent D is selected from any one of ethanol, methanol, dichloromethane and acetonitrile; Step (5): adding the compound represented by Formula 6, anhydrous potassium carbonate, dibromoalkane and organic solvent E into a third reaction vessel and reacting at 30-56° C. for 4-9 hours; after the reaction, removing the solvent under reduced pressure to obtain a crude product E, and then purifying it with petroleum ether / ethyl acetate through silica gel column chromatography to obtain a compound represented by Formula 7; The ratio of the compound represented by formula 6, anhydrous potassium carbonate and dibromoalkane is 0.5:1-2:1-2; The organic solvent E is selected from one or more of acetonitrile, dichloromethane, methanol, ethanol, and acetone; Step (6): adding the compound represented by formula 7, anhydrous potassium carbonate, tetrahydropyrrole and organic solvent F into a fourth reaction vessel and reacting at 60-85° C. until completion; after the reaction, removing the solvent under reduced pressure to obtain a crude product, which is then purified by petroleum ether / ethyl acetate silica gel column chromatography to obtain a compound represented by formula (I); The ratio of the compound represented by formula 7, anhydrous potassium carbonate and tetrahydropyrrole is 0.4-0.6:1.5-2:1.5-2; The organic solvent F is selected from one or more of acetonitrile, dichloromethane, methanol and ethanol.

7. The method for preparing the quinine derivative represented by formula (I) according to claim 6, characterized in that: In step (6), the compound represented by formula 7, anhydrous potassium carbonate, tetrahydropyrrole, and organic solvent F are added and reacted at 60-85° C. for 7-12 hours.

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