CN110194764B - Amide compound, preparation method and application thereof - Google Patents

Amide compound, preparation method and application thereof Download PDF

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CN110194764B
CN110194764B CN201810159850.4A CN201810159850A CN110194764B CN 110194764 B CN110194764 B CN 110194764B CN 201810159850 A CN201810159850 A CN 201810159850A CN 110194764 B CN110194764 B CN 110194764B
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stereoisomer
pharmaceutically acceptable
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dichloromethane
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CN110194764A (en
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秦俊
刘自宁
苟铨
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Yunnan University YNU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention relates to an amide compound shown as a formula I, a stereoisomer orA pharmaceutically acceptable salt thereof. The amide compound, the stereoisomer or the pharmaceutically acceptable salt thereof can inhibit the generation of beta-amyloid protein, and can be used for preparing the anti-Alzheimer disease medicine. The invention also relates to a preparation method of the amide compound or the stereoisomer thereof.

Description

Amide compound, preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an amide compound for inhibiting beta-amyloid protein generation, a stereoisomer or pharmaceutically acceptable salt thereof, and a preparation method and application thereof.
Background
Alzheimer's Disease (AD), a progressively developing lethal neurodegenerative Disease, is characterized by a progressive deterioration in cognitive and memory functions, a progressive decline in daily living capacity, a progressive progression of patients to severe dementia, and finally death due to organ failure. It is statistically estimated that the number of Alzheimer's disease patients is four times as large as five million patients in China in the world, and the number of patients after 2050 years is expected to be four times as large as the number of patients before (Journal of Experimental Medicine, 2014, 46, 1007-1029). The development of the medicine for preventing and treating the Alzheimer disease has important social and medical significance.
The precursor protein (APP) is a transmembrane glycoprotein consisting of 770 amino acid residues (Nature, 1987, 325, 733-152; Nature, 1993, 361, 260-263). Beta-amyloid (A beta) is produced from precursor protein by proteolysis by beta-secretase (BACE1) and gamma-secretase (gamma-secretase) (Trends in Molecular Medicine, 2001, 7, 264-. Beta-amyloid is a polypeptide fragment (A beta 37-42) composed of 37-42 amino acids, is secreted by cells, has strong neurotoxic effect after cell matrix precipitation is accumulated, and is a cause of senile plaque peripheral neuron degeneration and death in the brain of Alzheimer disease patients. Among them, a β 42 has strong hydrophobicity, is easy to form precipitation polymerization, has strong neurotoxicity, and is considered to be a main cause of alzheimer disease in the medical field.
Inhibiting the production of beta-amyloid protein would likely treat or delay alzheimer's disease for the beta-amyloid hypothesis. Representative clinical in-research drugs include the β -secretase inhibitor Verubecestat (Merck, clinical stage iii), the γ -secretase inhibitor semagacetat (Eli Lilly, clinical stage iii), the γ -secretase modulator E-2012(Eisai, clinical stage i).
Figure GDA0003605533750000021
In view of the fact that no medicine capable of treating the Alzheimer disease exists in the market, the research and development of the anti-Alzheimer disease medicine capable of effectively inhibiting the generation of the beta-amyloid protein has great significance and market demand.
Disclosure of Invention
According to one aspect of the invention, the amide compound shown as the following general formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof is provided,
Figure GDA0003605533750000022
wherein n is 0, 1,2 or 3;
R 1 and R 2 Each independently hydrogen, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted 3 to 8 membered non aromatic heterocyclic hydrocarbyl, substituted or unsubstituted C 6 -C 12 Aryl, or substituted or unsubstituted C 4 -C 10 An aromatic heterocyclic group, wherein the substituent for substitution is selected from the group consisting of unsubstituted or halogen-substituted C 1 -C 12 Alkyl, unsubstituted or halogen-substituted C 1 -C 12 Alkoxy, unsubstituted or halogen-substituted C 6 -C 12 Aryl, halogen, nitro, cyano, unsubstituted or selected from C 1 -C 12 Carbamoyl substituted by 1 or 2 in the alkyl radical, C 1 -C 12 Alkoxy formyl radical, C 1 -C 12 Alkylsulfonyl, unsubstituted or substituted by C 1 -C 12 Aminosulfonyl substituted by 1 or 2 of alkyl, unsubstitutedSubstitute or quilt C 1 -C 12 Sulfonamido substituted by alkyl, unsubstituted or by C 1 -C 12 Alkoxy-substituted sulfonamido, phenylthio, C 1 -C 12 One or more, preferably 1,2,3,4 or 5, of alkylthio, said C 4 -C 10 The aromatic heterocyclic group and the 3 to 8-membered non-aromatic heterocyclic hydrocarbon group contain one or more heteroatoms selected from N, O and S, respectively;
preferably, R 1 And R 2 Each independently hydrogen, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted 3 to 6 membered non aromatic heterocyclic hydrocarbon group, substituted or unsubstituted phenyl or naphthyl, or substituted or unsubstituted C 4 -C 10 An aromatic heterocyclic group, wherein the substituent for substitution is selected from the group consisting of unsubstituted or halogen-substituted C 1 -C 10 Alkyl, unsubstituted or halogen-substituted C 1 -C 10 Alkoxy, unsubstituted or halogen-substituted phenyl or naphthyl, halogen, nitro, cyano, unsubstituted or substituted by a group selected from C 1 -C 10 Carbamoyl substituted by 1 or 2 in the alkyl radical, C 1 -C 10 Alkoxy formyl radical, C 1 -C 10 Alkylsulfonyl, unsubstituted or substituted by C 1 -C 10 Aminosulfonyl substituted by 1 or 2 of alkyl, unsubstituted or by C 1 -C 10 Sulfonamido substituted by alkyl, unsubstituted or by C 1 -C 10 Alkoxy-substituted sulfonamido, phenylthio, C 1 -C 10 One or more, preferably 1,2,3,4 or 5, of alkylthio, said C 4 -C 10 (ii) the heteroaromatic group and the 3-to 6-membered non-heteroaromatic hydrocarbon contain one or more heteroatoms selected from N, O and S, respectively;
preferably, R 1 And R 2 Each independently hydrogen, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted 3 to 6 membered non aromatic heterocyclic hydrocarbon group, substituted or unsubstituted phenyl or naphthyl, or substituted or unsubstituted C 4 -C 10 Aromatic heterocyclic group (preferably C) 4 -C 9 Aromatic heterocyclic group), wherein, for substitution, there may be mentionedThe substituent is 1,2,3,4 or 5 selected from methyl, ethyl, halogen, methoxy, ethoxy, methoxy formyl, ethoxy formyl, thiophenyl, nitro, cyano, methylthio and ethylthio, and C 4 -C 10 (ii) the heteroaromatic group and the 3-to 6-membered non-heteroaromatic hydrocarbon contain one or more heteroatoms selected from N, O and S, respectively;
preferably, R 1 And R 2 Each independently is 1,2,3,4 or 5 of hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl substituted ethyl, 4-fluorophenyl substituted ethyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted quinolyl and substituted or unsubstituted isoquinolyl, wherein the substituent used for substitution is selected from methyl, ethyl, halogen, methoxy, ethoxy, methoxy formyl, ethoxy formyl, thiophenyl, nitro, cyano, methylthio and ethylthio;
specifically, the amide compound shown in the general formula I or the stereoisomer thereof is selected from the following compounds:
Figure GDA0003605533750000041
according to another aspect of the present invention, there is provided a process for the preparation of a compound of formula I or a stereoisomer thereof, which process comprises:
step one
Figure GDA0003605533750000051
Slowly adding di-tert-butyl dicarbonate into a mixed system of a compound 1 and sodium hydroxide in tert-butyl alcohol/water while stirring at 0 ℃, slowly raising the temperature to room temperature, performing TLC monitoring reaction, performing reduced pressure rotary evaporation to remove an organic solvent to obtain a water-phase crude product, washing with petroleum ether, adjusting the pH to 6, extracting with ethyl acetate, combining extract liquor, drying the extract liquor with anhydrous sodium sulfate, and performing reduced pressure rotary evaporation to remove the solvent to obtain a white solid 2;
step two
Figure GDA0003605533750000052
The compound 2, the compound 3, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 4-dimethylaminopyridine are stirred and reacted in dichloromethane at room temperature, after the reaction is finished, concentrated hydrochloric acid is added into a reaction system, stirring is carried out for 30-60 minutes, 1N sodium hydroxide is used for adjusting the pH value of the system to be 6-7, an organic phase is separated, a water phase is extracted by dichloromethane, the organic phase is combined, anhydrous sodium sulfate is used for drying the organic phase, the solvent is removed by reduced pressure rotary evaporation to obtain a crude product, and the compound 4 is obtained by column chromatography separation;
step three
Figure GDA0003605533750000061
The compound 4, the compound 5, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 4-dimethylaminopyridine are stirred and reacted at room temperature in dichloromethane/N, N-dimethylformamide under the protection of nitrogen. After the reaction is finished, diluting the reaction system with dichloromethane, adjusting the pH value of the system to be 7-8 with saturated sodium bicarbonate solution, separating an organic phase and an aqueous phase, extracting the aqueous phase with dichloromethane, combining the organic extract phase, drying the organic extract phase with anhydrous sodium sulfate, removing the solvent by rotary evaporation under reduced pressure to obtain a crude product, and separating by column chromatography to obtain a compound I,
wherein, n, R 1 And R 2 Is as defined above.
In the present invention, in the case of the present invention,
said C is 6 -C 12 Aryl groups include, but are not limited to, phenyl, naphthyl, and 1,2,3, 4-tetrahydronaphthyl, and the like;
said C is 4 -C 10 By aromatic heterocyclic group is meant an aromatic heterocyclic ring system having 4-10 carbon atoms in the ring and containing one or more heteroatoms selected from N, O or S, including but not limited to pyridyl, pyrimidinyl, thienyl, furyl, thiazolyl, quinolinyl, isoquinolinylEtc.;
the 3 to 8-membered non-aromatic heterocyclic ring refers to a cyclic hydrocarbon ring containing no carbon-carbon double bond and containing one or more heteroatoms selected from N, O or S, examples of which include, but are not limited to, tetrahydrofuran, azetidine, azepane, tetrahydropyrrole, piperidine, morpholine, or the like;
said C is 1 -C 12 Alkyl means a straight or branched chain alkyl group having 1 to 12 carbon atoms, including without limitation methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and the like;
said C is 1 -C 12 Alkoxy means-O- (C) 1 -C 12 Alkyl) in which C 1 -C 12 Alkyl is as defined above, non-limiting examples include methoxy, ethoxy, propoxy, butoxy, and the like;
halogen means fluorine, chlorine, bromine, iodine, preferably fluorine and chlorine.
According to another aspect of the present invention, there is provided a use of the compound represented by the general formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for preparing a medicament for inhibiting β -amyloid production.
According to another aspect of the present invention, there is provided a use of the compound represented by the general formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for preparing an a β 42 inhibitor.
According to another aspect of the present invention, there is provided a use of the compound represented by the general formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for preparing a medicament for preventing and/or treating alzheimer's disease.
According to another aspect of the present invention, there is provided a use of the compound represented by the general formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an a β 42 inhibitor for the preparation of a medicament for the prevention and/or treatment of alzheimer's disease.
Advantageous effects
The compound provided by the invention can inhibit the generation of beta-amyloid, particularly has an obvious effect of inhibiting A beta 42, wherein the inhibition rate of a part of the compound on the A beta 42 production of cells even reaches 100%, and can reach the inhibition rate equivalent to that of the existing E-2012, so that the compound can be developed into a medicament for treating or delaying Alzheimer's disease.
Detailed Description
Preparation example 1 preparation of Compound 6a
Figure GDA0003605533750000071
(S) -1- (3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzoyl) -N-phenylpyrrolidine-2-carboxamide (6a)
Step one
Figure GDA0003605533750000081
To a 100ml round bottom flask were added L-proline 1a (3.0g, 26.06mmol), sodium hydroxide (1.2g, 28.66mmol) and tert-butanol/water (20ml/20ml), respectively. Di-tert-butyl dicarbonate (6.3g, 28.66mmol) is slowly added to the reaction system with stirring and cooling at 0 ℃ and the temperature is then slowly raised to room temperature. After completion of the reaction by TLC, t-butanol was removed by rotary evaporation under reduced pressure to give a crude aqueous phase, which was washed three times with petroleum ether (3 × 30ml), then adjusted to pH 6 with 1N hydrochloric acid, and extracted with ethyl acetate (3 × 50 ml). The combined ethyl acetate extracts were dried over anhydrous sodium sulfate and the solvent removed by rotary evaporation under reduced pressure to give 2a as a white solid (5.49g, 98% yield).
Step two
Figure GDA0003605533750000082
To a 100ml round-bottomed flask were added compound 2a (415.8mg, 1.93mmol), aniline 3a (150.0mg, 1.61mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (370.6mg, 1.93mmol), 4-dimethylaminopyridine (39.4mg, 0.32mmol) and methylene chloride (30ml), respectively, and the reaction was stirred at room temperature. After completion of the reaction by TLC detection, 5ml of concentrated hydrochloric acid was added to the reaction system and stirred for 30 minutes. The reaction was then transferred to a separatory funnel and the pH of the system was adjusted to 6-7 with 1N sodium hydroxide. After separation of the organic and aqueous phases, the aqueous phase was extracted three times with dichloromethane (3 × 30ml), the combined organic phases were dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporation under reduced pressure to give the crude product, which was separated by column chromatography using dichloromethane/methanol (10/1) as eluent to give product 4a (293.9mg, 96% yield).
Step three
Figure GDA0003605533750000091
To a 25mL round-bottom flask were added compound 4a (60.0mg, 0.32mmol), compound 5(80.6mg, 0.35mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (90.8mg, 0.47mmol), 4-dimethylaminopyridine (7.7mg, 0.063mmol) and dichloromethane/N, N-dimethylformamide (5mL/1mL), respectively, and the reaction was stirred at room temperature under nitrogen. After completion of the reaction by TLC, the reaction system was diluted with dichloromethane and transferred to a separatory funnel, and the pH of the system was adjusted to 7 to 8 with a saturated sodium bicarbonate solution. The organic and aqueous phases were separated, the aqueous phase was extracted three times with dichloromethane (3 × 30ml), the combined organic phases were dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporation under reduced pressure to give the crude product, which was separated by column chromatography using dichloromethane/methanol (10/1) as eluent to give product 6a (121.1mg, 95% yield).
1 H NMR(300MHz，CDCl 3 ，ppm)：δ＝9.45(s，1H)，7.73(s，1H)，7.56(d，J＝8.1Hz，2H)，7.31–7.23(m，3H)，7.18(d，J＝8.1Hz，1H)，7.10–7.05(m，1H)，6.94(s，1H)，4.96(q，J＝5.1Hz，1H)，3.89(s，3H)，3.64–3.59(m，2H)，2.65–2.60(m，1H)，2.30(s，3H)，2.17–2.08(m，2H)，1.96–1.90(m，1H)； 13 C NMR(75MHz，CDCl 3 ，ppm)：δ＝170.4，168.7，152.3，138.3，136.9，135.9，128.9，128.4，124.8，124.1，119.8，116.3，111.7，61.0，56.2，50.7，26.8，25.5，13.6。
Preparation example 2 preparation of Compound 6b
Figure GDA0003605533750000092
(S) -N- (4-chlorophenyl) -1- (3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzoyl) pyrrolidine-2-carboxamide (6b)
Except that in step two compound 3a is added
Figure GDA0003605533750000101
Replacement by 3b
Figure GDA0003605533750000102
Except that, compound 6b (75%) was prepared in a similar manner to preparation example 1.
1 H NMR(300MHz，CDCl 3 ，ppm)：δ＝9.63(s，1H)，7.74(s，1H)，7.48(d，J＝6.9Hz，2H)，7.30(t，J＝8.1Hz，2H)，7.24–7.19(m，4H)，6.95(s，1H)，4.96(q，J＝5.4Hz，1H)，3.90(s，3H)，3.69–3.56(m，2H)，2.59(s，1H)，2.30(s，3H)，2.20–2.03(m，2H)，1.97–1.91(m，1H)； 13 C NMR(75MHz，CDCl 3 ，ppm)：δ＝170.4，168.9，152.3，138.3，136.9，135.7，128.8，128.5，124.8，120.9，119.9，116.3，111.7，61.0，56.2，50.9，27.2，25.5，13.7。
Preparation example 3 preparation of Compound 6c
Figure GDA0003605533750000103
(S) -1- (3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzoyl) -N- (p-tolyl) pyrrolidine-2-carboxamide (6c)
Except that in step two compound 3a is added
Figure GDA0003605533750000104
Substitution to 3c
Figure GDA0003605533750000105
Compound 6c (88%) was prepared in a similar manner to preparation example 1.
1 H NMR(300MHz，CDCl 3 ，ppm)：δ＝9.42(s，1H)，7.73(s，1H)，7.45(d，J＝8.7Hz，2H)，7.29(d，J＝8.1Hz，1H)，7.24(s，1H)，7.18(d，J＝7.8Hz，1H)，7.06(d，J＝8.1Hz，2H)，6.94(s，1H)，4.94(t，J＝7.8Hz，1H)，3.89(s，3H)，3.68–3.59(m，2H)，2.55(s，1H)，2.29(s，6H)，2.16–2.13(m，2H)，1.94–1.90(m，1H)； 13 C NMR(75MHz，CDCl 3 ，ppm)：δ＝170.1，168.8，152.2，138.2，136.9，136.0，135.7，133.6，129.3，128.3，124.7，119.9，119.8，116.3，111.7，60.9，56.1.50.7，27.2，25.5，20.8，13.6。
Preparation example 4 preparation of Compound 6d
Figure GDA0003605533750000111
(S) -methyl 3-methoxy-4- (1- (3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzoyl) pyrrolidine-2-carboxamido) benzoate (6d)
Except that in step two compound 3a is added
Figure GDA0003605533750000112
Replacement by 3d
Figure GDA0003605533750000113
Except that, compound 6d (70%) was prepared in a similar manner to preparation example 1.
1 H NMR(300MHz，CDCl 3 ，ppm)：δ＝9.26(s，1H)，8.47(d，J＝8.4Hz，1H)，7.75(s，1H)，7.66(d，J＝8.4Hz，1H)，7.52(s，1H)，7.34–7.23(m，3H)，6.97(s，1H)，4.97(m，1H)，3.91–3.89(m，9H)，3.74–3.63(m，2H)，2.50–2.44(m，1H)，2.30–2.11(m，5H)，1.99–1.93(m，1H)； 13 C NMR(75MHz，CDCl 3 ，ppm)：δ＝169.7，169.5，152.2，147.7，138.1，136.8，35.9，132.0，128.2，125.1，124.6，123.1，119.8，118.7，116.3，111.8，110.8，61.2，56.1，53.5，52.0，50.6，28.0，25.5，13.6。
Preparation example 5 preparation of Compound 6e
Figure GDA0003605533750000114
(S) -methyl 4- (1- (3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzoyl) pyrrolidine-2-amido) benzoate (6e)
Except that in step two compound 3a is added
Figure GDA0003605533750000115
Replacement by 3e
Figure GDA0003605533750000116
Otherwise, compound 6e (87%) was prepared in a similar manner to preparation example 1.
1 H NMR(300MHz，CDCl 3 ，ppm)：δ＝9.85(s，1H)，7.92(d，J＝7.2Hz，2H)，7.75(s，1H)，7.61(d，J＝8.7Hz，2H)，7.31(d，J＝7.8Hz，1H)，7.27–7.19(m，2H)，6.95(s，1H)，4.98(q，J＝5.1Hz，1H)，3.91–3.89(m，6H)，3.67–3.61(m，2H)，2.60(s，1H)，2.30(s，3H)，2.18–2.13(m，3H)，1.98–1.92(m，1H)； 13 C NMR(75MHz，CDCl 3 ，ppm)：δ＝170.3，169.4，166.6，152.1，142.7，137.9，136.8，136.0，130.4，128.1，124.9，124.7，119.9，118.8，116.4，111.7，61.2，56.1，53.5，51.9，50.8，28.7，25.4，13.5。
Preparation example 6 preparation of Compound 6f
Figure GDA0003605533750000121
(S) -1- (3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzoyl) -N- (3,4, 5-trifluorophenyl) pyrrolidine-2-carboxamide (6f)
Except that in step two compound 3a is added
Figure GDA0003605533750000122
Replacement by 3f
Figure GDA0003605533750000123
Except that, compound 6f (89%) was prepared in a similar manner to preparation example 1.
1 H NMR(300MHz，CDCl 3 ，ppm)：δ＝10.19(s，1H)，7.77(s，1H)，7.34(d，J＝8.1Hz，1H)，7.29–7.19(m，4H)，6.98(s，1H)，4.91(q，J＝5.1Hz，1H)，3.93(s，3H)，3.77–3.72(m，1H)，3.69–3.63(m，1H)，2.38–2.31(m，4H)，2.26–2.15(m，2H)，1.99–1.93(m，1H)； 13 C NMR(75MHz，CDCl 3 ，ppm)：δ＝169.9，169.8，152.3，138.2，136.9，135.8，134.3，134.2，128.5，124.9，119.9，116.4，111.6，104.0，103.6，61.2，56.1，50.9，28.5，25.4，13.6。
Preparation of 6g of Compound 7 example
Figure GDA0003605533750000131
(S) -1- (3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzoyl) -N- (naphthalen-1-yl) pyrrolidine-2-carboxamide (6g)
Except that in step two compound 3a is added
Figure GDA0003605533750000132
Replacement is 3g
Figure GDA0003605533750000133
Otherwise, compound 6g (92%) was prepared in a similar manner to preparation example 1.
1 H NMR(300MHz，CDCl 3 ，ppm)：δ＝9.85(s，1H)，8.16–8.11(m，2H)，7.83(d，J＝7.8Hz，1H)，7.72(s，1H)，7.65(d，J＝8.4Hz，1H)，7.51–7.43(m，3H)，7.29–7.24(m，2H)，7.17(d，J＝8.1Hz，1H)，6.93(s，1H)，5.16–5.12(m，1H)，3.86(m，3H)，3.61–3.65(m，2H)，2.72–2.68(m，1H)，2.29(s，3H)，2.19–2.10(m，2H)，1.97–1.92(m，1H)； 13 C NMR(75MHz，CDCl 3 ，ppm)：δ＝170.6，169.3，152.3，138.2，136.9，136.0，134.1，133.1，128.6，128.3，126.4，125.9，125.7，124.8，121.1，119.7，116.3，111.6，60.9，56.1，50.6，26.9，25.5，13.7。
Preparation example 8 preparation of Compound 6h
Figure GDA0003605533750000134
(S) -1- (3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzoyl) -N- (4-methoxyphenyl) pyrrolidine-2-carboxamide (6H)
Except that in step two compound 3a is added
Figure GDA0003605533750000135
Replacement is carried out for 3h
Figure GDA0003605533750000136
Compound 6h (88%) was prepared in a similar manner to preparation example 1.
1 H NMR(300MHz，CDCl 3 ，ppm)：δ＝9.30(s，1H)，7.73(s，1H)，7.47(d，J＝8.7Hz，2H)，7.30(d，J＝8.1Hz，1H)，7.24–7.17(m，2H)，6.94(s，1H)，6.80(d，J＝9.0Hz，2H)，4,96–4.92(m，1H)，3.89(m，3H)，3.77(s，1H)，3.68–3.57(m，2H)，2.62–2.56(m，1H)，2.29(s，3H)，2.21–2.13(m，3H)，1.95–1.89(m，1H)； 13 C NMR(75MHz，CDCl 3 ，ppm)：δ＝170.3，168.5，156.2，152.3，138.3，136.9，136.0，131.4，128.4，124.8，121.4，119.9，116.3，114.1，111.7，60.9，56.2，55.5，50.7，27.1，25.5，13.6。
Preparation example 9 preparation of Compound 6i
Figure GDA0003605533750000141
(S) -N- ((S) -1- (4-fluorophenyl) ethyl) -1- (3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzoyl) pyrrolidine-2-carboxamide (6i)
Except that in step two compound 3a is added
Figure GDA0003605533750000142
Is replaced by 3i
Figure GDA0003605533750000143
Except that, compound 6i (86%) was prepared in a similar manner to preparation example 1.
1 H NMR(300MHz，CDCl 3 ，ppm)：δ＝7.74(s，1H)，7.34–7.28(m，4H)，7.18(d，J＝7.8Hz，1H)，7.04–6.99(m，2H)，6.94(s，1H)，5.09–5.05(m，1H)，4.73–4.69(m，1H)，3.90(m，3H)，3.66–3.53(m，2H)，2.44–2.39(m，1H)，2.30(s，3H)，2.11–2.06(m，2H)，1.87–1.83(m，1H)，1.49–1.43(m，3H)； 13 C NMR(75MHz，CDCl 3 ，ppm)：δ＝170.0，169.9，163.7，160.3，152.3，139.3，138.1，136.9，136.2，127.8，127.7，124.8，119.8，116.3，115.6，115.3，111.6，60.2，56.1，50.7，48.6，27.4，25.5，22.2，13.6。
Preparation example 10 preparation of Compound 6j
Figure GDA0003605533750000151
(S) -N- (4-fluorophenyl) -1- (3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzoyl) pyrrolidine-2-carboxamide (6j)
Except that in step two compound 3a is added
Figure GDA0003605533750000152
Is replaced by 3j
Figure GDA0003605533750000153
Except that, compound 6j (79%) was prepared in a similar manner to preparation example 1.
1 H NMR(300MHz，CDCl 3 ，ppm)：δ＝9.62(d，J＝6.3Hz，1H)，7.74(s，1H)，7.49(q，J＝4.2Hz，2H)，7.30(d，J＝7.8Hz，1H)，7.25–7.20(m，2H)，6.95–6.89(m，3H)，4.98–4.93(m，1H)，3.90(m，3H)，3.71–3.60(m，2H)，2.56–2.51(m，1H)，2.30(s，3H)，2.22–2.13(m，2H)，1.97–1.91(m，1H)； 13 C NMR(75MHz，CDCl 3 ，ppm)：δ＝170.1，169.0，160.8，157.5，152.3，138.3，136.9，135.9，134.3，128.4，124.8，121.4，121.3，119.9，116.3，115.5，115.2，111.7，60.0，56.2，50.8，27.5，25.5，13.6。
Preparation of Compound 6k of EXAMPLE 11
Figure GDA0003605533750000154
(S) -1- (3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzoyl) -N-methyl-N-phenylpyrrolidine-2-carboxamide (6k)
Except that in step two compound 3a is reacted
Figure GDA0003605533750000155
Replacement is by 3k
Figure GDA0003605533750000156
In addition, compound 6k (77%) was prepared in a similar manner to preparation example 1.
1 H NMR(300MHz，CDCl 3 ，ppm)：δ＝7.73(s，1H)，7.47(d，J＝4.2Hz，4H)，7.40–7.38(m，1H)，7.30–7.27(m，1H)，7.25–7.23(m，2H)，6.94(s，1H)，4.57(t，J＝4.2Hz，1H)，3.88(s，3H)，3.79–3.70(m，1H)，3.56–3.49(m，1H)，3.33(s，1H)，2.30(s，3H)，2.13–2.02(m，1H)，1.99–1.95(m，2H)，1.78–1.72(m，1H)； 13 C NMR(75MHz，CDCl 3 ，ppm)：δ＝172.0，168.0，152.1，143.4，138.1，136.9，136.6，129.9，128.1，128.0，127.8，124.5，119.9，116.3，111.9，57.7，56.1，50.5，37.7，29.7，25.6，13.7。
Preparation example 12 preparation of 6l Compound
Figure GDA0003605533750000161
(S) -methyl 2- (1- (3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzoyl) pyrrolidine-2-amido) benzoate (6l)
Except that in step two compound 3a is added
Figure GDA0003605533750000162
Replacement by 3l
Figure GDA0003605533750000163
Except that, compound 6l (72%) was prepared in a similar manner to preparation example 1.
1 H NMR(300MHz，CDCl 3 ，ppm)：δ＝11.64(s，1H)，8.78(d，J＝8.4Hz,1H)，8.04–7.98(m，2H)，7.58–7.48(m，3H)，7.36(d，J＝7.8Hz，1H)，7.12–7.09(m，1H)，6.964(s，1H)，4.87(t，J＝4.2Hz，1H)，3.93(s，3H)，3.90(s，3H)，3.70–3.65(m，1H)，2.47–2.38(m，1H)，2.33–2.21(m，5H)，2.14–2.04(m，1H)，2.00–1.93(m，1H)； 13 C NMR(75MHz，CDCl 3 ，ppm)：δ＝170.7，169.8，168.8，152.1，141.2，136.9，136.7，134.7，130.8，127.7，124.6，122.8，120.6，120.4，116.7，115.2，112.4，62.6，56.2，52.3，50.7，30.0，25.5，13.0。
Preparation example 13 preparation of Compound 6m
Figure GDA0003605533750000171
(S) -1- (3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzoyl) -N- (2- (phenylthio) phenyl) pyrrolidine-2-carboxamide (6m)
Except that in step two compound 3a is added
Figure GDA0003605533750000172
Replacement is 3m
Figure GDA0003605533750000173
Except that, compound 6m (75%) was prepared in a similar manner to preparation example 1.
1 H NMR(300MHz，CDCl 3 ，ppm)：δ＝9.23(s，1H)，8.50(d，J＝8.4Hz,1H)，7.76(s，1H)，7.56–7.46(m,2H)，7.23–6.96(m，10H)，4.82(t，J＝5.7Hz，1H)，3.87(s，3H)，3.48(s，2H)，2.31(s，3H)，2.14–2.09(m，2H)，1.83–1.81(m，2H)； 13 C NMR(75MHz，CDCl 3 ，ppm)：δ＝169.9，169.5，152.2，139.7，138.2，136.9，136.4，135.8，131.0，129.3，128.3，127.0，126.2，124.9，124.5，121.1，120.4，120.0，116.3，112.0，61.5，56.2，50.6，28.6，25.3，13.7。
Preparation example 14 preparation of Compound 6n
Figure GDA0003605533750000174
(S) -1- (3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzoyl) -N- (pentafluorophenyl) pyrrolidine-2-carboxamide (6N)
Except that in step two compound 3a is added
Figure GDA0003605533750000181
Is replaced by 3n
Figure GDA0003605533750000182
In addition, compound 6n (65%) was prepared in a similar manner to preparation example 1.
1 H NMR(300MHz，CDCl 3 ，ppm)：δ＝9.65(s，1H)，8.23(s，1H)，7.33(d，J＝8.1Hz，1H)，7.21(s，1H)，7.12(d，J＝7.8Hz，1H)，6.99(s，1H)，5.11–5.07(m，1H)，3.88(s，3H)，3.67–3.59(m，2H)，2.59–2.53(m，1H)，2.35(s，3H)，2.29–2.12(m，2H)，2.00–1.94(m，1H)； 13 C NMR(75MHz，CDCl 3 ，ppm)：δ＝170.0，152.3，144.5，141.3，139.5，136.9，136.6，136.3，127.5，125.0，119.7，116.9，112.3，112.1，111.5，60.1，56.2，50.6，27.4，25.5，12.7。
Preparation of Compound 6o of EXAMPLE 15
Figure GDA0003605533750000183
(2S) -1- (3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzoyl) -N- (1-phenylethyl) pyrrolidine-2-carboxamide (6o)
Except that in step two compound 3a is reacted
Figure GDA0003605533750000184
Replacement by 3o
Figure GDA0003605533750000185
Except that, compound 6o (85%) was prepared in a similar manner to preparation example 1.
1 H NMR(300MHz，CDCl 3 ，ppm)：δ＝7.73(s，1H)，7.34–7.27(m，6H)，7.23(s，1H)，7.19–7.17(m，1H)，6.95(s，1H)，5.13–5.08(m，1H)，4,74–4.70(m，1H)，3.89(s，3H)，3.67–3.61(m，1H)，3.56–3.52(m，1H)，2.41–2.38(m，1H)，2.30(s，3H)，2.17–2.04(m，2H)，1.87–1.83(m，1H)，1.49(d，J＝6.9Hz，3H)； 13 C NMR(75MHz，CDCl 3 ，ppm)：δ＝170.0，169.8，152.3，143.4，138.2，136.9，136.3，128.7，128.2，127.2，126.1，124.7，119.9，116.3，111.6，60.2，56.1，50.7，49.2，27.5，25.6，22.2，13.7。
Preparation example 16 preparation of Compound 6p
Figure GDA0003605533750000191
(S) -1- (3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzoyl) -N- (4-nitrophenyl) pyrrolidine-2-carboxamide (6p)
Except that in step two compound 3a is added
Figure GDA0003605533750000192
Replacement by 3p
Figure GDA0003605533750000193
Except that, compound 6p (79%) was prepared in a similar manner to preparation example 1.
1 H NMR(300MHz，CDCl 3 ，ppm)：δ＝10.51(s，1H)，8.00(d，J＝9.0Hz，2H)，7.79(s，1H)，7.63(d，J＝9.0Hz，2H)，7.35(d，J＝8.1Hz，1H)，7.29(d，J＝3.0Hz，2H)，6.99(s，1H)，5.04–4.99(m，1H)，3.93(s，3H)，3.81–3.70(m，1H)，3.69–3.67(m，1H)，2.46–2.31(m，1H)，2.27–2.17(m，5H)，2.05–1.96(m，1H)； 13 C NMR(75MHz，CDCl 3 ，ppm)：δ＝170.3，169.9，152.2，144.4，143.0，138.1，136.9，135.6，128.5，124.9，124.6，120.0，119.0，116.4，111.6，61.4，56.2，51.0，28.4，25.5，13.6。
Preparation example 17 preparation of Compound 6q
Figure GDA0003605533750000194
(S) -1- (3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzoyl) -N- (quinolin-8-yl) pyrrolidine-2-carboxamide (6q)
Except that in step two compound 3a is added
Figure GDA0003605533750000201
Replacement by 3q
Figure GDA0003605533750000202
Except that, compound 6q (80%) was prepared in a similar manner to preparation example 1.
1 H NMR(300MHz，CDCl 3 ，ppm)：δ＝10.61(s，1H)，8.78(s，2H)，8.13(d，J＝8.1Hz，1H)，7.78(s，1H)，7.55–7.32(m，6H)，6.99(s，1H)，5.08–5.03(m，1H)，3.89(s，3H)，3.69–3.66(m，1H)，2.44–2.38(m，2H)，2.32(s，1H)，2.21–2.12(m，2H)，2.02–1.96(m，1H)； 13 C NMR(75MHz，CDCl 3 ，ppm)：δ＝169.8，169.7，152.2，148.3，138.6，138.1，136.9，136.4，136.3，134.1，128.2，127.9，127.3，124.6，121.9，121.7，120.1，116.5，116.4，112.0，61.7，56.2，50.7，29.4，25.6，13.7。
Preparation of Compound 6r of EXAMPLE 18
Figure GDA0003605533750000203
(S) -1- (3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzoyl) -N- (3-nitrophenyl) pyrrolidine-2-carboxamide (6r)
Except that in step two compound 3a is reacted
Figure GDA0003605533750000204
Is replaced by 3r
Figure GDA0003605533750000205
Except that, compound 6r (78%) was prepared in a similar manner to preparation example 1.
1 H NMR(300MHz，CDCl 3 ，ppm)：δ＝10.32(s，1H)，8.40(s，1H)，7.79(s，1H)，7.75–7.69(m，2H)，7.36(d，J＝8.1Hz，2H)，7.30–7.21(m，2H)，6.98(s，1H)，5.04–4.99(m，1H)，3.95(s，3H)，3.81–3.71(m，1H)，3.69–3.65(m，1H)，2.39–2.31(m，5H)，2.28–2.18(m，1H)，2.02–1.96(m，1H)； 13 C NMR(75MHz，CDCl 3 ，ppm)：δ＝170.3，169.8，152.4，148.2，139.6，138.1，136.9，135.9，129.3，128.4，124.9，124.8，119.8，118.1，116.4，114.1，111.6，61.3，56.3，51.0，28.9，25.4，13.6。
Preparation example 19 preparation of Compound 6s
Figure GDA0003605533750000211
(S) -1- (3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzoyl) -N- (2- (methylthio) phenyl) pyrrolidine-2-carboxamide (6S)
Except that in step two compound 3a is added
Figure GDA0003605533750000212
Substitution to 3s
Figure GDA0003605533750000213
Except that, compound 6s (66%) was prepared in a similar manner to preparation example 1.
1 H NMR(300MHz，CDCl 3 ，ppm)：δ＝9.34(s，1H)，8.34(d，J＝8.1Hz，1H)，7.78(s，1H)，7.47(d，J＝7.8Hz，1H)，7.35–7.28(m，4H)，7.08(t，J＝7.8Hz，1H)，6.97(s，1H)，4.96(q，J＝5.7Hz，1H)，3.90(s，3H)，3.78–74(m，1H)，3.66–3.62(m，1H)，2.46–2.42(m，1H)，2.33–2.26(m，7H)，2.16–2.10(m，1H)，1.96–1.954(m，1H)； 13 C NMR(75MHz，CDCl 3 ，ppm)：δ＝170.1，169.5，152.2，138.1，136.8，136.0，132.9，128.9，128.3，125.9，124.7，120.9，116.4，111.9，61.4，56.2，50.7，28.6，25.6，18.9，13.6。
Preparation example 20 preparation of Compound 6t
Figure GDA0003605533750000214
(S) -1- (3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzoyl) -N- (2-nitrophenyl) pyrrolidine-2-carboxamide (6t)
Except that in step two compound 3a is reacted
Figure GDA0003605533750000215
Replacement by 3t
Figure GDA0003605533750000216
In addition, the method and the preparationCompound 6t (65%) was prepared in a similar manner to example 1.
1 H NMR(300MHz，CDCl 3 ，ppm)：δ＝11.12(s，1H)，8.87(d，J＝8.7Hz，1H)，8.24(d，J＝7.8Hz，1H)，7.76(s，1H)，7.71–7.65(m，1H)，7.44(s，1H)，7.39–7.32(m，2H)，7.24–7.19(m，1H)，6.97(s，1H)，4.92(t，J＝6.6Hz，1H)，3.94(s，3H)，3.89–3.83(m，1H)，3.74–3.67(m，1H)，2.48–2.42(m，1H)，2.34–2.25(s，4H)，2.15–2.06(m，1H)，2.03–1.97(m，1H)； 13 C NMR(75MHz，CDCl 3 ，ppm)：δ＝170.8，152.2，138.2，136.9，136.5，136.2，135.5，134.7，128.5，125.8，124.7，123.6，122.2，120.2，116.3，112.1，62.5，56.2，50.9，29.7，25.6，13.7。
Preparation of Compound 6u of EXAMPLE 21
Figure GDA0003605533750000221
(S) -methyl 3- (1- (3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzoyl) pyrrolidine-2-amido) benzoate (6u)
Except that in step two compound 3a is reacted
Figure GDA0003605533750000222
Replacement is by 3u
Figure GDA0003605533750000223
Except that, compound 6u (80%) was prepared in a similar manner to preparation example 1.
1 H NMR(300MHz，CDCl 3 ，ppm)：δ＝9.97(s，1H)，8.17(s，1H)，7.78–7.73(m，2H)，7.66(d，J＝4.8Hz，1H)，7.32(d，J＝8.1Hz，2H)，7.24(d，J＝8.1Hz，2H)，6.97(s，1H)，4.97(t，J＝4.8Hz，1H)，3.91(s，3H)，3.88(s，3H)，3.75–3.69(m，1H)，3.66–3.60(m，1H)，2.44–2.42(m，1H)，2.30(s，3H)，2.26–2.14(m，2H)，2.94–1.90(m，1H)； 13 C NMR(75MHz，CDCl 3 ，ppm)：δ＝169.7，166.8，152.2，138.6，138.0，136.9，136.1，130.5，128.8，128.2，124.8，124.7，123.9，120.5，119.8，116.4，111.6，61.1，56.2，53.5，52.1，50.8，28.4，25.4，13.6。
Experimental examples
Unless otherwise indicated, the methods and apparatus employed below are those conventional in the art.
A biological activity screening method for inhibiting mouse neuroma blast from generating Abeta 42 by using the compound comprises the following steps:
N2a-APP695 Swe is a mouse neuroma blast (gift of Beijing university) which stably transfers a Swedish mutant gene APP 695.
At 3.5X 10 5 Density of individual cells/well, N2a-APP695 Swe The cells were seeded into 12-well cell culture plates and cultured using N2a-APP695 Swe The cells are cultured in serum-free or low-serum culture medium.
The morphology and growth of the cells were observed by light microscopy, after the cells grew to capacity in the wells, an equal volume of solvent control DMSO, positive control E-2012 (prepared according to the method of WO 2005115990) or screening compound (concentration 1.0 μ M) was added to each well of cells and treated in a 37 ℃ cell incubator for 24 hours.
After 24 hours of compound treatment, the morphology and growth of cells in each well was observed, and a 1.5ml centrifuge tube was placed on ice for cooling, and then 4. mu.l protease inhibitor (50X) was added thereto, and then 200. mu.l of the culture supernatant was taken out of the well, added to the 1.5ml centrifuge tube, mixed well, and placed on ice.
The medium supernatant was centrifuged at 2000rpm for 5min at 4 ℃ and 150. mu.l of the supernatant was taken in a new 1.5ml centrifuge tube and placed on ice.
50 mu l of culture medium supernatant is taken, the content of Abeta 42 secreted by cells into the culture medium supernatant is detected by using a Human Abeta 42 ELISA Kit, and the effect of the screening compound for inhibiting the generation of Abeta 42 is evaluated by referring to a solvent control group.
Table 1: inhibition of cell production of Abeta 42 by compounds
Compound numbering Inhibition ratio (%) of A.beta.42 production by cells with 1. mu.M concentration of the compound
6b 100
6f 100
6g 85
6i 100
6j 50
6m 100
6n 10
6r 40
E-2012 (Positive control) 100
DMSO (solvent control) 0

Claims (7)

1. Amide compounds shown as the following general formula I, stereoisomers thereof or pharmaceutically acceptable salts thereof,
Figure FDA0003605533740000011
wherein n is 1;
R 1 and R 2 One of which is hydrogen and the other is 4-fluorophenyl-substituted ethyl, phenyl substituted with 1,2 or 3 substituents selected from halogen, phenylthio-substituted phenyl, or naphthyl.
2. The amide-based compound according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the amide-based compound or the stereoisomer thereof is selected from the following compounds:
Figure FDA0003605533740000012
3. the process for producing an amide-based compound or a stereoisomer thereof according to claim 1 or 2, wherein the process comprises:
step one
Figure FDA0003605533740000013
Slowly adding di-tert-butyl dicarbonate into a mixed system of a compound 1 and sodium hydroxide in tert-butyl alcohol/water while stirring at 0 ℃, slowly raising the temperature to room temperature, performing TLC monitoring reaction, performing reduced pressure rotary evaporation to remove an organic solvent to obtain a water-phase crude product, washing with petroleum ether, adjusting the pH to 6, extracting with ethyl acetate, combining extract liquor, drying the extract liquor with anhydrous sodium sulfate, and performing reduced pressure rotary evaporation to remove the solvent to obtain a white solid 2;
step two
Figure FDA0003605533740000021
The compound 2, the compound 3, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 4-dimethylaminopyridine are stirred and reacted in dichloromethane at room temperature, after the reaction is finished, concentrated hydrochloric acid is added into a reaction system, stirring is carried out for 30-60 minutes, 1N sodium hydroxide is used for adjusting the pH value of the system to be 6-7, an organic phase is separated, a water phase is extracted by dichloromethane, the organic phase is combined, the organic phase is dried by anhydrous sodium sulfate, the solvent is removed by reduced pressure rotary evaporation to obtain a crude product, and the crude product is separated by column chromatography to obtain a compound 4;
step three
Figure FDA0003605533740000022
Stirring compound 4, compound 5, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 4-dimethylaminopyridine in dichloromethane/N, N-dimethylformamide under the protection of nitrogen at room temperature for reaction, after the reaction is finished, diluting the reaction system with dichloromethane, adjusting the pH of the system to 7-8 with saturated sodium bicarbonate solution, separating an organic phase and an aqueous phase, extracting the aqueous phase with dichloromethane, combining the organic extraction phases, drying the extraction phase with anhydrous sodium sulfate, removing the solvent by reduced pressure rotary evaporation to obtain a crude product, and performing column chromatography separation to obtain compound I,
wherein, n, R 1 And R 2 Is as defined in claim 1 or 2.
4. Use of a compound of claim 1 or 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting β -amyloid production.
5. Use of a compound of claim 1 or 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of an a β 42 inhibitor.
6. Use of a compound according to claim 1 or 2, a stereoisomer thereof or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention and/or treatment of alzheimer's disease.
7. Use of a compound according to claim 1 or 2, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an a β 42 inhibitor for the manufacture of a medicament for the prevention and/or treatment of alzheimer's disease.
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