Dihydropyrimidine[4,5-d]pyrimidine-2(h)-one nrf2 activators and methods of making and using the same

Abstract

The application discloses a dihydropyrimidine[4,5-d]pyrimidine-2(H)-ketone Nrf2 activator and a preparation method and application thereof. The compound has the following structural general formula: experiments prove that the compound can effectively activate the Nrf2 signal pathway to produce an antioxidative stress effect, thereby protecting nerve cells, and can be used for preventing and / or treating neurodegenerative diseases.

Description

Technical Field

[0001] This invention relates to a class of dihydropyrimidine[4,5-d]pyrimidine-2(H)-one Nrf2 activators, their preparation methods and uses, belonging to the field of chemical and pharmaceutical industries. Background Technology

[0002] Neurodegenerative diseases are a group of diseases characterized by degenerative changes in central nervous system tissues, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis. Pathologically, neurodegenerative diseases all exhibit alterations in tissue redox balance and glial cell activation; therefore, oxidative stress is considered to play a crucial role in the pathogenesis of these diseases. Studies have shown that when the degree of oxidative stress exceeds the cellular antioxidant capacity, it leads to excessive accumulation of oxidants and a reduction in reductants, placing cells in a state of oxidative stress. The resulting reactive oxygen species (ROS) trigger oxidative damage to proteins, lipids, and nucleic acids, leading to impaired cell function and even cell death. This oxidative damage is considered one of the important factors in the occurrence and development of neurodegenerative diseases. Traditionally, exogenous small-molecule antioxidants have been widely used to treat oxidative stress-related diseases, including neurodegenerative diseases. However, recent studies have found that the efficacy of these small-molecule antioxidants in treating these diseases is limited. On the one hand, exogenous antioxidants may have difficulty crossing the blood-brain barrier and cannot effectively reach the central nervous system. On the other hand, excessive use of exogenous antioxidants may disrupt intracellular redox balance and produce adverse side effects. Therefore, researchers have begun to shift their focus to activating endogenous antioxidant enzymes in the central nervous system to reduce ROS-induced damage.

[0003] The nuclear transcription factor E2-associated factor 2 (Nrf2) signaling pathway is considered an important target for reducing reactive oxygen species (ROS). Nrf2 is a transcription factor that regulates the expression of a series of antioxidant and detoxification enzymes, thereby enhancing cellular antioxidant capacity. Studies have shown that Nrf2 expression in the brain declines with age, leading to weakened antioxidant capacity and increased oxidative stress. Activating the Nrf2 signaling pathway with small molecule compounds such as thiols, polyphenols, and flavonoids can enhance intracellular antioxidant capacity and reduce damage caused by oxidative stress. Furthermore, activating the Nrf2 signaling pathway can also regulate inflammatory responses, improve mitochondrial function, and promote neuronal cell survival. Therefore, activating the Nrf2 signaling pathway is considered a potential strategy for treating neurodegenerative diseases. Summary of the Invention

[0004] The purpose of this invention is to provide a class of novel dihydropyrimidine[4,5-d]pyrimidine-2(H)-one Nrf2 activators, as shown in general formula I, with good in vitro and in vivo activity, or pharmaceutically acceptable salts thereof.

[0005]

[0006] Wherein, R is selected from (C3-C8)alkyl, (C3-C8)substituted alkyl, C1-C4 aminoalkyl, 4-6-membered heterocyclic group containing 1-3 heteroatoms, 4-6-substituted heterocyclic group containing 1-3 heteroatoms, 5-6-membered aromatic heterocyclic group containing 1-3 heteroatoms, 5-6-membered substituted aromatic heterocyclic group containing 1-4 heteroatoms, 4-6-membered heterocyclic alkyl group containing 1-3 heteroatoms, 4-6-substituted heterocyclic alkyl group containing 1-3 heteroatoms, 5-6-membered aromatic heterocyclic alkyl group containing 1-3 heteroatoms, and 5-6-membered substituted aromatic heterocyclic alkyl group containing 1-4 heteroatoms.

[0007] Specifically, the heteroatom is O or N.

[0008] Specifically, R is selected from furanyl, thiopheneyl, pyrroleyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrazinyl or triazinyl, furanyl, thiopheneyl, pyrroleyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrazinyl or triazinyl;

[0009] Specifically, R is selected from piperidinyl, piperazinyl, morpholinyl, epoxybutyl, piperidinyl, piperazinyl, morpholinyl, and epoxybutyl;

[0010] Specifically, R is selected from piperazine methyl, morpholine ethyl, and furan methyl.

[0011] Specifically, R is selected from butyl or isobutyl.

[0012] Specifically, R is selected from (dimethylamino)ethyl, (dimethylamino)methyl, (methylamino)propyl, (methylamino)ethyl, (methylethylamino)methyl, 2-aminoethyl, 3-aminopropyl, and aminomethyl.

[0013] Furthermore, the compound is any one of the following:

[0014]

[0015] Furthermore, the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, phosphate, hydrobromide, maleate, citrate, succinate, methanesulfonate, and toluenesulfonate.

[0016] A second objective of this invention is to provide a method for preparing the above-mentioned compound.

[0017] The method for preparing the dihydropyrimidine[4,5-d]pyrimidine-2(H)-one Nrf2 activator with anti-neurodegenerative disease properties shown in Formula I involves reducing the nitro group of the compound in Formula 3 with a reducing agent, followed by acylation with 3-trifluoromethylbenzoyl chloride in an alkaline catalyst to obtain the target compound of Formula I.

[0018]

[0019] Specifically, the reducing agent is a combination of iron powder and ammonium chloride, a combination of iron powder and ammonia, a combination of iron powder and acetic acid, a combination of iron powder and hydrochloric acid, a combination of ferric chloride and hydrazine, a combination of zinc and acetic acid, or a combination of zinc and hydrochloric acid; the alkaline catalyst is potassium carbonate, sodium carbonate, lithium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, triethylamine, diisopropylethylamine, diisopropylamine, tetrabutylammonium bromide, or tetrabutylammonium fluoride.

[0020] Furthermore, the reaction solvents in the acylation step are dichloromethane, chloroform, ethyl acetate, N,N-dimethylformamide, acetone, dimethyl sulfoxide, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, and pyridine.

[0021] Furthermore, the reaction temperature in the acylation step is 10℃~120℃; the reaction time is 30 minutes~12 hours.

[0022] More specifically, the preparation method includes the following steps:

[0023] Step a) Using the compound of formula 1 as the starting material,

[0024]

[0025] The reaction with an amino compound yields compound of formula 2.

[0026]

[0027] Step b) reacts compound 2 with bis(trichloromethyl) carbonate to yield compound 3.

[0028]

[0029] Step c): After the nitro group of compound 3 is reduced by a reducing agent, it is then acylated with 3-trifluoromethylbenzoyl chloride in an alkaline catalyst to obtain the target compound of general formula I.

[0030] The reaction formula is as follows:

[0031]

[0032] In step (a), compound 1 reacts with an amino compound (RHN2) to obtain compound 2; in step (b), compound 2 reacts with bis(trichloromethyl) carbonate to obtain compound 3; in step (c), compound 3 is reduced and then reacted with 3-trifluoromethylbenzoyl chloride in an alkaline catalyst to prepare the compound.

[0033] Specifically, the reactant RNH2 in step (a) is butylamine, N,N-dimethylethylenediamine, 3-oxetanebutylamine, 4-(2-aminoethyl)morpholine, furfurylamine, 2-aminoimidazolium, N-aminopiperidine, or 4-methyl-1-piperazine methylamine. More specifically, the reaction solvent is at least one selected from 1,4-dioxane, tetrahydrofuran, ethanol, methanol, N,N-dimethylformamide, toluene, dimethyl sulfoxide, hexamethylphosphoryltriamine, or 1,3-dimethylpropylene urea; and the catalyst is at least one selected from diisopropylethylamine, triethylamine, pyridine, N-methylmorpholine, or 4-dimethylaminopyridine.

[0034] Specifically, the cyclizing agent in step (b) is bis(trichloromethyl) carbonate, N,N'-carbonyldiimidazole, or chloroformyl chloride;

[0035] Specifically, the reducing agent in step (c) is a combination of iron powder and ammonium chloride, a combination of iron powder and ammonia, a combination of iron powder and acetic acid, a combination of iron powder and hydrochloric acid, a combination of ferric chloride and hydrazine, a combination of zinc and acetic acid, or a combination of zinc and hydrochloric acid.

[0036] Further, in step (c), the alkaline catalyst is potassium carbonate, sodium carbonate, lithium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, triethylamine, diisopropylethylamine, diisopropylamine, tetrabutylammonium bromide, or tetrabutylammonium fluoride.

[0037] Further, the reaction solvent in step (c) is at least one of dichloromethane, chloroform, ethyl acetate, N,N-dimethylformamide, acetone, dimethyl sulfoxide, 1,4-dioxane, tetrahydrofuran, and pyridine.

[0038] Furthermore, in step (c), the reaction temperature is 10℃~120℃; the reaction time is 30 minutes~12 hours.

[0039] A third objective of this invention is the use of the above-mentioned dihydropyrimidine[4,5-d]pyrimidine-2(H)-one Nrf2 activators in the preparation of drugs for the prevention and / or treatment of neurodegenerative diseases.

[0040] More specifically, the above-mentioned dihydropyrimidine [4,5-d]pyrimidine-2(H)-one Nrf2 activators are used in the preparation of drugs for the prevention and / or treatment of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, epilepsy, Huntington's disease, amyotrophic lateral sclerosis and multiple sclerosis.

[0041] A fourth objective of this invention is a pharmaceutical composition for the prevention and / or treatment of neurodegenerative diseases, comprising a dihydropyrimidine[4,5-d]pyrimidine-2(H)-one Nrf2 activator as shown in Formula I above, supplemented with pharmaceutically acceptable excipients.

[0042] Furthermore, the pharmaceutical composition is formulated as tablets, capsules, powders, syrups, liquids, suspensions, or injections.

[0043] The fifth objective of this invention is to provide a class of compounds represented by general formula 3.

[0044]

[0045]

[0046] Wherein, R is selected from (C3-C8)alkyl, (C3-C8)substituted alkyl, C1-C4 aminoalkyl, 4-6-membered heterocyclic group containing 1-3 heteroatoms, 4-6-substituted heterocyclic group containing 1-3 heteroatoms, 5-6-membered aromatic heterocyclic group containing 1-3 heteroatoms, 5-6-membered substituted aromatic heterocyclic group containing 1-4 heteroatoms, 4-6-membered heterocyclic alkyl group containing 1-3 heteroatoms, 4-6-substituted heterocyclic alkyl group containing 1-3 heteroatoms, 5-6-membered aromatic heterocyclic alkyl group containing 1-3 heteroatoms, and 5-6-membered substituted aromatic heterocyclic alkyl group containing 1-4 heteroatoms.

[0047] Specifically, the heteroatom is O or N.

[0048] Specifically, R is selected from furanyl, thiopheneyl, pyrroleyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrazinyl or triazinyl, furanyl, thiopheneyl, pyrroleyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrazinyl or triazinyl;

[0049] Specifically, R is selected from piperidinyl, piperazinyl, morpholinyl, epoxybutyl, piperidinyl, piperazinyl, morpholinyl, and epoxybutyl;

[0050] Specifically, R is selected from piperazine methyl, morpholine ethyl, and furan methyl.

[0051] Specifically, R is selected from butyl or isobutyl.

[0052] Specifically, R is selected from (dimethylamino)ethyl, (dimethylamino)methyl, (methylamino)propyl, (methylamino)ethyl, (methylethylamino)methyl, 2-aminoethyl, 3-aminopropyl, and aminomethyl.

[0053] The sixth objective of this invention is to provide a method for preparing the compound represented by formula 3.

[0054] Step (a) uses the compound of formula 1 as the starting material.

[0055]

[0056] It reacts with an amino compound to give compound of formula 2;

[0057]

[0058]

[0059] Step (b) reacts compound 2 with bis(trichloromethyl) carbonate to yield compound 3.

[0060]

[0061] In step (a), the compound of formula 1 reacts with an amino compound (RHN2) to obtain the compound of formula 2;

[0062] In step (b), the compound of formula 2 reacts with bis(trichloromethyl) carbonate to give the compound of formula 3.

[0063] Specifically, the reaction raw material RNH2 in step (a) is butylamine, N,N-dimethylethylenediamine, 3-oxetanebutylamine, 4-(2-aminoethyl)morpholine, furfurylamine, 2-aminoimidazolium, N-aminopiperidine, or 4-methyl-1-piperazinylmethylamine. More specifically, the reaction solvent is 1,4-dioxane, and the catalyst is diisopropylethylamine; specifically, the cyclizing agent in step (b) is bis(trichloromethyl) carbonate, N,N'-carbonyldiimidazole, or chloroformyl chloride.

[0064] The seventh object of this invention is the use of the compound of formula 3 in the preparation of the compound of formula I.

[0065] Beneficial effects: This invention evaluates the Nrf2 activating activity, neuroprotective effect, and Morris water maze test of dihydropyrimidine [4,5-d]pyrimidine-2(H)-one Nrf2 activators of general formula I in neurodegenerative diseases (taking Alzheimer's disease as an example). It was found that they have good in vitro and in vivo activities and have potential application prospects in the preparation of drugs for anti-Alzheimer's disease and other neurodegenerative diseases. Attached Figure Description

[0066] Figure 1 The survival rate of SH-SY5Y cells after H2O2-induced damage by the test compound is shown. (##P<0.01 vs normal group, **P<0.01 vs hydrogen peroxide damage group)

[0067] Figure 2 The effect of different concentrations of compound I-1 (0.1, 1, 10 μM) on the oscillation amplitude of the calcium signal synchronization network in hippocampal neurons was investigated (n = 14, which represents the number of replicates in this group; one-way ANOVA, **p < 0.01, and comparison with baseline values).

[0068] Figure 3 The effect of compounds I-1 to I-5 at a concentration of 10 μM on the oscillation amplitude of hippocampal neural networks (data are standardized values, %, numbers in the figure represent the number of replicates in the group, one-way ANOVA, **p<0.01, compared with baseline values).

[0069] Figure 4 This study describes a water maze experiment using transgenic ApoE model mice to measure the time mice spent in the target water area. (The numbers in the figure represent the number of replicates in each group. One-way ANOVA, *p<0.05, **p<0.01, compared with baseline values).

[0070] Figure 5 This study used a transgenic ApoE model mouse water maze experiment to measure the number of times the mice entered the target water area. (The numbers in the figure represent the number of replicates in each group. One-way ANOVA, *p<0.05, **p<0.01, compared with the baseline value). Detailed Implementation

[0071] The present invention will be further described in detail below with reference to specific embodiments. These embodiments are for illustrative purposes only and are not intended to limit the scope of the invention.

[0072] Example 1: Preparation of Compound 2

[0073]

[0074] The starting material, compound 1 (626 mg, 2 mmol), was dissolved in 10 mL of 1,4-dioxane, and an amino compound (4 mmol) and diisopropylethylamine (1 mL) were added. The reaction was carried out at 80 °C for 60 min. After the reaction was completed, the mixture was cooled to room temperature, the solvent was removed, and the crude product was extracted with dichloromethane / water. The organic phase was dried over anhydrous sodium sulfate and evaporated to obtain a crude residue, which was washed with diethyl ether to obtain the corresponding compound 2.

[0075]

[0076]

[0077] Compound of Formula 2-1: 586 mg, yield 84%. 1H NMR (600MHz, DMSO-d6) δ7.94(s,1H),7.45(t,J=5.5Hz,1H),7.40(d,J=8.1Hz,1H),7.25(d,J=8.1Hz,1H),7.19(s,1H),6.03(t,J=5. 7Hz,1H),4.23(d,J=5.6Hz,2H),3.40–3.37(m,2H),2.22(s,3H),1.58–1.52(m,2H),1.35–1.28(m,2H),0.89(t,J=7.4Hz,3H).ESI-MS m / z:350[M+H] + .

[0078] Compound of formula 2-2: 575 mg, yield 79%. 1 H NMR (600MHz, DMSO-d6) δ8.33(s,1H),7.65(d,J=8.4Hz,1H),7.25(d,J=7.5Hz,1H),7.18(s,1H),6.93(s,1H ),6.22(s,1H),4.51(s,2H),3.34(t,J=5.0Hz,2H),2.61(t,J=5.0Hz,2H),2.26(s,6H),2.01(s,2H).ESI-MS m / z:365[M+H] + .

[0079] Compound of formula 2-3: 523 mg, yield 75%. 1 H NMR (600MHz, DMSO-d6) δ8.37(s,1H),8.23(s,1H),7.70(d,J=7.5Hz,1H),7.29–7.24(m,2H),6.93( s,1H),4.87–4.84(m,2H),4.71–4.67(m,2H),4.51(s,2H),4.23–4.17(m,1H),2.01(s,3H).ESI-MS m / z:350[M+H] + .

[0080] Compound of formula 2-4: 552 mg, yield 68%. 1H NMR (600MHz, DMSO-d6) δ8.01(s,1H),7.82(d,J=7.5Hz,1H),7.35(s,1H),7.32(d,J=7.3Hz,1H),6.93(s,1H),6.22(s,1H),4 .51(s,2H),3.54(t,J=4.7Hz,4H),3.34(t,J=5.2Hz,2H),2.50(t,J=5.2Hz,2H),2.41(t,J=4.8Hz,4H),2.01(s,3H).ESI-MS m / z:407[M+H] + .

[0081] Compounds of formula 2-5: 529 mg, yield 71%. 1 H NMR(600MHz,Chloroform-d)δ8.00(s,1H),7.65(d,J=8.2Hz,1H),7.53(s,1H),7.32(s,1H),7.22(d,J=8.2Hz,1H),6.32–6.31(m,1H), 6.28(d,J=3.2Hz,1H),6.21(t,J=5.2Hz,1H),4.70(d,J=5.4Hz,2H),4.23(d,J=5.2Hz,2H),3.65(t,J=5.3Hz,1H),2.18(s,3H).ESI-MS m / z:374[M+H] + .

[0082] Compounds of formula 2-6: 595 mg, yield 83%. 1 H NMR(600MHz,Chloroform-d)δ12.66(s,1H),11.24(s,1H),7.95(s,1H),7.54(dd,J=1.4,7.6Hz,1H), 7.37(d,J=7.6Hz,1H),7.13(s,1H),7.10(d,J=1.4Hz),4.29(s,2H),4,32(s,1H),2.01(s,3H).ESI-MS m / z:360[M+H] + .

[0083] Compounds of formula 2-7: 503 mg, yield 67%. 1H NMR(600MHz,Chloroform-d)δ7.91(s,1H),7.54(dd,J=3.2,15.2Hz,1H),7.38(d,J=15.0Hz,1H), 7.11(d,J=2.9Hz),4.33(s,2H),3.97(s,1H),3.20(s,1H),2.01(s,3H),1.52-1.84(m,6H).ESI-MS m / z:377[M+H] + .

[0084] Compound of formula 2-8: 726 mg, yield 74%. 1 H NMR(600MHz,Chloroform-d)δ7.92(s,1H),7.55(dd,J=3.0,12.9Hz,1H),7.38(d,J=14.9Hz,1H),7.11(d,J= 2.9Hz),5.13(s,1H),4.67(s,1H),4.35(s,2H),3.19(m,4H),2.49(m,4H),2.01(s,3H),4.10(s,9H).ESI-MS m / z:492[M+H] + .

[0085] Example 2: Preparation of Compound 3

[0086]

[0087] Compound 2 (1 equivalent) was dissolved in 20 mL of tetrahydrofuran, and bis(trichloromethyl) carbonate (1 equivalent) and triethylamine (5 equivalents) were added. The reaction was carried out at 0 °C for 60 min, and the reaction was quenched with water. The solvent was removed, and the crude product was extracted with dichloromethane / water. The organic phase was dried over anhydrous sodium sulfate and evaporated to obtain a crude residue. The crude product was purified by silica gel rapid column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1:1, v / v) to obtain the corresponding compound 3.

[0088] Compound of Formula 3-1, Yield: 61%. 1 H NMR (600MHz, DMSO-d6) δ8.44(s,1H),8.30(s,1H),8.12(d,J=7.5Hz,1H),7.48(d,J=7.6Hz,1H),5.06(s,2H ),3.87(t,J=7.6Hz,2H),2.09(s,3H),1.66–1.60(m,2H),1.35–1.27(m,2H),0.91(t,J=7.9Hz,3H).ESI-MS m / z:376[M+H] + .

[0089] Compound of formula 3-2, Yield: 43%. 1 H NMR (600MHz, DMSO-d6) δ8.45(s,1H),8.30(s,1H),8.12(d,J=7.3Hz,1H),7.48(d,J=7.5Hz,1H ),5.06(s,2H),3.64(t,J=7.3Hz,2H),2.53(t,J=7.3Hz,2H),2.22(s,6H),2.09(s,3H).ESI-MS m / z:391[M+H] + .

[0090] Compound of formula 3-3, Yield: 72%. 1 H NMR (600MHz, DMSO-d6) δ8.47(s,1H),8.31(s,1H),8.13(d,J=7.3Hz,1H),7.49(d,J= 7.5Hz,1H),5.18–5.14(m,2H),5.06(s,2H),4.81–4.73(m,3H),2.09(s,3H).ESI-MS m / z:376[M+H] + .

[0091] Compounds of formula 3-4, Yield: 35%. 1 H NMR (600MHz, DMSO-d6) δ8.45(s,1H),8.30(s,1H),8.12(d,J=7.5Hz,1H),7.48(d,J=7.5Hz,1H),5.06(s,2H),3 .64(t,J=7.3Hz,2H),3.54(t,J=4.7Hz,4H),2.53(t,J=7.3Hz,2H),2.41(t,J=4.7Hz,4H),2.09(s,3H).ESI-MS m / z:433[M+H] + .

[0092] Compounds of formula 3-5, Yield: 76%. 1H NMR(600MHz,Chloroform-d)δ8.18–8.14(m,3H),7.48(d,J=8.3Hz,1H),7.34(s,1H),6.42(d,J=3.1Hz,1H) ,6.32–6.31(m,1H),5.37–5.28(m,2H),4.90(d,J=14.2Hz,1H),4.58(d,J=14.6Hz,1H),2.32(s,3H).ESI-MS m / z:400[M+H] + .

[0093] Compounds of formula 3-6, Yield: 23%. 1 H NMR(600MHz,Chloroform-d)δ8.66(d,J=3.0Hz,1H),7.93(s,1H),7.76(dd,J=3.0 ,15.2Hz,1H,7.44(d,J=3.0Hz,1H),7.10(s,2H),4.82(s,2H),2.10(s,3H).ESI-MS m / z:386[M+H] + .

[0094] Compounds of formula 3-7, Yield: 27%. 1 H NMR (600MHz, Chloroform-d) δ7.65 (d, J = 3.0 Hz, 1H), 7.93 (s, 1H), 7.77 (dd, J = 3.0, 14. 9Hz,1H),7.41(d,J=15.0Hz,1H),4.82(s,2H),2.09(s,3H),1.61-1.50(m,6H).ESI-MS m / z:403[M+H] + .

[0095] Compounds of formula 3-8, Yield: 21%. 1 H NMR(600MHz,Chloroform-d)δ8.68(d,J=3.0Hz,1H),7.92(s,1H),7.77(dd,J=3.0,14.9Hz,1H),7.42(d,J=15.2Hz,1H), 6.38(s,1H),5.37(s,1H),4.83(s,2H),3.19(t,J=10.0Hz,4H),2.46(t,J=10.0Hz,4H),2.07(s,3H),1.42(s,9H).ESI-MS m / z:518[M+H] + .

[0096] Preparation of Compound I-1 in Example 3

[0097]

[0098] The compound of formula 3-1 (110 mg, 1 equivalent) was dissolved in 14 mL of a tetrahydrofuran-methanol-water mixed solvent (4:2:1, volume ratio). Iron powder (10 equivalents) and ammonium chloride (20 equivalents) were added. The mixture was reacted at 80 °C for 60 minutes, then cooled to room temperature. The insoluble matter was filtered off, and the crude product obtained by concentrating the filtrate was extracted with dichloromethane / water. The organic phase was dried over anhydrous sodium sulfate and evaporated to obtain the crude product (unpurified and used directly in the next reaction).

[0099] The crude product was dissolved in 5 mL of dichloromethane, and then 54 μL of 3-fluoromethylbenzoyl chloride and 80 μL of diisopropylethylamine (0.48 mmol) were added to the reaction flask. The reaction was carried out at room temperature for 30 minutes. After the reaction was completed, the solvent was removed, and the crude product was extracted with ethyl acetate / water. The organic phase was dried over anhydrous sodium sulfate and evaporated to obtain a crude residue. The crude product was purified by silica gel rapid column chromatography (petroleum ether / ethyl acetate = 3 / 1, v / v) to give 53 mg of the corresponding compound of formula I-1, in 35% yield. 1 H NMR(600MHz,DMSO-d6)δ10.56(br s,1H),8.33(s,1H),8.31(s,1H),8.27(d,J=7.7Hz,1H),7.97(d,J=7.8Hz,1H), 7.82(s,1H),7.79(dd,J=7.8,7.8Hz,1H),7.65(d,J=6Hz,1H),7.32(d,J=8.3Hz, 1H),4.85(d,J=16.2Hz,1H),4.66(d,J=15.8Hz,1H),3.94(t,J=7.3Hz,2H),2.13 (s,3H),1.62–1.563(m,2H),1.352–1.312(m,2H),0.92(t,J=7.4Hz,3H).ESI-MS m / z:518[M+H] + .

[0100] Example 4: Preparation of compound I-2

[0101]

[0102] The compound of formula 3-2 (40 mg, 1 equivalent) was dissolved in 10 mL of a tetrahydrofuran-methanol-water mixed solvent (4:2:1, volume ratio). Iron powder (10 equivalents) and ammonium chloride (20 equivalents) were added. The mixture was reacted at 80 °C for 60 minutes, then cooled to room temperature. The insoluble matter was filtered off, and the crude product obtained by concentrating the filtrate was extracted with dichloromethane / water. The organic phase was dried over anhydrous sodium sulfate and evaporated to obtain the crude product (unpurified and used directly in the next reaction).

[0103] The crude product was dissolved in 10 mL of tetrahydrofuran, and then 60 μL of 3-fluoromethylbenzoyl chloride and 130 μL of diisopropylethylamine were added to the reaction flask. The reaction was carried out at 70 °C for 60 min. After the reaction was completed, the mixture was cooled to room temperature, the solvent was removed, and the crude product was extracted with ethyl acetate / water. The organic phase was dried over anhydrous sodium sulfate and evaporated to obtain a crude residue. The crude product was purified by silica gel rapid column chromatography (dichloromethane / methanol = 95 / 5, v / v) to give 39 mg of the corresponding compound of formula I-2, with a yield of 72%. 1 H NMR(600MHz,DMSO-d6)δ10.56(br s,1H),8.33(s,1H),8.30(s,1H),8.27(d,J=7.9Hz,1H),7.97(d,J=7.8Hz,1H),7.83(s,1H),7.79(dd,J=6,6Hz,1H),7.64(d,J=6Hz,1H), 7.32(d,J=8.3Hz,1H),4.84(d,J=16.2Hz,1H),4.66(d,J=16.0Hz,1H),4.07–4.03(m,2H),3.33(s,2H),2.22(s,6H),2.13(s,3H).ESI-MS m / z:533[M+H] + .

[0104] Example 5: Preparation of compound I-3

[0105]

[0106] The compound of formula 3-3 (99 mg, 1 equivalent) was dissolved in 10 mL of a tetrahydrofuran-methanol-water mixed solvent (4:2:1, volume ratio). Iron powder (10 equivalents) and ammonium chloride (20 equivalents) were added. The mixture was reacted at 80 °C for 60 minutes, then cooled to room temperature. The insoluble matter was filtered off, and the crude product obtained by concentrating the filtrate was extracted with dichloromethane / water. The organic phase was dried over anhydrous sodium sulfate and evaporated to obtain the crude product (unpurified and used directly in the next reaction).

[0107] The crude product was dissolved in 5 mL of N,N-dimethylformamide, and then 75 μL of 3-fluoromethylbenzoyl chloride and 60 mg of potassium carbonate were added to the reaction flask. The reaction was carried out at 120 °C for 120 min. After the reaction was completed, the mixture was cooled to room temperature, the solvent was removed, and the crude product was extracted with ethyl acetate / water. The organic phase was dried over anhydrous sodium sulfate and evaporated to obtain a crude residue. The crude product was purified by silica gel rapid column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to give 41 mg of the corresponding compound of formula I-3, in 30% yield. 1 H NMR(600MHz,DMSO-d6)δ10.55(br s,1H),8.42(s,1H),8.30(s,1H),8.26(d,J=7.9Hz,1H),7.97(d,J=7.8Hz,1H),7.81–7.78(m,2H),7.64(d,J= 6Hz,1H),7.32(d,J=8.3Hz,1H),5.03–4.98(m,1H),4.84–4.76(m,2H),4.75–4.66(m,4H),2.13(s,3H).ESI-MS m / z:518[M+H] + .

[0108] Example 6: Preparation of compound I-4

[0109]

[0110] Compound 3-4 (109 mg, 1 equivalent) was dissolved in 10 mL of a tetrahydrofuran-methanol-water mixture (4:2:1, volume ratio). Iron powder (10 equivalents) and ammonium chloride (20 equivalents) were added. The mixture was reacted at 80 °C for 60 minutes, then cooled to room temperature. The insoluble residue was filtered off, and the crude product obtained by concentrating the filtrate was extracted with dichloromethane / water. The organic phase was dried over anhydrous sodium sulfate and evaporated to obtain the crude product (unpurified and used directly in the next reaction).

[0111] The crude product was dissolved in 5 mL of pyridine, and then 75 μL of 3-fluoromethylbenzoyl chloride and 80 μL of triethylamine were added to the reaction flask. The reaction was carried out at 25 °C for 12 hours. After the reaction was completed, the solvent was removed, and the crude product was extracted with ethyl acetate / water. The organic phase was dried over anhydrous sodium sulfate and evaporated to obtain a crude residue. The crude product was purified by silica gel rapid column chromatography (dichloromethane / methanol = 95 / 5, v / v) to give 87 mg of the corresponding compound of formula I-4, in 60% yield. 1H NMR(600MHz,Chloroform-d)δ8.51(br s,1H),8.10(s,1H),8.08(s,1H),8.05(d,J=7.9Hz,1H),7.84(s,1H),7.78( d,J=7.7Hz,1H),7.60(dd,J=6,6Hz,1H),7.21(d,J=8.3Hz,1H),7.14(d,J=8. 2Hz,1H),4.76(d,J=15.0Hz,1H),4.52(d,J=15.3Hz,1H),4.34–4.27(m,2H) ,3.71(t,J=4.7Hz,4H),2.76–2.72(m,2H),2.64(s,4H),1.92(s,3H).ESI-MS m / z:575[M+H] + .

[0112] Example 7: Preparation of compound I-5

[0113]

[0114] Compound 3-5 (110 mg, 1 equivalent) was dissolved in 10 mL of a tetrahydrofuran-methanol-water mixture (4:2:1, volume ratio). Iron powder (10 equivalents) and ammonium chloride (20 equivalents) were added. The mixture was reacted at 80 °C for 60 minutes, then cooled to room temperature. The insoluble residue was filtered off, and the crude product obtained by concentrating the filtrate was extracted with dichloromethane / water. The organic phase was dried over anhydrous sodium sulfate and evaporated to obtain the crude product (unpurified and used directly in the next reaction).

[0115] The crude product was dissolved in 5 mL of dichloromethane, and then 80 μL of 3-fluoromethylbenzoyl chloride and 80 μL of diisopropylethylamine were added to the reaction flask. The reaction was carried out at 25 °C for 150 min. After the reaction was completed, the solvent was removed, and the crude product was extracted with ethyl acetate / water. The organic phase was dried over anhydrous sodium sulfate and evaporated to obtain a crude residue. The crude product was purified by silica gel rapid column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to give 72 mg of the corresponding compound of formula I-5, in 48% yield. 1H NMR(600MHz,Chloroform-d)δ8.84(br s,1H),8.15(s,1H),8.11(s,1H),8.04(d,J=8.0Hz,1H),7.74(d,J=7.8Hz,1H) ,7.62(d,J=2.2Hz,1H),7.51(dd,J=6,6Hz,1H),7.33(d,J=8.2,Hz,1H),7.29(s ,1H),7.04(d,J=7.9Hz,1H),6.41(d,J=2.4Hz,1H),6.28–6.29(m,1H),5.42–5. 31(m,2H),4.72(d,J=16.3Hz,1H),4.50(d,J=16.1Hz,1H),1.72(s,3H).ESI-MS m / z:542[M+H] + .

[0116] Example 8: Preparation of compound I-6

[0117]

[0118] Compound 3-6 (108 mg, 1 equivalent) was dissolved in 10 mL of a tetrahydrofuran-methanol-water mixture (4:2:1, volume ratio). Iron powder (10 equivalents) and ammonium chloride (20 equivalents) were added. The mixture was reacted at 80 °C for 60 minutes, then cooled to room temperature. The insoluble residue was filtered off, and the crude product obtained by concentrating the filtrate was extracted with dichloromethane / water. The organic phase was dried over anhydrous sodium sulfate and evaporated to obtain the crude product (unpurified and used directly in the next reaction).

[0119] The crude product was dissolved in 5 mL of pyridine, and then 75 μL of 3-fluoromethylbenzoyl chloride and 80 μL of triethylamine were added to the reaction flask. The reaction was carried out at 60 °C for 12 hours. After the reaction was completed, the solvent was removed, and the crude product was extracted with ethyl acetate / water. The organic phase was dried over anhydrous sodium sulfate and evaporated to obtain a crude residue. The crude product was purified by silica gel rapid column chromatography (dichloromethane / methanol = 95 / 5, v / v) to give 34 mg of the corresponding compound of formula I-6, in 23% yield. 1 H NMR(600MHz,Chloroform-d)δ9.15(s,1H),8.13(t,J=3,1H),7.95-7.93(m,2H),7.82(dt,J=3,15Hz ,1H),7.60(d,J=3.5Hz,1H),7.35-7.28(m,2H),7.15-7.12(m,3H),4.85(s,2H),2.09(s,3H).ESI-MS m / z:528[M+H] + .

[0120] Example 9: Preparation of compound I-7

[0121]

[0122] The compound of formula 3-7 (114 mg, 1 equivalent) was dissolved in 10 mL of a tetrahydrofuran-methanol-water mixed solvent (4:2:1, volume ratio). Iron powder (10 equivalents) and ammonium chloride (20 equivalents) were added. The mixture was reacted at 80 °C for 60 minutes, then cooled to room temperature. The insoluble matter was filtered off, and the crude product obtained by concentrating the filtrate was extracted with dichloromethane / water. The organic phase was dried over anhydrous sodium sulfate and evaporated to obtain the crude product (unpurified and used directly in the next reaction).

[0123] The crude product was dissolved in 5 mL of pyridine, and then 75 mg of 3-fluoromethylbenzoyl chloride and 80 μL of triethylamine were added to the reaction flask. The reaction was carried out at 60 °C for 5 hours. After the reaction was completed, the solvent was removed, and the crude product was extracted with ethyl acetate / water. The organic phase was dried over anhydrous sodium sulfate and evaporated to obtain a crude residue. The crude product was purified by silica gel rapid column chromatography (dichloromethane / methanol = 95 / 5, v / v) to give 57 mg of the corresponding compound of formula I-7, with a yield of 39%. 1 H NMR(600MHz,Chloroform-d)δ9.12(s,1H),8.12(t,J=3,1H),7.95(dt,J=2,15Hz,1H),7.93(s,1H),7.82(dt,J=3,15Hz,1H),7.60(d,J= 3.0Hz,1H),7.34(t,J=3.0Hz,1H)7.27(d,J=3.2Hz,1H),7.12(dd,J=3.0,15Hz,1H),4.84(s,2H),2.10(s,3H),1.58-1.51(m,6H).ESI-MS m / z:545[M+H] + .

[0124] Example 10: Preparation of compound I-8

[0125]

[0126] The compound of formula 3-8 (102 mg, 1 equivalent) was dissolved in 10 mL of a tetrahydrofuran-methanol-water mixed solvent (4:2:1, volume ratio). Iron powder (10 equivalents) and ammonium chloride (20 equivalents) were added. The mixture was reacted at 80 °C for 60 minutes, then cooled to room temperature. The insoluble matter was filtered off, and the crude product obtained by concentrating the filtrate was extracted with dichloromethane / water. The organic phase was dried over anhydrous sodium sulfate and evaporated to obtain the crude product (unpurified and used directly in the next reaction).

[0127] The crude product was dissolved in 5 mL of N,N-dimethylformamide, and then 75 μL of 3-fluoromethylbenzoyl chloride and 60 mg of potassium carbonate were added to the reaction flask. The reaction was carried out at 25 °C for 5 hours. After the reaction was completed, the solvent was removed, and the crude product was extracted with ethyl acetate / water. The crude product was then dissolved in 10 mL of dichloromethane, cooled to 0 °C in an ice bath, and 1 mL of trifluoroacetic acid was slowly added dropwise. After the addition was complete, the reaction temperature was raised to 25 °C, and stirring was continued for 30 minutes. After the reaction was completed, the solvent was removed, and the crude product was extracted with ethyl acetate / water. The organic phase was dried over anhydrous sodium sulfate and evaporated to obtain a crude residue. The crude product was purified by silica gel rapid column chromatography (dichloromethane / methanol = 95 / 5, v / v) to give 41 mg of the corresponding compound of formula I-8, with a yield of 37%. 1 H NMR(600MHz,Chloroform-d)δ9.14(s,1H),8.12(t,J=3,1H),7.94(dt,J=3.0,15Hz,1H ),7.93(s,1H),7.82(dt,J=3,15Hz,1H),7.59(d,J=3.0Hz,1H),7.35(t,J=5.0Hz,1H)7 .28(d,J=4.9Hz,1H),7.12(dd,J=3.0,15Hz,1H),6.27(s,1H),5.31(s,1H),4.82(s,2H ),2.66(t,J=10.2Hz,4H),2.34(t,J=10.3Hz,4H),2.11(s,3H),1.24(brs,1H).ESI-MS m / z:560[M+H] + .

[0128] The compound numbers and specific structural formulas are shown in Table 1 below.

[0129] Table 1. Numbering of Compounds of General Formula I

[0130]

[0131]

[0132] Example 11 Preparation of compound D-1

[0133]

[0134] Compound D-1 was prepared according to the reference (Journal of Medicinal Chemistry, 2018, 61(18), 8353-8373). The steps were as follows: 100 mg of the starting material compound of formula 4 was dissolved in 5 mL of dichloromethane, and then 52 μL of 3-fluoromethylbenzoyl chloride and 90 mg of potassium carbonate were added to the reaction flask. The reaction was carried out at 25 °C for 1 hour. After the reaction was completed, the solvent was removed, and the crude product was extracted with dichloromethane / water. The organic phase was dried with anhydrous sodium sulfate and evaporated to obtain a crude residue. The crude product was purified by silica gel rapid column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to obtain 52 mg of the corresponding compound of formula D-1, with a yield of 33%. ESI-MS m / z: 476 [M+H] + .

[0135] Example 12 Preparation of compound D-2

[0136]

[0137] The D-2 compound was synthesized according to the reference (Journal of Medicinal Chemistry, 2018, 61(18), 8353-8373). The steps were as follows: 140 mg of the starting material compound of formula 5 (1 equivalent) was dissolved in 5 mL of tetrahydrofuran. Then, bis(trichloromethyl) carbonate and triethylamine (5 equivalents) were added to the reaction flask at 0 °C, and the reaction was carried out at 70 °C for 1 hour. The reaction was quenched with water, the solvent was removed, and the crude product was extracted with dichloromethane / water. The organic phase was dried over anhydrous sodium sulfate and evaporated to obtain a crude residue. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to obtain 62 mg of the corresponding compound of formula D-2, with a yield of 42%. ESI-MS m / z: 544 [M+H] + .

[0138] Example 13: Nrf2 activation activity test

[0139] HeLa cells transfected with the ARE luciferase reporter gene plasmid were cultured in DMEM medium containing 10% fetal bovine serum at 37°C and 5% CO2 for 24 hours. Subsequently, HeLa-ARE-C8 cells were treated with 0.25% trypsin digestion solution to prepare a concentration of 4 × 10⁻⁶ cells / mL. 5 Cell suspensions were prepared. 100 μL of culture medium was added to each well of a 96-well plate and incubated for 12 hours. 100 μL of different concentrations (1 and 10 μM) of the test compound were added to each well, with tert-butylhydroquinone (tBHQ) as a positive control. The plates were incubated at 37°C and 5% CO2 for 12 hours. The luciferase activity of the cells was detected using a luciferase reporter gene assay kit (Beyotime, China).

[0140] The activity data of the compounds are shown in Table 2. Compared with the control compound t-BHQ, all eight compounds I-1 to I-8 tested showed better ARE reporter gene induction activity at 10 μM, indicating that they have better Nrf2 activation, while compounds D-1 and D-2 showed weaker activity. Among them, compounds I-4 and I-5 showed better activity, exhibiting 5.12 and 5.44 times the Nrf2 induction activity, respectively, at 10 μM. Preliminary structure-activity relationship studies suggest that extending the carbon chain length of the substituent R, introducing a nitrogen atom into the alkyl chain, or introducing a heterocycle helps to improve the Nrf2 activation activity of the compounds.

[0141] Table 2. Activation activity results of Nrf2 for compounds of general formula I. a

[0142]

[0143]

[0144] a The Nrf2-inducible activity of the compound was calculated compared with the blank control.

[0145] Example 14: SH-SY5Y Neurocytotoxicity Test

[0146] The concentration to be prepared is 1×10 5 100 μL of SH-SY5Y neuronal cell suspension (1 × 10⁶ cells / mL) was added to each well of a 96-well cell culture plate. 5 Cells were incubated at 37°C in a 5% CO2 incubator for 24 hours. The culture medium was discarded, and the cells were washed once with PBS buffer. 100 μL of different concentrations of the compound prepared in MEM / F12 culture medium was added to each well. The blank control group received only MEM / F12 culture medium without the compound. After incubating the 96-well plates at 37°C in a 5% CO2 incubator for 24 hours, 15 μL of MTT solution (5 mg / mL) was added to each well in the dark, and the plates were incubated for another 2 hours. The culture medium was discarded, and 100 μL of dimethyl sulfoxide was added to each well. The absorbance (OD) of each well was measured at 490 nm using a multi-mode microplate reader. Cell viability was calculated using the following formula: Cell viability = (OD value of the drug group - OD value of the blank group) / (OD value of the normal group - OD value of the blank group) × 100%.

[0147] Table 3. Growth and survival rates of compounds of general formula I on SH-SY5Y nerve cells.

[0148]

[0149] The seven compounds I-1 to I-7 showed a cell survival rate greater than 90% after treatment with SH-SY5Y nerve cells at 1 μM and 10 μM, while the eight compounds I-1 to I-8 showed a cell survival rate greater than 80% at a concentration of 20 μM, indicating that the compounds were not cytotoxic within this concentration range.

[0150] Example 15: Effect of compounds on H2O2-induced damage to SH-SY5Y cells

[0151] SH-SY5Y cells were incubated at 37°C in a 5% CO2 incubator for 24 hours. After digestion with 0.125% trypsin, stably growing SH-SY5Y cells were collected, and 100 μL of cell suspension (1 × 10⁶ cells per well) was added to each well of a 96-well plate. 5 Cells were incubated at 37°C in a 5% CO2 incubator for 24 hours. Fresh culture medium was then added, and the cells were divided into a normal group, an H2O2 damage model group, and a pretreatment group using compound of formula I. The pretreatment group received 10 μM of the test compound, while the hydrogen peroxide and normal groups received no addition. After 2 hours of incubation, H2O2 (final concentration 100 μM) was added to all groups except the normal group, and incubation continued for another 24 hours. Cell viability was then assessed using the MTT assay. Results are shown below. Figure 1 As shown, the cell survival rate of the injury model group (column 2) with only H2O2 added decreased. All eight compounds in the general formula I compound pretreatment group showed good neuroprotective activity, and their activity was better than that of the positive control N-acetyl-L-cysteine ​​(L-NAC).

[0152] Example 16: Functional effects of compounds on in vitro cultured hippocampal neural networks

[0153] C57 juvenile mice, p0 days old, were anesthetized on ice, decapitated, and had their hippocampal tissue harvested. The tissue was digested in Papain's tissue digestion solution at 37°C for 20 minutes, and cells were counted. The digested cells were seeded onto slides in 24-well plates and cultured in a cell culture incubator. On day 3, a fluorescent protein was introduced to label intracellular calcium ion activity. Cells were cultured until the neural network matured at day 14, and calcium imaging experiments were performed. Imaging was recorded for 2 hours, with 0.5 hours each for the baseline, 0.1, 1, and 10 μM compound groups. Changes in intracellular fluorescence intensity were recorded and analyzed to reflect the functional effects of the compounds on the neural network. Results are as follows: Figure 2 , 3 The results show that the compounds inhibited fluorescence intensity in a concentration-dependent manner, indicating that the compounds have an inhibitory effect on intracellular activity, thereby weakening the functional activity of neural networks. Compound I-1 showed a concentration-dependent reduction in calcium ions in hippocampal neurons, inhibiting neural network activity; compounds I-1 to I-5 all showed significant inhibitory effects on intracellular calcium at a concentration of 10 μM, and all had inhibitory effects on network activity.

[0154] Example 17: Effects of compounds on the behavior of water mazes

[0155] Spatial learning ability in mice was assessed using the Morris water maze (MWM) behavioral test. The simplified experimental procedure was as follows: Each mouse was placed in a circular pool and allowed to swim freely. The time required for the mouse to reach the platform in the northeast quadrant (escape latency) and its swimming speed were recorded for each experiment. Once a mouse found the platform, it was allowed to remain on it for 10 seconds. If a mouse could not find the platform within 120 seconds, it was placed on the platform and allowed to remain there for 10 seconds. Mice underwent four trials per day for four consecutive days, with a 20-minute interval between trials. Each trial began by randomly placing the animal in one of four starting positions. Video recordings, escape latency, and swimming speed were recorded. On day 5, a single exploration trial was conducted. In this trial, the platform was removed, and each mouse was placed from the southwest quadrant of the pool and allowed to swim for 120 seconds. The time spent by the mouse in the target quadrant (northeast) was recorded and calculated. ApoE4 transgenic mice were used as a dementia model, and the experiment was divided into four groups: a saline control group, and groups treated with compounds I-1, I-4, and I-5. Subcutaneous injection of 10 mg / kg was administered for one month, followed by evaluation of the effects of the compounds on learning and memory in mice. Data showed that all compounds increased the time and frequency of transgenic mice remaining in the target area.

[0156] like Figure 4 As shown, compared with the saline (NS) control group, the treatment groups of compounds I-1, I-4, and I-5 significantly increased the time that the model mice spent in the target water area, indicating that they had an improving effect on learning and memory.

[0157] like Figure 5 As shown, compared with the saline (NS) control group, the treatment groups of compounds I-1 and I-4 significantly increased the number of times the model mice entered the target water area, indicating that they have an improving effect on learning and memory.

[0158] The preliminary results indicate that these compounds possess significant activity and good cytoprotective properties, without cytotoxicity. Functional experiments show that the compounds can reduce the activity of primary hippocampal neural networks by decreasing intracellular calcium levels, and behaviorally, they significantly improve spatial learning ability in dementia mice. Literature reports that a sustained increase in intracellular calcium ions, especially in mitochondria, leads to the production of free radicals and reactive oxygen species (ROS). Therefore, disruption of calcium homeostasis results in enhanced oxidative stress, free radical formation, and neuronal degeneration in Alzheimer's disease (AD) mouse models. In other words, changes in intracellular calcium ions may be the root cause of neuronal damage and dysfunction in AD. The compounds of this invention all significantly reduce intracellular calcium levels, thereby exerting a neuroprotective effect and showing potential therapeutic effects on degenerative diseases of the central nervous system, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis.

[0159] Therefore, the dihydropyrimidine [4,5-d]pyrimidine-2(H)-ketone Nrf2 activators prepared in this invention have broad application prospects in the preparation of drugs for the treatment of neurodegenerative diseases. The series of compounds described in this invention, as active ingredients, can be combined with conventional pharmaceutical excipients to prepare drugs for the treatment of neurodegenerative diseases, which can be formulated into any of the following dosage forms: tablets, capsules, powders, syrups, liquids, suspensions, or injections.

[0160] The above specific embodiments illustrate the preparation steps, identification process, and pharmacological experimental process of the compounds of the present invention. However, those skilled in the art can make various modifications and variations thereto. Without departing from the spirit and scope of the present invention, the appended claims cover all such modifications within the scope of the present invention.

Claims

1. A compound, or a pharmaceutically acceptable salt thereof, characterized in that, The structure of the compound is shown in general formula I: R is selected from (C3-C8) alkyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrazinyl or triazinyl, piperidyl, piperazinyl, morpholinyl, epoxybutyl, (dimethylamino) ethyl, (dimethylamino) methyl, (methylamino) propyl, (methylamino) ethyl, (methylethylamino) methyl, 2-aminoethyl, 3-aminopropyl, aminomethyl.

2. A compound, or a pharmaceutically acceptable salt thereof, characterized in that, The compound is selected from any one of the following:

3. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-2, wherein, The pharmaceutically acceptable salt is selected from hydrochloride, sulfate, phosphate, hydrobromide, maleate, citrate, succinate, methanesulfonate, toluenesulfonate.

4. A process for preparing a compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The compound of formula 3 is reduced by a reducing agent, and then acylated with 3-trifluoromethylbenzoyl chloride in the presence of a basic catalyst to obtain the target compound of general formula I 5. The preparation method according to claim 4, characterized in that, The reducing agent is a combination of iron powder and ammonium chloride, a combination of iron powder and ammonia, a combination of iron powder and acetic acid, a combination of iron powder and hydrochloric acid, a combination of ferric chloride and hydrazine, a combination of zinc and acetic acid, a combination of zinc and hydrochloric acid; the basic catalyst is potassium carbonate, sodium carbonate, lithium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, triethylamine, diisopropylethylamine, diisopropylamine, tetrabutylammonium bromide or tetrabutylammonium fluoride.

6. A process for preparing a compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, The preparation method comprises the following steps: Step a) using a compound of formula 1 as a starting material, reacting with an amino compound to obtain a compound of formula 2 Step b) reacting the compound of formula 2 with bis(trichloromethyl) carbonate to obtain a compound of formula 3 Step c) the compound of formula 3 is reduced by a reducing agent, and then acylated with 3-trifluoromethylbenzoyl chloride in the presence of a basic catalyst to obtain the target compound of general formula I.

7. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-2 in the preparation of a medicament for the prevention and / or treatment of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, epilepsy, Huntington's disease, amyotrophic lateral sclerosis and multiple sclerosis.

8. A pharmaceutical composition for preventing and / or treating neurodegenerative diseases, characterized by, A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, and a pharmaceutically acceptable excipient.

9. The pharmaceutical composition of claim 8, wherein, The pharmaceutical composition is formulated as tablets, capsules, powders, syrups, liquids, suspensions or injections.

10. A compound of formula 3 wherein R is selected from (C3-C8) alkyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrazinyl or triazinyl, piperidyl, piperazinyl, morpholinyl, epoxybutyl, (dimethylamino) ethyl, (dimethylamino) methyl, (methylamino) propyl, (methylamino) ethyl, (methylethylamino) methyl, 2-aminoethyl, 3-aminopropyl, aminomethyl.

11. A preparation method of a compound of formula 3 according to claim 10, characterized in that, Step (a) using a compound of formula 1 as a starting material, reacting with an amino compound to obtain a compound of formula 2; Step (b) reaction of a compound of formula 2 with bis(trichloromethyl) carbonate to give a compound of formula 3

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