Atevane type diterpenoid compound as well as preparation method and application thereof

Abstract

The invention relates to an atestin diterpenoid compound as well as a preparation method and application thereof, and belongs to the technical field of medicinal chemistry. The preparation method of the atestin diterpenoid compound comprises the following steps: S1, taking commercially available paranitroaniline 1a as a raw material to obtain an intermediate 2a; carrying out amide condensation and reduction on the intermediate 2a and corresponding amine to obtain intermediates 4a-4c; s2, taking commercially available m-nitrophenol 1d as a raw material to obtain an intermediate 3d; s3, taking commercially available 1-(t-butyloxycarbonyl) piperidine-3-carboxylic acid 1e as a raw material to obtain an intermediate 3e; s4, taking a compound J10 separated from a natural plant sea lacquer as a raw material to obtain compounds HXY1-6; and S5, taking a compound J12 separated from a natural plant sea lacquer as a raw material to obtain compounds HXY7-23. The invention aims to explore a preferable compound with a novel structure, better activity and high safety through structural optimization of a natural product, and provides support for research and development of a novel sEH inhibitor and an anti-AD drug.

Description

Technical Field

[0001] This application relates to the field of medicinal chemistry, and in particular to an atezonitrile-type diterpenoid compound, its preparation method, and its application. Background Technology

[0002] Alzheimer's disease (AD) is the most common type of dementia, which can cause problems such as loss of memory, thinking and behavior, interfering with patients' daily life and social autonomy, and ultimately leading to death.

[0003] Alzheimer's disease (AD) has an insidious onset and progressive development, involving multiple factors such as aging, genetics, immunity, and environment, posing a significant challenge to global healthcare systems. Currently, drugs approved for clinical use in China for AD symptomatic treatment include acetylcholinesterase inhibitors such as donepezil, rivastin, galantamine, and huperzine A, and N-methyl-D-aspartate receptor antagonists such as memantine. These can temporarily relieve related symptoms but cannot stop the long-term progression of the disease. Drugs characterized by disease-modifying therapy (DMT) include sodium mannitol capsules (GV-971) and the new drug Lecanemab (trade name Lecanemab), which aim to target β-amyloid protein to intervene in disease progression; however, their clinical efficacy still requires further evaluation. In summary, the number and efficacy of AD drugs on the market are far from meeting clinical needs, thus urgently requiring the development of novel drugs based on new targets.

[0004] Recent studies have shown that neuroinflammation is closely related to the progression of neurodegenerative diseases and has become the third major pathological feature of Alzheimer's disease (AD) after Aβ deposition and neurofibrillary tangles. In clinical research, anti-inflammatory therapy accounts for a large proportion of DMT (digestive disease treatment) therapy, and targeting neuroinflammation may become a highly effective method for the prevention and treatment of AD. Epoxy fatty acids (EpFA), derivatives of arachidonic acid metabolized via the (CYP) P450 pathway, possess anti-inflammatory activity. EpFA is further hydrolyzed by soluble epoxide hydrolases (sEH), thereby terminating its beneficial anti-inflammatory effects. Recently, increasing the level of the anti-inflammatory molecule epoxyeicosatrienoic acid (EETs) by blocking the hydrolytic degradation of EpFA by sEH has been shown to reduce central nervous system damage, and sEH inhibitors have demonstrated improved cognitive and memory effects in AD animal models. However, there is a lack of currently marketed sEH inhibitors, and novel sEH inhibitors with strong inhibitory activity and high safety profiles urgently need to be developed for AD treatment. This application aims to discover novel, highly active, and low-toxicity compounds by using medicinal chemistry methods and optimizing the structure of natural products, thereby providing active lead compounds and theoretical support for the development of AD drugs in cutting-edge fields. Summary of the Invention

[0005] In view of this, this application provides an atescenane-type diterpenoid compound, its preparation method and application. Most of the atescenane-type diterpenoid compounds have acceptable sEH inhibitory activity, show good improvement in cognitive and memory functions in AD model mice, and have a certain degree of safety, which can effectively overcome the defects of the prior art.

[0006] The first aspect of this application provides an atescenane-type diterpenoid compound, said atescenane-type diterpenoid compound being a compound of formula I or II, a pharmaceutically acceptable salt of a compound of formula I or II, an optical isomer of a compound of formula I or II, a hydrate of a compound of formula I or II, and a solvate of a compound of formula I or II, the structures of formula I and formula II being shown below:

[0007]

[0008] In the compounds shown in Formula I or Formula II, R1 and R2 are both selected from at least one of alkyl and cycloalkyl groups with 1-6 carbon atoms, morpholine rings, piperidine rings, piperazine rings, and substituted benzene rings; X1 and X2 are both O or N atoms.

[0009] Preferably, the atigenane-type diterpenoid compound is selected from methyl 3-((2S,3S,4aS,7R,8R,8aR)-3-hydroxy-3,8-dimethyl-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphthyl-8-yl)propionate, N-cyclopropyl-3-((2S,3S,4aS,7R,8R,8aR)-3-hydroxy-3,8-dimethyl-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphthyl-8-yl)propionamide, N-(cyclohexylmethyl)-3-((2S,3S,4aS,7R,8R,8aR)-3-hydroxy-3,8-dimethyl-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphthyl-8-yl)propionamide, and N-(cyclohexylmethyl)-3-((2S,3S,4aS,7R,8R,8aR)-3-hydroxy-3,8-dimethyl-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphthyl-8-yl)propionamide. Naphthyl-8-yl)propamide, 3-((2S,3S,4aS,7R,8R,8aR)-3-hydroxy-3,8-dimethyl-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethylidene-naphthyl)-N-(1H-pyrazol-5-yl)propamide, N-cyclohexyl-3-((2S,3S,4aS,7R,8R,8aR)-3-hydroxy-3,8-dimethyl-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphthyl)propamide, N-(cyclohexylmethyl)-3-((2S,3S,4aS,7R,8R,8aR)-3-hydroxy-3,8-dimethyl-7-(prop-1-en-2-yl)octahydro-2H-2,4a-yl) -Ethanenaphthalene-8-yl)propamide, N-cyclohexyl-4-(3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphthalene-8-yl)propamide)benzamide, N-cyclopentyl-4-(3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphthalene-8-yl)propamide)benzamide, N,N-diethyl-4-(3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphthalene) -8-yl)propionamide)benzamide, N-(cyclohexylmethyl)-3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propionamide, N-cyclohexyl-3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propionamide, N-(4-fluorophenylethyl)-3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propionamide, N,N-Diethyl-1-(3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propionyl)piperidine-3-carboxamide, 3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)-N-(3-(3-morpholinopropoxy)phenyl)propionamide, N-(adamantane-1-ylmethyl)-3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-( Prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propamide, N-cyclopropyl-3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propamide, N-(cyclopropylmethyl)-3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propamide, N-cyclopentyl-3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene N-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propamide, N-(cyclopentylmethyl)-3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propamide, N-(4-fluorophenyl)-3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propamide, N-(4-fluorophenyl)-3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propamide, N-(4-fluorophenyl)-3-((2S,4aR,7R,8R,8aR) One of the following: 8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propamide, 3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)-N-(4-(trifluoromethyl)phenyl)propamide, and 3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)-N-(4-(trifluoromethyl)phenylmethyl)propamide.

[0010] A second aspect of this application also provides a method for preparing the above-mentioned atrazine-type diterpenoid compound, comprising the steps of the following reaction formula:

[0011]

[0012] S1. Using commercially available p-nitroaniline 1a as raw material, in the presence of oxaloyl chloride, dry dichloromethane is used as solvent to react and obtain intermediate 2a; intermediate 2a is condensed with the corresponding amine by amide condensation and reduction to obtain intermediates 4a to 4c.

[0013] S2. Using commercially available m-nitrophenol 1d as a raw material and 4-(3-chloropropyl)morpholine as a reactant, in the presence of NaH and with tetrahydrofuran as a solvent, the reaction yields intermediate 2d; intermediate 2d is reduced to obtain intermediate 3d.

[0014] S3. Using commercially available 1-(tert-butyloxycarbonyl)piperidine-3-carboxylic acid 1e as raw material, it is amide condensed with diethylamine to obtain intermediate 2e, and intermediate 2e is then deprotected to obtain intermediate 3e.

[0015] S4. Using compound J10, which was isolated from natural plant lacquer, as a raw material, it was esterified with methanol to obtain compound HXY1; J10 was condensed with the corresponding commercially available amine to obtain compounds HXY2-6.

[0016] S5. Using compound J12, which is isolated from the natural plant lacquer, as a raw material, and intermediates 4a-4c, 3d, 3e or commercially available small molecule amines are amide-condensed to obtain compounds HXY7-23.

[0017] Preferably, step S1 specifically includes the following steps:

[0018] S1. Using 1a and oxalyl chloride as raw materials, dry dichloromethane as solvent, and N,N-dimethylformamide as catalyst, the reaction was carried out at room temperature for 4 hours to obtain intermediate 2a; 2a, commercially available amine, and triethylamine were dissolved in tetrahydrofuran and reacted at room temperature for 6 hours to obtain intermediates 3a-3c; 3a-3c were mixed with Pd(OH)2 in ethanol and reduced under a hydrogen atmosphere for 6 hours to obtain intermediates 4a-4c.

[0019] Preferably, step S2 specifically includes the following steps:

[0020] S2. Using 1d and 4-(3-chloropropyl)morpholine as raw materials, the reaction was carried out at room temperature for 4 hours in the presence of NaH to obtain intermediate 2d; 2d was mixed with Pd / C in ethanol and reduced under hydrogen atmosphere for 12 hours to obtain intermediate 3d.

[0021] Preferably, in step S4, the specific process of separating compound J10 from the natural plant E. agallocha is as follows: the stems and branches of E. agallocha are crushed, extracted with ethanol, and concentrated under reduced pressure to obtain a brown extract; the extract is suspended in water and extracted sequentially with n-hexane and ethyl acetate; the ethyl acetate phase is separated by silica gel column chromatography with chloroform-methanol gradient elution, the fraction is collected, and further purified by C18 reversed-phase silica gel column chromatography; finally, compound J10 is obtained by further separation by semi-preparative HPLC.

[0022] Preferably, in step S5, the specific process of separating compound J12 from the natural plant E. agallocha is as follows: the stems and branches of E. agallocha are crushed, extracted with ethanol, and concentrated under reduced pressure to obtain a brown extract; the extract is suspended in water and extracted sequentially with n-hexane and ethyl acetate; the ethyl acetate phase is separated by silica gel column chromatography with chloroform-methanol gradient elution, the fraction is collected, and further purified by C18 reversed-phase silica gel column chromatography; finally, compound J12 is obtained by further separation by semi-preparative HPLC.

[0023] A third aspect of this application also provides a pharmaceutical composition comprising the above-described atezonitrile-type diterpenoid compound and optionally pharmaceutically acceptable adjuvants or excipients.

[0024] The fourth aspect of this application also provides the use of the above-mentioned atezonitrile-type diterpenoids in the preparation of sEH inhibitors.

[0025] The fifth aspect of this application also provides the use of the above-mentioned atezonigenin-type diterpenoids in the preparation of medicaments for the prevention or treatment of Alzheimer's disease.

[0026] Compared with the prior art, this application has the following advantages:

[0027] This application represents a novel drug discovery model in the field of Alzheimer's disease (AD) treatment. Through structural optimization of natural products, it provides sEH inhibitors with high sEH inhibitory activity and drug development potential for AD treatment. The atezogene-type diterpenoid sEH inhibitors of this application mostly exhibit significant sEH inhibitory activity, good biocompatibility, and unique anti-neuroinflammatory activity. They have also demonstrated good cognitive and memory function improvement and neuroprotective effects in AD model mice. Therefore, this application is of great significance in the development of sEH inhibitors and their application in AD treatment. Attached Figure Description

[0028] To more clearly illustrate the technical solutions in this application or the prior art, the drawings used in the description of this application or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of this application. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0029] Figure 1 The image shows the proton NMR spectrum of compound HXY14.

[0030] Figure 2 The image shows the carbon NMR spectrum of compound HXY14.

[0031] Figure 3 This is the high-resolution mass spectrum of compound HXY14. Detailed Implementation

[0032] To make the objectives, technical solutions, and advantages of this application clearer, the technical solutions of this application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this application, not all embodiments. Based on the embodiments of this application, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this application.

[0033] Unless otherwise specified, the experimental methods used in the embodiments of this application are all conventional methods.

[0034] In the following examples, unless otherwise specified, all raw materials can be obtained by commercial purchase or conventional methods.

[0035] In the embodiments of this application, the term "substituted" refers to one or more hydrogen atoms in a group being independently replaced by a corresponding number of substituent groups.

[0036] In the embodiments of this application, the excipients or additives are substances, other than the active ingredient, that have undergone reasonable safety assessments and are included in the pharmaceutical formulation. These may include gum arabic, syrup, lanolin, starch, magnesium chloride, cyclodextrin, sebacic acid, dextrin, pharmaceutical-grade calcium sulfate, glycerin, mannitol, sorbitol, inositol, thiols, tromethamine, phenol, m-cresol, benzyl alcohol, parabens, methylparaben, tert-butanol, benzalkonium chloride, chlorobutanol, thimerosal, etc.

[0037] In the embodiments of this application, the derivatives of the compound of general formula I are used as prodrugs, indicating that they may have weak or even no activity on their own, but after administration, they are converted into the corresponding biologically active form under physiological conditions (e.g., through metabolism, solvation or other means).

[0038] The chemical structures of the embodiments in this application have all been verified. 1 H-NMR, 13 Confirmed by C-NMR and MS. Rapid column chromatography was performed on silica gel H (10-40 μM).

[0039] It should be noted that in the embodiments of this application, the stems and branches of E. agallocha were pulverized, extracted with ethanol, and concentrated under reduced pressure to obtain a brown extract; the extract was suspended in water and extracted successively with n-hexane and ethyl acetate; the ethyl acetate phase was separated by silica gel column chromatography with chloroform-methanol gradient elution, the fraction was collected, and further purified by C18 reversed-phase silica gel column chromatography; finally, compounds J10 and J12 were further separated by semi-preparative HPLC.

[0040] Example 1

[0041] Preparation of methyl 3-((2S,3S,4aS,7R,8R,8aR)-3-hydroxy-3,8-dimethyl-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propionate (HXY1):

[0042] Compound 3-((2S,3S,4aS,7R,8R,8aR)-3-hydroxy-3,8-dimethyl-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propionic acid (J10) (10.0 mg, 0.03 mmol) was dissolved in methanol (5 mL), and p-toluenesulfonic acid (2.7 mg, 0.015 mmol) and anhydrous MgSO4 were added. The reaction mixture was stirred under reflux for 9 hours and filtered through diatomaceous earth. The solvent was removed under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (Agilent 1260 HPLC system) using a reversed-phase C18 column (YMC, 250 mm × 10 mm inner diameter, 5 μm). The solvent system was acetonitrile / deionized water (80:20), the flow rate was 3 mL / min, and the UV detection wavelength was 195 nm / 254 nm. The target compound HXY1 was obtained as a white oily substance with a yield of 80%.

[0043] 1H NMR (400MHz, Chloroform-d) δ (ppm): 4.85 (p, J = 1.6 Hz, 1H), 4.67 (d, J = 2.1 Hz, 1H), 3.64 (s, 3 H),2.36(ddd,J=15.2,10.6,6.2Hz,1H),2.30–2.19(m,1H),1.97(ddd,J=14.8,9.3,2.8Hz,2H ),1.86(ddt,J=14.1,11.4,3.2Hz,1H),1.74(t,J=2.5Hz,4H),1.70–1.60(m,2H),1.54(td,J =7.0,3.2Hz,3H),1.27(d,J=13.7Hz,7H),1.23–1.08(m,3H),0.96(s,3H),0.87–0.80(m,1H). 13 C NMR(101MHz,Chloroform-d)δ(ppm):176.53,147.65,114.12,72.06,57.43,51.69,51.17,42.63,39.8 1,38.38,38.10,33.91,33.73,30.67,28.83,26.97,24.81,23.91,23.72,23.26,17.81.HRMS(ESI)m / z calcd for C 21 H 35 O3[M+H] + :335.2586,found 335.2590.

[0044] Example 2

[0045] Preparation of N-cyclopropyl-3-((2S,3S,4aS,7R,8R,8aR)-3-hydroxy-3,8-dimethyl-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propionamide (HXY2):

[0046] At 0 °C, a mixture of compounds 3-((2S,3S,4aS,7R,8R,8aR)-3-hydroxy-3,8-dimethyl-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propionic acid (J10) (10.0 mg, 0.03 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 6.9 mg, 0.036 mmol), 1-hydroxybenzotriazole (HOBt, 4.9 mg, 0.036 mmol), and N,N-diisopropylethylamine (DIPEA, 11.6 mg, 0.09 mmol) was stirred in dichloromethane (5 mL) for 30 minutes, followed by the addition of cyclopropylamine (3.4 mg, 0.06 mmol). The reaction mixture was then heated to room temperature and stirred for 8 hours. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC (Agilent 1260 liquid chromatography system) using a reversed-phase C18 column (YMC, 250 mm × 10 mm inner diameter, 5 μm). Acetonitrile / deionized water (60:40 to 100:0) was used as the solvent system at a flow rate of 3 mL / min and UV detection wavelengths of 195 nm / 254 nm to obtain HXY2, a white solid with a yield of 84%.

[0047] 1 H NMR (400MHz, Chloroform-d) δ (ppm): 5.60 (s, 1H), 4.85 (t, J = 1.9 Hz, 1H), 4.67 (d, J = 2.2 Hz, 1H), 2.67 (dq, J =7.1,3.5Hz,1H),2.18(ddd,J=14.2,10.1,6.6Hz,1H),2.09–2.01(m,1H),1.99–1.90(m,2H),1.85(ddt,J= 14.1,11.4,3.1Hz,1H),1.75(t,J=2.3Hz,4H),1.56–1.42(m,5H),1.34–1.26(m,7H),1.20(dd,J=13.6,3.0 Hz,2H),1.14–1.06(m,1H),0.95(s,3H),0.87–0.81(m,1H),0.74(td,J=7.0,5.2Hz,2H),0.53–0.38(m,2H). 13CNMR(101MHz,Chloroform-d)δ(ppm):175.09,148.00,113.42,72.18,57.38,51.27,42.66,39.87,38.42,38 .08,34.49,33.90,30.96,30.67,26.97,24.80,23.92,23.67,23.33,22.75,17.92,6.77,6.75.HRMS(ESI)m / z calcd for C 23 H 38 NO2[M+H] + :360.2902,found360.2900.

[0048] Example 3

[0049] Preparation of N-(cyclohexylmethyl)-3-((2S,3S,4aS,7R,8R,8aR)-3-hydroxy-3,8-dimethyl-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propionamide (HXY3): Following the synthesis method in Example 2, a white solid HXY3 was obtained in 81% yield.

[0050] 1 H NMR(400MHz,Chloroform-d)δ(ppm):5.46(s,1H),4.86(t,J=1.9Hz,1H),4.68(d,J=2.2Hz,1H),3.11–3.01(m,2H) ,2.29–2.18(m,1H),2.08(ddd,J=14.2,11.3,8.1Hz,1H),1.97(dq,J=11.1,4.9,3.9Hz,2H),1.86(ddt,J=14.2,11. 4,3.1Hz,1H),1.76(d,J=1.3Hz,3H),1.70(td,J=13.5,3.3Hz,6H),1.59(s,3H),1.55–1.50(m,3H),1.44(dtd,J=14 .7,7.3,4.2Hz,2H),1.31(d,J=21.0Hz,7H),1.24–1.17(m,4H),1.17–1.07(m,2H),0.96(s,3H),0.93–0.88(m,1H). 13C NMR(101MHz,Chloroform-d)δ(ppm):173.62,148.05,113.38,72.14,57.40,51.26,45.83,42.68,39.89,38.42,38.09,38 .07,34.71,33.90,31.31,30.95(2C),30.66,26.97,26.54(2C),25.95,24.79,23.91,23.66,23.31,17.92.HRMS(ESI)m / z calcd for C 27 H 46 NO2[M+H] + :416.3483,found416.3530.

[0051] Example 4

[0052] Preparation of 3-((2S,3S,4aS,7R,8R,8aR)-3-hydroxy-3,8-dimethyl-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethylenenaphthyl-8-yl)-N-(1H-pyrazol-5-yl)propionamide (HXY4): Following the synthesis method in Example 2, white solid HXY4 was obtained in 77% yield.

[0053] 1 H NMR (400MHz, Chloroform-d) δ (ppm): 8.00 (d, J=3.0Hz, 1H), 5.88 (d, J=3.0Hz, 1H), 4.86 (d, J= 13.2Hz,1H),4.72(d,J=12.0Hz,1H),3.01–2.85(m,2H),2.12–1.96(m,2H),1.88(ddt,J=14.0 ,11.3,3.1Hz,1H),1.78(d,J=4.0Hz,1H),1.75(s,3H),1.67–1.59(m,3H),1.57–1.45(m,3H), 1.41–1.31(m,3H),1.29(s,3H),1.28–1.11(m,3H),1.00(s,3H),0.86(td,J=12.3,6.3Hz,1H). 13C NMR(101MHz,Chloroform-d)δ(ppm):172.40,157.72,147.64,129.96,113.61,100.84,72.27,57.41,51.01,42.52 ,39.91,38.33,38.13,33.98,33.05,30.52,28.20,27.02,24.82,23.95,23.70,23.31,18.08.HRMS(ESI)m / zcalcd for C 23 H 36 N3O2[M+H] + :386.2807,found386.2810.

[0054] Example 5

[0055] Preparation of N-cyclohexyl-3-((2S,3S,4aS,7R,8R,8aR)-3-hydroxy-3,8-dimethyl-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propionamide (HXY5): Following the synthesis method in Example 2, white solid HXY5 was obtained in 86% yield.

[0056] 1 H NMR (400MHz, Chloroform-d) δ (ppm): 5.40 (s, 1H), 4.86 (q, J = 1.7Hz, 1H), 4.68 (d, J = 2.3Hz, 1H), 4.17 (q, J = 6.9H z,1H),2.20(ddd,J=14.1,9.5,6.6Hz,1H),2.13–2.02(m,1H),1.96(ddd,J=12.7,5.0,1.8Hz,3H),1.86(ddt,J= 14.1,11.4,3.1Hz,1H),1.76(d,J=1.4Hz,3H),1.72–1.58(m,9H),1.56–1.45(m,4H),1.39–1.30(m,5H),1.29(s ,3H),1.26–1.18(m,3H),1.11(td,J=14.3,13.4,4.2Hz,1H),0.96(s,3H),0.84(ddt,J=14.0,12.0,4.6Hz,1H). 13C NMR(101MHz,Chloroform-d)δ(ppm):173.24,148.06,113.39,72.19,57.42,51.25(2C),42.67,39.89,38.44,38.08, 34.62,33.91,33.31(2C),31.27,30.66,29.84,26.97,24.81,23.92,23.85(2C),23.69,23.34,17.93.HRMS(ESI)m / z calcd for C 26 H 44 NO2[M+H] + :402.3372,found 402.3370.

[0057] Example 6

[0058] Preparation of N-(cyclohexylmethyl)-3-((2S,3S,4aS,7R,8R,8aR)-3-hydroxy-3,8-dimethyl-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propionamide (HXY6): Following the synthesis method in Example 2, a white solid HXY6 was obtained in 80% yield.

[0059] 1 H NMR (400MHz, Chloroform-d) δ (ppm): 5.29 (d, J = 8.2 Hz, 1H), 4.86 (t, J = 1.9 Hz, 1H), 4.68 (d, J = 2.2 Hz, 1H), 3.72 (dddd, J =14.6,10.6,8.0,3.9Hz,1H),2.23–2.14(m,1H),2.10–1.99(m,1H),1.96(dt,J=11.0,2.6Hz,2H),1.91–1.84(m,3H),1. 76(s,3H),1.73–1.64(m,4H),1.63–1.56(m,1H),1.56–1.43(m,3H),1.33(td,J=12.8,12.0,3.3Hz,5H),1.28(s,3H),1. 21(dd,J=13.7,3.6Hz,2H),1.10(dqd,J=15.3,12.0,10.9,3.7Hz,4H),0.95(s,3H),0.84(tdd,J=12.5,7.2,3.9Hz,1H). 13C NMR(101MHz,Chloroform-d)δ(ppm):172.68,148.05,113.38,72.14,57.42,51.22,48.14,42.67,39.89,38.43,38.0 8,34.67,33.90,33.36,33.34,31.42,30.66,26.96,25.69,24.98,24.80,23.92,23.69,23.32,17.91.HRMS(ESI)m / z calcd for C 25 H 42 NO2[M+H] + :388.3215,found 388.3220.

[0060] Example 7

[0061] Preparation of N-cyclohexyl-4-(3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propionamide)benzamide (HXY7):

[0062] At 0 °C, oxalyl chloride (2.50 g, 20.0 mmol) was added dropwise to a dry dichloromethane solution (25 mL) of 1a (1.7 g, 10.0 mmol), followed by 5 drops of N,N-dimethylformamide. After stirring the mixture at room temperature for 4 hours, the solvent was removed under reduced pressure to obtain intermediate 2a. 2a (0.90 g, 5.0 mmol), cyclohexylamine (0.74 g, 7.5 mmol), and triethylamine (1.01 g, 10.0 mmol) were dissolved in tetrahydrofuran (10 mL), and stirred at room temperature for 6 hours. The residue was purified by column chromatography to obtain intermediate 3a. 3a (0.20 g, 1.0 mmol) was dissolved in ethanol (5 mL) with Pd(OH)₂ (20%), and the reaction was reduced under a hydrogen atmosphere for 6 hours. The mixture was filtered through diatomaceous earth, and the solvent was concentrated under reduced pressure to obtain intermediate 4a. Compound 3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propionic acid (J12) was amide condensed with intermediate 4a (see the synthesis method in Example 2) to give white solid HXY7 in 82% yield.

[0063] 1H NMR(400MHz,Chloroform-d)δ(ppm):7.70(d,J=8.1Hz,2H),7.55(d,J=7.9Hz,2H),5.91(s,1H),4.90(d,J =1.9Hz,1H),4.75(t,J=2.2Hz,2H),4.59(q,J=2.1Hz,1H),3.96(s,1H),2.44(ddd,J=15.9,10.3,6.1Hz,1 H),2.27(t,J=3.4Hz,1H),2.26–2.16(m,1H),2.12–1.81(m,7H),1.79(s,3H),1.75(td,J=7.8,6.8,3.7Hz ,2H),1.69–1.62(m,3H),1.55–1.48(m,2H),1.41(tt,J=12.0,3.2Hz,4H),1.35–1.13(m,8H),1.02(s,3H). 13 CNMR(101MHz,Chloroform-d)δ(ppm):172.51,171.82,152.30,148.26,140.90,130.91,128.01(2C),119.10(2C),113.55,105.07,51.74,48.83,48. 38,44.43,39.95,38.33,36.48,34.38,33.64,33.43,31.76(2C),29.38,2 8.68,28.48,27.19,25.74,25.07(2C),24.84,23.38,17.91.HRMS(ESI)m / z calcd for C 33 H 47 N₂O₂[M+H] + :503.3637,found503.3616.

[0064] Example 8

[0065] Preparation of N-cyclopentyl-4-(3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propionamide)benzamide (HXY8): Following the synthesis method in Example 7, a white solid HXY8 was obtained in 70% yield.

[0066] 1H NMR (400MHz, Chloroform-d) δ (ppm): 7.69 (d, J = 8.4Hz, 2H), 7.56 (d, J = 8.4Hz, 2H), 7.42 (d, J = 8.2Hz, 1H), 6.01 (d, J = 7.3Hz, 1H), 4.89 (s,1H),4.74(t,J=2.3Hz,2H),4.58(d,J=2.2Hz,1H),4.38(h,J=7.0Hz,1H),2.44(ddd,J=14.5,10.5,6.1Hz,1H),2.29–2.17(m,2H),2 .13–2.04(m,3H),1.99(td,J=10.6,8.8,2.9Hz,2H),1.92(d,J=3.5Hz,1H),1.90–1.81(m,1H),1.78(s,3H),1.76–1.68(m,2H),1.67–1 .61(m,4H),1.49(dt,J=12.3,6.2Hz,3H),1.40(tt,J=11.8,3.0Hz,2H),1.35–1.23(m,5H),1.16(td,J=13.4,4.1Hz,1H),1.01(s,3H). 13 C NMR(101MHz,Chloroform-d)δ(ppm):171.62,166.61,152.31,148.21,141.18,127.99(3C),119.09(2C),113.55,105.05,51.85,51.66,4 8.36,44.39,39.92,38.31,36.46,34.33,33.62,33.41(2C),29.46,28.63,28.47,27.18,24.81,23.97(2C),23.39,17.91.HRMS(ESI)m / z calcd for C 32 H 45 N₂O₂[M+H] + :489.3481,found489.3456.

[0067] Example 9

[0068] Preparation of N,N-diethyl-4-(3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propionamide)benzamide (HXY9): Following the synthesis method in Example 7, a white solid HXY9 was obtained in 80% yield.

[0069] 1H NMR (400MHz, Chloroform-d) δ (ppm): 7.53 (s, 1H), 7.45 (d, J = 7.9Hz, 2H), 7.27 (d, J = 11.8Hz, 2H), 4.90 (d, J = 2.3Hz, 1H), 4.75 (d, J = 2.4Hz, 2H), 4.59 (q, J = 2.0Hz, 1H), 3.39 (d, J = 83.7Hz, 4H), 2.43 (dt, J = 15.4, 7.3Hz, 1H), 2.27 (p, J = 2.6Hz,1H),2.20(dd,J=13.4,7.4Hz,1H),2.14–1.92(m,4H),1.92–1.82(m,1H),1.79(s,3H),1.63–1.56(m,4H),1. 56–1.46(m,2H),1.41(ddt,J=13.8,9.6,3.1Hz,2H),1.36–1.25(m,3H),1.18(td,J=13.3,4.1Hz,6H),1.02(s,3H). 13 C NMR(101MHz,Chloroform-d)δ(ppm):172.09,171.22,152.35,148.20,139.09,127.42,119.68,113.54,105.03,51.59,48 .39,44.38(3C),39.97,38.34,36.50,34.39,33.64,32.13,28.64,28.48,27.22,24.85,23.47,17.91(3C).HRMS(ESI)m / z calcd for C 31 H 45 N₂O₂[M+H] + :477.3481,found 477.3465.

[0070] Example 10

[0071] Preparation of N-(cyclohexylmethyl)-3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propionamide (HXY10): Following the synthesis method in Example 2, white solid HXY10 was obtained in 67% yield.

[0072] 1H NMR (400MHz, Chloroform-d) δ (ppm): 5.50–5.31 (m, 1H), 4.86 (d, J = 2.0Hz, 1H), 4.71 (dd, J = 17.4, 2.3Hz, 2H), 4.57 (t, J=2.3Hz,1H),3.05(t,J=6.4Hz,2H),2.28–2.16(m,2H),2.10–1.79(m,6H),1.76(s,3H),1.73(d,J=3.8Hz,1H),1.67(d t,J=8.6,3.6Hz,5H),1.59(dq,J=10.5,3.1Hz,2H),1.54(d,J=6.5Hz,1H),1.52–1.47(m,2H),1.47–1.33(m,3H),1.27( ddt,J=19.7,12.9,3.2Hz,2H),1.21–1.09(m,3H),1.07–0.99(m,1H),0.97(s,3H),0.90(qd,J=12.6,11.9,3.9Hz,2H). 13 C NMR(101MHz,Chloroform-d)δ(ppm):173.46,152.43,148.10,113.41,104.91,51.30,48.35,45.82,44.15,39.96,38. 33,38.07,36.49,34.67,33.58,31.27,30.95,28.59,28.46,27.22,26.54,25.94,24.84,23.57,17.90.HRMS(ESI)m / z calcd for C 27 H 44 NO[M+H] + :398.3423,found 398.3402.

[0073] Example 11

[0074] Preparation of N-cyclohexyl-3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propionamide (HXY11): Following the synthesis method in Example 2, white solid HXY11 was obtained in 79% yield.

[0075] 1H NMR (400MHz, Chloroform-d) δ (ppm): 5.23 (d, J = 8.3Hz, 1H), 4.86 (t, J = 1.9Hz, 1H), 4.73 (q, J = 2.4Hz, 1 H),4.69(d,J=2.2Hz,1H),4.56(q,J=2.1Hz,1H),3.72(tdt,J=11.1,8.0,3.9Hz,1H),2.29–2.14(m,2H ),2.09–1.94(m,4H),1.89(ddt,J=16.6,5.5,3.2Hz,3H),1.76(s,3H),1.73–1.64(m,3H),1.63–1.53( m,4H),1.52–1.44(m,3H),1.33(dddd,J=31.7,19.2,10.7,5.1Hz,5H),1.20–0.99(m,5H),0.97(s,3H). 13 C NMR(101MHz,Chloroform-d)δ(ppm):172.52,152.44,148.08,113.40,104.89,77.48,77.16,76.84,51.24,48.35,48.12,44.13,39 .96,38.33,36.49,34.60,33.57,33.36,33.34,31.39,28.59,28.44,27.20,25.68,24.96,24.84(2C),23.61,17.89.HRMS(ESI)m / z calcd forC 26 H 42 NO[M+H] + :384.3266,found 384.3251.

[0076] Example 12

[0077] Preparation of N-(4-fluorophenylethyl)-3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propionamide (HXY12): Following the synthesis method in Example 2, white solid HXY12 was obtained in 88% yield.

[0078] 1H NMR (400MHz, Chloroform-d) δ (ppm): 7.15–7.10 (m, 2H), 7.03–6.94 (m, 2H), 5.34 (d, J=6.0Hz, 1H), 4.81 (t, J= 1.9Hz,1H),4.74(q,J=2.4Hz,1H),4.64(d,J=2.2Hz,1H),4.57(q,J=2.1Hz,1H),3.50–3.39(m,2H),2.76(t,J =6.9Hz,2H),2.25(p,J=3.0Hz,1H),2.21–2.12(m,1H),2.09–1.75(m,6H),1.74(s,3H),1.62–1.49(m,3H),1. 48–1.28(m,5H),1.25(dt,J=10.7,4.3Hz,1H),1.13(td,J=13.4,4.1Hz,1H),1.07–0.98(m,1H),0.96(s,3H). 13 C NMR(101MHz,Chloroform-d)δ(ppm):173.53,163.01,160.58,152.40,148.06,134.67,130.35,130.27,115.65,115.44,113.39,104.95 ,51.35,48.33,44.12,40.71,39.90,38.28,36.47,35.01,34.64,33.57,31.16,28.56,28.45,27.20,24.81,23.47,17.92.HRMS(ESI)m / z calcd for C 28 H 39 FNO[M+H] + :424.3015,found 424.2990.

[0079] Example 13

[0080] Preparation of N,N-diethyl-1-(3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propionyl)piperidine-3-carboxamide (HXY13):

[0081] Under a nitrogen atmosphere and at 0 °C, a mixture of 1e (2.3 g, 10.0 mmol), EDCI (2.3 g, 12.0 mmol), HOBt (1.6 g, 1.2 mmol), and DIPEA (2.6 g, 20.0 mmol) was stirred in dichloromethane (20 mL) for 30 min, followed by the addition of diethylamine. The mixture was then heated to room temperature and stirred for 8 h. The residue was purified by column chromatography to give intermediate 2e. Yield 63%, 0.18 g. MS (ESI) m / z: 307.36 [M + Na] + 322.41[M+K] + A mixture of 2e (0.28 g, 1.0 mmol) and hydrochloric acid (37%) was stirred at room temperature for 4 hours. The mixture was concentrated under vacuum to give 3e. A white oily substance was obtained in 66% yield. 1 H NMR (400MHz, Chloroform-d) δ (ppm): 3.40–3.27 (m, 5H), 3.27–3.18 (m, 2H), 3.12 (dd, J=12.3, 9.4Hz, 1H), 2.92 (ddd, J=14.0, 10.6, 3.3Hz,1H),2.03–1.94(m,1H),1.93–1.80(m,2H),1.69(ddt,J=16.7,9.8,5.2Hz,1H),1.17(t,J=7.1Hz,3H),1.03(t,J=7.1Hz,3H).

[0082] Compound J12 was condensed with intermediate 3e via amide condensation (refer to the synthesis method in Example 2) to give a white oily substance HXY13 in 65% yield. 1HNMR(400MHz,Chloroform-d)δ(ppm):4.83(d,J=12.2Hz,1H),4.75–4.67(m,2H),4.60–4.55(m,1H),3.83(h,J=6.6 ,5.4Hz,1H),3.51–3.21(m,7H),3.01(t,J=13.0Hz,1H),2.62(td,J=12.5,12.0,3.9Hz,1H),2.49(qd,J=10.0,9.2, 5.3Hz,2H),2.39–2.28(m,1H),2.27–2.18(m,2H),2.16–2.03(m,1H),2.01–1.91(m,3H),1.79–1.72(m,6H),1.66–1 .53(m,4H),1.54–1.45(m,3H),1.44–1.36(m,3H),1.19(td,J=7.0,3.5Hz,3H),1.08(t,J=7.2Hz,3H),0.99(s,3H). 13 C NMR(101MHz,Chloroform-d)δ(ppm):172.27,172.18,152.60,148.71,113.48,105.46,51.54,47.99,46.43,45.21,44.34,42.01,40.27 ,40.07,39.29,38.27,36.53,34.29,33.62,28.65,28.50,27.85,27.65,27.26,25.91,24.97,23.61,17.29,15.06,12.56.HRMS(ESI)m / z calcd for C 30 H 49 N₂O₂[M+H] + :469.3794,found469.3782.

[0083] Example 14

[0084] Preparation of 3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)-N-(3-(3-morpholinopropoxy)phenyl)propionamide (HXY14):

[0085] 1d (0.14 g, 1.0 mmol) and NaH (0.06 g, 1.5 mmol) were dissolved in tetrahydrofuran (5 mL) and stirred at 0 °C for 30 min. Then, 4-(3-chloropropyl)morpholine (0.16 g, 1.0 mmol) was added. The mixture was then heated to room temperature and stirred for 4 h. After removing the solvent under reduced pressure, the mixture was purified by column chromatography to give intermediate 2d (yield 87%, 0.23 g). 2d (0.23 g, 0.9 mmol) was mixed with Pd / C (10%) in ethanol (5 mL) and reduced under a hydrogen atmosphere for 12 h. The mixture was filtered through diatomaceous earth and concentrated under reduced pressure to give intermediate 3d, a white solid, yield 79%, 0.17 g. 1 H NMR (400MHz, Chloroform-d) δ (ppm): 7.04 (t, J = 8.0 Hz, 1H), 6.29 (ddd, J = 13.3, 7.9, 2.3 Hz, 2H), 6.24 (t, J = 2.3 Hz, 1H), 3.97 (t,J=6.3Hz,2H),3.74–3.70(m,4H),2.53–2.49(m,2H),2.48–2.43(m,4H),1.94(p,J=6.7Hz,2H).MS(ESI)m / z:237.43[M+H] + .

[0086] Compound J12 was amide condensed with intermediate 3d (see the synthesis method in Example 2) to give white solid HXY14 in 88% yield. 1H NMR (400MHz, Chloroform-d) δ (ppm): 7.36 (s, 1H), 7.24 (s, 1H), 7.16 (t, J = 8.1H z,1H),6.85(dd,J=7.9,2.0Hz,1H),6.62(dd,J=8.2,2.5Hz,1H),4.88(t,J=1.8 Hz,1H),4.74(dt,J=5.2,2.3Hz,2H),4.58(q,J=2.0Hz,1H),4.00(t,J=6.3Hz,2 H),3.71(t,J=4.6Hz,4H),2.49(t,J=7.4Hz,2H),2.46–2.43(m,4H),2.41–2.34 (m,1H),2.26(q,J=3.4Hz,1H),2.20–2.12(m,1H),2.06(ddd,J=18.8,16.6,2.5 Hz,2H),1.99–1.91(m,4H),1.89–1.81(m,2H),1.78(s,3H),1.61(dt,J=10.3,4 .6Hz,3H),1.49(ddd,J=13.0,6.8,2.4Hz,1H),1.40(tt,J=11.3,3.3Hz,2H),1. 34–1.23(m,2H),1.16(td,J=13.3,4.0Hz,1H),1.11–1.01(m,1H),1.00(s,3H). 13 CNMR(101MHz,Chloroform-d)δ(ppm):171.79,159.71,152.34,148.19,139 .38,129.69,113.51,111.61,110.72,106.00,105.02,67.10(2C),66.24,55 .69,53.86(2C),51.60,48.36,44.36,39.91,38.32,36.47,34.44,33.61,3 2.30,28.62,28.47,27.19,26.52,24.83,23.44,17.91.HRMS(ESI)m / zcalcd forC 33 H 49 N₂O₃[M+H] + :521.3743,found 521.3752.

[0087] Figure 1 The image shows the proton NMR spectrum of compound HXY14. Figure 2 The image shows the carbon NMR spectrum of compound HXY14. Figure 3 This is the high-resolution mass spectrum of compound HXY14.

[0088] Example 15

[0089] Preparation of N-(adamantane-1-ylmethyl)-3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propionamide (HXY15): Following the synthesis method in Example 2, white solid HXY15 was obtained in 81% yield.

[0090] 1 H NMR (400MHz, Chloroform-d) δ (ppm): 5.39 (s, 1H), 4.87 (s, 1H), 4.76–4.68 (m, 2H), 4.57 (d, J = 3. 0Hz,1H),2.98–2.84(m,2H),2.27–2.17(m,2H),2.11–1.86(m,8H),1.86–1.79(m,1H),1.77(s,3 H),1.71(d,J=12.0Hz,4H),1.61(d,J=12.7Hz,5H),1.53(ddd,J=13.7,6.6,2.7Hz,3H),1.45(d, J=3.0Hz,6H),1.42–1.25(m,3H),1.15(tt,J=13.1,3.6Hz,1H),1.08–1.01(m,1H),1.00(s,3H). 13 C NMR(101MHz,Chloroform-d)δ(ppm):173.60,152.42,148.18,113.41,104.92,51.41,50.98,48.37,44.20,40.38(3C),40.00 ,38.35,37.11(3C),36.51,34.87,33.80,33.60,31.44,28.61,28.48,28.37(3C),27.24,24.84,23.51,17.91.HRMS(ESI)m / z calcd for C 31 H 48 NO[M+H] + :450.3736,found 450.3704.

[0091] Example 16

[0092] Preparation of N-cyclopropyl-3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propionamide (HXY16): Following the synthesis method in Example 2, a white solid HXY16 was obtained in 64% yield, MS (ESI) m / z: 342.32 [M+H]. + .

[0093] Example 17

[0094] Preparation of N-(cyclopropylmethyl)-3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propionamide (HXY17): Following the synthesis method in Example 2, a white solid HXY17 was obtained in 75% yield, MS (ESI) m / z: 356.45 [M+H]. + .

[0095] Example 18

[0096] Preparation of N-cyclopentyl-3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propionamide (HXY18): Following the synthesis method in Example 2, a white solid HXY18 was obtained in 77% yield, MS (ESI) m / z: 370.41 [M+H]. + .

[0097] Example 19

[0098] Preparation of N-(cyclopentylmethyl)-3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propionamide (HXY19): Following the synthesis method in Example 2, a white solid HXY19 was obtained in 60% yield, MS (ESI) m / z: 384.46 [M+H]. + .

[0099] Example 20

[0100] Preparation of N-(4-fluorobenzyl)-3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propionamide (HXY20): Following the synthesis method in Example 2, a white solid HXY20 was obtained in 56% yield, MS (ESI) m / z: 410.21 [M+H]. + .

[0101] Example 21

[0102] Preparation of N-(4-fluorophenyl)-3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)propionamide (HXY21): Following the synthesis method in Example 2, white solid HXY21 was obtained in 79% yield, MS (ESI) m / z: 396.38 [M+H] + .

[0103] Example 22

[0104] Preparation of 3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)-N-(4-(trifluoromethyl)phenyl)propionamide (HXY22): Following the synthesis method in Example 2, a white solid HXY22 was obtained in 71% yield, MS (ESI) m / z: 446.51 [M+H]. + .

[0105] Example 23

[0106] Preparation of 3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanenaphth-8-yl)-N-(4-(trifluoromethyl)benzyl)propionamide (HXY23): Following the synthesis method in Example 2, white solid HXY23 was obtained in 79% yield, MS (ESI) m / z: 460.41 [M+H] + .

[0107] Test case

[0108] 1. The activity data of the compounds in Examples 1 to 23 are shown in Table 1. Most of the compounds showed improved inhibitory activity against sEH.

[0109]

[0110] Table 1

[0111]

[0112]

[0113] sEH inhibitory activity: A: High, B: Moderate, C: Low

[0114] As can be seen from the data in Table 1, most compounds exhibit good inhibitory activity against sEH.

[0115] 2. Aβ 1-42 Induced AD model mice were treated with compound HXY14 (10.0 mg / kg, 30.0 mg / kg, ip) and donepezil (2.0 mg / kg, ip) for 15 days. The results showed that compound HXY14 alleviated memory impairment in AD mice and demonstrated cognitive improvement.

[0116] 3. Treatment with compound HXY14 for two weeks had no effect on the average daily body weight of mice. Serum biochemical tests showed no significant differences in liver and kidney function indicators such as total bilirubin (T-Bil), alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), urea (UREA), and the AST / ALT ratio compared to the blank control group. Hematoxylin-eosin (H&E) staining showed no abnormalities in the number of neurons and nuclear morphology in the CA1, CA3, and DG regions of the hippocampus of mice. The results indicate that compound HXY14 has no significant toxicity and good safety.

[0117] 4. HXY14 can reduce neuroinflammation and microglial activation in AD mice, which plays a crucial role in cognitive improvement during AD treatment.

[0118] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of this application, and are not intended to limit them. Although this application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of this application.

Claims

1. An atisine-type diterpene compound, characterized in that, The atisine-type diterpenoid compound is a compound shown in formula I or formula II, a pharmaceutically acceptable salt of the compound shown in formula I or formula II, an optical isomer of the compound shown in formula I or formula II, a hydrate of the compound shown in formula I or formula II, and a solvate of the compound shown in formula I or formula II, and the formula I and formula II are shown as follows: In the compound shown in formula I or formula II, R1 and R2 are at least one selected from alkyl and cycloalkyl with 1-6 carbon atoms, a morpholine ring, a piperidine ring, a piperazine ring, and a substituted benzene ring; X1 and X2 are O or N atoms.

2. The altisine-type diterpenoid compound of claim 1, wherein, The atisine-type diterpenoid is selected from the group consisting of methyl 3-((2S,3S,4aS,7R,8R,8aR)-3-hydroxy-3,8-dimethyl-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanophenantrene-8-yl)propanoate, N-cyclopropyl-3-((2S,3S,4aS,7R,8R,8aR)-3-hydroxy-3,8-dimethyl-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanophenantrene-8-yl)propanamide, N-(cyclohexylmethyl)-3-((2S,3S,4aS,7R,8R,8aR)-3-hydroxy-3,8-dimethyl-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanophenantrene-8-yl)propanamide, 3-((2S,3S,4aS,7R,8R,8aR)-3-hydroxy-3,8-dimethyl-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanophenantrene-8-yl)-N-(1H-pyrazol-5-yl)propanamide, N-cyclohexyl-3-((2S,3S,4aS,7R,8R,8aR)-3-hydroxy-3,8-dimethyl-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanophenantrene-8-yl)propanamide, N-(cyclohexylmethyl)-3-((2S,3S,4aS,7R,8R,8aR)-3-hydroxy-3,8-dimethyl-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanophenantrene-8-yl)propanamide, N-cyclohexyl-4-(3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanophenantrene-8-yl)propanamido)benzamide, N-cyclopentyl-4-(3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanophenantrene-8-yl)propanamido)benzamide, N,N-diethyl-4-(3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanophenantrene-8-yl)propanamido)benzamide, N-(cyclohexylmethyl)-3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanophenantrene-8-yl)propanamide, N-cyclohexyl-3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanophenantrene-8-yl)propanamide, N-(4-fluorophenethyl)-3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanophenantrene-8-yl)propanamide, N,N-diethyl-1-(3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanophthalen-8-yl)propanoyl)piperidine-3-carboxamide, 3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanophthalen-8-yl)-N-(3-(3-morpholinopropoxy)phenyl)propanamide, N-(adamantan-1-ylmethyl)-3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanophthalen-8-yl)propanamide, N-cyclopropyl-3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanophthalen-8-yl)propanamide, N-(cyclopropylmethyl)-3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanophthalen-8-yl)propanamide, N-cyclopentyl-3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanophthalen-8-yl)propanamide, N-(cyclopentylmethyl)-3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanophthalen-8-yl)propanamide, N-(4-fluorobenzyl)-3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanophthalen-8-yl)propanamide, N-(4-fluorophenyl)-3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanophthalen-8-yl)propanamide, 3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanophthalen-8-yl)-N-(4-(trifluoromethyl)phenyl)propanamide, 3-((2S,4aR,7R,8R,8aR)-8-methyl-3-methylene-7-(prop-1-en-2-yl)octahydro-2H-2,4a-ethanophthalen-8-yl)-N-(4-(trifluoromethyl)benzyl)propanamide, 3. A method for preparing the altisporine diterpene compound according to claim 1 or 2, characterized by, The method comprises the following steps according to the reaction formula: S1, using commercially available p-nitroaniline 1a as a raw material, reacting in the presence of oxalyl chloride to obtain an intermediate 2a in dry dichloromethane as a solvent; the intermediate 2a is subjected to amide condensation and reduction with a corresponding amine to obtain an intermediate 4a-4c; S2, using commercially available m-nitrophenol 1d as a raw material, reacting in the presence of NaH in tetrahydrofuran as a solvent to obtain an intermediate 2d; the intermediate 2d is subjected to reduction to obtain an intermediate 3d; S3, using commercially available 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid 1e as a raw material, reacting with diethylamine to obtain an intermediate 2e through amide condensation, and then the intermediate 2e is subjected to deprotection to obtain an intermediate 3e; S4, using a compound J10 separated from a natural plant of sea buckthorn as a raw material, reacting with methanol to obtain a compound HXY1 through esterification; the compound J10 is subjected to amide condensation with a corresponding amine to obtain compounds HXY2-6; S5, using a compound J12 separated from a natural plant of sea buckthorn as a raw material, reacting with the intermediate 4a-4c, 3d, 3e or a corresponding small molecule amine to obtain compounds HXY7-23 through amide condensation.

4. The method for preparing atrazine-type diterpenoids according to claim 3, characterized in that, The step S1 specifically comprises the following steps: S1, using 1a and oxalyl chloride as raw materials, dry dichloromethane as a solvent, and N,N-dimethylformamide as a catalyst, reacting at room temperature for 4 hours to obtain an intermediate 2a; 2a, a commercially available amine and triethylamine are dissolved in tetrahydrofuran, and reacting at room temperature for 6 hours to obtain an intermediate 3a-3c; 3a-3c are mixed with Pd(OH)2 in ethanol, and subjected to reduction reaction under hydrogen atmosphere for 6 hours to obtain an intermediate 4a-4c.

5. The method of claim 3, wherein the at least one solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetonitrile, acetone, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, and mixtures thereof. The step S2 specifically comprises the following steps: S2, using 1d and 4-(3-chloropropyl)morpholine as raw materials, reacting in the presence of NaH at room temperature for 4 hours to obtain an intermediate 2d; 2d is mixed with Pd / C in ethanol, and subjected to reduction reaction under hydrogen atmosphere for 12 hours to obtain an intermediate 3d.

6. The process for the preparation of altisine-type diterpenoid compounds according to claim 3, wherein, In the step S4, the specific process of the compound J10 separated from a natural plant of sea buckthorn is as follows: the stems and branches of sea buckthorn are crushed, and then extracted with ethanol; the brown extract is obtained by concentration under reduced pressure; the extract is suspended in water, and then extracted with n-hexane and ethyl acetate in sequence; the ethyl acetate phase is separated by silica gel column chromatography, eluted with chloroform-methanol gradient, and then collected; further purification is performed by C18 reverse phase silica gel column chromatography; finally, further separation is performed by semi-preparative HPLC to obtain the compound J10.

7. The method of claim 3, wherein the at least one solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetonitrile, acetone, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, and mixtures thereof. The specific process of the compound J12 separated from the natural plant Xylococcus Bauhinii is as follows: the branches of Xylococcus Bauhinii are crushed, and then extracted with ethanol, and concentrated under reduced pressure to obtain a brown extract; the extract is suspended in water, and then extracted with n-hexane and ethyl acetate in sequence; the ethyl acetate phase is separated by silica gel column chromatography, eluted with chloroform-methanol gradient, and then collected; the fractions are further purified by C18 reverse phase silica gel column chromatography; finally, the compound J12 is further separated by semi-preparative HPLC.

8. A pharmaceutical composition comprising a compound of the formula: ###0003### or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier. The pharmaceutical composition contains the atisine-type diterpenoid compound according to claim 1 or 2, and optionally a pharmaceutically acceptable additional agent or excipient.

9. Use of the atisine-type diterpenoid compound according to claim 1 or 2 in the preparation of an sEH inhibitor.

10. Use of the atisine-type diterpenoid compound according to claim 1 or 2 in the preparation of a drug for preventing or treating Alzheimer's disease.

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