Process for the preparation of adamantylamine nitrate compounds having neuroprotective effects

Abstract

The present invention relates to a preparation method of a nitrated amantadine compound with neuroprotective effect. The compound has multiple mechanisms of action, including inhibition of NMDA receptor, release of NO, inhibition of calcium ion influx, and good protection for cells, especially nerve cells. The compound can be used for preparing a drug with cell protection effect, for preventing or treating diseases related to NMDA receptor, intracellular calcium ion increase, etc., such as neurodegenerative diseases including senile dementia, Parkinson, cerebral stroke, glaucoma, etc., and diseases related to cardiovascular system such as Parkinson syndrome combined with cerebral arteriosclerosis, and prevention or treatment of respiratory tract infection caused by influenza virus.

Description

[0001] This application is a divisional application of the Chinese invention patent filed on May 29, 2014, with application number 201410235747.5, entitled "Adamantane nitrate compound with neuroprotective effect, its preparation and pharmaceutical application thereon". Technical Field

[0002] This invention belongs to the field of pharmaceutical technology and relates to an adamantane derivative with neuroprotective effects, its synthesis method, pharmaceutical uses, and applications in the prevention or treatment of diseases. Background Technology

[0003] Amantadine and its derivatives possess various biological activities and have wide applications in the pharmaceutical field. Rimantadine (1-aminoethyladamantane) is currently a widely used drug in clinical practice for the prevention and treatment of influenza. Amantadine is also widely used in the treatment of influenza and Parkinson's Disease (PD) (Schwab et al., J.Am.Med.Assoc.1969,208:1168). Memantine (1,3-dimethylamantadine) is currently the only NMDA receptor antagonist approved by the US FDA for the treatment of moderate to severe Alzheimer's Disease (AD). NMDA receptors are a subtype of an important class of excitatory amino acid ionotropic glutamate receptors in the central nervous system, and are important receptors in learning and memory processes. Once the NMDA receptor pathway is opened, it can non-selectively allow certain cations, such as Ca2+, to pass through. 2+ K + and Na +Once inside the cell, these ions, especially calcium ions, trigger a series of biochemical reactions, ultimately leading to neurotoxicity and neuronal apoptosis. Memantine is a non-competitive antagonist of NMDA receptor opening channels. It binds to binding sites within ion channels, blocking ion influx and exerting a neuroprotective effect. Memantine's binding to NMDA receptors is reversible and has a moderate dissociation rate, ensuring both its pharmacological effect and preventing accumulation within the channel that could impair normal physiological function (Lipton et al., Journal of Neurochemistry. 2006, 97:1611-1626). Meanwhile, the antagonistic effect of methimazole on NMDA receptors is highly voltage-dependent, binding only to receptors during neuronal depolarization. Therefore, it can block NMDA receptor activation during sustained neuronal depolarization under pathological conditions, but not under normal physiological conditions (Wenk et al., CNS drugreviews. 2003, 9(3):275-308; McKeage., Drugs & Aging. 2010, 27(2):177-179). This protective mechanism is also significant for the treatment of other central nervous system diseases such as stroke, PD, and ALS, thus showing promising potential for their treatment.

[0004] Nitric oxide (NO) also possesses various biological activities in the body, acting as a signaling molecule. Nitric oxide molecules can penetrate cell walls to enter smooth muscle cells, relaxing them, dilating blood vessels, and lowering blood pressure. Simultaneously, it can enter platelet cells, reducing their activity and thus inhibiting aggregation and adhesion to the vascular endothelium, preventing thrombosis and atherosclerosis. NO is a free radical gas with an unpaired electron, making it extremely unstable in the body and readily reacting with free radicals, thereby reducing their numbers. The accumulation of free radicals can cause nucleic acid breakage, enzyme inactivation, polysaccharide depolymerization, lipid peroxidation, and ultimately neuronal death (Yan et al. Free Radic. Biol. Med. 2013, 62:90-101). NO has a strong reactivity with various free radicals and can effectively reduce their numbers, but its synthesis in the body requires the participation of nitric oxide synthase (NOS). Under normal circumstances, the activity of NOS is relatively low, requiring activation by nitro molecules or saponins. Introducing NO-releasing groups into small molecule drugs can increase the NO content in the body and has significant therapeutic effects, such as nitroglycerin.

[0005] Due to the complex pathogenesis of Alzheimer's disease (AD), current clinical treatment options for AD are limited, consisting of only four acetylcholinesterase inhibitors and one NMDA receptor inhibitor. These drug molecules, which target a single site, can only alleviate certain clinical symptoms of AD but cannot fundamentally cure the disease or halt the neurodegenerative process. Summary of the Invention

[0006] The purpose of this invention is to provide an amantadine nitrate compound with multiple targets and neuroprotective effects. This type of compound, through pharmacophore-based drug design theory, integrates multiple pharmacophores with clearly defined targets into the same molecule, simultaneously exhibiting NMDA inhibitory activity, releasing NO, inhibiting calcium ion influx, and scavenging free radicals, thus exerting a neuroprotective effect. This type of compound possesses multiple mechanisms of action, which can enhance its efficacy and reduce the toxic side effects of combined drug use.

[0007] Another objective of this invention is to provide a method for preparing the aforementioned adamantane nitrate compound with neuroprotective effects.

[0008] Another objective of this invention is to provide the application of the aforementioned neuroprotective compound, adamantane nitrate, in pharmaceutical manufacturing.

[0009] The compounds provided in this invention have the structure of general formula (I):

[0010]

[0011] in:

[0012] R1, R2, and R3 may be the same or different, and are respectively hydrogen, straight-chain or branched alkyl, substituted or unsubstituted aryl, aromatic heterol, or nitrate ester group, and at least one of R1, R2, and R3 contains a nitrate ester group.

[0013] Further preferred compounds of general formula (I) have the structure of general formula (II):

[0014]

[0015] in:

[0016] R1 and R2 may be the same or different, and represent hydrogen, straight-chain or branched alkyl, substituted or unsubstituted aryl, or aromatic heterol, respectively.

[0017] Z1 is a straight or branched carbon chain connected to the R3 nitrate ester group, wherein Z1 may be substituted with heteroatoms, alkyl, aryl or aromatic heteroatoms, and Z1 contains 1-6, 1-5, 2-5 or 2-4 carbon atoms.

[0018] Compounds of general formula (II), preferably wherein at least one of R1 and R2 is hydrogen.

[0019] The compound of general formula (II) preferably has R2 as hydrogen, R1 as a straight-chain or branched alkyl group, and the sum of the number of carbon atoms in Z1 and the number of carbon atoms in R1 is not less than 3, preferably not less than 4, for example 4-6.

[0020] The compound of general formula (I), more preferably, wherein R1 and R3 are nitrate ester groups, that is, the compound has the structure of general formula (III):

[0021]

[0022] in:

[0023] R2 is hydrogen, straight-chain or branched alkyl, substituted or unsubstituted aryl, or aromatic heterol.

[0024] Z1 and Z2, whether the same or different, are straight or branched carbon chains that connect the respective nitrate ester groups on R1 and R3, wherein Z1 and Z2 may each be substituted with heteroatoms, alkyl, aryl or aromatic heteroatoms, and Z1 and Z2 each contain 1-6, 1-5, 2-5 or 2-4 carbon atoms.

[0025] Compounds of general formula (III) are preferably those having one of the following structures:

[0026]

[0027] The compound of general formula (I), more preferably, wherein R1, R2 and R3 are nitrate ester groups, that is, the compound has the structure of general formula (IV):

[0028]

[0029] in:

[0030] Z1, Z2, and Z3, whether identical or different, are straight or branched carbon chains connecting the respective nitrate ester groups on R1, R2, and R3, wherein each of Z1, Z2, and Z3 may be substituted with heteroatoms, alkyl groups, aryl groups, or aromatic heteroatoms, and each of Z1, Z2, and Z3 contains 1-6, 1-5, 2-5, or 2-4 carbon atoms.

[0031] Based on general formula (I), some specific optimized compounds include, but are not limited to, the following compounds:

[0032]

[0033] The present invention also provides a method for synthesizing the adamantaneamine nitrate compound. The synthesis comprises: using adamantane substituted with or unsubstituted with a brominated, alkyl, or alkylcarboxylic acid group as a starting material, first introducing an amino group via a Ritter reaction, and then generating a nitrate ester by esterification of the hydroxyl group on the adamantane ring with fuming nitric acid on the substituted side chain.

[0034] The compounds provided by this invention have good protective effects on cells, especially nerve cells, and can be used to prepare drugs with cell-protective effects. The drug may comprise an effective therapeutic dose of a compound having the aforementioned structural formula (I) or a pharmaceutically acceptable salt thereof, to be administered to a patient.

[0035] This invention provides a compound with multiple mechanisms of action, including inhibiting NMDA receptors, releasing NO, inhibiting intracellular calcium ion elevation, scavenging free radicals, and exhibiting good protective effects on cells, especially nerve cells. The compound can be used to prepare a drug with cytoprotective effects for the prevention or treatment of diseases related to elevated intracellular calcium ions, excessive free radical production, or overactivation of NMDA receptors, such as Alzheimer's disease, Parkinson's disease, stroke, Huntington's disease, amyotrophic lateral sclerosis, myasthenia gravis, and glaucoma. Methods for preventing or treating the above-mentioned diseases include administering to a patient a drug prepared from the compound of this invention, comprising an effective therapeutic dose of a compound having the aforementioned general formulas (I) to (V) or a pharmaceutically acceptable salt thereof or a corresponding drug complex.

[0036] The following definitions are used to clarify and define the meaning and scope of the various terms used in this invention.

[0037] As used herein, the term "alkyl" refers to an alkyl carbon chain of up to 10 carbon atoms, whether unsubstituted or substituted, and whether straight-chain, branched, or cyclic. Straight-chain alkyl includes saturated alkyl groups such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl, as well as unsaturated alkyl groups containing substituents such as olefinic, alkyneic, carbonyl, or cyano groups. Branched alkyl includes isopropyl, sec-butyl, isobutyl, tert-butyl, and neopentyl. Cyclic alkyl ("cycloalkyl") includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Alkyl groups may be substituted with one or more hydrophobic substituents. Non-limiting examples of the aforementioned substituents include N(CH3)2, F, Cl, Br, I, OCH3, CO2CH3, CN, aryl, and heteroaryl. The term "alkyl" also refers to an unsubstituted or substituted straight-chain, branched, or cyclic alkyl group containing up to 10 carbon atoms and at least one heteroatom (e.g., nitrogen, oxygen, or sulfur) on the chain. Straight-chain alkyl groups include, for example, CH2CH2OCH3, CH2CH2N(CH3)2, and CH2CH2SCH3. Branched groups include, for example, CH2CH(OCH3)CH3, CH2CH(N(CH3)2)CH3, and CH2CH(OCH3)CH3. Cyclic groups include, for example, six-membered rings CH(CH2CH2)2O, CH(CH2CH2)2NCH3, and CH(CH2CH2)2S, and corresponding five-membered rings, etc.

[0038] As used herein, the term "aryl" refers to unsubstituted or substituted aromatic compounds, carbocyclic groups, and heteroaryl groups. Aryl compounds can be monocyclic or polycyclic fused compounds. Aryl groups can be substituted by one or more substituents, non-limiting examples of which include N(CH3)2, F, Cl, Br, I, OCH3, CO2CH3, CN, aryl, and heteroaryl groups.

[0039] Heteroaryl groups involve substituted or unsubstituted monocyclic or polycyclic groups, with at least one heteroatom, such as nitrogen, oxygen, or sulfur, within the ring. For example, typical heterocyclic groups include one or more nitrogen atoms such as tetrazolium, pyrrole, pyridinium (e.g., 4-pyridinium, 3-pyridinium, 2-pyridinium), pyridazinium, indolium, quinolinium (e.g., 2-quinolinium, 3-quinolinium), imidazolyl, isoquinolinium, pyrazolium, pyrazinium, pyrimidinium, pyridoneyl, or pyridazinium; typical heterocyclic groups containing one oxygen atom include 2-furanyl, 3-furanyl, or benzofuranyl; typical sulfur heteroatom groups include thiopheneyl and benzothiopheneyl; typical mixed heteroatom groups include furazolidone, oxazolyl, isoxazolyl, thiazolyl, and phenthiazolyl. Heterocyclic groups can be substituted by one or more substituents. These substituents include O-alkyl, NH-alkyl, N(alkyl)2, NHC(O)-alkyl, F, Cl, Br, I, OH, OCF3, CO2-alkyl, CN, as well as aryl and polyaryl groups.

[0040] As used herein, the term "pharmaceutically acceptable" refers to compounds, such as salts or excipients, that do not possess unacceptable toxicity. Pharmaceutically acceptable salts include inorganic anions such as chloride, bromide, iodide, sulfate, sulfite, nitrate, nitrite, phosphate, and hydrogen phosphate. Organic anions include acetate, propionate, cinnamate, benzosulfonate, citrate, lactate, and gluconate. Pharmaceutically acceptable excipients are described later; see E.W. Martin, in Remington's Pharmaceutical Sciences, Mack Publishing Company (1995), Philadelphia, PA, 19th ed.

[0041] The novel compounds involved in this invention include the aforementioned structural formulas (I) to (VIII). These novel compounds contain at least one additional substituent group selected from amino, ester, and nitrate ester groups on the adamantane structure. Therefore, these compounds possess multiple mechanisms of action, inhibiting monoamine oxidase and cholinesterase, releasing NO and H2S, scavenging free radicals, and exhibiting good protective effects on cells, especially nerve cells. They can be used to prepare drugs with cell-protective effects for prevention or treatment, and for the treatment of diseases related to monoamine oxidase, cholinesterase, or free radicals. Generally, this refers to diseases related to neurodegeneration and free radicals, including but not limited to diseases related to monoamine oxidase such as Parkinson's disease, Alzheimer's disease, dementia, hypertension, diarrhea, depression, asthma, and allergies; and diseases related to cholinesterase such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, myasthenia gravis, glaucoma, Alzheimer's disease, hyperthyroidism, hypertension, bronchial asthma, and type IV hyperlipidemia. Proteinemia, renal failure; also includes diseases related to NO or oxidative stress damage or free radicals such as stroke, brain trauma, epilepsy, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Alzheimer's disease, hypoxic-ischemic brain injury, cerebral hemorrhage, dementia, ischemic heart disease, vascular embolism, arteriosclerosis, hypercholesterolemia, emphysema, cataracts, diabetes, acute pancreatitis, alcohol-induced liver disease, kidney damage, and cancer; it can also be used for prevention and treatment. H2S-related diseases include cardiovascular and cerebrovascular diseases, inflammation, atherosclerosis, diabetes, Alzheimer's disease, Parkinson's disease, obesity, cancer, stroke, and traumatic brain injury; it can also be used to prevent and treat neurodegenerative diseases such as cerebral ischemia, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia-telangiectasia, bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, cerebellar atrophy, multiple sclerosis, primary lateral sclerosis, and spinal muscular atrophy.

[0042] This invention relates to substances having ester groups (including substituted or unsubstituted carbamate groups), amino groups, nitrate groups, and their derivatives, which can be administered to patients in the form of a pharmaceutically acceptable salt or pharmaceutical complex. A particular complex needs to be mixed with a suitable carrier or excipient to form a pharmaceutical composition to ensure an effective therapeutic dose. "Effective therapeutic dose" refers to the dose necessary for the class of compounds and their derivatives to achieve a therapeutic effect.

[0043] Compounds with multiple mechanisms of action and their derivatives can be formulated into various dosage forms, including solid dosage forms, semi-solid dosage forms, liquid formulations, and aerosols (Remington's Pharmaceutical Sciences, Mack Publishing Company (1995), Philadelphia, PA, 19th ed.). Specific dosage forms within these categories include tablets, pills, sugar tablets, granules, gels, ointments, solutions, suppositories, injections, inhalers, and sprays. These dosage forms can be used for both local and systemic administration, as well as for immediate-release or sustained-release administration. There are many routes of administration for these drugs, including, in addition to the methods mentioned above, oral administration, buccal administration, rectal administration, peritoneal administration, intraperitoneal administration, topical administration, subcutaneous administration, and intratracheal administration.

[0044] When these compounds with multiple mechanisms of action and their derivatives are administered by injection, they can be formulated into solutions, suspensions, and emulsions using water-soluble or lipid-soluble solvents. Lipid-soluble solvents specifically include vegetable oils and similar oils, synthetic fatty acid glycerides, higher fatty acid esters, and proylene glycol esters. These compounds are more readily soluble in Hank's solution, Ringer's solution, or physiological saline.

[0045] When these compounds with multiple mechanisms of action and their derivatives are administered orally, they can be formulated into complexes with pharmaceutically acceptable excipients using common techniques. These excipients can then be used to formulate these compounds into various patient-compatible dosage forms, such as tablets, pills, suspensions, and gels. There are several methods for preparing oral formulations, such as first mixing the compound and solid excipients, thoroughly grinding the mixture, adding appropriate excipients, and then processing it into granules. Excipients that can be used to formulate oral dosage forms include: sugars such as lactose, sucrose, mannitol, or sorbitol; and celluloses such as corn starch, wheat starch, potato starch, gelatin, taro gum, methylcellulose, hydroxyproylmethylcellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone.

[0046] This invention relates to compounds and their derivatives with multiple mechanisms of action, which can also be formulated into aerosols. This dosage form is achieved through a pressurizer and a nebulizer or a dry powder inhalation device. Suitable propellants that can be used in the nebulizer include dichlorodifluoromethane, chloroform, dichlorotetrafluoroethane, carbon dioxide, and dimethyl ether. The dosage of the aerosol can be adjusted by a valve on the nebulizer.

[0047] The various dosage forms involved in this invention relate to the effective therapeutic dose of these multi-mechanism compounds and their derivatives. The effective therapeutic dose of these compounds depends on the patient receiving treatment. In determining the appropriate dose, the patient's weight, condition, method of administration, and the prescribing physician's subjective judgment must be taken into account. The therapeutically effective dose of these multi-mechanism compounds and their derivatives should be determined by a competent and experienced prescribing physician.

[0048] Although the effective therapeutic dose of such compounds and their derivatives with multiple mechanisms of action may vary depending on the patient’s condition, the usual appropriate dosage range is 10 mg to 10 g.

[0049] Compared with the prior art, the present invention has the following advantages: The present invention provides a substance with a novel structure and multiple mechanisms of action, which can inhibit NMDA receptors, inhibit calcium ion influx, scavenge free radicals, and have a good protective effect on cells, especially nerve cells. It can be used to prepare drugs with cell-protective effects for prevention or treatment, usually referring to diseases related to neurodegeneration such as Alzheimer's disease, Parkinson's disease, and stroke, as well as diseases related to free radicals, including heart disease and diabetes. Attached Figure Description

[0050] Figure 1 Describe the synthesis of compound NM-002.

[0051] Figure 2 Describe the synthesis of compound NM-004.

[0052] Figure 3 Describe the synthesis of compound NM-005.

[0053] Figure 4 Describe the synthesis of compound NM-008.

[0054] Figure 5 Describe the synthesis of compound NM-009.

[0055] Figure 6 Describe the synthesis of compound NM-011.

[0056] Figure 7 Describe the synthesis of compound NM-012.

[0057] Figure 8 The protective effect of compound NM-008 against cerebral infarction in a rat model of permanent cerebral ischemia is described. * in the figure indicates a significant difference compared to the control group. Detailed Implementation

[0058] Example 1: Synthesis of compound NM-002a

[0059] 1.48 g (5 mmol) of compound AD-003e was dissolved in 30 mL of dried dichloromethane and cooled in an ice-water bath. 3 mL of a mixture of acetic anhydride and fuming nitric acid (acetic anhydride:fuming nitric acid volume ratio = 3:2) was added. The reaction was maintained in an ice-water bath for 10-15 minutes. The reaction mixture was poured into 30 mL of 1 N sodium bicarbonate solution. After separating the dichloromethane, the aqueous layer was extracted with dichloromethane (20 mL × 3). The dichloromethanes were combined, washed with 30 mL of water, dried over anhydrous sodium sulfate, filtered, and the dichloromethane was distilled under reduced pressure to obtain a colorless oily crude product. Separation by silica gel column chromatography (petroleum ether:dichloromethane = 10:1) yielded 1.07 g (62.9%) of a colorless oily substance NM-002a. ESI-MS: m / z 340.2 ([M]) + ). 1 H-NMR(DMSO-d6,ppm):0.83(s,3H),1.15-1.24(m,2H),1.26-1.47(m,14H),1.56-1.80(m,5H),2.06-2.14(m,1H),4.22(s,2H),6.51(s,1H).

[0060] Example 2: Synthesis of compound NM-002

[0061] 680 mg (2 mmol) of compound NM-002a was added to 5 mL of a saturated diethyl ether solution containing hydrogen chloride. The reaction was carried out at room temperature and monitored by TLC. At the end of the reaction, a white solid precipitated. The mixture was filtered, and the white solid was washed with anhydrous diethyl ether to obtain 390 mg (70.7%) of pure NM-002. ESI-MS: m / z 341.0 ([M+H) + ). 1 H-NMR(DMSO-d6,ppm):0.88(s,3H),1.19-1.29(m,2H),1.30-1.38(m,2H),1.38-1.52(m, 4H),1.54-1.64(m,2H),1.66-1.73(m,2H),2.18-2.24(m,1H),4.29(s,2H),8.11(s,3H).

[0062] Example 3: Synthesis of compound NM-004a

[0063] A 50 mL round-bottom flask was placed in an ice-water bath for cooling. 20 mL of concentrated sulfuric acid, 2 mL of n-hexane, and 970 mg (4 mmol) of compound NM-003a were added to the flask. While maintaining the ice-water bath, formic acid (1.8 mL) was slowly added dropwise. After the addition was complete, the reaction was continued in the ice-water bath for 3 hours. The reaction solution was poured into 100 mL of ice water, and a solid precipitated. After standing, the solid was filtered to obtain a pale yellow solid. The solid was dried and dissolved in ethyl acetate. The solution was alkalized with sodium hydroxide aqueous solution to approximately pH 9-10, and the aqueous layer was separated. The organic layer was extracted with sodium hydroxide aqueous solution (30 mL × 3). The aqueous solutions were combined, and the aqueous layer was acidified with dilute hydrochloric acid solution to approximately pH 3. The solution was filtered and dried to obtain 640 mg (77%) of pure compound NM-004a. ESI-MS: m / z 207 ([MH) - ). 1 H-NMR(DMSO-d6,ppm):0.76(t,3H,J=7.5Hz),1.11(q,2H,J=7.5Hz),1.31-1.44(m, 4H),1.47(s,2H),1.51-1.64(m,2H),1.66-1.81(m,4H),2.01(m,2H),11.99(s,1H).

[0064] Example 4: Synthesis of compound NM-004b

[0065] Add 624 mg (3 mmol) of compound NM-004a to a 50 mL round-bottom flask and cool in an ice bath. Add 0.55 mL of concentrated nitric acid and stir until homogeneous. Add 3.5 mL of concentrated sulfuric acid dropwise to the mixture and react in an ice bath for 1 hour. Then add 2.5 mL (4.8 mmol) of acetonitrile dropwise and continue reacting in an ice bath for 1 hour. Pour the reaction mixture into 20 mL of ice water, stir vigorously for 30 minutes, and let stand overnight. A white solid precipitates, is filtered, washed with an appropriate amount of water, and dried to obtain compound NM-004b (580 g, 73%). No purification is required; it can be directly added to the next reaction. ESI-MS: m / z 266 ([M+H) + ). 1 H-NMR(DMSO-d6,ppm):0.74(t,3H,J=7.5Hz),1.15(q,2H,J=7.5Hz),1.26-1.35(m,2H),1.36-1 .47(m,2H),1.52-1.70(m,4H),1.72-1.86(m,5H),1.88-1.98(m,2H),2.13(m,1H),7.43(s,1H).

[0066] Example 5: Synthesis of compound NM-004c

[0067] Dissolve 878 mg (3.3 mmol) of compound NM-004b in 10 mL of dry tetrahydrofuran and cool in an ice-water bath. Add 0.5 mL of triethylamine and 0.5 mL of ethyl chloroformate sequentially to the mixture, incubate in an ice-water bath for 30 minutes, then remove the ice bath and react at room temperature for 4 hours. Filter, wash the filter cake with an appropriate amount of tetrahydrofuran, and collect the filtrate. Add 1.5 g of sodium borohydride to the filtrate, and slowly add 1 mL of water dropwise using a dropping funnel, completing the addition within 1 hour. After the addition is complete, continue the reaction at room temperature for 1 hour. Monitor the reaction by TLC. After the reaction is complete, add 30 mL of water to the reaction system, and evaporate the tetrahydrofuran to dryness under reduced pressure. Extract the aqueous layer with ethyl acetate (20 mL × 4), combine the ethyl acetate layers, wash with 25 mL of 0.5 N hydrochloric acid, saturated sodium chloride aqueous solution, and water, and dry over anhydrous sodium sulfate. Evaporate the solvent under reduced pressure to obtain an oily crude product. Separation was performed using silica gel column chromatography (petroleum ether:ethyl acetate = 1:1), yielding a white solid NM-004c 348 mg (42%). ESI-MS: m / z 252.2 ([M+H) + ). 1 H-NMR(DMSO-d6,ppm):0.76(t,3H,J=7.5Hz),1.03-1.20(m,4H),1.28(m,4H),1.58(m,4 H), 1.75 (m, 5H), 2.09 (s, 1H), 3.02 (d, 2H, J = 5.5Hz), 4.38 (t, 1H, J = 5.5Hz), 7.33 (s, 1H).

[0068] Example 6: Synthesis of compound NM-004d

[0069] 1.26 g (5 mmol) of compound NM-004c, 3 g of solid sodium hydroxide, and 20 mL of diethylene glycol were added to a 250 mL round-bottom flask and refluxed at 170 °C for 15 hours. After cooling to room temperature, the reaction mixture was poured into 40 g of crushed ice and stirred thoroughly. The mixture was then extracted with ethyl acetate (20 mL × 4). The combined ethyl acetate layers were washed with 30 mL of water and 30 mL of saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness to obtain a pale yellow, oily crude product. The crude product was dissolved in 50 mL of dry ethyl acetate, and dry HCl was passed through while stirring, resulting in the precipitation of a large amount of white solid. The solid was filtered, washed with an appropriate amount of dry ethyl acetate, and dried to obtain 850 mg (69.4%) of white solid NM-004d. ESI-MS: m / z 210.3 ([M+H) + ). 1H-NMR(DMSO-d6,ppm):0.74(t,3H,J=7.6Hz),1.15(q,2H,J=7.6Hz),1.26-1.35(m,2H),1.36-1 .47(m,2H),1.53-1.68(m,4H),1.74-1.85(m,3H),1.88-1.96(m,2H),2.13(m,1H),7.43(s,3H).

[0070] Example 7: Synthesis of compound NM-004e

[0071] 2.45 g (10 mmol) of compound NM-004d was dissolved in 20 mL of water, alkalized with sodium hydroxide solution to approximately pH 10, and extracted with ethyl acetate (30 mL × 4). The ethyl acetates were combined, washed with 30 mL of water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 1.57 g (7.5 mmol) of a colorless oily free amine. Without purification, it was directly dissolved in 50 mL of redistilled tetrahydrofuran, and 1.56 g (15.6 mmol) of triethylamine, 2.55 g (11.7 mmol) of Boc anhydride, and 10 mg of DMAP were added sequentially. The reaction was carried out at room temperature for 5 hours, and the reaction was monitored by TLC. After the reaction was complete, 30 mL of saturated ammonium chloride solution was added to the reaction solution to quench the reaction. The solvent was removed under reduced pressure, and the product was extracted with ethyl acetate (50 mL × 4). The ethyl acetates were combined, washed with 30 mL of 0.1 N hydrochloric acid and 30 mL of saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain a colorless oily crude product. The crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give 1.58 g (68%) of a white solid NM-004e. ESI-MS: m / z 310.3 ([M+H] + ). 1 H-NMR(DMSO-d6,ppm):0.75(t,3H,J=7.5Hz),1.03-1.19(m,4H),1.24(m,4H),1.36(s,9H),1.44-1.5 8(m,4H),1.52-1.73(m,2H),2.08(s,1H),3.02(d,2H,J=5.5Hz),4.38(t,1H,J=5.5Hz),6.36(s,1H).

[0072] Example 8: Synthesis of compound NM-004f

[0073] 620 mg (2 mmol) of compound NM-004e was dissolved in 10 mL of dried, dehydrated dichloromethane and cooled in an ice-water bath. 2 mL of a mixture of acetic anhydride and fuming nitric acid (volume ratio of acetic anhydride to fuming nitric acid = 3:2) was added. The reaction mixture was reacted in an ice-water bath for 10-15 minutes. The reaction solution was poured into 10 mL of 1N sodium bicarbonate solution. After separating the dichloromethane, the aqueous layer was extracted with dichloromethane (10 mL × 3). The dichloromethane layers were combined and washed with 10 mL of water. The solution was dried over anhydrous sodium sulfate, filtered, and the dichloromethane was distilled under reduced pressure to obtain a colorless, oily crude product. Separation by silica gel column chromatography (petroleum ether:dichloromethane = 10:1) yielded 505 mg (73.4%) of a colorless oily substance, NM-004f. ESI-MS: m / z 377.2 ([M+Na)). + ). 1 H-NMR (DMSO-d6, ppm): 0.76 (t, 3H, J = 7.5Hz), 1.08-1.23 (m, 4H), 1.26-1.49 (m, 14H), 1.56-1.82 (m, 5H), 2.12 (m, 1H), 4.23 (s, 2H), 6.50 (s, 1H).

[0074] Example 9: Synthesis of compound NM-004

[0075] 710 mg (2 mmol) of compound NM-004f was added to 5 mL of a saturated diethyl ether solution containing hydrogen chloride, and the reaction was carried out at room temperature. At the end of the reaction, a white solid precipitated. The solid was filtered and washed with anhydrous diethyl ether to obtain pure NM-004. After drying, 380 mg (65.5%) of NM-004 was obtained. ESI-MS: m / z 255.1 ([M+H) + ). 1 H-NMR(DMSO-d6,ppm):0.78(t,3H,J=7.5Hz),1.15-1.28(m,4H),1.30-1.39(m,2H),1.4 0-1.55(m,4H),1.57-1.67(m,2H),1.71(s,2H),2.23(m,1H),4.30(s,2H),8.21(s,3H).

[0076] Example 10: Synthesis of compound NM-005a

[0077] 3.66 g (15.0 mmol) of compound NM-003a was dissolved in 45 mL of dry toluene. 0.122 g (0.74 mol) of AIBN, 4.95 g (16.7 mmol) of n-Bu3SnH, and 3.10 g (31.0 mmol) of ethyl acrylate were added sequentially. The mixture was refluxed at 110 °C for 3 hours under nitrogen protection, and the reaction was monitored by TLC. After the reaction was complete, the mixture was cooled, and the reaction solution was poured into 105 mL of 0.2 M ammonia solution. The mixture was stirred for 1 hour, extracted with ethyl acetate (100 mL × 4), and the organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed under reduced pressure to obtain a colorless and transparent liquid. Separation was performed by silica gel column chromatography (petroleum ether:ethyl acetate = 6:1) to obtain a colorless and transparent liquid NM-005a (2.50 g, 62.8%). 1 H-NMR (DMSO-d6, ppm): 0.72 (t, 3H, J = 7.5Hz), 1.10 (m, 4H), 1.17 (t, 3H, J = 7.8Hz), 1. 32(m,10H),1.53(s,2H),1.97(s,2H),2.21(t,2H,J=8.1Hz),4.02(q,1H,J=7.2Hz).

[0078] Example 11: Synthesis of compound NM-005b

[0079] 2.50 g (9.5 mmol) of compound NM-005a was dissolved in 60 mL of methanol and 5 mL of water by stirring. Then, 3.2 g (57 mmol) of potassium hydroxide was added, and the mixture was reacted at room temperature for 12 hours. The reaction was monitored by TLC. After the reaction was complete, the solvent was removed under reduced pressure, and the mixture was extracted with 30 mL of water and 20 mL of ethyl acetate to remove organic impurities. The pH of the aqueous layer was adjusted to 1-2 with concentrated hydrochloric acid, at which point a large amount of white solid precipitated. The mixture was filtered under reduced pressure, and the filter cake was washed with a small amount of water and dried to obtain 1.60 g (71.6%) of white solid NM-005b. ESI-MS: m / z 237.1 ([M+H) + ). 1 H-NMR (DMSO-d6, ppm): 0.75 (t, 3H, J = 7.5Hz), 1.10 (m, 4H), 1.32 (m, 10H), 1.54 (s, 2H), 1.97 (s, 2H), 2.14 (t, 2H, J = 8.1Hz), 11.98 (s, 1H).

[0080] Example 12: Synthesis of compound NM-005c

[0081] 1.6 g (6.8 mmol) of compound NM-005b was placed in a 50 mL round-bottom flask and cooled in an ice bath. 1.1 mL of concentrated nitric acid was added and stirred until homogeneous. 6.8 mL of concentrated sulfuric acid was slowly added dropwise to the mixture, and the reaction was continued in an ice bath for 1 hour after the addition was complete. 5 mL of acetonitrile was slowly added dropwise, and the reaction was continued in an ice bath for another hour. The reaction mixture was poured into 30 mL of ice water and stirred vigorously for 30 minutes. The mixture was extracted with ethyl acetate (50 mL × 5), and the organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed under reduced pressure to obtain a colorless viscous liquid. Separation was performed by silica gel column chromatography (eluent: ethyl acetate) to obtain 1.60 g (80.6%) of a colorless, transparent, viscous semi-solid NM-005c. 1 H-NMR(DMSO-d6,ppm):0.75(t,3H,J=7.5Hz),1.11(m,4H),1.28(m,6H),1.54(m,4H),1.7 3(m,5H),2.08(s,1H),2.16(m,2H),3.16(s,1H),1.77(m,1H),4.38(m,2H),4.40(s,1H).

[0082] Example 13: Synthesis of compound NM-005d

[0083] 2.8 g (9.5 mmol) of compound NM-005c was dissolved in 10 mL of dry tetrahydrofuran and cooled in an ice bath. 1.5 mL of triethylamine and 1.5 mL (15.8 mmol) of ethyl chloroformate were added sequentially. The mixture was kept in an ice-water bath for 30 minutes, then the ice bath was removed, and the reaction was continued at room temperature for 4 hours. The mixture was filtered, and the filter cake was washed with tetrahydrofuran. The filtrate was collected. 2.7 g (0.07 mol) of sodium borohydride was added to the filtrate, followed by the slow addition of 1.8 mL of water. After the addition was complete, the reaction was continued at room temperature for 2 hours. 50 mL of water was added to the reaction system, and the tetrahydrofuran was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (50 mL × 5). The organic phases were combined, washed with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed under reduced pressure to obtain an oily crude product. Separation was performed by silica gel column chromatography (methanol:ethyl acetate = 1:6) to obtain 1.7 g (63.75%) of a colorless, transparent, viscous semi-solid NM-005d. ESI-MS: m / z 280.1 ([M+H]) + ). 1 H-NMR (DMSO-d6, ppm): 0.75 (t, 3H, J = 7.5Hz), 1.11 (m, 4H), 1.36 (m, 6H), 1.54 (m, 4H), 1.73 (m, 5H), 2.08 (s, 1H), 2.18 (m, 2H), 3.57 (m, 2H).

[0084] Example 14: Synthesis of compound NM-005e

[0085] To a 100 mL round-bottom flask, add 1.7 g (6.1 mmol) of compound NM-005d, 5.5 g (0.14 mol) of sodium hydroxide, and 35 mL of diethylene glycol. Reflux the mixture at 175 °C for 16 h. After cooling to room temperature, pour the reaction mixture into 50 g of crushed ice, stir thoroughly, and then extract with a mixed solvent of ethyl acetate and methyl tert-butyl ether (V... 乙酸乙酯 :V 甲基叔丁基醚 =4:1, 50mL×6). Combine the organic phases, wash with saturated sodium chloride solution, and dry with anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure to obtain 1.1g of brown liquid. Without purification, add redistilled and dried dichloromethane (50mL), followed by 2.5mL of triethylamine and 1.1g (5mmol) of Boc anhydride. Stir at room temperature for 5 hours, and monitor the reaction by TLC. After the reaction is complete, wash the reaction solution several times with saturated sodium chloride solution, and dry the organic phase with anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure to obtain a brown oily substance. Separate by silica gel column chromatography (petroleum ether:ethyl acetate = 1:5), yielding 0.48g (23.38%) of colorless liquid NM-005e. 1 H-NMR (CDCl3-d, ppm): 0.80 (t, 3H, J = 7.5Hz), 1.14 (m, 2H), 1.20 (m, 4H), 1.33 (m, 6H), 1.43 (s, 9H), 1 .51(m,2H),1.61(m,2H),1.72(m,1H),1.78(m,2H),2.17(m,1H),3.61(m,2H,J=6.3Hz),4.43(s,1H).

[0086] Example 15: Synthesis of compound NM-005f

[0087] Dissolve 380 mg (1.1 mmol) of compound NM-005e in 8 mL of dry dichloromethane and cool in an ice bath. Add 1.2 mL of a mixture of acetic anhydride and fuming nitric acid (V... 乙酸酐 :V 发烟硝酸 =3:2. The reaction was carried out for 10-15 minutes, and the reaction was monitored by TLC. After the reaction was complete, the reaction solution was poured into 40 mL of 1N sodium bicarbonate solution, and further extracted with dichloromethane (20 mL × 3). The dichloromethane was combined, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solution was filtered, and the solvent was removed under reduced pressure to obtain a colorless oil. The solution was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 230 mg (53.41%) of colorless oil NM-005f. 1H-NMR (CDCl3-d, ppm): 0.76 (t, 3H, J = 7.5Hz), 1.10 (m, 2H), 1.23 (m, 6H), 1.33 (m, 2H), 1.4 0(s,9H),1.51(m,2H),1.68(m,4H),1.68(m,4H),1.77(m,1H),4.38(m,2H),4.40(s,1H).

[0088] Example 16: Synthesis of compound NM-005

[0089] Compound NM-005f, 110 mg (0.29 mmol), was placed in a 25 mL round-bottom flask, and 10 mL of a hydrogen chloride-saturated diethyl ether solution was added. The reaction was carried out at room temperature for 30–45 minutes, and the reaction was monitored by TLC. After the reaction was complete, the solvent was removed under reduced pressure to obtain a colorless oily substance. Then, 20 mL of anhydrous diethyl ether was added, and the solvent was removed under reduced pressure. This process was repeated several times until a solid precipitated. The solid was filtered, washed with a small amount of anhydrous diethyl ether, and dried to obtain a white solid NM-005 (32 mg, 39.4%). ESI-MS: m / z 283.1 ([M+H) + ). 1 H-NMR(DMSO-d6,ppm):0.77(t,3H,J=7.5Hz),1.18(m,6H),1.30(m,4H),1.46(m, 4H), 1.60 (m, 2H), 1.67 (m, 2H), 2.18 (m, 1H), 4.49 (t, 2H, J = 6.6Hz), 8.18 (s, 3H).

[0090] Example 17: Synthesis of compound NM-008a

[0091] 8.4 g (50 mmol) of 1,3-adamantanediol was added to a 250 mL two-necked round-bottom flask equipped with a condenser and cooled in an ice-water bath. 56 mL of concentrated sulfuric acid was added, and after stirring thoroughly, 5 mL of anhydrous formic acid was slowly added dropwise. After the addition was complete, the reaction was maintained in an ice-water bath for 2 hours, followed by a 10-hour reaction at room temperature. The pale yellow, viscous, and transparent reaction solution was slowly poured into 200 g of ice water, at which point a large amount of white solid precipitated. The mixture was filtered, the filter cake was washed with water, and dried to obtain 8.9 g (79.5%) of compound NM-008a. ESI-MS: m / z 223.2 ([MH) - ). 1 H-NMR(DMSO-d6,ppm):1.56-1.88(m,12H),2.06(s,2H),12.12(s,2H).

[0092] Example 18: Synthesis of compound NM-008b

[0093] 2.24 g (10 mmol) of compound NM-008a was dissolved in 100 mL of redistilled tetrahydrofuran and cooled in an ice-water bath. 3.0 mL of triethylamine and 3.0 mL of ethyl chloroformate were added sequentially to the mixture, and the mixture was kept in an ice-water bath for 30 minutes. The ice bath was then removed, and the reaction was continued at room temperature for 4 hours. The mixture was filtered, and the filter cake was washed with an appropriate amount of tetrahydrofuran. The filtrate was collected. 6 g of sodium borohydride was added to the filtrate, and 3 mL of water was slowly added dropwise using a dropping funnel, completing the addition over 1 hour. After the addition was complete, the reaction was continued at room temperature for 1 hour. TLC monitoring was performed. After the reaction was complete, 50 mL of water was added to the reaction system, and the tetrahydrofuran was evaporated to dryness under reduced pressure. The aqueous layer was extracted with ethyl acetate (40 mL × 4). The combined ethyl acetate layers were washed with 50 mL of 0.5 N hydrochloric acid, saturated sodium chloride aqueous solution, and water, respectively, and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness under reduced pressure to obtain a white crude solid. The white solid was washed with ethyl acetate, and 1.08 g (55%) of white solid NM-008b was finally obtained. ESI-MS: m / z 274.2 ([M+2K]). 2+ ). 1 H-NMR (DMSO-d6, ppm): 1.14 (s, 2H), 1.26-1.47 (m, 8H), 1.54 (s, 2H), 1.99 (m, 2H), 2.99 (d, 4H, J = 5.5Hz), 4.30 (t, 1H, J = 5.5Hz).

[0094] Example 19: Synthesis of compound NM-008c

[0095] 784 mg (4 mmol) of compound NM-008b, a white solid, was added to a 25 mL round-bottom flask, along with 5 mL of acetic anhydride, and stirred until homogeneous. 2-3 drops (catalytic amount) of perchloric acid were added to the suspension, and the mixture was reacted at room temperature for 3 hours. The reaction solution was poured into 20 g of ice water and extracted with ethyl acetate (20 mL × 3). The ethyl acetates were combined and washed with 30 mL of 1 N sodium bicarbonate solution and 30 mL of water. The mixture was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, a colorless oily crude product was obtained. Separation was performed by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1), finally yielding 1.0 g (90%) of colorless oily NM-008c. ESI-MS: m / z 298.3 ([M+H2O]). + ). 1 H-NMR(DMSO-d6,ppm):1.284(s,2H),1.36-1.52(m,8H),1.59(s,2H),2.02(s,8H),3.66(s,4H).

[0096] Example 20: Synthesis of compound NM-008d

[0097] Add 840 mg (3 mmol) of compound NM-008c to a 25 mL round-bottom flask and cool in an ice bath. Add 0.55 mL of concentrated nitric acid and stir until homogeneous. Slowly add 3.5 mL of concentrated sulfuric acid to the mixture, and after the addition is complete, react in an ice bath for 1 hour. Slowly add acetonitrile (2.5 mL, 4.8 mmol), and continue reacting in an ice bath for 1 hour. Pour the reaction mixture into 20 mL of ice water, and extract the aqueous layer with ethyl acetate (20 mL × 4). Combine the ethyl acetate, wash with 30 mL of 1 N sodium bicarbonate solution and 30 mL of water, and dry over anhydrous sodium sulfate. Evaporate the solvent under reduced pressure to obtain a colorless oily crude product. Separate by silica gel column chromatography (petroleum ether:ethyl acetate = 1:3) to obtain 425 mg (42%) of the oily compound NM-008d. ESI-MS: m / z 360.3 ([M+Na) + ). 1 H-NMR(DMSO-d6,ppm):1.22-1.43(m,6H),1.67(s,4H),1.74(s,3H),1.81(s,2H),2.02(s,6H),2.15(m,1H),3.70(s,4H).

[0098] Example 21: Synthesis of compound NM-008e

[0099] 670 mg (2 mmol) of compound NM-008d was added to a 25 mL round-bottom flask, followed by 10 mL of 18% HCl. The mixture was refluxed for 48 hours. After evaporating the water under reduced pressure, the solid was dried to obtain a white solid. The solid was washed with ethyl acetate and dried to give 296 mg (60%) of NM-008e. ESI-MS: m / z 21.3 ([M+H) + ). 1 H-NMR (DMSO-d6, ppm):

[0100] Example 22: Synthesis of compound NM-008f

[0101] 500 mg (2 mmol) of compound NM-008e was added to a 25 mL round-bottom flask, followed by 5 mL of DMF. Triethylamine (800 mg, 8 mmol), Boc anhydride (650 mg, 3 mmol), and DMAP (2 mg) were added sequentially. The mixture was stirred at room temperature for 5 hours, and the reaction was monitored by TLC. After the reaction was complete, 20 mL of saturated ammonium chloride solution was added to quench the reaction mixture. After evaporating the solvent under reduced pressure, the aqueous layer was extracted with ethyl acetate (10 mL × 4). The combined ethyl acetate layers were washed with 10 mL of 0.1 N hydrochloric acid and 10 mL of saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, a colorless oily crude product was obtained. The crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 404 mg (65%) of white solid NM-008f. ESI-MS: m / z 312.3 ([M+H) + ). 1 H-NMR(DMSO-d6,ppm):1.07(m,2H),1.20-1.29(m,4H),1.39(s,9H),1.43-1.59(m,4H),1 .62-1.72(m,2H),2.08(m,1H),3.02(d,4H,J=5.5Hz),4.38(t,2H,J=5.5Hz),6.39(s,1H).

[0102] Example 23: Synthesis of compound NM-008g

[0103] 624 mg (2 mmol) of compound NM-008f was dissolved in 10 mL of dried dichloromethane and cooled in an ice-water bath. 2 mL of a mixture of acetic anhydride and fuming nitric acid (acetic anhydride:fuming nitric acid volume ratio = 3:2) was added. The reaction was maintained in an ice-water bath for 10-15 minutes. The reaction mixture was poured into 10 mL of 1N sodium bicarbonate solution. After separating the dichloromethane, the aqueous layer was extracted with dichloromethane (10 mL × 3). The combined dichloromethane liquids were washed with 10 mL of water and dried over anhydrous sodium sulfate. After filtration and vacuum distillation of the dichloromethane, a colorless oily crude product was obtained. Separation by silica gel column chromatography (petroleum ether:dichloromethane = 10:1) yielded 600 mg (75%) of the colorless oily substance NM-008f. ESI-MS: m / z 419.3 ([M+H) + ). 1 H-NMR(DMSO-d6,ppm):1.37(s,9H),1.40(m,6H),1.60(m,2H),1.72-1.82(m,4H),2.17(m,1H),4.23(s,4H),6.66(s,1H).

[0104] Example 24: Synthesis of compound NM-008

[0105] 401 mg (1 mmol) of compound NM-008 was added to 5 mL of a saturated diethyl ether solution containing hydrogen chloride. The reaction was carried out at room temperature and monitored by TLC. At the end of the reaction, a white solid precipitated. The mixture was filtered, and the white solid was washed with anhydrous diethyl ether to obtain pure NM-008. After drying, 380 mg (65.5%) of NM-008 was obtained. ESI-MS: m / z 255.1 ([M+H) + ). 1 H-NMR(DMSO-d6,ppm):1.38-1.54(m,6H),1.60-1.77(m,6H),2.27(m,1H),4.32(s,4H),8.27(s,3H).

[0106] Example 25: Synthesis of compound NM-009a

[0107] 2.52 g (10 mmol) of compound 1,3-adamantanediacetic acid was added to 100 mL of redistilled tetrahydrofuran and cooled in an ice-water bath. Triethylamine (3.0 mL) and ethyl chloroformate (3.0 mL) were added sequentially to the suspension, and the mixture was kept in an ice-water bath for 30 minutes. The ice bath was then removed, and the reaction was continued at room temperature for 4 hours. The mixture was filtered, and the filter cake was washed with an appropriate amount of tetrahydrofuran. The filtrate was collected. 6 g of sodium borohydride was added to the filtrate, and 3 mL of water was slowly added dropwise using a dropping funnel, completing the addition over 1 hour. After the addition was complete, the reaction was continued at room temperature for 1 hour. TLC monitoring was performed. After the reaction was complete, 50 mL of water was added to the reaction system, and the tetrahydrofuran was evaporated to dryness under reduced pressure. The aqueous layer was extracted with ethyl acetate (40 mL × 4). The ethyl acetate layers were combined and washed with 50 mL of 0.5 N hydrochloric acid, saturated sodium chloride aqueous solution, and water, respectively, and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness under reduced pressure to obtain a white crude solid. The white solid was washed with ethyl acetate, and finally a white solid NM-009a1.43 g (63.8%) was obtained. ESI-MS: m / z 247.2 ([M+Na]). + ). 1 H-NMR (DMSO-d6, ppm): 1.21-1.26 (m, 6H), 1.33-1.45 (m, 4H), 1.54 (m, 2H), 1.93 (m, 2H), 3.40-3.47 (m, 4H), 4.20 (t, 2H, J = 5.5Hz).

[0108] Example 26: Synthesis of compound NM-009b

[0109] Add 1.12 g (5 mmol) of white solid NM-009a and 5 mL of acetic anhydride to a 25 mL round-bottom flask and stir until homogeneous. Add 2-3 drops (catalytic amount) of perchloric acid to the suspension and react at room temperature for 3 hours. Pour the reaction solution into 20 g of ice water and extract with ethyl acetate (20 mL × 3). Combine the ethyl acetates and wash with 30 mL of 1 N sodium bicarbonate solution and 30 mL of water. Dry over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, a colorless oily crude product is obtained. Separate by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to finally obtain 1.43 g (92.9%) of colorless oily NM-009b. ESI-MS: m / z 309.3 ([M+H2O]) + ). 1 H-NMR(DMSO-d6,ppm):1.25(s,2H),1.35-1.47(m,12H),1.55(s,2H),1.98(s,8H),4.04(t,4H).

[0110] Example 27: Synthesis of compound NM-009c

[0111] 616 mg (2 mmol) of compound NM-009b was placed in a 25 mL round-bottom flask and cooled in an ice bath. 0.4 mL of concentrated nitric acid was added and stirred until homogeneous. 2.5 mL of concentrated sulfuric acid was slowly added dropwise to the mixture, and the reaction was continued in an ice bath for 1 hour. Then, 2 mL (4.8 mmol) of acetonitrile was slowly added dropwise, and the reaction was continued in an ice bath for another 1 hour. The reaction mixture was poured into 20 mL of ice water, and the aqueous layer was extracted with ethyl acetate (20 mL × 4). The ethyl acetate was combined, washed with 30 mL of 1 N sodium bicarbonate solution and 30 mL of water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain a colorless, oily crude product. Separation was performed by silica gel column chromatography (petroleum ether:ethyl acetate = 1:3), yielding 423 mg (57.9%) of the oily compound NM-009c. ESI-MS: m / z 366.3 ([M+H) + ). 1 H-NMR(DMSO-d6,ppm):1.22-1.43(m,6H),1.67(s,4H),1.74(s,3H),1.81(s,2H),2.02(s,6H),2.15(m,1H),3.70(s,4H).

[0112] Example 28: Synthesis of compound NM-009d

[0113] 1 g (2.7 mmol) of compound NM-009c, 1.5 g of solid sodium hydroxide, and 30 mL of diethylene glycol were added sequentially to a 100 mL round-bottom flask, and the mixture was reacted at 170 °C for 15 hours. After cooling to room temperature, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3) to remove impurities. The water was then evaporated under reduced pressure. 30 mL of tetrahydrofuran, 1.18 g (5.4 mmol) of Boc anhydride, 540 mg (5.4 mmol) of triethylamine, and 10 mg of DMAP were added to the remaining solution, and the mixture was reacted at room temperature for 5 hours. The reaction was monitored by TLC. After the reaction was complete, 20 mL of saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 4). The combined ethyl acetate layers were washed successively with 30 mL of water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, a pale yellow oily crude product was obtained. Separation was performed using silica gel column chromatography (petroleum ether:ethyl acetate = 2:1), yielding 700 mg (75.4%) of an oily compound, NM-009d. ESI-MS: m / z 340.4 ([M+H]). + ). 1 H-NMR(DMSO-d6,ppm):1.22-1.43(m,6H),1.67(s,4H),1.74(s,3H),1.81(s,2H),2.02(s,6H),2.15(m,1H),3.70(s,4H).

[0114] Example 29: Synthesis of compound NM-009e

[0115] Dissolve 680 mg (2 mmol) of compound NM-009d in 10 mL of dried dichloromethane and cool in an ice-water bath. Add 2 mL of a mixture of acetic anhydride and fuming nitric acid (acetic anhydride:fuming nitric acid volume ratio equal to 3:2). Maintain the ice-water bath and react for 10-15 minutes. Pour the reaction solution into 10 mL of 1N sodium bicarbonate solution. After separating the dichloromethane, extract the aqueous layer with dichloromethane (10 mL × 3). Combine the dichloromethane liquids, wash with 10 mL of water, and dry with anhydrous sodium sulfate. Filter, and distill the dichloromethane under reduced pressure to obtain a colorless oily crude product. Separate by silica gel column chromatography (petroleum ether:dichloromethane = 10:1) to obtain 620 mg (72.3%) of colorless oily NM-009e. ESI-MS: m / z 452.1 ([M+Na) + ). 1 H-NMR(DMSO-d6,ppm):1.37(s,9H),1.40(m,6H),1.60(m,2H),1.72-1.82(m,4H),2.17(m,1H),4.23(s,4H),6.66(s,1H).

[0116] Example 30: Synthesis of compound NM-009

[0117] 401 mg (1 mmol) of compound NM-009e was added to 5 mL of a saturated diethyl ether solution containing hydrogen chloride. The reaction was carried out at room temperature and monitored by TLC. At the end of the reaction, a white solid precipitated. The mixture was filtered, and the white solid was washed with anhydrous diethyl ether to obtain pure NM-009. After drying, 380 mg (65.5%) of NM-009 was obtained. ESI-MS: m / z 255.1 ([M+H) + ). 1 H-NMR(DMSO-d6,ppm):1.38-1.54(m,6H),1.60-1.77(m,6H),2.27(m,1H),4.32(s,4H),8.27(s,3H).

[0118] Example 31: Synthesis of compound NM-011a

[0119] 3 g (10 mmol) of compound 1,3-dibromoadamantane was dissolved in 30 mL of toluene. 250 mg (1.5 mmol) of AIBN, 7 g (24 mmol) of tri-n-butyltin hydrogen, and 3 g (30 mmol) of ethyl acrylate were added sequentially. The mixture was refluxed at 110 °C for 3 hours under nitrogen protection. After cooling the reaction solution to room temperature, it was poured into 30 mL of 0.2 M ammonia water and stirred thoroughly. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (20 mL × 4). The organic layers were combined and washed with 30 mL of water and 30 mL of saturated sodium chloride solution. The solution was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, a colorless oily crude product was obtained. Separation was performed by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain 2 g (46.6%) of a colorless oily liquid compound NM-011a. ESI-MS: m / z 337.4 ([M+H) + ). 1 H-NMR (DMSO-d6, ppm): 1.11 (s, 2H), 1.15-1.19 (m, 6H), 1.28-1.39 (m, 12H), 1.53 (s, 2H), 1.97 (s, 2H), 2.19-2.24 (m, 2H), 4.03 (q, 4H, J = 7.1Hz).

[0120] Example 32: Synthesis of compound NM-011b

[0121] 2.2 g (6 mmol) of compound NM-011a was placed in a 50 mL round-bottom flask and cooled in an ice bath. 1.2 mL of concentrated nitric acid was added and stirred until homogeneous. 8.5 mL of concentrated sulfuric acid was slowly added dropwise to the mixture, and the reaction was continued in an ice bath for 1 hour. Then, 5.6 mL (13.4 mmol) of acetonitrile was slowly added dropwise, and the reaction was continued in an ice bath for another 1 hour. The reaction mixture was poured into 20 mL of ice water, and the aqueous layer was extracted with ethyl acetate (20 mL × 4). The ethyl acetate was combined, washed with 30 mL of 1 N sodium bicarbonate solution and 30 mL of water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain a colorless, oily crude product. Separation was performed by silica gel column chromatography (petroleum ether:ethyl acetate = 1:3) to obtain 2 g (57.9%) of the oily compound NM-011b. ESI-MS: m / z 394.2 ([M+H) + ). 1 H-NMR(DMSO-d6,ppm):1.22-1.43(m,6H),1.67(s,4H),1.74(s,3H),1.81(s,2H),2.02(s,6H),2.15(m,1H),3.70(s,4H).

[0122] Example 33: Synthesis of compound NM-011c

[0123] 1 g (2.5 mmol) of compound NM-011b was dissolved in 20 mL of redistilled tetrahydrofuran, and 450 mg of sodium borohydride was added. 1.33 g of aluminum trichloride was dissolved in 10 mL of tetrahydrofuran and slowly added dropwise to the starting material. After the addition was complete, the mixture was stirred overnight at room temperature. The reaction mixture was poured into 50 mL of ice water, stirred thoroughly, and extracted with ethyl acetate (30 mL × 4). The extracts were combined, washed with 30 mL of saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain a colorless oily crude product. Separation was performed by silica gel column chromatography (ethyl acetate:methanol = 10:1), yielding 470 mg (60.8%) of colorless oily NM-011c. ESI-MS: m / z 310.1 ([M+H) + ). 1 H-NMR(DMSO-d6,ppm):1.05-1.09(m,6H),1.22-1.39(m,8H),1.51-1.60(m,4H),1.73(s ,3H),1.76(s,2H),2.07(m,1H),3.30-3.36(m,4H),4.39(t,2H,J=5.2Hz),7.36(s,1H).

[0124] Example 34: Synthesis of compound NM-011d

[0125] 440 mg (1.4 mmol) of compound NM-011c, 750 mg of solid sodium hydroxide, and 10 mL of diethylene glycol were added sequentially to a 50 mL round-bottom flask, and the mixture was reacted at 170 °C for 15 hours. After cooling to room temperature, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3) to remove impurities. The water was then removed by rotary evaporation under reduced pressure. 30 mL of tetrahydrofuran, 560 mg (2.8 mmol) of Boc anhydride, 280 mg (2.8 mmol) of triethylamine, and 10 mg of DMAP were added to the remaining solution, and the mixture was reacted at room temperature for 5 hours. The reaction was monitored by TLC. After the reaction was complete, 20 mL of saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 4). The combined ethyl acetate layers were washed sequentially with 30 mL of water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain a pale yellow oily crude product. Separation was performed using silica gel column chromatography (petroleum ether:ethyl acetate = 2:1), yielding an oily compound NM-011d 320 mg (55.9%). ESI-MS: m / z 340.4 ([M+H]). + ). 1 H-NMR(DMSO-d6,ppm):1.22-1.43(m,6H),1.67(s,4H),1.74(s,3H),1.81(s,2H),2.02(s,6H),2.15(m,1H),3.70(s,4H).

[0126] Example 35: Synthesis of compound NM-011e

[0127] Dissolve 680 mg (2 mmol) of compound NM-011d in 10 mL of dried dichloromethane and cool in an ice-water bath. Add 2 mL of a mixture of acetic anhydride and fuming nitric acid (acetic anhydride:fuming nitric acid volume ratio equal to 3:2). Maintain the ice-water bath and react for 10-15 minutes. Pour the reaction solution into 10 mL of 1N sodium bicarbonate solution. After separating the dichloromethane, extract the aqueous layer with dichloromethane (10 mL × 3). Combine the dichloromethane liquids, wash with 10 mL of water, and dry with anhydrous sodium sulfate. Filter, and distill the dichloromethane under reduced pressure to obtain a colorless oily crude product. Separate by silica gel column chromatography (petroleum ether:dichloromethane = 10:1) to obtain 620 mg (72.3%) of colorless oily NM-011e. ESI-MS: m / z 452.1 ([M+Na) + ). 1 H-NMR(DMSO-d6,ppm):1.37(s,9H),1.40(m,6H),1.60(m,2H),1.72-1.82(m,4H),2.17(m,1H),4.23(s,4H),6.66(s,1H).

[0128] Example 36: Synthesis of compound NM-011

[0129] 401 mg (1 mmol) of compound NM-011e was added to 5 mL of a saturated diethyl ether solution containing hydrogen chloride. The reaction was carried out at room temperature and monitored by TLC. At the end of the reaction, a white solid precipitated. The mixture was filtered, and the white solid was washed with anhydrous diethyl ether to obtain pure NM-011. After drying, 380 mg (65.5%) of NM-011 was obtained. ESI-MS: m / z 255.1 ([M+H) + ). 1 H-NMR(DMSO-d6,ppm):1.38-1.54(m,6H),1.60-1.77(m,6H),2.27(m,1H),4.32(s,4H),8.27(s,3H).

[0130] Example 37: Synthesis of compound NM-012a

[0131] 3 g (10 mmol) of compound 1,3-dibromoadamantane was dissolved in 30 mL of toluene. 250 mg (1.5 mmol) of AIBN, 7 g (24 mmol) of tri-n-butyltin hydrogen, and 3 g (30 mmol) of 2-methyl methacrylate were added sequentially. The mixture was refluxed at 110 °C for 3 hours under nitrogen protection. After cooling the reaction solution to room temperature, it was poured into 30 mL of 0.2 M ammonia water and stirred thoroughly. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (20 mL × 4). The combined organic layers were washed with 30 mL of water and 30 mL of saturated sodium chloride solution. The solution was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, a colorless oily crude product was obtained. Separation was performed by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain 1.6 g (43.1%) of a colorless oily liquid compound NM-012a. ESI-MS: m / z 337.4 ([M+H) + ). 1 H-NMR(DMSO-d6,ppm):0.97(s,2H),1.02-1.08(m,8H),1.15-1.20(m,7H),1.22-1.40(m, 7H),1.50(s,2H),1.57-1.65(m,2H),1.93(s,2H),2.39-2.47(m,2H),3.98-4.11(m,4H).

[0132] Example 38: Synthesis of compound NM-012b

[0133] 2 g (5.5 mmol) of compound NM-012a was placed in a 50 mL round-bottom flask and cooled in an ice bath. 1.1 mL of concentrated nitric acid was added and stirred until homogeneous. 7.7 mL of concentrated sulfuric acid was slowly added dropwise to the mixture, and the reaction was continued in an ice bath for 1 hour. Then, 4.9 mL (11.7 mmol) of acetonitrile was slowly added dropwise, and the reaction was continued in an ice bath for another 1 hour. The reaction mixture was poured into 20 mL of ice water, and the aqueous layer was extracted with ethyl acetate (20 mL × 4). The ethyl acetate was combined, washed with 30 mL of 1 N sodium bicarbonate solution and 30 mL of water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain a colorless, oily crude product. Separation was performed by silica gel column chromatography (petroleum ether:ethyl acetate = 1:3), yielding 1.6 g (69.2%) of the oily compound NM-012b. ESI-MS: m / z 422.2 ([M+H) + ). 1 H-NMR(DMSO-d6,ppm):1.22-1.43(m,6H),1.67(s,4H),1.74(s,3H),1.81(s,2H),2.02(s,6H),2.15(m,1H),3.70(s,4H).

[0134] Example 39: Synthesis of compound NM-012c

[0135] 2 g (4.7 mmol) of compound NM-012b was dissolved in 30 mL of redistilled tetrahydrofuran, and 900 mg of sodium borohydride was added. 2.6 g of aluminum trichloride was dissolved in 20 mL of tetrahydrofuran and slowly added dropwise to the starting material. After the addition was complete, the mixture was stirred overnight at room temperature. The reaction solution was poured into 50 mL of ice water, stirred thoroughly, and extracted with ethyl acetate (30 mL × 4). The extracts were combined, washed with 30 mL of saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain a colorless oily crude product. Separation was performed by silica gel column chromatography (ethyl acetate:methanol = 10:1), yielding 880 mg (55.6%) of colorless oily NM-012c. ESI-MS: m / z 338.1 ([M+H) + ). 1 H-NMR(DMSO-d6,ppm):1.05-1.09(m,6H),1.22-1.39(m,8H),1.51-1.60(m,4H),1.73(s ,3H),1.76(s,2H),2.07(m,1H),3.30-3.36(m,4H),4.39(t,2H,J=5.2Hz),7.36(s,1H).

[0136] Example 40: Synthesis of compound NM-012d

[0137] 670 mg (2 mmol) of compound NM-012c, 1 g of solid sodium hydroxide, and 10 mL of diethylene glycol were added to a 50 mL round-bottom flask and reacted at 170 °C for 15 hours. After cooling to room temperature, 20 mL of water and ethyl acetate (20 mL × 3) were added for washing. Water was removed by rotary evaporation under reduced pressure. 30 mL of tetrahydrofuran, 900 mg (4 mmol) of Boc anhydride, 400 mg (4 mmol) of triethylamine, and 10 mg of DMAP were added to the remaining solution, and the reaction was carried out at room temperature for 5 hours. The reaction was monitored by TLC. After the reaction was complete, 20 mL of saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 4). The combined ethyl acetate layers were washed successively with 30 mL of water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, a pale yellow oily crude product was obtained. Separation was performed by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1), yielding 500 mg (63.3%) of the oily compound NM-012d. ESI-MS: m / z 340.4 ([M+H]) + ). 1 H-NMR(DMSO-d6,ppm):1.22-1.43(m,6H),1.67(s,4H),1.74(s,3H),1.81(s,2H),2.02(s,6H),2.15(m,1H),3.70(s,4H).

[0138] Example 41: Synthesis of compound NM-012e

[0139] Dissolve 680 mg (2 mmol) of compound NM-012d in 10 mL of dried dichloromethane and cool in an ice-water bath. Add 2 mL of a mixture of acetic anhydride and fuming nitric acid (acetic anhydride:fuming nitric acid volume ratio = 3:2). Maintain the ice-water bath and react for 10-15 minutes. Pour the reaction solution into 10 mL of 1N sodium bicarbonate solution. After separating the dichloromethane, extract the aqueous layer with dichloromethane (10 mL × 3). Combine the dichloromethane liquids, wash with 10 mL of water, and dry with anhydrous sodium sulfate. Filter, and distill the dichloromethane under reduced pressure to obtain a colorless oily crude product. Separate by silica gel column chromatography (petroleum ether:dichloromethane = 10:1) to obtain 620 mg (72.3%) of colorless oily NM-012e. ESI-MS: m / z 508.1 ([M+Na) + ). 1 H-NMR(DMSO-d6,ppm):1.37(s,9H),1.40(m,6H),1.60(m,2H),1.72-1.82(m,4H),2.17(m,1H),4.23(s,4H),6.66(s,1H).

[0140] Example 42: Synthesis of compound NM-012

[0141] 401 mg (1 mmol) of compound NM-012e was added to 5 mL of a saturated diethyl ether solution containing hydrogen chloride. The reaction was carried out at room temperature and monitored by TLC. At the end of the reaction, a white solid precipitated. The mixture was filtered, and the white solid was washed with anhydrous diethyl ether to obtain pure NM-012. After drying, 380 mg (65.5%) of NM-012 was obtained. ESI-MS: m / z 255.1 ([M+H) + ). 1 H-NMR(DMSO-d6,ppm):1.38-1.54(m,6H),1.60-1.77(m,6H),2.27(m,1H),4.32(s,4H),8.27(s,3H).

[0142] Example 43: Protective effect of the compound on primary cerebellar granule cells in rats

[0143] Primary isolated neonatal rat cerebellar granule cells were isolated at a concentration of 1.2 × 10⁻⁶. 5 Cells were seeded in 96-well plates using BME medium containing 10% FBS, 25mM KCl, 2mM Glutamine, and 1% penicillin-dextrose antibody. After 24 hours, cytarabine was added to a final concentration of 10 μM to inhibit glial cell proliferation. From day 4 onwards, glucose was added every 4 days to a final concentration of 5 mM to replenish cellular energy metabolism and water evaporation. The cells were then cultured in a cell culture incubator (37°C, 5% CO2) for 10 days. Excitotoxic damage to primary cerebellar granule cells was induced using 200 μM glutamate, and the cells were divided into a normal control group, a glutamate group, groups pretreated with different memantine nitrate compounds, and a memantine pretreated control group. After adding different concentrations of compounds NM-001, NM-002, NM-003, NM-004, NM-005, NM-008, NM-009, NM-011, and NM-012, along with memantine, to the experimental groups for 2 hours of pre-protection, 200 μM glutamate was added to induce cell damage for 24 hours. Then, MTT was added for further culture for 4 hours. After aspirating the supernatant, 150 μL of DMSO was added to each well to dissolve the cells. The mixture was shaken and the absorbance was measured at 570 nm using a microplate reader to calculate cell viability. Cell viability (%) = Absorbance of different treatment groups / Absorbance of normal control group × 100%.

[0144] Table 1 describes the protective effects of the compounds on rat brain nerve cells.

[0145] NM-001 24.62 NM-009 5.20 NM-002 25.2 NM-011 5.86 NM-003 15.36 NM-012 9.30 NM-004 8.12 YQW-036 31.4 NM-005 6.06 Megatron 2.72 NM-008 4.37

[0146] Example 44: Protective effect of compound NM-008 on rat model of cerebral ischemia-MCAo.

[0147] Female SD rats weighing 280-295g were anesthetized with isoflurane. The proximal end of the common carotid artery and the external carotid artery were separated and ligated. A small suture was inserted into the internal carotid artery through the common carotid artery. After suture insertion, changes in local cerebral blood flow were measured using a blood flow meter. Before modeling and 5 minutes after embolization, changes in blood flow in the right cerebral ischemic area were monitored using a laser Doppler blood flow meter. The successful model was judged when cerebral blood flow decreased to less than 60% of the normal value after embolization.

[0148] Rats were administered the drug intravenously at 3 and 6 hours after successful model establishment (60 mg / kg). Twenty-four hours after model establishment, the animals were anesthetized with sodium pentobarbital, decapitated, and brain sections were harvested. TTC staining was performed, and the infarct area was calculated. Compared with the model group, NM-008 significantly reduced the infarct area in the stroke model (P<0.05), with a protection rate of 15.3%. Figure 8 ).

Claims

1. A method for preparing adamantane nitrate compound NM-004 and its pharmaceutically acceptable salt, characterized in that, The structural formula of the adamantane nitrate compound NM-004 is as follows: ； The adamantane nitrate compound NM-004 is derived from compound NM-004f; the structural formula of compound NM-004f is as follows: 。 2. The method for preparing the adamantane nitrate compound NM-004 and its pharmaceutically acceptable salt according to claim 1, characterized in that, The compound NM-004f is derived from compound NM-004e, and the structural formula of compound NM-004e is as follows: 。 3. The method for preparing the adamantane nitrate compound NM-004 and its pharmaceutically acceptable salt according to claim 2, characterized in that, The compound NM-004e is derived from compound NM-004d, and the structural formula of compound NM-004d is as follows: 。 4. The method for preparing the adamantane nitrate compound NM-004 and its pharmaceutically acceptable salt according to claim 3, characterized in that, The compound NM-004d is derived from compound NM-004c, and the structural formula of compound NM-004c is as follows: 。 5. The method for preparing the adamantane nitrate compound NM-004 and its pharmaceutically acceptable salt according to claim 4, characterized in that, The compound NM-004c is derived from compound NM-004b, and the structural formula of compound NM-004b is as follows: 。 6. The method for preparing the adamantane nitrate compound NM-004 and its pharmaceutically acceptable salt as described in claim 1, characterized in that, The following synthesis route was adopted: 。 7. A method for preparing adamantane nitrate compound NM-005 and its pharmaceutically acceptable salt, characterized in that, The structural formula of the adamantane nitrate compound NM-005 is as follows: ； The adamantaneamine nitrate compound NM-005 is derived from compound NM-005f; the structural formula of compound NM-005f is as follows: 。 8. The method for preparing the adamantane nitrate compound NM-005 and its pharmaceutically acceptable salt according to claim 7, characterized in that, The compound NM-005f is derived from compound NM-005e, and the structural formula of compound NM-005e is as follows: 。 9. The method for preparing the adamantane nitrate compound NM-005 and its pharmaceutically acceptable salt according to claim 8, characterized in that, The compound NM-005e is derived from compound NM-005d, and the structural formula of compound NM-005d is as follows: 。 10. The method for preparing the adamantane nitrate compound NM-005 and its pharmaceutically acceptable salt according to claim 9, characterized in that, The compound NM-005d is derived from compound NM-005c, and the structural formula of compound NM-005c is as follows: 。 11. The method for preparing the adamantane nitrate compound NM-005 and its pharmaceutically acceptable salt according to claim 7, characterized in that, The following reaction route is adopted: 。 12. A method for preparing adamantane nitrate compound NM-008 and its pharmaceutically acceptable salt, characterized in that, The structural formula of the adamantane nitrate compound NM-008 is as follows: ； The adamantane nitrate compound NM-008 is derived from compound NM-008g; the structural formula of compound NM-008g is as follows: 。 13. The method for preparing the adamantane nitrate compound NM-008 and its pharmaceutically acceptable salt according to claim 12, characterized in that, The compound NM-008g is derived from compound NM-008f, and the structural formula of compound NM-008f is as follows: 。 14. The method for preparing the adamantane nitrate compound NM-008 and its pharmaceutically acceptable salt according to claim 13, characterized in that, The compound NM-008f is derived from compound NM-008e, and the structural formula of compound NM-008e is as follows: 。 15. The method for preparing the adamantane nitrate compound NM-008 and its pharmaceutically acceptable salt according to claim 12, characterized in that, The following reaction route is adopted: 。 16. A method for preparing adamantane nitrate compound NM-009 and its pharmaceutically acceptable salt, characterized in that, The structural formula of the adamantane nitrate compound NM-009 is as follows: ； The adamantane nitrate compound NM-009 is derived from compound NM-009e; the structural formula of compound NM-009e is as follows: 。 17. The method for preparing the adamantane nitrate compound NM-009 and its pharmaceutically acceptable salt according to claim 16, characterized in that, The adamantaneamine nitrate compound NM-009e is derived from compound NM-009d; the structural formula of compound NM-009d is as follows: 。 18. The method for preparing the adamantane nitrate compound NM-009 and its pharmaceutically acceptable salt according to claim 17, characterized in that, The adamantane nitrate compound NM-009d is derived from compound NM-009c; the structural formula of compound NM-009c is as follows: 。 19. The method for preparing the adamantane nitrate compound NM-009 and its pharmaceutically acceptable salt according to claim 18, characterized in that, The adamantaneamine nitrate compound NM-009c is derived from compound NM-009b; the structural formula of compound NM-009b is as follows: 。 20. The method for preparing the adamantane nitrate compound NM-009 and its pharmaceutically acceptable salt according to claim 16, characterized in that, The following reaction route is adopted: 。 21. A method for preparing the adamantane nitrate compound NM-011 and its pharmaceutically acceptable salt, characterized in that, The structural formula of the adamantane nitrate compound NM-011 is as follows: ； The adamantaneamine nitrate compound NM-011 is derived from compound NM-011e; the structural formula of compound NM-011e is as follows: 。 22. The method for preparing the adamantane nitrate compound NM-011 and its pharmaceutically acceptable salt according to claim 21, characterized in that, The adamantaneamine nitrate compound NM-011e is derived from compound NM-011d; the structural formula of compound NM-011d is as follows: 。 23. The method for preparing the adamantane nitrate compound NM-011 and its pharmaceutically acceptable salt according to claim 22, characterized in that, The adamantaneamine nitrate compound NM-011d is derived from compound NM-011c; the structural formula of compound NM-011c is as follows: 。 24. The method for preparing the adamantane nitrate compound NM-011 and its pharmaceutically acceptable salt according to claim 23, characterized in that, The adamantaneamine nitrate compound NM-011c is derived from compound NM-011b; the structural formula of compound NM-011b is as follows: 。 25. The method for preparing the adamantane nitrate compound NM-011 and its pharmaceutically acceptable salt according to claim 21, characterized in that, The following synthesis route was adopted: 。 26. A method for preparing the adamantane nitrate compound NM-012 and its pharmaceutically acceptable salt, characterized in that, The structural formula of the adamantane nitrate compound NM-012 is as follows: ； The adamantaneamine nitrate compound NM-012 is derived from compound NM-012e; the structural formula of compound NM-012e is as follows: 。 27. The method for preparing the adamantane nitrate compound NM-012 and its pharmaceutically acceptable salt according to claim 26, characterized in that, The adamantaneamine nitrate compound NM-012e is derived from compound NM-012d; the structural formula of compound NM-012d is as follows: 。 28. The method for preparing the adamantane nitrate compound NM-012 and its pharmaceutically acceptable salt according to claim 27, characterized in that, The adamantane nitrate compound NM-012d is derived from compound NM-012c; the structural formula of compound NM-012c is as follows: 。 29. The method for preparing the adamantane nitrate compound NM-012 and its pharmaceutically acceptable salt according to claim 28, characterized in that, The adamantaneamine nitrate compound NM-012c is derived from compound NM-012b; the structural formula of compound NM-012b is as follows: 。 30. The method for preparing the adamantane nitrate compound NM-012 and its pharmaceutically acceptable salt according to claim 26, characterized in that, The following synthetic route was adopted: 。 31. Adamantane nitrate compound having any of the following structures: ； ； ； ； ； 。 32. The use of the adamantaneamine nitrate compound according to claim 31 in the preparation of compounds, characterized in that, The specific application is as follows: Compound NM-004f was used to prepare compound NM-004. The structural formula of compound NM-004 is as follows: ； Compound NM-005 was prepared from compound NM-005f. The structural formula of compound NM-005 is as follows: ； Compound NM-008 was prepared from compound NM-008g. The structural formula of compound NM-008 is as follows: ； Compound NM-009 was prepared from compound NM-009e. The structural formula of compound NM-009 is as follows: ； Compound NM-011 was prepared from compound NM-011e. The structural formula of compound NM-011 is as follows: ； Compound NM-012 was prepared from compound NM-012e. The structural formula of compound NM-012 is as follows: 。

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