A diterpenoid natural product derivative with anti-neuroinflammatory activity, its preparation method and pharmaceutical uses.

Abstract

This invention belongs to the fields of medicinal chemistry and pharmaceutical technology, specifically relating to a diterpenoid natural product derivative with anti-neuroinflammatory activity as shown in formula (I), its preparation method, and its pharmaceutical uses. (I).

Description

Technical Field

[0001] This invention belongs to the fields of medicinal chemistry and pharmaceutical technology, specifically relating to a diterpenoid natural product derivative with anti-neuroinflammatory activity, its preparation method, and its pharmaceutical uses. Background Technology

[0002] According to statistics, approximately 219 million people worldwide live at altitudes above 2000 meters. With economic development and improved transportation, the number of people traveling to high-altitude areas for tourism, religious activities, and military training continues to grow. Emerg. Med. Clin. N. Am. 2004, 22(2):329-355. However, when individuals lacking acclimatization enter high-altitude areas from low-altitude regions, they may experience hypoxia due to a decrease in the partial pressure of inhaled oxygen, leading to acute altitude-related illnesses, including acute mountain sickness, high-altitude cerebral edema, and high-altitude pulmonary edema. Nat. Rev. Dis. Primers.2024, 10(1):43. Acute mountain sickness is the earliest clinical manifestation, with main symptoms including headache, nausea, fatigue, dizziness, and sleep disturbances. High Alt. Med. Biol.2018, 19(1):4-6. High-altitude cerebral edema, a terminal manifestation of acute mountain sickness, typically occurs after a rapid ascent to 2500 meters. Clinical manifestations include headache, ataxia, fatigue, cognitive impairment, altered mental status, and the potential to trigger seizures. Although its incidence is low, without timely diagnosis and intervention, it can easily lead to coma and even death. Rambam Maimonides Med. J. 2011, 2(1):e0022. Chronic altitude sickness is common in people who live or are exposed to high-altitude, low-pressure, and low-oxygen environments for extended periods. It primarily reflects the body's poor adaptation to persistent hypoxia and its complications, often presenting with symptoms such as headache, fatigue, sleep disturbances, difficulty breathing, and cyanosis. Current clinical treatment mainly focuses on symptomatic relief. Signal. Transduct. Target Ther. 2026, 11:27 To safeguard the health and well-being of people in plateau regions and promote regional economic development, there is an urgent need to develop safe and effective new preventative and therapeutic drugs.

[0003] Andrographis paniculata ( Andrographis paniculata (Burm.f.)Nees) is an annual herb belonging to the genus Andrographis in the family Acanthaceae. It is listed in Part I of the 2020 edition of the Chinese Pharmacopoeia. Native to India and Sri Lanka, it is now widely distributed throughout Asia and is known as the "King of Bitterness" due to its pronounced bitterness. J. Ethnopharmacol. 2021, 275:114054. Andrographolide dehydrated is one of the main active components of Andrographis paniculata, exhibiting relatively clear pharmacological activities in anti-inflammatory and antioxidant effects. It can alleviate cellular inflammatory responses, oxidative stress, and pyroptosis by regulating signaling pathways such as NF-κB, MAPK, Nrf2, and AMPK, thereby mitigating related tissue damage. Eur. J. Med. Chem. 224 (2021): 11371; Biomolecules. 2025, 15(11)Therefore, the discovery of dehydrated andrographolide derivatives with superior pharmacological activity through structural modification, which can alleviate neuroinflammation in the brain, and are intended for the development of drugs for the prevention and / or treatment of neuroinflammation-related neurological diseases such as high-altitude cerebral edema, high-altitude brain injury, hypoxic-ischemic encephalopathy in newborns, ischemic / hemorrhagic stroke, traumatic brain injury, Alzheimer's disease, Huntington's disease, Parkinson's disease, delayed encephalopathy after carbon monoxide poisoning, epilepsy, and post-traumatic stress disorder, is of significant research importance and has a promising market application prospect. Summary of the Invention

[0004] The purpose of this invention is to provide a diterpenoid natural product derivative with anti-neuroinflammatory activity, a method for preparing the same, and its use in the preparation of drugs for the prevention and / or treatment of neuroinflammatory-related diseases, including high-altitude cerebral edema, high-altitude brain injury, hypoxic-ischemic encephalopathy of newborns, ischemic / hemorrhagic stroke, traumatic brain injury, Alzheimer's disease, Huntington's disease, Parkinson's disease, delayed encephalopathy after carbon monoxide poisoning, epilepsy, post-traumatic stress disorder, and other neurological diseases.

[0005] A first aspect of the present invention provides a diterpenoid natural product derivative, or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, metabolite, polymorph, or isotope label thereof, the structure of which is shown in formula (I):

[0006] In formula (Ⅰ): Ring A is selected from substituted or unsubstituted C6-C14 aryl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted 5- to 14-membered heteroaryl groups containing 1-3 heteroatoms selected from N, O, and S, and substituted or unsubstituted 5- to 10-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O, and S. "Substitution" refers to the presence of 1 to 3 substituents R. 1 ; R 1 Each of the substituents is independently selected from hydrogen, hydroxyl, amino, nitro, halogen atom, C1-C6 alkyl, C1-C6 alkoxy, and iminourea; X is selected from saturated or unsaturated substituted or unsubstituted 5- to 10-membered heterocyclic alkyl C1-C6 alkyl containing 1-3 heteroatoms selected from N, O, and S, or saturated or unsaturated substituted or unsubstituted 5- to 10-membered heterocyclic alkyl C2-C6 alkenyl containing 1-3 heteroatoms selected from N, O, and S, wherein “substituted” means containing 1 to 3 substituents independently selected from hydrogen, hydroxyl, amino, oxo, C1-C6 alkyl, and C1-C6 alkoxy. Y is selected from C1-C6 alkylene, C1-C6 alkoxy, and carbonyl groups; Z is selected from hydrogen, hydroxyl, C2-C6 diacid monoester, C2-C6 diacid diester, C1-C6 acyloxy, halogenated C1-C6 acyloxy, C3-C8 cycloalkylamino, substituted or unsubstituted C6-C10 arylamino, C6-C10 arylC1-C6 acyloxy, substituted or unsubstituted 5- to 10-membered heteroaryl containing 1-3 heteroatoms selected from N, O, S, substituted or unsubstituted 5- to 10-membered heteroarylC1-C6 alkylamino containing 1-3 heteroatoms selected from N, O, S, substituted or unsubstituted 5- to 10-membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O, S, wherein “substituted” means containing 1 to 3 substituents each independently selected from hydrogen, hydroxyl, amino, halogen atom, C1-C6 alkyl, C1-C6 alkoxy, -CF3; Preferably, ring A is selected from substituted or unsubstituted C6-C10 aryl groups, substituted or unsubstituted C5-C6 cycloalkyl groups, substituted or unsubstituted 5- to 9-membered heteroaryl groups containing 1-3 heteroatoms selected from N and S, or substituted or unsubstituted 5- to 9-membered heterocycloalkyl groups containing 1-3 heteroatoms selected from N and S. "Substitution" refers to the presence of 1 or 2 substituents R. 1 ; More preferably, ring A is selected from substituted or unsubstituted C6-C10 aryl groups, substituted or unsubstituted C5-C6 cycloalkyl groups, substituted or unsubstituted 5- to 9-membered heteroaryl groups containing 1-3 heteroatoms selected from N and S, and substituted or unsubstituted 5- to 9-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N and S, wherein "substituted" refers to containing 1 or 2 substituents R. 1 ; More preferably, ring A is selected from substituted or unsubstituted 5- to 9-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N and S, or substituted or unsubstituted 5- to 9-membered heterocyclic alkyl groups containing 1 to 3 heteroatoms selected from N and S, wherein "substituted" refers to containing 1 or 2 substituents R. 1 ; More preferably, ring A and ring R 1 Together, we select from the following structures: , , , , , ; More preferably, ring A and ring R 1 Selected together , , .

[0007] Preferably, R 1 Each substituent is independently selected from hydrogen, hydroxyl, amino, C1-C3 alkyl, and C1-C3 alkoxy groups; Preferably, R 1 Each substituent is independently selected from hydrogen, hydroxyl, amino, and C1-C3 alkoxy groups; Preferably, R 1 Each substituent is independently selected from hydrogen, amino, methoxy, ethoxy, propoxy, C1-C3 alkoxy, and iminourea groups; Preferably, R 1 Selected from hydrogen substitution.

[0008] Preferably, X is selected from saturated or unsaturated substituted or unsubstituted 5- to 6-membered heterocyclic alkyl C1-C3 alkyl containing one or two heteroatoms selected from N and O, or saturated or unsaturated substituted or unsubstituted 5- to 6-membered heterocyclic alkyl C2-C3 alkenyl containing one or two heteroatoms selected from N and O, wherein “substituted” means containing one or two substituents independently selected from hydrogen, hydroxyl, amino, oxo, C1-C3 alkyl, and C1-C3 alkoxy. Preferably, X is selected from saturated or unsaturated substituted or unsubstituted 5- to 6-membered heterocyclic alkyl C1-C3 alkyl containing one or two heteroatoms selected from N and O, or saturated or unsaturated substituted or unsubstituted 5- to 6-membered heterocyclic alkyl C2-C3 alkenyl containing one or two heteroatoms selected from N and O, wherein “substituted” means containing one or two substituents independently selected from hydrogen, hydroxyl, and oxo groups; Preferably, X is selected from the following structures: , ; More preferably, X is selected from .

[0009] Preferably, Y is selected from C1-C3 alkylene, C1-C3 alkeneoxy, and carbonyl groups; More preferably, Y is a methylene or carbonyl group; More preferably, Y is a carbonyl group.

[0010] Preferably, Z is selected from hydrogen, hydroxyl, C2-C4 diacid monoester, C2-C4 diacid diester, C1-C3 acyloxy, halogenated C1-C3 acyloxy, C3-C6 cycloalkylamino, substituted or unsubstituted phenylamino, phenyl C1-C3 acyloxy, substituted or unsubstituted 5- to 9-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, S, substituted or unsubstituted 5- to 6-membered heteroaryl C1-C3 alkylamino containing 1 or 2 heteroatoms selected from N, O, S, substituted or unsubstituted 5- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O, S, wherein “substituted” means containing 1 or 2 to 3 substituents each independently selected from hydrogen, hydroxyl, amino, halogen atom, C1-C3 alkyl, C1-C3 alkoxy, -CF3; Preferably, Z is selected from hydroxyl, acetoxy, bromoacetoxy, succinate, methylsuccinate, glutarate, methylglutarate, adipate, phenylpropionate, cyclopropylamino, cyclopentanamino, cyclohexylamino, aniline, 2-methyl-5-indoleamino, benzylamino, 4-bromobenzylamino, 2-thiophenemethylamino, 3-pyridinemethylamino, tryptamine, 2-fluoro-5-methylaniline, 2,5-difluoroaniline, 2-fluoro-5-hydroxyaniline, 2-fluoro-4-hydroxyaniline, 2-methoxyaniline, 4-trifluoromethyl-2-hydroxyaniline, 3-methoxyaniline, 3-methoxy-4-hydroxyaniline, 3-hydroxy-4-methoxyaniline, 2-methoxy-phenylethylamino, 2-morpholinoethylamino, 2-( N (-methylpiperazine)ethylamino; preferably aniline, chromoamino, 2,5-difluoroaniline, 2-fluoro-5-hydroxyaniline, 2-fluoro-4-hydroxyaniline, 2-methoxyaniline, 3-methoxyaniline, 2-methoxy-phenylethylamino; Preferably, Z is selected from the following structures: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ; More preferably, Z is selected from , , , , , , , .

[0011] According to some embodiments of the present invention, the diterpenoid natural product derivative represented by formula (I) above can be a compound represented by formulas (II), (III), (IV), (V), (VI) or (VII):

[0012] In the formula, R 1 The definitions of the substituents X, Y and Z are the same as in equation (I).

[0013] In particular, the diterpenoid natural product derivatives represented by formulas (I), (II), (III), (IV), (V), (VI), or (VII) of this invention are selected from the following compounds:

[0014] .

[0016] A second aspect of the present invention provides a method for synthesizing diterpenoid natural product derivatives as shown in formula (I) of the first aspect of the present invention, comprising the following synthetic route: Synthesis Route 1:

[0017] Andrographolide (II-1) reacts with 2,2-dimethoxypropane via a nucleophilic substitution reaction to give intermediate II-2; the solvent used in the nucleophilic substitution reaction is selected from acetone, acetonitrile, dichloromethane, ethyl acetate, with acetone being preferred; Intermediate II-2 was reacted with tert-butyldimethylchlorosilane under alkaline conditions via nucleophilic substitution, followed by acid hydrolysis to remove the dimethylene protecting group, yielding intermediate II-3; the base used was selected from imidazole. N , N -Diisopropylethylamine, potassium carbonate, preferably imidazole; the acid used is selected from acetic acid, phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, preferably acetic acid; Intermediate II-3 undergoes a nucleophilic substitution reaction with tert-butyldimethylchlorosilane to give intermediate II-4; the solvent used in the nucleophilic substitution reaction is selected from dichloromethane and acetonitrile. N , N -Dimethylformamide, ethyl acetate, tetrahydrofuran, preferably dichloromethane; Intermediate II-4 undergoes an oxidation reaction under the action of an oxidizing agent to obtain intermediate II-5; the oxidizing agent used is selected from Des Martin oxidizing agent, 2-iodobenzoic acid, m-chloroperoxybenzoic acid, with Des Martin oxidizing agent being preferred. Intermediate II-5 and different R 1The substituted phenylhydrazine hydrochloride was synthesized by Fischer indole under acidic conditions to give intermediate II-6; the acid used was selected from acetic acid, phosphoric acid, sulfuric acid, and hydrochloric acid, with acetic acid being preferred; Intermediate II-6 was deprotected and epoxidized with a pentyl lactone to prepare compound (II); the deprotecting agent used was selected from pyridine hydrogen fluoride, tetrabutylammonium fluoride, trifluoroacetic acid, preferably pyridine hydrogen fluoride; the oxidizing agent used was selected from alumina, Des Martin oxidant, 2-iodobenzoic acid, preferably alumina.

[0018] Synthesis Route 2:

[0019] Intermediate II-5 was brominated to give intermediate III-1; the brominating reagents used were pyridinium tribromide and bromine water. N - Bromosuccinimide, preferably pyridinium tribromide; Intermediate III-1 reacts with thiourea via cyclization and deprotection to yield aminothiazole intermediate III-2; the solvents used in the cyclization reaction are selected from ethanol, n-butanol, and acetonitrile. N , N - Dimethylformamide, preferably ethanol; the deprotecting agent used is selected from pyridine hydrogen fluoride, tetrabutylammonium fluoride, trifluoroacetic acid, preferably pyridine hydrogen fluoride; Intermediate III-2 was prepared by epoxidation of a five-membered lactone to obtain compound (III); the oxidant used was selected from alumina, Des Martin oxidant, 2-iodobenzoic acid, peracetic acid, and preferably alumina. Intermediate III-2 was prepared by rearrangement addition reaction under acidic conditions to obtain compound (IV); the acid used was selected from hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, hydrobromic acid, with hydrochloric acid being preferred.

[0020] Synthesis Route 3:

[0021] Brominated intermediate III-1 reacts with o-phenylenediamine via an elimination cyclization reaction to yield quinoxaline intermediate IV-1; the solvent used in the cyclization reaction is selected from... N , N -Dimethylformamide, n-butanol, acetonitrile, preferred N , N -Dimethylformamide; Intermediate IV-1 was prepared by deprotection and epoxidation of a pentyl lactone to obtain compound (IV); the deprotection reagent used was selected from pyridine hydrogen fluoride, trifluoroacetic acid, tetrabutylammonium fluoride, preferably pyridine hydrogen fluoride; the oxidant used was selected from alumina, Des Martin oxidant, 2-iodobenzoic acid, preferably alumina.

[0022] Synthesis Route 4:

[0023] Intermediate II-2 reacts with tert-butyldiphenylchlorosilane under alkaline conditions via a nucleophilic substitution reaction followed by acid hydrolysis to yield intermediate V-1; the base used is selected from imidazole. N , N -Diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, potassium carbonate, preferably imidazole; the acid used is selected from acetic acid, hydrobromic acid, hydrochloric acid, preferably acetic acid; Intermediate V-1 was subjected to nucleophilic substitution of tert-butyldiphenylchlorosilane and oxidation with a secondary alcohol to obtain intermediate V-2; the oxidant used was selected from Dys-Martin oxidant, 2-iodobenzoic acid, peracetic acid, manganese dioxide, with Dys-Martin oxidant being preferred; Intermediate V-2 reacts with aminourea hydrochloride via an addition-elimination reaction to yield intermediate V-3; the reaction solvents used are selected from ethanol, n-butanol, tert-butanol, and acetonitrile. N , N -Dimethylformamide, preferably ethanol; Intermediate V-3 was deprotected and epoxidized with a pentyl lactone to prepare compound (V); the deprotecting agent used was selected from pyridine hydrogen fluoride, trifluoroacetic acid, tetrabutylammonium fluoride, preferably pyridine hydrogen fluoride; the oxidizing agent used was selected from alumina, Des Martin oxidant, 2-iodobenzoic acid, preferably alumina.

[0024] Synthesis Route 5:

[0025] Intermediate V-3 is reacted with a thiodiazole reagent via an elimination cyclization reaction to yield 1,2,3-thiadiazole intermediate VII-1; the thiodiazole reagent includes thionyl chloride, phenyl thiochloroformate, elemental sulfur, preferably thionyl chloride. Intermediate VII-1 was deprotected and epoxidized with a pentyl lactone to obtain intermediate VII-2; the deprotecting agent used was selected from pyridine hydrogen fluoride, trifluoroacetic acid, tetrabutylammonium fluoride, preferably pyridine hydrogen fluoride; the oxidizing agent used was selected from alumina, Des Martin oxidant, 2-iodobenzoic acid, preferably alumina; Intermediate VII-2 was esterified with different alkyl acids in the presence of a coupling agent to prepare compound (VII); the coupling agent used was selected from 2-(7-azabenzotriazole)- N , N , N' , N' -Tetramethylurea hexafluorophosphate (HATU), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), preferably EDCI; Intermediate VII-2 undergoes an oxidation reaction under the action of an oxidizing agent to give aldehyde intermediate VII-3; the oxidizing agent used is selected from 2,2,6,6-tetramethylpiperidine oxide, pyridinium chlorochromate, Jones reagent, Des Martin oxidizing agent, preferably 2,2,6,6-tetramethylpiperidine oxide; Intermediate VII-3 is further oxidized under the action of an oxidant to obtain carboxylic acid intermediate VII-4; the oxidant used is selected from sodium hypochlorite, potassium permanganate, and m-chloroperoxybenzoic acid, with sodium hypochlorite being preferred; The intermediate VII-4 was reacted with different aliphatic or aromatic amines via amide condensation to prepare compounds of formula (VII); the reaction solvents used were selected from tetrahydrofuran, dichloromethane, acetonitrile, ethyl acetate, chloroform, acetone, with tetrahydrofuran being preferred.

[0026] The definitions of each group in the above synthetic route are as described in the first aspect of this invention.

[0027] The "compounds" described in this invention include diterpenoid natural product derivatives and their pharmaceutically acceptable salts, prodrugs, stereoisomers, solvates, polymorphs, isotope-labeled compounds, metabolites, enantiomers, diastereomers, tautomers, or mixtures thereof.

[0028] The "pharmaceutically acceptable salt" described in this invention can be an inorganic or organic acid salt of a diterpenoid natural product derivative as shown in formula (I). The inorganic acid can include, but is not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, nitric acid, etc., and the organic acid can include, but is not limited to, acetic acid, glycolic acid, propionic acid, pyruvic acid, oxalic acid, malonic acid, malic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, benzoic acid, citric acid, cinnamic acid, mandelic acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.

[0029] The diterpenoid natural product derivatives and pharmaceutically acceptable salts described in this invention also include solvated or hydrated forms. Generally, solvated or hydrated forms are considered equivalent to non-solvated forms in use and are included within the scope of this invention. Furthermore, some compounds in this invention may exist in polymorphic or amorphous crystalline forms. Regardless of their physical crystalline form, they are considered equivalent and included within the scope of this invention.

[0030] In a third aspect, the present invention provides a pharmaceutical composition comprising a diterpenoid natural product derivative of formula (I) or a pharmaceutically acceptable salt thereof, a prodrug, a stereoisomer, a solvate, a polymorph, an isotope label, a metabolite, an enantiomer, a diastereomer or a tautomer, and at least one pharmaceutically acceptable carrier, excipient, stabilizer, excipient, solubilizer, diluent or sustained-release material.

[0031] In a fourth aspect, the present invention provides a route of administration comprising a diterpenoid natural product derivative or pharmaceutical composition of formula (I), selected from at least one of oral administration, sublingual administration, rectal administration, intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, intrathecal injection, inhalation administration, nasal administration, transdermal administration, and intraperitoneal injection.

[0032] In a fifth aspect, the present invention provides a pharmaceutical formulation comprising a diterpenoid natural product derivative of formula (I) or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, polymorph, isotope label, metabolite, enantiomer, diastereomer, or tautomer thereof, or a pharmaceutical dosage form of a pharmaceutical composition as described in the third aspect of the present invention, selected from at least one of tablets, capsules, granules, powders, pills, drop pills, oral solutions, oral suspensions, syrups, injections, powder for injection, large-volume infusions, lyophilized powder for injection, aerosols, sprays, inhalers, powder mists, gels, ointments, creams, patches, transdermal patches, lotions, liniments, suppositories, films, sublingual tablets, orally disintegrating tablets, emulsions, nanoformulations, liposome formulations, sustained-release formulations, or controlled-release formulations.

[0033] In a sixth aspect, the present invention provides the use of a diterpenoid natural product derivative of formula (I), or the pharmaceutical composition, or the pharmaceutical preparation, in the preparation of a medicament for treating neuroinflammatory-related neurological diseases; wherein the neuroinflammatory-related neurological diseases include high-altitude cerebral edema, high-altitude brain injury, hypoxic-ischemic encephalopathy of newborns, ischemic / hemorrhagic stroke, traumatic brain injury, Alzheimer's disease, Huntington's disease, Parkinson's disease, delayed encephalopathy after carbon monoxide poisoning, epilepsy, and post-traumatic stress disorder.

[0034] Beneficial effects The diterpenoid natural product derivatives described in this invention exhibit good in vitro anti-hypoxic neuroinflammatory activity against astrocyte C8-D1A cells with low cytotoxicity. These compounds are simple to prepare, using inexpensive and readily available raw materials, and hold promise as novel preventative and / or therapeutic agents for diseases such as high-altitude cerebral edema, high-altitude brain injury, neonatal hypoxic-ischemic encephalopathy, ischemic / hemorrhagic stroke, traumatic brain injury, Alzheimer's disease, Huntington's disease, Parkinson's disease, delayed encephalopathy after carbon monoxide poisoning, epilepsy, and post-traumatic stress disorder. Experiments show that compounds 2, 4, 36, and 37 enhance cell viability in hypoxic neuroinflammatory cells by over 80%, demonstrating promising clinical application and market potential. Attached Figure Description

[0035] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0036] Figure 1 The diterpenoid natural product derivatives described in this invention exhibit anti-hypoxic neuroinflammatory activity against C8-D1A cells at a concentration of 20 μM.

[0037] Figure 2 The diterpenoid natural product derivatives described in this invention exhibit normoxic activity against C8-D1A cells at a concentration of 20 μM.

[0038] Figure 1 and Figure 2 In the middle, compared with the normoxia group, #### P<0.0001; There was no difference in ns compared with the hypoxia + LPS group, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001. Detailed Implementation

[0039] The present invention will now be described in detail. Before proceeding with the description, it should be understood that the terminology used in this specification and the appended claims should not be construed as limited to its general or dictionary meaning, but rather should be interpreted according to the meaning and concept corresponding to the technical aspects of the invention, based on the principle that the inventors are allowed to appropriately define the terms for the best interpretation. Therefore, the description presented herein is merely a preferred example for illustrative purposes and is not intended to limit the scope of the invention. It should be understood that other equivalents or modifications can be obtained from it without departing from the spirit and scope of the invention.

[0040] In this document, the terms “comprising,” “including,” “having,” “containing,” or any other similar terms are open-ended conjunctions intended to cover non-exclusive inclusions. For example, a composition or article containing a plurality of elements is not limited to those listed herein, but may also include other elements not explicitly listed but typically inherent to the composition or article. Furthermore, unless explicitly stated to the contrary, the term “or” is inclusive, not exclusive. For example, the condition “A or B” is satisfied in any of the following cases: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); A and B are both true (or exist). Moreover, in this document, the terms “comprising,” “including,” “having,” and “containing” should be interpreted as specifically disclosed and simultaneously cover closed or semi-closed conjunctions such as “composed of” and “substantially composed of.”

[0041] In this document, all features or conditions defined in the form of numerical ranges or percentage ranges are for the sake of brevity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges should be considered as covering and specifically disclosing all possible secondary ranges and individual values ​​within those ranges, particularly integer values. For example, a range description of "1 to 8" should be considered as specifically disclosing all secondary ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly secondary ranges defined by all integer values, and should be considered as specifically disclosing individual values ​​within those ranges such as 1, 2, 3, 4, 5, 6, 7, 8, etc. Unless otherwise specified, the foregoing interpretation applies to all content throughout this invention, regardless of its scope.

[0042] If a quantity or other numerical value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that this document has specifically disclosed all ranges consisting of any upper or preferred value of that range and the lower or preferred value of that range, regardless of whether such ranges are separately disclosed. Furthermore, when a range of numerical values ​​is mentioned herein, unless otherwise stated, the range shall include its endpoints and all integers and fractions within the range.

[0043] In this document, numerical values ​​are to be understood as having a precision with significant digits, provided that the purpose of the invention can be achieved. For example, the number 40.0 should be understood to cover a range from 39.50 to 40.49.

[0044] In this document, when Markush groups or alternative terms are used to describe features or examples of the invention, those skilled in the art should understand that subgroups of all elements within a Markush group or option list, or any individual element, can also be used to describe the invention. For example, if X is described as "selected from the group consisting of X1, X2, and X3," it also indicates that the claim that X is X1 and the claim that X is X1 and / or X2 have been fully described. Furthermore, when Markush groups or alternative terms are used to describe features or examples of the invention, those skilled in the art should understand that any combination of subgroups of all elements within a Markush group or option list, or any combination of individual elements, can also be used to describe the invention. Accordingly, for example, if X is described as "selected from the group consisting of X1, X2, and X3," and Y is described as "selected from the group consisting of Y1, Y2, and Y3," it indicates that the claim that X is X1 or X2 or X3 and Y is Y1 or Y2 or Y3 has been fully described.

[0045] definition The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 8 carbon atoms ("C..."). 1-8 Alkyl group). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C6”). 1-6 Alkyl group). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C1”). 1-5 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C”). 1-4 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C”). 1-3 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C”). 1-2 Alkyl group (“C1 alkyl”). In some embodiments, the alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, the alkyl group has 2 to 6 carbon atoms (“C1 alkyl”). 2-6 Alkyl group). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl), and hexyl (C6) (e.g., n-hexyl). Further examples of alkyl groups include n-heptyl (C7), etc.

[0046] "Alkoxy" signifies a monovalent -O-alkyl group, wherein the alkyl moiety has a specified number of carbon atoms. In this disclosure, alkoxy groups typically contain 1-6 carbon atoms ("C..."). 1-6 Alkoxy groups, such as methoxy, ethoxy, isopropoxy, tert-butyloxy, etc.

[0047] "Cycloalkyl" refers to a non-aromatic ring system having 3 to 10 ring carbon atoms ("C"). 3-10 A group consisting of a cycloalkyl group and a non-aromatic cycloalkyl group with zero heteroatoms. An example C 3-6 Cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. As shown in the foregoing examples, in some embodiments, the cycloalkyl group is a monocyclic (“monocyclic cycloalkyl”) or contains a fused ring, bridged ring, or spirocyclic system, such as a bicyclic system (“bicyclic cycloalkyl”), and may be saturated or may be partially unsaturated. “Cycloalkyl” also includes ring systems in which the cycloalkyl group as defined above is fused with one or more aryl or heteroaryl groups at the junction point on the carbon ring, and in this case, the carbon number continues to refer to the number of carbons in the carbon ring system. Unless otherwise stated, each instance of a cycloalkyl group is optionally substituted independently, i.e., unsubstituted or substituted by one or more substituents.

[0048] "Heterocyclic alkyl" refers to a group having a four- to eight-membered non-aromatic ring system having a ring carbon atom and one to three ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("four- to eight-membered heterocyclic group"). In heterocyclic groups containing one or more nitrogen atoms, the linkage can be a carbon atom or a nitrogen atom, provided that the valence allows. Heterocyclic alkyl can be monocyclic ("monocyclic heterocyclic alkyl group") or fused, bridged, or spirocyclic, such as bicyclic ("bicyclic heterocyclic alkyl"), and can be saturated or partially unsaturated. Heterocyclic bicyclic systems can contain one or more heteroatoms in one or both rings. "Heterocyclic alkyl" also includes ring systems in which the linkage of a heterocycle as defined above with one or more carbocyclic groups is on the carbocyclic group or the heterocycle, or ring systems in which the linkage of a heterocycle as defined above with one or more aryl or heteroaryl groups is on the heterocycle, and in this case, the number of ring members continues to refer to the number of ring members in the heterocyclic system.

[0049] "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the ring array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system. 6-14 Aryl group (“C6 aryl”). In some embodiments, the aryl group has 6 ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has 10 ring carbon atoms (“C6 aryl”). 10 Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms (“C”). 14"Aryl" (e.g., anthracene). "Aryl" also includes ring systems in which the aryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the groups or linkages are on the aromatic ring, and in this case, the number of carbon atoms continues to refer to the number of carbon atoms in the aromatic ring system.

[0050] "Heteroaryl" refers to a group having a five- to eight-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 π electrons shared in a cyclic array) having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("five- to eight-membered heteroaryl"). In heteroaryls containing one or more nitrogen atoms, the linkage can be a carbon atom or a nitrogen atom, provided the valence allows. Heteroaryl bicyclic systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes a ring system in which the heteroaryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the linkage is on the heteroaryl ring, and in this case, the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes a ring system in which a heteroaryl ring as defined above is fused with one or more aryl groups, wherein the connection point is on the aryl or heteroaryl ring, and in this case, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system.

[0051] "Halogen" or "halogen atom" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0052] This invention further illustrates the clarity and completeness of the research scheme through specific embodiments. In particular, the scientific terms used in the embodiments are all well-known in the field, and the preparation methods provided in the embodiments are merely illustrative descriptions and do not constitute an exclusive limitation of the invention. Simple modifications made to the preparation methods under the core concept of this invention are all within the protection scope of this invention. The chemical reagents and materials used in this invention are all available through commercial channels.

[0053] Example 1: The chemical name in this invention is ( S , E )-4-hydroxy-3-(2-((6) S 6 aS 10 R 10 aS )-6-(hydroxymethyl)-6,10 a -Dimethyl-9-methylene-6,6 a ,7,8,9,10,10 a ,11-octahydro-5 H -benzo[ b [Carbazole-10-yl)ethylene)dihydrofuran-2(3] HThe synthetic route for the synthesis of )-ketones (compound 1) is shown below:

[0054] Step 1: ( S , E )-4-hydroxy-3-(2-((4 aR 6 aS 7 R 10 aS 10 bR )-3,3,6 a 10 b -Tetramethyl-8-methylenedecahydro-1 H -naphtho[2,1- d [1,3]dioxane-7-yl)ethylene)dihydrofuran-2(3 H Synthesis of )-ketones (intermediates 1-2) In a solution of andrographolide (intermediate 1-1) (2.50 g, 7.1 mmol) and pyridine 4-methylbenzenesulfonic acid (1.78 g, 7.1 mmol) in acetone (20 ml), 2,2-dimethoxypropane (2.62 ml, 21.3 mmol) was slowly added dropwise. The reaction was stirred at room temperature for 2 h. After the reaction was complete, the mixture was concentrated under reduced pressure, extracted with ethyl acetate-sodium bicarbonate, and the organic phase was washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane:methanol = 80:1 - 40:1) to give 2.71 g of white solid, 98% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 6.63 (td, J = 6.8, 1.8Hz, 1H), 5.74 (d, J = 6.0 Hz, 1H), 4.92 (t, J = 5.6 Hz, 1H), 4.85 (s, 1H), 4.68(s, 1H), 4.40 (dd, J = 9.6, 6.4 Hz, 1H), 4.04 (dd, J = 10.0, 2.4 Hz, 1H), 3.88(d, J = 11.6 Hz, 1H), 3.41 (dd, J = 8.8, 4.4 Hz, 1H), 3.11 (d, J = 11.6 Hz, 1H), 2.53 (s, 1H), 2.34 (dt,J = 12.8, 3.2 Hz, 1H), 2.02–1.96 (m, 1H), 1.96–1.88(m, 2H), 1.72 (dt, J = 9.6, 4.8 Hz, 1H), 1.70–1.62 (m, 2H), 1.33 (s, 3H), 1.28(s, 2H), 1.25 (s, 3H), 1.24–1.19 (m, 1H), 1.13 (s, 3H), 0.87 (s, 3H). Step 2: ( S , E )-4-((tert-butyldimethylsilyl)oxy)-3-(2-((1 R 4 aS 5 R 6 R 8 aS )-6-hydroxy-5-(hydroxymethyl)-5,8 a -dimethyl-2-methylenedehydronaphthyl-1-yl)ethylidene)dihydrofuran-2(3 H Synthesis of )-ketones (intermediates 1-3) Intermediate 1-2 (5.00 g, 12.8 mmol) and imidazole (1.71 g, 25.2 mmol) were dissolved in... N , N In a 20 ml solution of dimethylformamide, tert-butyldimethylsilicon chloride (1.51 g, 10.1 mmol) was added in portions at 0 °C, followed by stirring at room temperature for 10 h. After the reaction was complete, the mixture was concentrated under reduced pressure and extracted with ethyl acetate and saturated ammonium chloride. After concentration, acetic acid:water = 7:4 (22 ml) was added. The reaction mixture was stirred at room temperature for 30 min, and the reaction was terminated by adding saturated sodium bicarbonate solution. The aqueous layer was then extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and finally purified by silica gel column chromatography (dichloromethane:methanol = 50:1 - 40:1) to give 4.68 g of white solid, with a yield of 80%. 1 HNMR (400 MHz, DMSO- d 6) δ 6.60 (td, J = 6.4, 1.8 Hz, 1H), 5.19 (d, J = 5.8 Hz, 1H), 5.07 (d, J = 4.9 Hz, 1H), 4.79 (s, 1H), 4.50 (s, 1H), 4.46 (dd, J= 10.0, 5.9 Hz, 1H), 4.12 (dd, J = 7.6, 2.8 Hz, 1H), 4.00 (dd, J = 9.9, 2.2 Hz, 1H), 3.83 (dd, J = 11.0, 2.9 Hz, 1H), 3.30–3.18 (m, 2H), 2.44 (t, J = 7.0 Hz, 2H), 2.31 (d, J = 13.5 Hz, 1H), 1.97–1.89 (m, 2H), 1.74 (d, J = 13.4 Hz, 1H), 1.68–1.58 (m, 3H), 1.35 (qd, J = 13.0, 4.0 Hz, 1H), 1.27–1.19 (m, 2H), 1.08 (s,3H), 0.86 (s, 9H), 0.65 (s, 3H), 0.15 (s, 3H), 0.12 (s, 3H). Step 3: ( S , E )-4-((tert-butyldimethylsilyl)oxy)-3-(2-((1 R 4 aS 5 R 6 R 8 aS )-5-(((tert-butyldimethylsilyl)oxy)methyl)-6-hydroxy-5,8 a -dimethyl-2-methylenedehydronaphthyl-1-yl)ethylidene)dihydrofuran-2(3 H Synthesis of )-ketones (intermediates 1-4) Intermediates 1-3 (1.50 g, 3.2 mmol) and imidazole (0.65 g, 9.6 mmol) were dissolved in dichloromethane (15 mL), and tert-butyldimethylsilicon chloride (0.87 g, 5.8 mmol) was added in portions. The mixture was stirred at room temperature for 1 h. After the reaction was complete, the solution was concentrated under reduced pressure and extracted with dichloromethane and saturated ammonium chloride. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to give 1.39 g of white solid, in 75% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 6.62(t, J = 6.3 Hz, 1H), 5.20 (d, J= 5.8 Hz, 1H), 4.80 (s, 1H), 4.55–4.43 (m, 3H), 4.05–3.97 (m, 1H), 3.80 (d, J = 10.5 Hz, 1H), 3.65 (d, J = 10.5 Hz, 1H), 3.24–3.08 (m, 1H), 2.46 (t, J = 7.0 Hz, 3H), 2.29 (d, J = 12.4 Hz, 1H), 1.98–1.84(m, 2H), 1.78 (d, J = 13.4 Hz, 1H), 1.72–1.50 (m, 4H), 1.32–1.20 (m, 1H), 1.22–1.10 (m, 2H), 1.03 (s, 3H), 0.86 (d, J = 5.8 Hz, 19H), 0.74 (s, 3H), 0.14(d, J = 14.5 Hz, 6H), 0.00 (s, 6H). Step 4: ( S , E )-4-((tert-butyldimethylsilyl)oxy)-3-(2-((1 R 4 aS 5 R 8 aS )-5-(((tert-butyldimethylsilyl)oxy)methyl)-5,8 a -dimethyl-2-methylene-6-oxodecahydronaphth-1-yl)ethylidene)dihydrofuran-2(3 H Synthesis of )-ketones (intermediates 1-5) Intermediate 1-4 (2.00 g, 3.5 mmol) was dissolved in dichloromethane (15 ml), and Dys-Martin oxidant (2.20 g, 5.2 mmol) was added in portions. The mixture was stirred at room temperature for 1 h. After the reaction was complete (detected by TLC), sodium thiosulfate and saturated sodium bicarbonate solution were added and the mixture was quenched by vigorous stirring for 15 min. The mixture was extracted with dichloromethane and saturated sodium bicarbonate. The organic phase was washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give 1.79 g of white solid, in 89% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 6.61 (t, J= 6.1 Hz, 1H), 5.22 (d, J = 5.7 Hz, 1H), 4.86 (s, 1H), 4.58 (s, 1H), 4.47 (dd, J = 10.0, 6.0 Hz, 1H), 4.01 (dd, J = 9.9, 2.4 Hz, 1H), 3.86 (d, J = 10.1 Hz, 1H), 3.50(d, J = 10.2 Hz, 1H), 2.63 (td, J = 14.5, 5.7 Hz, 1H), 2.53 (d, 1H), 2.45 (d,1H), 2.36 (d, J = 13.1 Hz, 1H), 2.22 (d, J = 14.6 Hz, 1H), 2.09 (d, J = 8.9 Hz,1H), 2.06–1.99 (m, 1H), 1.98–1.91 (m, 1H), 1.77–1.65 (m, 2H), 1.59 (td, J =13.6, 4.5 Hz, 1H), 1.54–1.44 (m, 1H), 1.02 (s, 3H), 0.91 (s, 3H), 0.87 (s,9H), 0.80 (s, 9H), 0.14 (d, J = 16.3 Hz, 6H), -0.03 (s, 6H). Step 5: ( S,E )-4-((tert-butyldimethylsilyl)oxy)-3-(2-((6 S 6 aS 10 R 10 aS )-6-(((tert-butyldimethylsilyl)oxy)methyl)-6,10 a -Dimethyl-9-methylene-6,6 a ,7,8,9,10,10 a ,11-octahydro-5 H -benzo[ b [Carbazole-10-yl)ethylene)dihydrofuran-2(3] H Synthesis of )-ketones (intermediates 1-6) Phenyzine hydrochloride (0.15 g, 1.04 mmol) was dissolved in acetic acid (8 ml) and heated to 90 °C. Intermediate 1-5 (0.50 g, 0.87 mmol) was added dropwise under an argon atmosphere, and the mixture was stirred for 4 h. After the reaction was complete, sodium thiosulfate and saturated sodium bicarbonate solution were added, and the mixture was quenched by vigorous stirring for 15 min. The mixture was extracted with dichloromethane and saturated sodium bicarbonate solution, and the organic layers were combined, concentrated under reduced pressure, and then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1 - 10:1) to give 0.42 g of a white solid, in 75% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 10.40 (s, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.98 (t, J = 7.3 Hz, 1H), 6.78 (t, J = 6.2 Hz, 1H), 5.36 (d, J = 5.7 Hz, 1H), 4.95 (s, 1H), 4.67 (s,1H), 4.56 (dd, J = 10.0, 5.9 Hz, 1H), 4.10 (dd, J = 10.0, 2.2 Hz, 1H), 3.81 (q, J = 10.2 Hz, 2H), 2.88 (d, J = 14.9 Hz, 1H), 2.78–2.65 (m, 2H), 2.55–2.39 (m,2H), 2.29 (d, J = 9.7 Hz, 1H), 2.16–2.04 (m, 2H), 1.88 (d, J = 14.1 Hz, 1H),1.68–1.54 (m, 1H), 1.37 (s, 3H), 0.92 (d, J = 18.6 Hz, 18H), 0.81 (s, 3H), 0.25 (d, J = 28.1 Hz, 6H), 0.04 (d, J = 31.5 Hz, 6H). Step 6: ( S ,E )-4-hydroxy-3-(2-((6) S 6 aS 10 R 10 aS )-6-(hydroxymethyl)-6,10 a -Dimethyl-9-methylene-6,6 a ,7,8,9,10,10 a ,11-octahydro-5 H -benzo[ b [Carbazole-10-yl)ethylene)dihydrofuran-2(3] H Synthesis of )-ketones (compound 1) Intermediates 1-6 (0.40 g, 0.62 mmol) were dissolved in tetrahydrofuran (4 ml) solution, and pyridine hydrogen fluoride (2 ml, 65-80 wt%) was slowly added dropwise at 0 °C. The mixture was stirred overnight at room temperature. After the reaction was complete, saturated sodium bicarbonate solution was added to terminate the reaction, and the mixture was extracted with dichloromethane. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1 - 2:1) to give 0.23 g of white solid, yield 89%. 1 H NMR (400 MHz, DMSO- d 6) δ 10.29 (s, 1H), 7.38 (d, J = 7.7 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 6.98 (t, J =7.5 Hz, 1H), 6.90 (t, J = 7.4 Hz, 1H), 6.71 (t, J = 6.0 Hz, 1H), 5.82 (d, J =6.0 Hz, 1H), 5.05 (t, J = 6.1 Hz, 1H), 4.90 (s, 1H), 4.80 (t, J = 4.8 Hz, 1H), 4.72 (s, 1H), 4.45 (dd, J = 9.9, 6.1 Hz, 1H), 4.09 (dd, J = 9.9, 2.0 Hz, 1H), 3.62 (dd, J = 10.4, 5.0 Hz, 1H), 3.53 (dd, J= 10.4, 4.9 Hz, 1H), 2.89 (d, J =14.9 Hz, 1H), 2.80–2.65 (m, 2H), 2.48–2.39 (m, 2H), 2.19 (d, J = 10.6 Hz, 1H), 2.10–1.94 (m, 2H), 1.81 (dd, J = 13.0, 2.8 Hz, 1H), 1.58–1.42 (m, 1H), 1.33(s, 3H), 0.75 (s, 3H); HRMS (ESI) m / z Calculated for C 26 H 31 NNaO4[M+Na] + 444.2145, found 444.2129. Example 2: The chemical name in this invention is 3-(( E )-2-((6 S 6 aS 10 R 10 aR )-6-(hydroxymethyl)-6,10 a -Dimethyl-9-methylene-6,6 a ,7,8,9,10,10 a ,11-octahydro-5 H -benzo[ b [Carbazole-10-yl)vinyl)furan-2(5] H Synthesis of )-ketones (compound 2)

[0055] Compound 1 (0.42 g, 1.00 mmol) was dissolved in pyridine (10 mL, 0.1 M) solution, and alumina (0.10 g, 1.00 mmol) was added. The mixture was refluxed and stirred at 125 °C for 12 h. After the reaction was complete, the pyridine was removed by concentration under reduced pressure, and residual pyridine was removed by extraction with ethyl acetate and hydrochloric acid (0.1 M) solution. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 - 2:1) to give 0.28 g of white solid, 70% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 10.29 (s, 1H), 7.75 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.24 (d,J = 7.8 Hz,1H), 7.05–6.91 (m, 2H), 6.90–6.78 (m, 1H), 6.30 (d, J = 15.8 Hz, 1H), 4.94 (s,2H), 4.81 (s, 2H), 4.53 (s, 1H), 3.64 (dd, J = 10.5, 5.0 Hz, 1H), 3.56 (dd, J =10.4, 4.8 Hz, 1H), 2.70 (d, J = 10.2 Hz, 1H), 2.46 (s, 2H), 2.37 (d, J = 15.4Hz, 1H), 2.11 (t, J = 11.4 Hz, 1H), 1.97 (d, J = 12.7 Hz, 1H), 1.81 (d, J = 10.0Hz, 1H), 1.62–1.48 (m, 1H), 1.34 (s, 3H), 0.85 (s, 3H); HRMS (ESI) m / z Calculated for C 26 H 29 NNaO3[M+Na] + 426.2040, found 426.2027. Example 3: The chemical name in this invention is ( S , E )-4-hydroxy-3-(2-((6) S 6 aS 10 R 10 aS )-6-(hydroxymethyl)-2-methoxy-6,10 a -Dimethyl-9-methylene-6,6 a ,7,8,9,10,10 a ,11-octahydro-5 H -benzo[ b [Carbazole-10-yl)ethylene)dihydrofuran-2(3] H Preparation of )-ketones (compound 3) By adapting the raw materials (replacing phenylhydrazine hydrochloride in step 5 of Example 1 with 4-methoxyphenylhydrazine hydrochloride), and following the same steps as in Example 1, a white solid was obtained with a yield of 71%. 1H NMR (400 MHz, DMSO- d 6) δ 10.11 (s, 1H), 7.20 (d, J = 8.6 Hz, 1H), 6.88 (d, J = 2.4 Hz, 1H), 6.70 (t, J = 6.6 Hz, 1H), 6.62 (dd, J = 8.7, 2.5 Hz, 1H), 5.82 (d, J = 6.0 Hz, 1H), 5.06 (s, 1H), 4.90(s, 1H), 4.79 (s, 1H), 4.70 (s, 1H), 4.45 (dd, J = 10.0, 6.1 Hz, 1H), 4.09(dd, J = 10.0, 2.0 Hz, 1H), 3.74 (s, 3H), 3.60 (d, J = 10.3 Hz, 1H), 3.51 (d, J = 10.3 Hz, 1H), 2.86 (d, J = 15.0 Hz, 1H), 2.81–2.66 (m, 2H), 2.46–2.37 (m,2H), 2.20 (d, J = 10.2 Hz, 1H), 2.11–1.92 (m, 2H), 1.80 (dd, J = 12.9, 2.9 Hz,1H), 1.55–1.41 (m, 1H), 1.32 (s, 3H), 0.75 (s, 3H); HRMS (ESI) m / z calculated for C 27 H 33 NNaO5[M+Na] + 474.2251, found 474.2247. Example 4: The chemical name in this invention is 3-(( E )-2-((6 S 6 aS 10 R 10 aR )-6-(hydroxymethyl)-2-methoxy-6,10 a -Dimethyl-9-methylene-6,6 a ,7,8,9,10,10a ,11-octahydro-5 H -benzo[ b [Carbazole-10-yl)vinyl)furan-2(5] H Preparation of )-ketones (compound 4) By adapting the raw materials (replacing compound 2 with compound 3 in Example 2), and otherwise remaining the same as in Example 2, a white solid was obtained with a yield of 75%. 1 H NMR (400 MHz, DMSO- d 6) δ 10.13 (s, 1H), 7.76 (s, 1H), 7.21 (d, J = 8.6 Hz, 1H), 6.99 (dd, J = 15.8, 10.1 Hz, 1H), 6.72 (d, J = 2.4 Hz, 1H), 6.61 (dd, J = 8.7, 2.4 Hz, 1H), 6.31 (d, J = 15.8 Hz, 1H), 4.96 (s, 2H), 4.87–4.80 (m, 2H), 4.52 (s, 1H), 3.71 (s, 3H), 3.63 (dd, 1H), 3.55 (dd, J = 10.5, 4.9 Hz, 1H), 2.70 (d, J = 10.2 Hz, 1H), 2.49 (s, 1H), 2.47–2.41 (m, 1H), 2.35(d, J = 15.4 Hz, 1H), 2.11 (t, J = 13.0 Hz, 1H), 1.98 (d, J = 13.0 Hz, 1H), 1.81(d, J = 13.1 Hz, 1H), 1.62–1.47 (m, 1H), 1.33 (s, 3H), 0.86 (s, 3H); HRMS(ESI) m / z Calculated for C 27 H 31 NNaO4[M+Na] + 456.2145, found 456.2128. Example 5: The chemical name in this invention is 2-(2-fluorophenoxy)- N -(4-((2S ,3 R 4 S 5 S 6 R )-3,4,5-Trihydroxy-6-(hydroxymethyl)tetrahydro-2 H The preparation of pyran-2-yl)oxy)phenyl)acetamide (compound 5) is shown below via the following synthetic route:

[0056] Step 1: (4) S , E )-3-(2-((1 R 4 aS 5 R 8 aS )-7-bromo-5-(((tert-butyldimethylsilyl)oxy)methyl)-5,8 a -dimethyl-2-methylene-6-oxodecahydronaphthyl-1-yl)ethylidene)-4-((tert-butyldimethylsilyl)oxy)dihydrofuran-2(3 H Synthesis of )-ketones (intermediate 5-1) Intermediate 1-5 (1.00 g, 1.7 mmol) was dissolved in tetrahydrofuran (10 ml) solution, and pyridinium tribromide (0.80 g, 2.5 mmol) was dissolved in tetrahydrofuran (5 ml). Pyridinium tribromide was added dropwise at 0 °C, and the reaction was stirred for 1 h. The reaction was then quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 40:1 - 10:1) to give 0.95 g of pale yellow solid, yield 85%. 1 H NMR (400 MHz, DMSO- d 6) δ 6.58 (t, J = 5.5 Hz, 1H), 5.44 (dd, J = 13.9, 5.4 Hz, 1H), 5.23 (d, J = 5.6Hz, 1H), 4.88 (s, 1H), 4.60 (s, 1H), 4.46 (dd, J = 10.0, 5.9 Hz, 1H), 4.04–4.00 (m, 1H), 4.00–3.96 (m, 1H), 3.46 (d, J = 10.4 Hz, 1H), 2.53 (d, J = 5.7Hz, 1H), 2.49–2.44 (m, 1H), 2.34 (d,J = 14.2 Hz, 1H), 2.17 (d, J = 10.8 Hz, 1H), 2.10 (t, J = 13.2 Hz, 1H), 1.98 (d, J = 25.9 Hz, 1H), 1.76 (dd, J = 12.7,2.5 Hz, 1H), 1.73–1.66 (m, 1H), 1.53–1.43 (m, 1H), 1.23 (s, 1H), 1.13 (s,3H), 1.02 (s, 3H), 0.87 (s, 9H), 0.79 (s, 10H), 0.15 (d, J = 22.2 Hz, 6H), -0.02 (s, 6H). Step 2: ( S , E )-3-(2-((4 S 4 aS 8 R 8 aS )-2-amino-4-(hydroxymethyl)-4,8 a -Dimethyl-7-methylene-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d ]Thiazolyl(8-yl)ethylene)-4-hydroxydihydrofuran-2(3 H Synthesis of )-ketones (compound 5) Intermediate 5-1 (0.40 g, 0.63 mmol) was dissolved in anhydrous ethanol (8 ml), and thiourea (0.19 g, 2.52 mmol) was added. The mixture was refluxed and stirred at 85 °C for 3 h. After the reaction was complete, the anhydrous ethanol was removed by concentration under reduced pressure. Then, the mixture was purified by silica gel column chromatography (dichloromethane:methanol = 120:1 - 80:1) using the synthesis method of B1 to obtain 0.17 g of a white solid, with a yield of 68%. 1 H NMR (400 MHz, DMSO- d 6) δ 6.84 (s, 2H), 6.42 (t, J = 7.1 Hz, 1H), 5.83(d, J = 5.1 Hz, 1H), 4.84 (s, 1H), 4.68 (s, 2H), 4.54 (s, 1H), 4.37 (dd, J=9.5, 6.3 Hz, 1H), 3.94 (dd, J = 9.6, 3.4 Hz, 1H), 3.54 (d, J = 10.4 Hz, 1H),3.47–3.41 (m, 1H), 3.00–2.86 (m, 1H), 2.69 (d, J = 6.3 Hz, 1H), 2.57 (d, J =15.6 Hz, 1H), 2.46–2.32 (m, 2H), 2.09–1.94 (m, 2H), 1.88 (s, 1H), 1.70 (d, J =12.7 Hz, 1H), 1.49–1.37 (m, 1H), 1.18 (s, 3H), 0.71 (s, 3H); HRMS (ESI) m / z Calculated for C 21 H 29 N₂O₄S [M+H] + 405.1843, found 405.1840. Example 6: 3-(( E )-2-((4 S 4 aS 8 R 8 aR )-2-amino-4-(hydroxymethyl)-4,8 a -Dimethyl-7-methylene-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d ]Thiazolyl-8-yl)vinyl)furan-2(5 H Preparation of )-ketones (compound 6) By adapting the raw materials (replacing compound 2 in Example 2 with compound 5), and otherwise following the same procedure as in Example 2, a white solid was obtained with a yield of 82%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.70 (s, 1H), 6.86 (dd, J = 15.9, 10.2Hz, 1H), 6.80 (s, 2H), 6.21 (d, J = 15.8 Hz, 1H), 4.90 (s, 2H), 4.79 (s, 1H), 4.68 (d, J= 7.4 Hz, 1H), 4.49 (s, 1H), 3.56 (d, J = 10.4 Hz, 1H), 3.50–3.39(m, 1H), 2.61 (d, J = 10.2 Hz, 1H), 2.43 (d, J = 11.7 Hz, 1H), 2.33 (d, J = 15.8Hz, 1H), 2.15 (d, J = 15.6 Hz, 1H), 2.11–2.00 (m, 1H), 1.89 (d, J = 10.7 Hz, 1H), 1.71 (dd, J = 12.9, 2.9 Hz, 1H), 1.55–1.40 (m, 1H), 1.18 (s, 3H), 0.83(s, 3H); HRMS (ESI) m / z Calculated for C 21 H 27 N₂O₃S [M+H] + 387.1737, found 387.1730. Example 7: ( S , E )-4-hydroxy-3-(2-((6) aS 7 R 10 aS ,11 S )-11-(hydroxymethyl)-6 a ,11-Dimethyl-8-methylene-6,6 a ,7,8,9,10,10 a ,11-octahydrobenzo[ b ]Phenazine-7-yl)ethylene)dihydrofuran-2(3 H Preparation of )-ketones (compound 7)

[0057] Step 1: ( S , E )-4-((tert-butyldimethylsilyl)oxy)-3-(2-((6 aS 7 R 10 aS ,11 S )-11-(((tert-butyldimethylsilyl)oxy)methyl)-6 a ,11-Dimethyl-8-methylene-6,6 a,7,8,9,10,10 a ,11-octahydrobenzo[ b ]Phenazine-7-yl)ethylene)dihydrofuran-2(3 H Synthesis of )-ketones (intermediate 7-1) Intermediate 5-1 (2.00 g, 3.1 mmol) was dissolved in polyethylene glycol 400: N , N In a solution of dimethylformamide (5:1, 30 ml), o-phenylenediamine (0.67 g, 6.2 mmol) and cerium(III) chloride heptahydrate (0.11 g, 0.3 mmol) were added, followed by stirring at 50 °C for 48 h. After the reaction was complete, the mixture was extracted with ethyl acetate and water. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 - 5:1) to give 0.92 g of white solid, yield 45%. 1 H NMR (400MHz, DMSO- d 6) δ 8.08–7.98 (m, 2H), 7.85–7.79 (m, 2H), 6.79 (s, 1H), 5.39 (s,1H), 5.01 (s, 1H), 4.71 (s, 1H), 4.59 (dd, J = 10.0, 6.0 Hz, 1H), 4.50 (d, J =10.0 Hz, 1H), 4.29 (t, J = 6.6 Hz, 1H), 4.11 (d, J = 10.3 Hz, 1H), 3.81 (d, J =10.0 Hz, 1H), 3.28 (d, J = 15.8 Hz, 1H), 3.10 (d, J = 15.7 Hz, 1H), 2.84–2.76(m, 1H), 2.75–2.66 (m, 1H), 2.45 (d, J = 10.9 Hz, 1H), 2.23 (d, J = 12.0 Hz, 2H), 2.12 (d, J = 13.3 Hz, 1H), 1.48–1.40 (m, 1H), 1.29 (s, 3H), 0.93 (s, 9H), 0.70 (s, 3H), 0.68 (s, 9H), 0.23 (d, J= 16.6 Hz, 6H), 0.00 (s, 3H), -0.21 (s, 3H). Step 2: ( S , E )-4-hydroxy-3-(2-((6) aS 7 R 10 aS ,11 S )-11-(hydroxymethyl)-6 a ,11-Dimethyl-8-methylene-6,6 a ,7,8,9,10,10 a ,11-octahydrobenzo[ b ]Phenazine-7-yl)ethylene)dihydrofuran-2(3 H Synthesis of )-ketones (compound 7) The raw materials were modified (intermediates 1-6 in step 6 of Example 1 were replaced with intermediates 7-1), while the rest remained the same as step 6 of Example 1. The mixture was purified by silica gel column chromatography (dichloromethane:methanol = 80:1 - 50:1) to obtain a white solid in 83% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 8.05–7.95 (m, 2H), 7.79–7.72 (m, 2H), 6.75 (t, J =6.4 Hz, 1H), 5.84 (d, J = 6.0 Hz, 1H), 5.05 (t, J = 6.2 Hz, 1H), 4.97 (s, 1H), 4.76 (s, 1H), 4.57 (t, J = 5.2 Hz, 1H), 4.46 (dd, J = 9.9, 6.1 Hz, 1H), 4.17(dd, J = 10.8, 5.3 Hz, 1H), 4.09 (dd, J = 9.9, 2.1 Hz, 1H), 3.65 (dd, J = 10.7, 5.0 Hz, 1H), 3.29 (d, J = 16.0 Hz, 1H), 3.01 (d, J = 15.9 Hz, 1H), 2.80 (dd,1H), 2.67–2.56 (m, 1H), 2.48 (d, 1H), 2.25 (d, J= 11.3 Hz, 1H), 2.11 (dd, J =12.6, 3.4 Hz, 2H), 2.03 (d, J = 13.1 Hz, 1H), 1.83–1.67 (m, 1H), 1.26 (s, 3H), 0.70 (s, 3H); HRMS (ESI) m / z Calculated for C 26 H 30 N₂NaO₄[M+Na] + 457.2098, found 457.2097. Example 8: 3-(( E )-2-((6 aR 7 R 10 aS ,11 S )-11-(hydroxymethyl)-6 a ,11-Dimethyl-8-methylene-6,6 a ,7,8,9,10,10 a ,11-octahydrobenzo[ b ]Phenazine-7-yl)vinyl)furan-2(5 H Preparation of )-ketones (compound 8) By adapting the raw materials (replacing compound 2 in Example 2 with compound 7), and otherwise following the same procedure as in Example 2, a white solid product was obtained with a yield of 79%. 1 H NMR (400 MHz, DMSO- d 6) δ 8.02–7.97 (m, 1H), 7.96–7.90 (m,1H), 7.78 (s, 1H), 7.76–7.72 (m, 2H), 6.90 (dd, J = 15.8, 10.2 Hz, 1H), 6.32(d, J = 15.8 Hz, 1H), 4.96 (s, 2H), 4.88 (s, 1H), 4.61 (t, J = 5.1 Hz, 1H), 4.58 (s, 1H), 4.20 (dd, J = 10.9, 5.5 Hz, 1H), 3.66 (dd, J = 10.7, 5.1 Hz, 1H), 2.94 (d, J = 16.4 Hz, 1H), 2.85 (d, J= 16.0 Hz, 1H), 2.79 (d, J = 10.4 Hz, 1H), 2.55 (s, 1H), 2.24–2.14 (m, 1H), 2.11 (dd, J = 12.7, 3.4 Hz, 1H), 2.02 (d, J =12.7 Hz, 1H), 1.89–1.73 (m, 1H), 1.26 (s, 3H), 0.78 (s, 3H); HRMS (ESI) m / z Calculated for C 26 H 28 N₂NaO₃[M+Na] + 439.1992, found 439.1975. Example 9: 2-((1) S 4 aS 5 R 8 aS , E )-5-((E)-2-(( S )-4-hydroxy-2-oxodihydrofuran-3(2 H )-(methylene)ethyl)-1-(hydroxymethyl)-1,4 a -Dimethyl-6-methyleneoctahydronaphthalene-2(1 H Preparation of 1-(-)-alkyl(-)hydrazine-1-carboxamide (Compound 9)

[0058] Step 1: ( S , E )-4-((tert-butyldiphenylsilyl)oxy)-3-(2-((1 R 4 aS 5 R 6 R 8 aS )-6-hydroxy-5-(hydroxymethyl)-5,8 a -dimethyl-2-methylenedehydronaphthyl-1-yl)ethylidene)dihydrofuran-2(3 H Synthesis of )-ketones (intermediate 9-1) Intermediate 1-2 (2.50 g, 6.4 mmol) and imidazole (1.31 g, 19.2 mmol) were dissolved in... N , NIn a 30 ml solution of dimethylformamide, tert-butyldiphenylsilane chloride (3.52 g, 12.8 mmol) was slowly added dropwise at 0 °C, followed by stirring at room temperature for 4 h. After the reaction was complete, the solution was concentrated under reduced pressure and extracted with ethyl acetate and saturated ammonium chloride. After concentration, acetic acid:water = 7:4 (22 ml) was added. The mixture was stirred at room temperature for 30 min, quenched with saturated sodium bicarbonate solution, and extracted with ethyl acetate. The solution was purified by silica gel column chromatography (dichloromethane:methanol = 50:1) to give 3.24 g of white solid, yield 86%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.66 (t, J = 6.9 Hz, 4H), 7.55–7.43 (m, 6H), 6.62 (t, J = 6.8 Hz, 1H), 5.10 (d, J = 4.9 Hz, 1H), 4.78 (s, 1H), 4.37 (s, 1H), 4.17 (dd, J = 10.2, 5.0 Hz, 1H), 4.09 (d, J = 8.7 Hz, 1H), 3.77 (d, J = 11.0 Hz, 1H), 3.20 (d, J =10.9 Hz, 1H), 3.11 (dd, J –10.8, 5.3 Hz, 1H), 2.27 (d, J = 13.0 Hz, 1H), 2.13–2.02 (m, 2H), 1.83 (td, J = 12.8, 4.8 Hz, 1H), 1.72–1.62 (m, 2H), 1.55–1.44 (m,2H), 1.27 (dd, J = 13.0, 4.1 Hz, 1H), 1.12–1.04 (m, 2H), 1.03 (s, 4H), 0.98 (s,9H), 0.91–0.80 (m, 1H), 0.41 (s, 3H). Step 2: ( S , E )-4-((tert-butyldiphenylsilyl)oxy)-3-(2-((1 R 4 aS 5 R 6 R 8 aS)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-6-hydroxy-5,8 a -dimethyl-2-methylenedehydronaphthyl-1-yl)ethylidene)dihydrofuran-2(3 H Synthesis of )-ketones (intermediate 9-2) Intermediate 9-1 (1.00 g, 1.7 mmol) and imidazole (0.35 g, 5.1 mmol) were dissolved in dichloromethane (17 mL), and tert-butyldiphenylsilane chloride (0.58 g, 2.1 mmol) was slowly added dropwise while stirring at room temperature for 1 h. After the reaction was complete, the solution was concentrated under reduced pressure and extracted with dichloromethane and saturated ammonium chloride. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 - 5:1) to give 1.18 g of white solid, yield 84%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.65 (t, J = 6.8 Hz, 4H), 7.62–7.57 (m, 4H), 7.54–7.40 (m, 12H), 6.63 (t, J =6.7 Hz, 1H), 5.09 (d, J = 4.9 Hz, 1H), 4.79 (s, 1H), 4.47 (d, J = 4.8 Hz, 1H), 4.37 (s, 1H), 4.16 (dd, J = 10.2, 5.0 Hz, 1H), 4.08 (d, J = 10.3 Hz, 1H), 3.73(d, J = 10.6 Hz, 1H), 3.67 (d, J = 10.6 Hz, 1H), 3.03 (d, J = 10.4 Hz, 1H), 2.28(d, J = 9.2 Hz, 1H), 2.13–2.04 (m, 2H), 1.89–1.78 (m, 2H), 1.72–1.57 (m, 2H), 1.32 (td, 1H), 1.09 (s, 3H), 1.06 (d, J = 13.2 Hz, 2H), 0.98 (d, J = 2.8 Hz,17H), 0.92–0.81 (m, 2H), 0.37 (s, 3H). Step 3: ( S , E )-4-((tert-butyldiphenylsilyl)oxy)-3-(2-((1 R 4 aS 5 R 8 aS )-5-(((tert-butyldiphenylsilyl)oxy)methyl)-5,8 a -dimethyl-2-methylene-6-oxodecahydronaphth-1-yl)ethylidene)dihydrofuran-2(3 H Synthesis of )-ketones (intermediate 9-3) The raw materials were modified (intermediates 1-4 in step 4 of Example 1 were replaced with intermediate 9-2), while the remaining steps were the same as step 4 of Example 1. A white solid was obtained, with a yield of 89%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.65 (t, J = 6.3Hz, 4H), 7.57–7.50 (m, 6H), 7.50–7.41 (m, 10H), 6.56 (t, 1H), 5.11 (d, J = 4.9Hz, 1H), 4.79 (s, 1H), 4.35 (s, 1H), 4.19 (dd, J = 10.1, 5.0 Hz, 1H), 4.11(dd, J = 10.1, 1.5 Hz, 1H), 3.88 (d, J = 10.2 Hz, 1H), 3.48 (d, J = 10.2 Hz, 1H), 2.25 (d, J = 12.7 Hz, 1H), 2.19–2.08 (m, 1H), 2.03–1.95 (m, 2H), 1.94–1.88 (m, 1H), 1.88–1.79 (m, 1H), 1.73 (d, J = 9.9 Hz, 1H), 1.61 (d, J = 12.7Hz, 1H), 1.47 (dd, J = 12.8, 2.5 Hz, 1H), 1.30–1.20 (m, 1H), 1.18–1.10 (m,2H), 1.07 (s, 3H), 0.96 (d, J = 4.5 Hz, 18H), 0.38 (s, 3H). Step 4: 2-((1) S 4 aS 5 R 8 aS , E )-5-(( E )-2-(( S )-4-((tert-butyldiphenylsilyl)oxy)-2-oxodihydrofuran-3(2 H )-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4 a -Dimethyl-6-methyleneoctahydronaphthalene-2(1 H Synthesis of 1-(-)-subunit)hydrazine-1-carboxamide (intermediate 9-4) In anhydrous ethanol (25 ml) solution containing intermediate 9-3 (2.00 g, 2.4 mmol) and sodium acetate (0.30 g, 3.6 mmol), aminourea hydrochloride (0.40 g, 3.6 mmol) and 4A molecular sieve, the mixture was refluxed at 80 °C and stirred for 3 h. After the reaction was complete, the mixture was concentrated under reduced pressure and extracted with ethyl acetate and saturated sodium bicarbonate. The organic phase was washed successively with saturated sodium chloride solution and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the mixture was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 - 30:1) to give 1.74 g of white solid, yield 82%. 1 H NMR (400 MHz, DMSO- d 6) δ 9.28 (s, 1H), 7.65 (t, J =6.6 Hz, 4H), 7.57–7.50 (m, 6H), 7.49–7.42 (m, 10H), 6.57 (d, J = 6.5 Hz, 1H), 6.15 (s, 2H), 5.10 (d, J = 4.8 Hz, 1H), 4.78 (s, 1H), 4.33 (s, 1H), 4.19 (dd, J = 10.2, 5.1 Hz, 1H), 4.11 (dd, J = 10.2, 1.5 Hz, 1H), 3.66 (d, J = 9.9 Hz, 1H), 3.45 (d, J = 10.0 Hz, 1H), 2.66 (d, J = 14.7 Hz, 1H), 2.27 (d, J= 12.2 Hz, 1H),1.98–1.95 (m, 1H), 1.91–1.81 (m, 1H), 1.76–1.66 (m, 2H), 1.54–1.42 (m, 1H),1.34 (d, J = 12.7 Hz, 1H), 1.29–1.20 (m, 2H), 1.19 (s, 3H), 1.06–0.98 (m, 2H), 0.96 (d, J = 7.1 Hz, 18H), 0.86–0.77 (m, 1H), 0.30 (s, 3H). Step 5: 2-((1) S 4 aS 5 R 8 aS , E )-5-((E)-2-(( S )-4-hydroxy-2-oxodihydrofuran-3(2 H )-(methylene)ethyl)-1-(hydroxymethyl)-1,4 a -Dimethyl-6-methyleneoctahydronaphthalene-2(1 H Synthesis of 1-(-)-alkylhydrazine-1-carboxamide (Compound 9) The raw materials were modified (compounds 1-6 in step 6 of Example 1 were replaced with 9-4), otherwise the process was the same as in Example 1. The product was a white solid with a yield of 90%. 1 H NMR (400 MHz, DMSO- d 6) δ 9.17 (s, 1H), 6.67–6.59 (m, 1H), 6.16 (s, 2H), 5.86 (d, J = 6.0 Hz, 1H), 4.93 (d, J = 6.0 Hz, 1H), 4.84 (s, 1H), 4.67(s, 1H), 4.39 (dd, J = 9.8, 6.1 Hz, 1H), 4.33 (d, J = 5.1 Hz, 1H), 4.05 (dd, J =9.9, 2.2 Hz, 1H), 3.64 (dd, J = 10.8, 5.4 Hz, 1H), 3.34–3.26 (m, 2H), 2.83 (d, J= 14.9 Hz, 1H), 2.53 (s, 5H), 2.48 (s, 3H), 2.34 (d, J = 11.4 Hz, 1H), 2.10–1.88 (m, 4H), 1.87–1.75 (m, 2H), 1.43 (s, 1H), 1.22–1.16 (m, 1H), 1.12 (s,3H), 0.81 (s, 3H); HRMS (ESI) m / z Calculated for C 21 H 31 N3NaO5[M+Na] + 428.2156, found 428.2157. Example 10: 2-((1) S 4 aR 5 R 8 aS , E )-1-(hydroxymethyl)-1,4 a -Dimethyl-6-methylene-5-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)octahydronaphthalene-2-(1 H Preparation of 1-(-)-alkyl(-)hydrazine-1-carboxamide (Compound 10) By adapting the raw materials (replacing compound 2 with compound 9 in Example 2), and otherwise remaining the same as in Example 2, a white solid was obtained with a yield of 81%. 1 H NMR (400 MHz, DMSO- d 6) δ 9.09 (s, 1H), 7.66 (s, 1H), 6.76 (dd, J = 15.8, 10.0 Hz, 1H), 6.14 (d, J = 15.8 Hz, 3H), 4.89 (s, 2H), 4.77 (s, 1H), 4.46 (s, 1H), 4.28 (t, J = 5.5 Hz, 1H), 3.64 (dd, J = 10.8, 5.5 Hz, 1H), 2.78(d, J = 15.0 Hz, 1H), 2.46–2.36 (m, 2H), 2.07–1.88 (m, 2H), 1.78 (d, J= 11.2Hz, 1H), 1.58–1.47 (m, 1H), 1.13 (s, 3H), 1.11 (s, 4H), 0.91 (s, 3H); HRMS(ESI) m / z Calculated for C 21 H 29 N3NaO4[M+Na] + 410.2050, found 410.2055. Example 11: ( S , E )-4-hydroxy-3-(2-((4 S 4 aS 8 R 8 aS )-4-(hydroxymethyl)-4,8 a -Dimethyl-7-methylene-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d [1,2,3]thiadiazole-8-yl)ethylene)dihydrofuran-2(3 H Preparation of )-ketones (compound 11)

[0059] Step 1: ( S , E )-4-((tert-butyldiphenylsilyl)oxy)-3-(2-((4 S 4 aS 8 R 8 aS )-4-(((tert-butyldiphenylsilyl)oxy)methyl)-4,8 a -Dimethyl-7-methylene-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d [1,2,3]thiadiazole-8-yl)ethylene)dihydrofuran-2(3 H Synthesis of )-ketones (intermediate 11-1) Under argon protection, thionyl chloride (1.00 g, 8.8 mmol) and 4A molecular sieve were added to a 25 ml solution of dichloromethane containing intermediate 9-4 (1.00 g, 1.1 mmol). The mixture was added at 0 °C and stirred overnight at room temperature. After the reaction was complete (detected by TLC), the reaction was quenched with saturated sodium bicarbonate. The organic phase was washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 - 5:1) to give 1.74 g of white solid, yield 45%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.74–7.62 (m, 5H), 7.57–7.40 (m, 15H), 6.53 (t, J = 6.3 Hz, 1H), 5.12 (d, J = 5.0 Hz, 1H), 4.86 (s, 1H), 4.31 (s, 1H), 4.25–4.17(m, 1H), 4.12–4.06 (m, 1H), 3.60 (s, 1H), 3.10 (dd, J = 13.1, 6.6 Hz, 1H), 2.31 (d, J = 12.4 Hz, 1H), 2.10–1.99 (m, 1H), 1.92–1.84 (m, 2H), 1.79 (d, J =12.5 Hz, 1H), 1.47 (s, 1H), 1.44 (s, 3H), 1.36–1.24 (m, 2H), 1.15–1.09 (m,1H), 0.98 (s, 18H), 0.89–0.80 (m, 1H), 0.38 (s, 3H). Step 2: ( S , E )-4-hydroxy-3-(2-((4 S 4 aS 8 R 8 aS )-4-(hydroxymethyl)-4,8 a -Dimethyl-7-methylene-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d [1,2,3]thiadiazole-8-yl)ethylene)dihydrofuran-2(3 H Synthesis of )-ketones (compound 11) By adapting the raw materials (replacing compounds 1-6 in step 6 of Example 1 with compounds 11-1), and otherwise remaining the same as in Example 1, a white solid was obtained with a yield of 88%. 1 H NMR (400 MHz, DMSO- d 6) δ 6.68 (t, J = 5.8 Hz, 1H), 5.79 (s, 1H), 4.99 (s, 1H), 4.95 (s, 1H), 4.74 (s, 1H), 4.62 (s, 1H), 4.43(dd, J = 9.9, 6.1 Hz, 1H), 4.07 (dd, J = 9.9, 2.1 Hz, 1H), 3.90 (d, J = 11.2 Hz, 1H), 3.73 (d, J = 11.2 Hz, 1H), 3.44 (d, 1H), 2.70 (d, J = 16.7 Hz, 1H), 2.66(s, 1H), 2.64–2.61 (m, 1H), 2.49–2.40 (m, 1H), 2.22 (t, J = 7.1 Hz, 1H), 2.12–1.96 (m, 2H), 1.87 (dd, J = 12.8, 2.7 Hz, 1H), 1.72–1.59 (m, 1H), 1.36 (s, 3H), 0.71 (s, 3H); HRMS (ESI) m / z Calculated for C 20 H 26 N₂NaO₄S [M+Na] + 413.1505, found 413.1502. Example 12: 3-(( E )-2-((4 S 4 aS 8 R 8 aR )-4-(hydroxymethyl)-4,8 a -Dimethyl-7-methylene-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d [1,2,3]thiadiazole-8-yl)vinyl)furan-2(5 H Preparation of )-ketones (compound 12) By adapting the raw materials (replacing compound 2 with compound 11 in Example 2), and otherwise remaining the same as in Example 2, a white solid was obtained with a yield of 76%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.74 (s, 1H), 6.88 (dd, J = 15.9, 10.2Hz, 1H), 6.26 (d, J = 15.9 Hz, 1H), 4.92 (s, 2H), 4.84 (s, 1H), 4.69 (s, 1H), 4.53 (s, 1H), 3.91 (d, J = 11.1 Hz, 1H), 3.73 (d, J = 11.1 Hz, 1H), 2.94 (d, J =16.9 Hz, 1H), 2.72 (d, J = 10.2 Hz, 1H), 2.61 (d, J = 16.9 Hz, 1H), 2.47 (s,1H), 2.15–2.07 (m, 1H), 2.02 (d, J = 11.0 Hz, 1H), 1.86 (dd, J = 12.7, 2.9 Hz, 1H), 1.69 (dd, J = 13.0, 4.3 Hz, 1H), 1.33 (s, 3H), 0.78 (s, 3H); HRMS (ESI) m / z Calculated for C 20 H 24 N₂NaO₃S [M+Na] + 395.1400, found 395.1396. Example 13: 3-((3) aR 5 aS 6 S 10 aR )-8-amino-6-(hydroxymethyl)-3 a ,6,10 a -trimethyl-1,2,3 a ,4,5,5 a ,6,10,10 a 10 b -Decahydrofurano[3',2':5,6]naphtho[2,3-d ]Thiazolyl)furan-2(5 H Preparation of )-ketones (compound 13)

[0060] Compound 5 (1.20 g, 3.0 mmol) was dissolved in concentrated hydrochloric acid (15 ml) and stirred at room temperature for 24 h. After the reaction was complete (detected by TLC), it was quenched with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane, and the organic phase was washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane:methanol = 50:1 - 30:1) to give 0.36 g of white solid, yield 30%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.49 (d, J = 4.7 Hz, 1H), 6.83 (d, J = 9.3 Hz, 2H), 4.87 (s, 2H), 4.64–4.54 (m, 1H), 3.68–3.58 (m, 1H), 3.52–3.43 (m, 2H), 2.38–2.30 (m, 1H), 2.26–2.05 (m, 3H), 1.92 (d, J = 11.6 Hz,1H), 1.77–1.67 (m, 1H), 1.62–1.31 (m, 5H), 1.20 (d, J = 12.3 Hz, 3H), 1.11 (d, J = 23.6 Hz, 3H), 0.89 (d, J = 31.8 Hz, 3H); HRMS (ESI) m / z Calculated for C 21 H 29 N₂O₄S [M+H] + 405.1843, found 405.1842. Example 14: (4) S 4 aS 8 R 8 aR )-4,8 a -Dimethyl-7-methylene-8-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)-4,4 a ,5,6,7,8,8 a,9-octahydronaphtho[2,3- d Preparation of [1,2,3]thiadiazole-4-carboxaldehyde (compound 14)

[0061] Compound 12 (1.60 g, 4.3 mmol) was dissolved in dichloromethane (30 ml). 2,2,6,6-Tetramethylpiperidine oxide (0.13 g, 0.86 mmol), tetrabutylammonium bromide (0.28 g, 0.86 mmol), and potassium carbonate-sodium bicarbonate buffer solution (0.21–1.26 g, 30 ml) were added at 0 °C, followed by stirring at room temperature for 9 h. After the reaction was complete (detected by TLC), the aqueous layer was extracted with dichloromethane, and the organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give 1.26 g of a white solid, yield 79%. 1 H NMR (400 MHz, DMSO- d 6) δ 9.72 (s, 1H), 7.78 (s, 1H), 6.87 (dd, J = 15.8, 10.3 Hz, 1H), 6.29 (d, J = 15.9 Hz, 1H), 4.94 (s, 2H), 4.88 (s, 1H), 4.57 (s, 1H), 3.09 (d, J HRMS (ESI) m / z Calculated for C 20 H 22 N₂NaO₃S [M+Na] + 393.1243, found 393.1265. Example 15: Acetic acid ((4) S 4 aS 8 R 8 aR )-4,8 a -Dimethyl-7-methylene-8-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3-d Preparation of [1,2,3]thiadiazole-4-yl)methyl ester (compound 15)

[0062] Acetic acid (1.5 mmol, 1.5 eq), N -(3-Dimethylaminopropyl)- N ′-ethylcarbodiimide hydrochloride (2.0 mmol, 2.0 eq) and 4-(dimethylamino)pyridine (1.0 mmol, 1.0 eq) were dissolved in 0.1 M dichloromethane. After stirring at 0 °C for 1 h, compound 12 (1.0 mmol, 1.0 eq) was added, and the reaction was carried out at room temperature for 3 h. After the reaction was complete, the mixture was extracted with dichloromethane, and the organic phase was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate = 5:1 - 1:1). A white solid was given in 79% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 7.76 (s, 1H), 6.91 (dd, J = 15.8, 10.2 Hz, 1H), 6.28 (d, J = 15.8 Hz, 1H), 4.94 (s, 2H), 4.87 (s, 1H), 4.57 (s, 1H), 4.49(d, J = 11.4 Hz, 1H), 4.30 (d, J = 11.5 Hz, 1H), 3.01 (d, J = 17.0 Hz, 1H), 2.77(d, J = 10.2 Hz, 1H), 2.67 (d, J = 17.1 Hz, 1H), 2.53 (s, 1H), 2.20–1.96 (m,3H), 1.93 (s, 3H), 1.51 (d, J = 4.4 Hz, 1H), 1.46 (s, 3H), 0.79 (s, 3H); HRMS(ESI) m / z Calculated for C 22 H 26 N₂NaO₄S [M+Na] + 437.1505, found 437.1498. Example 16: ((4) S 4 aS 8 R8 aR )-4,8 a -Dimethyl-7-methylene-8-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d Preparation of [1,2,3]thiadiazol-4-yl)methyl 2-bromoacetate (compound 16) By adapting the raw materials (replacing acetic acid with 2-bromoacetic acid in Example 15), and following the same steps as in Example 15, a pale yellow solid was obtained with a yield of 62%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.76 (s, 1H), 6.91 (dd, J =15.8, 10.2 Hz, 1H), 6.28 (d, J = 15.8 Hz, 1H), 4.93 (s, 2H), 4.87 (s, 1H), 4.62 (d, J = 11.5 Hz, 1H), 4.57 (s, 1H), 4.40 (d, J = 11.3 Hz, 1H), 4.33 (d, J =1.7 Hz, 2H), 3.58 (s, 1H), 3.02 (d, J = 17.1 Hz, 1H), 2.77 (d, J = 10.2 Hz, 1H), 2.67 (d, J = 17.1 Hz, 1H), 2.52 (s, 1H), 2.22–2.04 (m, 2H), 1.98 (dd, J =12.6, 2.9 Hz, 1H), 1.59–1.51 (m, 1H), 1.49 (s, 3H), 0.79 (s, 3H); HRMS (ESI) m / z Calculated for C 22 H 25 BrN₂NaO₄S [M+Na] + 515.0611, found 515.0610. Example 17: 4-(((4) S 4 aS 8 R 8aR )-4,8 a -Dimethyl-7-methylene-8-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d Preparation of [1,2,3]thiadiazol-4-yl)methoxy)-4-oxobutyric acid (compound 17) By adapting the raw materials (replacing acetic acid with succinic acid in Example 15), and following the same steps as in Example 15, a pale yellow solid was obtained with a yield of 71%. 1 H NMR (400 MHz, DMSO- d 6) δ 12.21 (s, 1H), 7.76 (s, 1H), 6.91 (dd, J = 15.8, 10.2 Hz, 1H), 6.27 (d, J = 15.8 Hz, 1H), 4.94 (s, 2H), 4.87(s, 1H), 4.57 (s, 1H), 4.51 (d, J = 11.5 Hz, 1H), 4.29 (d, J = 11.5 Hz, 1H), 3.01 (d, J = 17.0 Hz, 1H), 2.76 (d, J = 10.2 Hz, 1H), 2.67 (d, J = 17.1 Hz, 1H),2.44 (s, 3H), 2.34 (t, J = 7.5 Hz, 1H), 2.23–2.10 (m, 1H), 2.07 (d, J = 15.2Hz, 1H), 1.96 (d, J = 11.6 Hz, 1H), 1.57–1.48 (m, 2H), 1.47 (s, 3H), 0.79 (s,3H); HRMS (ESI) m / z Calculated for C 24 H 28 N₂NaO₆S [M+Na] + 495.1560, found 495.1579. Example 18: ((4) S 4 aS8 R 8 aR )-4,8 a -Dimethyl-7-methylene-8-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d Preparation of methyl 1,2,3]thiadiazole-4-yl)methylsuccinate (compound 18) By adapting the raw materials (replacing acetic acid with monomethyl succinate in Example 15), and following the same steps as in Example 15, a white solid was obtained, with a yield of 79%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.76 (s, 1H), 6.91 (dd, J =15.9, 10.2 Hz, 1H), 6.28 (d, J = 15.8 Hz, 1H), 4.94 (s, 2H), 4.87 (s, 1H), 4.57 (s, 1H), 4.51 (d, J = 11.4 Hz, 1H), 4.29 (d, J = 11.4 Hz, 1H), 3.58 (s, 3H), 3.01 (d, J = 17.1 Hz, 1H), 2.77 (d, J = 10.3 Hz, 1H), 2.67 (d, J = 17.1 Hz,1H), 2.60–2.50 (m, 4H), 2.50–2.41 (m, 2H), 2.22–2.08 (m, 1H), 2.06 (d, J =13.1 Hz, 1H), 1.97 (d, J = 13.5 Hz, 1H), 1.59–1.46 (m, 3H), 1.46 (s, 3H), 0.79(s, 3H); HRMS (ESI) m / z Calculated for C 25 H 30 N₂NaO₆S [M+Na] + 509.1717, found 509.1706. Example 19: 5-(((4) S 4aS 8 R 8 aR )-4,8 a -Dimethyl-7-methylene-8-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d Preparation of [1,2,3]thiadiazol-4-yl)methoxy)-5-oxovalerate (compound 19) By adapting the raw materials (replacing acetic acid with glutaric acid in Example 15), and otherwise remaining the same as in Example 15, a pale yellow solid was obtained, with a yield of 64%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.77 (s, 1H), 6.91 (dd, J = 15.9, 10.2Hz, 1H), 6.28 (d, J = 15.8 Hz, 1H), 4.94 (s, 2H), 4.87 (s, 1H), 4.56 (s, 1H), 4.50 (d, J = 11.4 Hz, 1H), 4.30 (d, J = 11.5 Hz, 1H), 3.00 (d, J = 17.0 Hz, 1H), 2.77 (d, J = 10.2 Hz, 1H), 2.67 (d, J = 17.1 Hz, 2H), 2.24 (td, J = 7.4, 1.8 Hz,2H), 2.18–2.12 (m, 1H), 2.05 (t, J = 7.3 Hz, 2H), 1.97 (dd, J = 13.0, 2.9 Hz, 1H), 1.65 (t, J = 7.5 Hz, 2H), 1.55–1.49 (m, 1H), 1.46 (s, 3H), 1.45–1.41 (m,1H), 0.78 (s, 3H); HRMS (ESI) m / z Calculated for C 25 H 30 N₂NaO₆S [M+Na] +509.1717, found 509.1707. Example 20: Glutaric acid ((4) S 4 aS 8 R 8 aR )-4,8 a -Dimethyl-7-methylene-8-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d Preparation of [1,2,3]thiadiazole-4-yl)methyl methyl ester (compound 20) By adapting the raw materials (replacing acetic acid with monomethyl glutarate in Example 15), and following the same steps as in Example 15, a white solid was obtained, with a yield of 75%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.76 (s, 1H), 6.91 (dd, J =15.8, 10.2 Hz, 1H), 6.28 (d, J = 15.8 Hz, 1H), 4.93 (s, 2H), 4.87 (s, 1H), 4.57 (s, 1H), 4.51 (d, J = 11.5 Hz, 1H), 4.30 (d, J = 11.4 Hz, 1H), 3.57 (s, 3H), 3.01 (d, J = 17.0 Hz, 1H), 2.77 (d, J = 10.2 Hz, 1H), 2.67 (d, J = 17.1 Hz,1H), 2.49 (s, 1H), 2.33–2.21 (m, 4H), 2.20–2.02 (m, 2H), 1.97 (dd, J = 12.8, 3.0 Hz, 1H), 1.70 (p, J = 7.4 Hz, 2H), 1.56–1.47 (m, 1H), 1.47 (s, 3H), 0.78(s, 3H); HRMS (ESI) m / z Calculated for C 26 H 32 N₂NaO₆S [M+Na] +523.1873, found 523.1876. Example 21: 6-(((4) S 4 aS 8 R 8 aR )-4,8 a -Dimethyl-7-methylene-8-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d Preparation of [1,2,3]thiadiazol-4-yl)methoxy)-6-oxohexanoic acid (compound 21) By adapting the raw materials (replacing acetic acid with adipic acid in Example 15), and following the same steps as in Example 15, a white solid was obtained with a yield of 69%. 1 H NMR (400 MHz, DMSO- d 6) δ 12.00 (s, 1H), 7.76 (s, 1H), 6.91(dd, J = 15.8, 10.2 Hz, 1H), 6.27 (d, J = 15.8 Hz, 1H), 4.93 (s, 2H), 4.87 (s,1H), 4.56 (s, 1H), 4.49 (d, J = 11.4 Hz, 1H), 4.31 (d, J = 11.5 Hz, 1H), 3.01(d, J = 17.0 Hz, 1H), 2.77 (d, J = 10.2 Hz, 1H), 2.66 (d, J = 17.1 Hz, 1H), 2.51(s, 1H), 2.23 (t, J = 6.8 Hz, 2H), 2.17 (t, J = 6.9 Hz, 3H), 2.07 (d, J = 15.0Hz, 1H), 1.97 (dd, J = 12.8, 3.0 Hz, 1H), 1.55–1.49 (m, 1H), 1.47 (s, 3H), 1.46–1.38 (m, 4H), 0.79 (s, 3H); HRMS (ESI) m / zCalculated for C 26 H 32 N₂NaO₆S [M+Na] + 523.1873, found 523.1885. Example 22: ((4) S 4 aS 8 R 8 aR )-4,8 a -Dimethyl-7-methylene-8-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d Preparation of [1,2,3]thiadiazole-4-yl)methyl 3-phenylpropionate (compound 22) By adapting the raw materials (replacing acetic acid with phenylpropionic acid in Example 15), and following the same steps as in Example 15, a white solid was obtained, with a yield of 81%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.76 (s, 1H), 7.30–7.22 (m, 2H), 7.21–7.11 (m, 3H), 6.90 (dd, J = 15.8, 10.2 Hz, 1H), 6.27 (d, J = 15.8 Hz, 1H), 4.93 (s, 2H), 4.87 (s, 1H), 4.56 (s, 1H), 4.44 (d, J = 11.5 Hz, 1H), 4.31 (d, J = 11.5 Hz, 1H), 2.99 (d, J = 17.0 Hz, 1H), 2.85–2.71 (m, 3H), 2.65 (d, J = 17.1Hz, 1H), 2.58–2.52 (m, 2H), 2.45 (d, J = 11.4 Hz, 1H), 2.19–2.05 (m, 1H), 2.04–1.91 (m, 2H), 1.43 (s, 3H), 1.39–1.28 (m, 1H), 0.74 (s, 3H); HRMS (ESI) m / z Calculated for C29 H 32 N₂NaO₄S [M+Na] + 527.1975, found 527.1982. Example 23: (4) S 4 aS 8 R 8 aR )-4,8 a -Dimethyl-7-methylene-8-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d Preparation of [1,2,3]thiadiazole-4-carboxylic acid (compound 23)

[0063] Compound 14 (1.60 g, 4.3 mmol) and 2-methyl-2-butene (3.62 g, 51.6 mmol) were dissolved in a tert-butanol:tetrahydrofuran (3:1, 60 ml) solution. A sodium hypochlorite-sodium dihydrogen phosphate buffer solution (1.40–2.40 g, 23 ml) was added at 0 °C, and the mixture was then stirred overnight at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure. The aqueous layer was extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 100:1) to give 1.33 g of a white solid, 80% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 12.77 (s, 1H), 7.76 (s, 1H), 6.87 (dd, J = 15.8, 10.2 Hz, 1H), 6.27 (d, J = 15.8 Hz, 1H), 4.93 (s, 2H), 4.87 (s, 1H), 4.56 (s,1H), 3.02 (d, J = 17.0 Hz, 1H), 2.76 (d, J = 10.1 Hz, 1H), 2.70 (d, J = 17.1 Hz,1H), 2.48 (s, 1H), 2.24–2.06 (m, 2H), 1.98 (dd, J= 12.7, 3.1 Hz, 1H), 1.64(s, 3H), 1.48–1.34 (m, 1H), 0.80 (s, 3H); HRMS (ESI) m / z Calculated for C 20 H 22 N₂NaO₄S [M+Na] + 409.1192, found 409.1191. Example 24: (4) S 4 aS 8 R 8 aR )- N -Cyclopropyl-4,8 a -Dimethyl-7-methylene-8-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d Preparation of [1,2,3]thiadiazole-4-carboxamide (compound 24)

[0064] Compound 23 (1.2 mmol, 1.0 eq) was dissolved in 0.1 M tetrahydrofuran, and two drops were added. N , N Dimethylformamide was added to oxalyl chloride (3.6 mmol, 3.0 eq) at 0 °C under argon protection and stirred for 2 h. After the reaction was complete, the mixture was concentrated under reduced pressure and then added to dimethylformamide. N , N -Diisopropylethylamine (3.6 mmol, 3.0 eq) and 0.1 M tetrahydrofuran. Cyclopropylamine (1.6 mmol, 1.3 eq) was then added, and the reaction was carried out at 40 °C for 5 h. After the reaction was complete, the mixture was concentrated under reduced pressure, extracted with ethyl acetate and saturated ammonium chloride, and the organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 - 1:3). A white solid was given in 65% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 7.75 (s, 1H), 7.35 (d, J = 3.7 Hz, 1H), 6.86 (dd, J = 15.8, 10.2 Hz, 1H), 6.25 (d, J= 15.8 Hz, 1H), 4.93 (s, 2H), 4.85(s, 1H), 4.53 (s, 1H), 2.96 (d, J = 17.2 Hz, 1H), 2.74–2.69 (m, 1H), 2.65 (d, J = 17.2 Hz, 1H), 2.62–2.55 (m, 1H), 2.46 (d, J = 4.1 Hz, 1H), 2.19–2.01 (m,2H), 1.86 (dd, J = 12.8, 2.8 Hz, 1H), 1.61 (s, 3H), 1.37–1.26 (m, 1H), 0.80 (s, 3H), 0.62–0.54 (m, 2H), 0.51–0.38 (m, 2H); HRMS (ESI) m / z Calculated for C 23 H 27 N3NaO3S [M+Na] + 448.1665, found 448.1661. Example 25: (4) S 4 aS 8 R 8 aR )- N -Cyclopentyl-4,8 a -Dimethyl-7-methylene-8-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d Preparation of [1,2,3]thiadiazole-4-carboxamide (compound 25) By adapting the raw materials (replacing cyclopropylamine with cyclopentylamine in Example 24), and following the same steps as in Example 24, a white solid was obtained, with a yield of 70%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.75 (s, 1H), 7.07 (d, J = 7.3 Hz, 1H), 6.86 (dd, J = 15.8, 10.2 Hz, 1H), 6.26 (d, J= 15.8 Hz, 1H), 4.93 (s, 2H), 4.85 (s, 1H), 4.53 (s, 1H), 4.03 (q, J = 7.2 Hz, 1H), 2.97 (d, J = 17.2 Hz, 1H), 2.71 (d, J = 10.3 Hz, 1H), 2.65 (d, J = 17.2 Hz, 1H), 2.46 (d, J = 5.1 Hz,1H), 2.25–2.04 (m, 2H), 1.87 (dd, J = 12.6, 2.7 Hz, 1H), 1.80–1.71 (m, 2H), 1.64 (s, 4H), 1.63–1.56 (m, 2H), 1.52–1.44 (m, 3H), 1.43–1.31 (m, 2H), 0.83(s, 3H); HRMS (ESI) m / z Calculated for C 25 H 31 N3NaO3S [M+Na] + 476.1978, found476.1976. Example 26: (4) S 4 aS 8 R 8 aR )- N -Cyclohexyl-4,8 a -Dimethyl-7-methylene-8-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d Preparation of [1,2,3]thiadiazole-4-carboxamide (compound 26) By adapting the raw materials (replacing cyclopropylamine with cyclohexylamine in Example 24), and otherwise remaining the same as in Example 24, a white solid was obtained with a yield of 68%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.75 (s, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.86 (dd, J= 15.8, 10.1 Hz, 1H), 6.26 (d, J = 15.8 Hz, 1H), 4.93 (s, 2H), 4.85(s, 1H), 4.53 (s, 1H), 3.57 (s, 1H), 2.97 (d, J = 17.2 Hz, 1H), 2.77–2.59 (m,2H), 2.46 (d, J = 4.4 Hz, 1H), 2.24–2.05 (m, 2H), 1.86 (dd, J = 12.8, 2.7 Hz,1H), 1.67 (s, 4H), 1.64 (s, 3H), 1.57 (d, J = 12.5 Hz, 1H), 1.37 (dd, J = 13.0, 4.1 Hz, 1H), 1.29 (d, J = 12.8 Hz, 1H), 1.25–1.14 (m, 3H), 1.14–1.00 (m, 1H),0.83 (s, 3H); HRMS (ESI) m / z Calculated for C 26 H 33 N3NaO3S [M+Na] + 490.2135, found 490.2115. Example 27: (4) S 4 aS 8 R 8 aR )-4,8 a -Dimethyl-7-methylene-8-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)- N -Phenyl-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d Preparation of [1,2,3]thiadiazole-4-carboxamide (compound 27) By adapting the raw materials (replacing cyclopropylamine with aniline in Example 24), and following the same steps as in Example 24, a white solid was obtained with a yield of 72%. 1 H NMR (400 MHz, DMSO- d 6) δ 9.01 (s, 1H), 7.76 (s, 1H), 7.52 (d,J = 7.2 Hz, 2H), 7.31 (t, J = 7.9 Hz, 2H), 7.09 (t, J = 7.3 Hz, 1H), 6.88 (dd, J = 15.9, 10.2 Hz, 1H), 6.28 (d, J = 15.9 Hz, 1H), 4.93 (s, 2H), 4.84 (s, 1H), 4.54 (s, 1H), 3.03 (d, J = 17.2 Hz, 1H), 2.83–2.63 (m, 2H), 2.49 (s, 1H), 2.34–2.26 (m, 1H), 2.23–2.13 (m, 1H), 2.01 (dd, J = 12.9, 3.2 Hz, 1H), 1.82(s, 3H), 1.49–1.31 (m, 1H), 0.86 (s, 3H); HRMS (ESI) m / z Calculated for C 26 H 27 N3NaO3S [M+Na] + 484.1665, found 484.1682. Example 28: (4) S 4 aS 8 R 8 aR )-4,8 a -dimethyl- N -(2-methyl-1 H -indol-5-yl)-7-methylene-8-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d Preparation of [1,2,3]thiadiazole-4-carboxamide (compound 28) By adapting the raw materials (replacing cyclopropylamine with 5-amino-2-methylindole in Example 24), and otherwise remaining the same as in Example 24, a white solid was obtained with a yield of 64%. 1 H NMR (400 MHz, DMSO- d 6) δ 10.83 (s, 1H), 8.84 (s,1H), 7.76 (s, 1H), 7.46 (d,J = 1.9 Hz, 1H), 7.17 (d, J = 8.6 Hz, 1H), 7.02(dd, J = 8.6, 2.0 Hz, 1H), 6.88 (dd, J = 15.9, 10.1 Hz, 1H), 6.28 (d, J = 15.8Hz, 1H), 6.06 (s, 1H), 4.93 (s, 2H), 4.85 (s, 1H), 4.54 (s, 1H), 3.02 (d, J =17.2 Hz, 1H), 2.81–2.65 (m, 2H), 2.52 (s, 1H), 2.35 (s, 3H), 2.34–2.28 (m,1H), 2.17 (dt, J = 15.6, 7.7 Hz, 1H), 2.03–1.94 (m, 1H), 1.81 (s, 3H), 1.56–1.40 (m, 1H), 0.90 (s, 3H); HRMS (ESI) m / z Calculated for C 29 H 30 N4NaO3S [M+Na] + 537.1931, found 537.1933. Example 29: (4) S 4 aS 8 R 8 [[ID= )- N -Benzyl-4,8 a -Dimethyl-7-methylene-8-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d Preparation of [1,2,3]thiadiazole-4-carboxamide (compound 29) By adapting the raw materials (replacing cyclopropylamine with benzylamine in Example 24), and following the same steps as in Example 24, a white solid was obtained with a yield of 79%. 1 H NMR (400 MHz, DMSO- d 6) ​ 7.88 (t, J= 6.0 Hz, 1H), 7.75 (s,1H), 7.31–7.20 (m, 5H), 6.85 (dd, J = 15.8, 10.1 Hz, 1H), 6.25 (d, J = 15.8 Hz,1H), 4.93 (s, 2H), 4.82 (s, 1H), 4.51 (s, 1H), 4.25 (t, J = 6.7 Hz, 2H), 2.97(d, J = 17.2 Hz, 1H), 2.73–2.64 (m, 2H), 2.47–2.39 (m, 1H), 2.18–2.04 (m, 2H), 1.89 (dd, J = 12.8, 2.8 Hz, 1H), 1.69 (s, 3H), 1.40–1.29 (m, 1H), 0.77 (s, 3H); HRMS (ESI) ​ Calculated for C 27 H 29 N3NaO3S [M+Na] + 498.1822, found 498.1825. Example 30: (4) S 4 ​ 8 R 8 ​ )- N -(4-Bromobenzyl)-4,8 a -Dimethyl-7-methylene-8-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d Preparation of [1,2,3]thiadiazole-4-carboxamide (compound 30) By adapting the raw materials (replacing cyclopropylamine with benzyl butylbromide in Example 24), the remaining steps were the same as in Example 24, yielding a pale yellow solid with a yield of 80%. 1 H NMR (400 MHz, DMSO- d 6) ​ 7.90 (t, J = 6.0 Hz, 1H), 7.75(d, J = 2.0 Hz, 1H), 7.50 (d, J= 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 6.85 (dd, J = 15.8, 10.2 Hz, 1H), 6.25 (d, J = 15.8 Hz, 1H), 4.93 (s, 2H), 4.83 (s,1H), 4.51 (s, 1H), 4.20 (t, J = 5.1 Hz, 2H), 2.97 (d, J = 17.2 Hz, 1H), 2.75–2.62 (m, 2H), 2.47–2.40 (m, 1H), 2.11 (d, J = 11.5 Hz, 2H), 1.93–1.82 (m, 1H), 1.68 (s, 3H), 1.34–1.26 (m, 1H), 0.76 (s, 3H); HRMS (ESI) ​ Calculated for C 27 H 28 BrN3NaO3S [M+Na] + 576.0927, found 576.0922. Example 31: (4) S 4 ​ 8 R 8 ​ )-4,8 a -Dimethyl-7-methylene-8-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)- N -(thien-2-ylmethyl)-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d Preparation of [1,2,3]thiadiazole-4-carboxamide (compound 31) By adapting the raw materials (replacing cyclopropylamine with 2-thiophenemethylamine in Example 24), and otherwise remaining the same as in Example 24, a white solid was obtained with a yield of 85%. 1 H NMR (400 MHz, DMSO- d 6) ​ 7.97 (t, J = 5.9 Hz, 1H), 7.75 (s,1H), 7.36 (t, 1H), 6.92 (d, J= 3.5 Hz, 2H), 6.85 (dd, J = 15.8, 10.2 Hz, 1H), 6.25 (d, J = 15.8 Hz, 1H), 4.93 (s, 2H), 4.82 (s, 1H), 4.50 (s, 1H), 4.48–4.33(m, 2H), 2.96 (d, J = 17.4 Hz, 1H), 2.76–2.59 (m, 2H), 2.46–2.37 (m, 1H), 2.18–2.03 (m, 2H), 1.88 (dd, J = 12.8, 2.8 Hz, 1H), 1.67 (s, 3H), 1.43–1.30(m, 1H), 0.76 (s, 3H); HRMS (ESI) ​ Calculated for C 25 H 27 N3NaO3S2[M+Na] + 504.1386 was found; 504.1379 was also found. Example 32: (4) S 4 ​ 8 R 8 ​ )-4,8 a -Dimethyl-7-methylene-8-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)- N -(pyridin-3-ylmethyl)-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d Preparation of [1,2,3]thiadiazole-4-carboxamide (compound 32) By adapting the raw materials (replacing cyclopropylamine with 3-aminomethylpyridine in Example 24), and following the same steps as in Example 24, a white solid was obtained, with a yield of 81%. 1 H NMR (400 MHz, DMSO- d 6) ​ 8.47 (s, 1H), 8.43 (d, J =4.8 Hz, 1H), 7.93 (t, J = 6.0 Hz, 1H), 7.75 (s, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.34 (dd,J = 8.0, 4.9 Hz, 1H), 6.84 (dd, J = 15.8, 10.2 Hz, 1H), 6.25 (d, J =15.9 Hz, 1H), 4.93 (s, 2H), 4.82 (s, 1H), 4.50 (s, 1H), 4.40–4.14 (m, 2H), 2.97 (d, J = 17.2 Hz, 1H), 2.77–2.63 (m, 2H), 2.46–2.37 (m, 1H), 2.17–2.04 (m,2H), 1.89 (d, J = 11.3 Hz, 1H), 1.68 (s, 3H), 1.30–1.22 (m, 1H), 0.73 (s, 3H); HRMS (ESI) ​ Calculated for C 26 H 28 N4NaO3S [M+Na] + 499.1774, found 499.1766. Example 33: (4) S 4 ​ 8 R 8 ​ )- N -(2-(1 H -indol-3-yl)ethyl)-4,8 a -Dimethyl-7-methylene-8-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d Preparation of [1,2,3]thiadiazole-4-carboxamide (compound 33) By adapting the raw materials (replacing cyclopropylamine with tryptamine in Example 24), and following the same steps as in Example 24, a white solid was obtained with a yield of 77%. 1 H NMR (400 MHz, DMSO- d 6) ​ 10.81 (s, 1H), 7.74 (s, 1H), 7.55(d, J = 7.9 Hz, 1H), 7.48 (t, J = 5.7 Hz, 1H), 7.33 (d, J= 8.0 Hz, 1H), 7.14(s, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.97 (t, J = 7.4 Hz, 1H), 6.86 (dd, J = 15.8, 10.2 Hz, 1H), 6.25 (d, J = 15.8 Hz, 1H), 4.93 (s, 2H), 4.82 (s, 1H), 4.51 (s,1H), 3.35–3.29 (m, 2H), 2.98 (d, J = 17.2 Hz, 1H), 2.81 (t, J = 7.6 Hz, 2H),2.75–2.61 (m, 2H), 2.46–2.36 (m, 1H), 2.15–2.00 (m, 2H), 1.86 (dd, J = 12.9,2.7 Hz, 1H), 1.66 (s, 3H), 1.42–1.29 (m, 1H), 0.83 (s, 3H); HRMS (ESI) m / z Calculated for C 30 H 32 N4NaO3S [M+Na] + 551.2060, found 551.2087. Example 34: (4) S 4 ​ 8 R 8 ​ )- N -(2-Fluoro-5-methylphenyl)-4,8 a -Dimethyl-7-methylene-8-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d Preparation of [1,2,3]thiadiazole-4-carboxamide (compound 34) By adapting the raw materials (replacing cyclopropylamine with 2-fluoro-5-methylaniline in Example 24), the remaining steps were the same as in Example 24, yielding a pale yellow solid with a yield of 55%. 1 H NMR (400 MHz, DMSO- d 6) ​8.88 (s, 1H), 7.76 (s,1H), 7.15–7.07 (m, 2H), 7.06–7.00 (m, 1H), 6.89 (dd, J = 15.8, 10.1 Hz, 1H), 6.28 (d, J = 15.8 Hz, 1H), 4.94 (s, 2H), 4.88 (s, 1H), 4.55 (s, 1H), 3.02 (d, J = 17.2 Hz, 1H), 2.76 (d, J = 10.3 Hz, 1H), 2.74–2.69 (m, 1H), 2.52 (s, 1H), 2.29 (s, 1H), 2.26 (s, 3H), 2.22–2.11 (m, 1H), 2.01 (d, J = 3.0 Hz, 1H), 1.80(s, 3H), 1.60–1.52 (m, 1H), 0.87 (s, 3H); HRMS (ESI) ​ Calculated for C 27 H 28 FN3NaO3S [M+Na] + 537.1931, found 537.1933. Example 35: (4) S 4 ​ 8 R 8 ​ )- N -(2,5-Difluorophenyl)-4,8 a -Dimethyl-7-methylene-8-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d Preparation of [1,2,3]thiadiazole-4-carboxamide (compound 35) By adapting the raw materials (replacing cyclopropylamine with 2,5-difluoroaniline in Example 24), and following the same steps as in Example 24, a pale yellow solid was obtained, with a yield of 37%. 1 H NMR (400 MHz, DMSO- d 6) ​9.03 (s, 1H), 7.77 (s,1H), 7.35–7.21 (m, 2H), 7.15–7.06 (m, 1H), 6.89 (dd, J = 15.8, 10.1 Hz, 1H), 6.28 (d, J = 15.9 Hz, 1H), 4.94 (s, 2H), 4.87 (s, 1H), 4.56 (s, 1H), 3.03 (d, J = 17.3 Hz, 1H), 2.82–2.67 (m, 2H), 2.51 (s, 1H), 2.27 (d, J = 13.5 Hz, 1H), 2.17 (t, J = 13.3 Hz, 1H), 2.02 (dd, J = 12.9, 3.1 Hz, 1H), 1.81 (s, 3H), 1.61–1.50 (m, 1H), 0.86 (s, 3H); HRMS (ESI) ​ Calculated for C 26 H 25 F2N3NaO3S [M+Na] + 520.1477, found 520.1472. Example 36: (4) S 4 ​ 8 R 8 ​ )- N -(2-Fluoro-5-hydroxyphenyl)-4,8 a -Dimethyl-7-methylene-8-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d Preparation of [1,2,3]thiadiazole-4-carboxamide (compound 36) By adapting the raw materials (replacing cyclopropylamine with 2-fluoro-4-hydroxyaniline in Example 24), the remaining steps were the same as in Example 24, yielding a pale yellow solid with a yield of 41%. 1 H NMR (400 MHz, DMSO- d 6) ​ 9.39 (s, 1H), 8.77 (s,1H), 7.76 (s, 1H), 7.01 (t,J = 9.5 Hz, 1H), 6.88 (dd, J = 15.8, 10.1 Hz, 1H), 6.83–6.74 (m, 1H), 6.62–6.53 (m, 1H), 6.28 (d, J = 15.8 Hz, 1H), 4.94 (s, 2H), 4.87 (s, 1H), 4.55 (s, 1H), 3.02 (d, J = 17.2 Hz, 1H), 2.81–2.68 (m, 2H), 2.53(s, 1H), 2.28 (d, J = 13.4 Hz, 1H), 2.17 (t, J = 13.1 Hz, 1H), 2.00 (dd, J =12.8, 3.1 Hz, 1H), 1.79 (s, 3H), 1.61–1.50 (m, 1H), 0.86 (s, 3H); HRMS (ESI) ​ Calculated for C 26 H 26 FN3NaO4S [M+Na] + 518.1520, found 518.1534. Example 37: (4) S 4 ​ 8 R 8 ​ )- N -(2-Fluoro-4-hydroxyphenyl)-4,8 a -Dimethyl-7-methylene-8-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d Preparation of [1,2,3]thiadiazole-4-carboxamide (compound 37) By adapting the raw materials (replacing cyclopropylamine with 2-fluoro-3-hydroxyaniline in Example 24), and otherwise remaining the same as in Example 24, a pale yellow solid was obtained with a yield of 45%. 1 H NMR (400 MHz, DMSO- d 6) ​ 9.82 (s, 1H), 8.73 (s, 1H),7.76 (s, 1H), 7.02 (t, J= 9.0 Hz, 1H), 6.88 (dd, J = 15.9, 9.9 Hz, 1H), 6.62–6.53 (m, 2H), 6.27 (d, J = 15.9 Hz, 1H), 4.93 (s, 2H), 4.87 (s, 1H), 4.55 (s,1H), 3.00 (d, J = 17.3 Hz, 1H), 2.79–2.69 (m, 2H), 2.51 (s, 1H), 2.26 (d, J =13.5 Hz, 1H), 2.20–2.12 (m, 1H), 1.99–1.90 (m, 1H), 1.77 (s, 3H), 1.61–1.51(m, 1H), 0.87 (s, 3H); HRMS (ESI) ​ Calculated for C 26 H 26 FN3NaO4S [M+Na] + 518.1520, found 518.1523. Example 38: (4) S 4 ​ 8 R 8 ​ )- N -(2-Methoxyphenyl)-4,8 a -Dimethyl-7-methylene-8-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d Preparation of [1,2,3]thiadiazole-4-carboxamide (compound 38) By adapting the raw materials (replacing cyclopropylamine with 2-methoxyaniline in Example 24), and following the same steps as in Example 24, a white solid was obtained, with a yield of 49%. 1 H NMR (400 MHz, DMSO- d 6) ​ 7.95 (dd, J = 7.9, 1.7 Hz,1H), 7.51 (s, 1H), 7.10–6.85 (m, 4H), 6.32 (d, J = 15.8 Hz, 1H), 4.89 (s, 2H), 4.87 (d,J = 1.7 Hz, 1H), 4.61 (d, J = 1.6 Hz, 1H), 3.73 (s, 3H), 3.12 (d, J =17.5 Hz, 1H), 2.82–2.71 (m, 2H), 2.60–2.52 (m, 1H), 2.35–2.26 (m, 1H), 2.26–2.15 (m, 1H), 2.05 (d, 1H), 1.88 (s, 3H), 1.85–1.76 (m, 1H), 0.92 (s, 3H); HRMS (ESI) ​ Calculated for C 27 H 29 N3NaO4S [M+Na] + 514.1771, found 514.1785. Example 39: (4) S 4 ​ 8 R 8 ​ )- N -(2-hydroxy-4-(trifluoromethyl)phenyl)-4,8 a -Dimethyl-7-methylene-8-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d Preparation of [1,2,3]thiadiazole-4-carboxamide (compound 39) By adapting the raw materials (replacing cyclopropylamine in Example 24 with 2-hydroxy-4-(trifluoromethyl)aniline), and following the same steps as in Example 24, a pale yellow solid was obtained, with a yield of 37%. 1 H NMR (400 MHz, CD3OD) ​ 8.17 (d, J = 7.9Hz, 1H), 7.53 (s, 1H), 7.09 (dd, J = 8.6, 2.5 Hz, 1H), 7.04–6.96 (m, 2H), 6.33(d, J = 15.8 Hz, 1H), 4.90 (s, 2H), 4.86 (s, 1H), 4.61 (s, 1H), 3.13 (d, J=17.5 Hz, 1H), 2.83–2.72 (m, 2H), 2.60–2.53 (m, 1H), 2.36–2.28 (m, 1H), 2.28–2.18 (m, 1H), 2.08 (dd, J = 12.8, 3.2 Hz, 1H), 1.90 (s, 3H), 1.81–1.68 (m,1H), 0.92 (s, 3H); HRMS (ESI) ​ Calculated for C 27 H 26 F3N3NaO4S [M+Na] + 568.1488, found 568.1493. Example 40: (4) S 4 ​ 8 R 8 ​ )- N -(3-Methoxyphenyl)-4,8 a -Dimethyl-7-methylene-8-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d Preparation of [1,2,3]thiadiazole-4-carboxamide (compound 40) The raw material was modified (cyclopropylamine in Example 24 was replaced with 3-methoxyaniline), otherwise the same as in Example 24. The product was a white solid with a yield of 54%. 1 H NMR (400 MHz, DMSO- d 6) ​ 8.96 (s, 1H), 7.76 (s, 1H), 7.24–7.18 (m, 2H), 7.18–7.14 (m, 1H), 6.88 (dd, J = 15.8, 10.1 Hz, 1H), 6.76–6.63(m, 1H), 6.28 (d, J = 15.8 Hz, 1H), 4.94 (s, 2H), 4.84 (s, 1H), 4.54 (s, 1H), 3.72 (s, 3H), 3.03 (d, J= 17.2 Hz, 1H), 2.81–2.66 (m, 2H), 2.48 (s, 1H), 2.37–2.29 (m, 1H), 2.22–2.10 (m, 1H), 2.01 (dd, J = 12.9, 3.0 Hz, 1H), 1.82(s, 3H), 1.44–1.31 (m, 1H), 0.85 (s, 3H); HRMS (ESI) ​ Calculated for C 27 H 29 N3NaO4S [M+Na] + 514.1771, found 514.1794. Example 41: (4) S 4 ​ 8 R 8 ​ )- N -(4-hydroxy-3-methoxyphenyl)-4,8 a -Dimethyl-7-methylene-8-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d Preparation of [1,2,3]thiadiazole-4-carboxamide (compound 41) By adapting the raw materials (replacing cyclopropylamine with 2-hydroxy-3-methoxyaniline in Example 24), and following the same steps as in Example 24, a white solid was obtained, with a yield of 42%. 1 H NMR (400 MHz, CD3OD) ​ 7.52 (s, 1H), 7.08–6.96 (m, 2H), 6.79 (dd, J = 8.5, 2.4 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H), 6.33 (d, J =15.8 Hz, 1H), 4.90 (s, 2H), 4.62 (s, 1H), 3.82 (s, 3H), 3.09 (d, J = 17.2 Hz,1H), 2.80–2.70 (m, 2H), 2.62–2.53 (m, 1H), 2.40–2.31 (m, 1H), 2.29–2.19 (m,1H), 2.03 (dd,J = 12.8, 3.2 Hz, 1H), 1.84 (s, 3H), 1.66–1.57 (m, 1H), 0.97 (s, 3H); HRMS (ESI) ​ Calculated for C 27 H 29 N3NaO5S [M+Na] + 530.1720, found 530.1693. Example 42: ( E )-3-(2-fluorophenyl)- N -(5-(4-(2-((2 R ,3 R 4 S 5 S 6 R )-3,4,5-Trihydroxy-6-(hydroxymethyl)tetrahydro-2 H Preparation of pyran-2-yl)oxy)ethyl)phenyl)pyridin-2-yl)acrylamide (compound 42) By adapting the raw materials (replacing cyclopropylamine in Example 24 with 2-hydroxy-4-methoxyaniline), and following the same steps as in Example 24, a white solid was obtained, with a yield of 45%. 1 H NMR (400 MHz, DMSO- d 6) ​ 9.03 (s, 1H), 8.81 (s, 1H), 7.76 (s, 1H), 7.05 (s, 1H), 6.92–6.82 (m, 3H), 6.27 (d, J = 15.8 Hz,1H), 4.94 (s, 2H), 4.85 (s, 1H), 4.54 (s, 1H), 3.72 (s, 3H), 3.01 (d, J = 17.2Hz, 1H), 2.76 (d, J = 10.3 Hz, 1H), 2.70 (d, J = 17.2 Hz, 1H), 2.48 (s, 1H), 2.32–2.26 (m, 1H), 2.16 (t, J = 12.4 Hz, 1H), 1.98 (dd, J = 12.4, 3.3 Hz, 1H),1.79 (s, 3H), 1.45–1.33 (m, 1H), 0.86 (s, 3H); HRMS (ESI) ​Calculated for C 27 H 29 N3NaO5S [M+Na] + 530.1720, found 530.1724. Example 43: 2-(2-fluorophenoxy)- N -(5-(4-(2-(((2 R ,3 R 4S, 5S, 6 R )-3,4,5-Trihydroxy-6-(hydroxymethyl)tetrahydro-2 H Preparation of pyran-2-yl)oxy)ethyl)phenyl)pyridin-2-yl)acetamide (compound 43) By adapting the raw materials (replacing cyclopropylamine with 2-methoxyphenylethylamine in Example 24), and following the same steps as in Example 24, a white solid was obtained, with a yield of 58%. 1 H NMR (400 MHz, DMSO- d 6) ​ 7.75 (s, 1H), 7.41 (t, J =5.6 Hz, 1H), 7.19 (td, J = 7.8, 1.7 Hz, 1H), 7.13 (dd, J = 7.4, 1.7 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.91–6.81 (m, 2H), 6.25 (d, J = 15.9 Hz, 1H), 4.93(s, 2H), 4.84 (s, 1H), 4.52 (s, 1H), 3.77 (s, 3H), 3.30–3.21 (m, 2H), 2.96(d, J = 17.2 Hz, 1H), 2.78–2.61 (m, 4H), 2.46–2.37 (m, 1H), 2.18–2.01 (m, 2H), 1.84 (dd, J = 12.8, 2.8 Hz, 1H), 1.63 (s, 3H), 1.36–1.27 (m, 1H), 0.79 (s,3H); HRMS (ESI) ​ Calculated for C 29 H 33 N3NaO4S [M+Na] + 542.2084, found 542.2092. Example 44: (4) S 4 ​ 8 R 8 ​ )-4,8 a -Dimethyl-7-methylene- N -(2-(4-methylpiperazin-1-yl)ethyl)-8-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d Preparation of [1,2,3]thiadiazole-4-carboxamide (compound 44) By adapting the raw materials (replacing cyclopropylamine with 4-morpholinoethylamine in Example 24), and following the same steps as in Example 24, a white solid was obtained, with a yield of 38%. 1 H NMR (400 MHz, CD3OD) ​ 7.52 (d, J = 3.3 Hz, 1H), 7.01(dd, J = 15.9, 10.1 Hz, 1H), 6.33 (d, J = 15.8 Hz, 1H), 4.90 (s, 2H), 4.62 (s,1H), 3.45–3.32 (m, 2H), 3.28–3.19 (m, 3H), 3.07 (d, J = 17.4 Hz, 2H), 2.85 (s,5H), 2.77–2.68 (m, 3H), 2.60–2.48 (m, 4H), 2.28–2.23 (m, 1H), 2.22–2.17 (m,1H), 1.96 (dd, J = 12.8, 3.0 Hz, 1H), 1.74 (s, 3H), 1.64–1.58 (m, 1H), 0.91(s, 3H); HRMS (ESI) ​ Calculated for C 27 H 38 N5O3S [M+H] + 512.2690, found 512.2687. Example 45: (4) S 4 ​ 8 R ,8a R )-4,8 a-Dimethyl-7-methylene- N -(2-morpholinylethyl)-8-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)-4,4 a ,5,6,7,8,8 a ,9-octahydronaphtho[2,3- d Preparation of [1,2,3]thiadiazole-4-carboxamide (compound 45) Adapt to changes in raw materials (replacing cyclopropylamine in Example 24 with...) N (-methyl-4-piperazineethylamine), the remaining steps are the same as in Example 24, yielding a white solid, yield: 42%; 1 H NMR (400 MHz, CD3OD) ​ 7.53 (s, 1H), 7.00 (dd, J = 15.8, 10.2 Hz, 1H), 6.32 (d, J = 15.9 Hz, 1H), 4.89 (s, 2H), 4.87 (s, 1H), 4.61 (s, 1H), 3.70–3.61 (m, 4H), 3.37–3.31 (m, 1H), 3.07 (d, J = 17.4 Hz, 1H),2.80–2.66 (m, 2H), 2.60–2.44 (m, 7H), 2.27–2.16 (m, 2H), 2.00–1.92 (m, 1H),1.74 (s, 3H), 1.69–1.61 (m, 1H), 0.91 (s, 3H); HRMS (ESI) ​ Calculated for C 26 H 35 N4O4S [M+H] + 499.2374, found 499.2384. Example 46: Evaluation of the in vitro anti-hypoxic neuroinflammatory activity of the diterpenoid natural product derivatives described in this invention. The anti-hypoxic neuroinflammatory activity of the diterpenoid natural product derivatives described in this invention against astrocyte C8-D1A cells was detected using a hypoxia workstation and the MTT method.

[0065] Experimental procedure: C8-D1A cells in logarithmic growth phase were seeded in 96-well plates (8 × 10⁶ cells / well). 3Cells were cultured in 100 μL / well medium for 24 h until adherence. Subsequently, normoxic control, hypoxic neuroinflammation model group, hypoxic neuroinflammation + compound treatment group, and hypoxic neuroinflammation + positive control group were established. Except for the normoxic control group, which used normal culture medium, the other groups were cultured in medium containing the corresponding compound (containing 1 μg / mL LPS). Cells were first cultured in normoxic medium for 4 h (LPS pre-stimulation), followed by hypoxia (1% O2, 5% CO2, 94% N2) for 24 h. After treatment, 10 μL of MTT solution (5 mg / mL) was added to each well, and the cells were incubated in the dark for 4 h. After incubation, the supernatant was carefully discarded, and DMSO (100 μL / well) was added to each well to fully dissolve the generated formazan crystals. After shaking at room temperature for 15 min, the OD value was measured at 490 nm, and cell viability was calculated.

[0066] Cell viability (%) = A 实验 / A 对照 ×100% like ​ As shown, most of the diterpenoid natural product derivatives described in this invention exhibit strong anti-hypoxic neuroinflammatory activity against C8-D1A cells. At a dosage concentration of 20 μM, compounds 1, 2, 4, 5, 27-31, 33, 35-38, 40, and 43 show significant differences in their anti-hypoxic neuroinflammatory activity. While compounds 3, 8, 12, 14, 15, 19, 34, and 42 show no significant difference in their anti-hypoxic neuroinflammatory activity, they still possess activity. In particular, compounds 2, 4, 36, and 37 exhibit greater than 80% activity against hypoxic neuroinflammatory disease, providing potent compounds for further in-depth research on their mechanisms of action and indications.

[0067] Example 47: Evaluation of the in vitro cytotoxic activity of the diterpenoid natural product derivatives described in this invention. The antiproliferative activity of the diterpenoid natural product derivatives described in this invention against astrocyte C8-D1A cells was detected using the MTT assay.

[0068] Experimental procedure: Cell culture was the same as in Example 46. Then, a normoxic control group and a normoxic + compound treatment group were set up. The culture medium was replaced with a medium containing diterpenoid natural product derivatives (20 μM) (100 μL / well) and cultured for another 24 h at 37 ℃ in a 5% CO2 incubator. The subsequent MTT detection procedure was the same as in Example 46.

[0069] like ​As shown, the diterpenoid natural product derivatives of the present invention, except for compounds 1-3, 5, 7, 8, 11, 16 and 19, showed no significant cytotoxicity to astrocyte C8-D1A cells at a concentration of 20 μM, and have good in vitro safety.

[0070] These compounds are simple to synthesize, use inexpensive and readily available raw materials, and exhibit significant anti-neuroinflammatory activity. They are expected to become novel drugs for the prevention and / or treatment of neuroinflammatory-related neurological diseases such as high-altitude cerebral edema, high-altitude brain injury, neonatal hypoxic-ischemic encephalopathy, ischemic / hemorrhagic stroke, traumatic brain injury, Alzheimer's disease, Huntington's disease, Parkinson's disease, delayed encephalopathy after carbon monoxide poisoning, epilepsy, and post-traumatic stress disorder.

[0071] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A diterpenoid natural product derivative, or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, metabolite, polymorph, or isotope label thereof, wherein the structure of the derivative is shown in formula (I): In formula (Ⅰ): Ring A is selected from substituted or unsubstituted C6-C14 aryl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted 5- to 14-membered heteroaryl groups containing 1-3 heteroatoms selected from N, O, and S, and substituted or unsubstituted 5- to 10-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O, and S. "Substitution" refers to the presence of 1 to 3 substituents R. 1 ; R 1 Each of the substituents is independently selected from hydrogen, hydroxyl, amino, nitro, halogen atom, C1-C6 alkyl, C1-C6 alkoxy, and iminourea; X is selected from saturated or unsaturated substituted or unsubstituted 5- to 10-membered heterocyclic alkyl C1-C6 alkyl containing 1-3 heteroatoms selected from N, O, and S, or saturated or unsaturated substituted or unsubstituted 5- to 10-membered heterocyclic alkyl C2-C6 alkenyl containing 1-3 heteroatoms selected from N, O, and S, wherein "substituted" means containing 1 to 3 substituents independently selected from hydrogen, hydroxyl, amino, oxo, C1-C6 alkyl, and C1-C6 alkoxy. Y is selected from C1-C6 alkylene, C1-C6 alkoxy, and carbonyl groups; Z is selected from hydrogen, hydroxyl, C2-C6 diacid monoester, C2-C6 diacid diester, C1-C6 acyloxy, halogenated C1-C6 acyloxy, C3-C8 cycloalkylamino, substituted or unsubstituted C6-C10 arylamino, C6-C10 arylC1-C6 acyloxy, substituted or unsubstituted 5- to 10-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, substituted or unsubstituted 5- to 10-membered heteroarylC1-C6 alkylamino containing 1-3 heteroatoms selected from N, O, and S, and substituted or unsubstituted 5- to 10-membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O, and S, wherein "substituted" means containing 1 to 3 substituents, each independently selected from hydrogen, hydroxyl, amino, halogen atom, C1-C6 alkyl, C1-C6 alkoxy, and -CF3.

2. The diterpenoid natural product derivative according to claim 1, or its pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, metabolite, polymorph, or isotope label, is characterized in that, Preferably, ring A is selected from substituted or unsubstituted C6-C10 aryl groups, substituted or unsubstituted C5-C6 cycloalkyl groups, substituted or unsubstituted 5- to 9-membered heteroaryl groups containing 1-3 heteroatoms selected from N and S, or substituted or unsubstituted 5- to 9-membered heterocycloalkyl groups containing 1-3 heteroatoms selected from N and S. "Substitution" refers to the presence of 1 or 2 substituents R. 1 ; More preferably, ring A is selected from substituted or unsubstituted C6-C10 aryl groups, substituted or unsubstituted C5-C6 cycloalkyl groups, substituted or unsubstituted 5- to 9-membered heteroaryl groups containing 1-3 heteroatoms selected from N and S, and substituted or unsubstituted 5- to 9-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N and S, wherein "substituted" refers to containing 1 or 2 substituents R. 1 ; More preferably, ring A is selected from substituted or unsubstituted 5- to 9-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N and S, or substituted or unsubstituted 5- to 9-membered heterocyclic alkyl groups containing 1 to 3 heteroatoms selected from N and S, wherein "substituted" refers to containing 1 or 2 substituents R. 1 ; More preferably, ring A and ring R 1 Together, we select from the following structures: 、 、 、 、 、 ； More preferably, ring A and ring R 1 Selected together , , ; Preferably, R 1 Each substituent is independently selected from hydrogen, hydroxyl, amino, C1-C3 alkyl, and C1-C3 alkoxy groups; Preferably, R 1 Each substituent is independently selected from hydrogen, hydroxyl, amino, and C1-C3 alkoxy groups; Preferably, R 1 Each substituent is independently selected from hydrogen, amino, methoxy, ethoxy, propoxy, C1-C3 alkoxy, and iminourea groups; Preferably, R 1 Selected from hydrogen substitution; Preferably, X is selected from saturated or unsaturated substituted or unsubstituted 5- to 6-membered heterocyclic alkyl C1-C3 alkyl containing one or two heteroatoms selected from N and O, or saturated or unsaturated substituted or unsubstituted 5- to 6-membered heterocyclic alkyl C2-C3 alkenyl containing one or two heteroatoms selected from N and O, wherein "substituted" means containing one or two substituents independently selected from hydrogen, hydroxyl, amino, oxo, C1-C3 alkyl, and C1-C3 alkoxy. Preferably, X is selected from saturated or unsaturated substituted or unsubstituted 5- to 6-membered heterocyclic alkyl C1-C3 alkyl containing one or two heteroatoms selected from N and O, or saturated or unsaturated substituted or unsubstituted 5- to 6-membered heterocyclic alkyl C2-C3 alkenyl containing one or two heteroatoms selected from N and O, wherein "substituted" means containing one or two substituents independently selected from hydrogen, hydroxyl, and oxo groups; Preferably, X is selected from the following structures: , ; More preferably, X is selected from ; Preferably, Y is selected from C1-C3 alkylene, C1-C3 alkeneoxy, and carbonyl groups; More preferably, Y is a methylene or carbonyl group; More preferably, Y is a carbonyl group; Preferably, Z is selected from hydrogen, hydroxyl, C2-C4 diacid monoester, C2-C4 diacid diester, C1-C3 acyloxy, halogenated C1-C3 acyloxy, C3-C6 cycloalkylamino, substituted or unsubstituted phenylamino, phenyl C1-C3 acyloxy, substituted or unsubstituted 5- to 9-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, S, substituted or unsubstituted 5- to 6-membered heteroaryl C1-C3 alkylamino containing 1 or 2 heteroatoms selected from N, O, S, substituted or unsubstituted 5- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O, S, wherein "substituted" means containing 1 or 2 to 3 substituents each independently selected from hydrogen, hydroxyl, amino, halogen atom, C1-C3 alkyl, C1-C3 alkoxy, -CF3; Preferably, Z is selected from hydroxyl, acetoxy, bromoacetoxy, succinate, methylsuccinate, glutarate, methylglutarate, adipate, phenylpropionate, cyclopropylamino, cyclopentanamino, cyclohexylamino, aniline, 2-methyl-5-indoleamino, benzylamino, 4-bromobenzylamino, 2-thiophenemethylamino, 3-pyridinemethylamino, tryptamine, 2-fluoro-5-methylaniline, 2,5-difluoroaniline, 2-fluoro-5-hydroxyaniline, 2-fluoro-4-hydroxyaniline, 2-methoxyaniline, 4-trifluoromethyl-2-hydroxyaniline, 3-methoxyaniline, 3-methoxy-4-hydroxyaniline, 3-hydroxy-4-methoxyaniline, 2-methoxy-phenylethylamino, 2-morpholinoethylamino, 2-( N (-methylpiperazine)ethylamino; preferably aniline, chromoamino, 2,5-difluoroaniline, 2-fluoro-5-hydroxyaniline, 2-fluoro-4-hydroxyaniline, 2-methoxyaniline, 3-methoxyaniline, 2-methoxy-phenylethylamino; Preferably, Z is selected from the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； More preferably, Z is selected from , , , , , , , .

3. The diterpenoid natural product derivative according to claim 1, or its pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, metabolite, polymorph, or isotope label, is characterized in that, It is a compound represented by the following formulas (II), (III), (IV), (V), (VI), or (VII): In the formula, R 1 The definitions of the substituents X, Y and Z are the same as those in formula (I) of claim 1.

4. The diterpenoid natural product derivative according to any one of claims 1 to 3, or its pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, metabolite, polymorph, or isotope label, characterized in that, It is selected from the following compounds: 。 5. A method for synthesizing the diterpenoid natural product derivative represented by formula (I) according to any one of claims 1 to 4, selected from the following synthetic routes: Synthesis Route 1: Andrographolide (II-1) reacts with 2,2-dimethoxypropane via a nucleophilic substitution reaction to give intermediate II-2; the solvent used in the nucleophilic substitution reaction is selected from acetone, acetonitrile, dichloromethane, ethyl acetate, with acetone being preferred; Intermediate II-2 was reacted with tert-butyldimethylchlorosilane under alkaline conditions via nucleophilic substitution, followed by acid hydrolysis to remove the dimethylene protecting group, yielding intermediate II-3; the base used was selected from imidazole. N , N -Diisopropylethylamine, potassium carbonate, preferably imidazole; the acid used is selected from acetic acid, phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, preferably acetic acid; Intermediate II-3 undergoes a nucleophilic substitution reaction with tert-butyldimethylchlorosilane to give intermediate II-4; the solvent used in the nucleophilic substitution reaction is selected from dichloromethane and acetonitrile. N , N -Dimethylformamide, ethyl acetate, tetrahydrofuran, preferably dichloromethane; Intermediate II-4 undergoes an oxidation reaction under the action of an oxidizing agent to obtain intermediate II-5; the oxidizing agent used is selected from Des Martin oxidizing agent, 2-iodobenzoic acid, m-chloroperoxybenzoic acid, with Des Martin oxidizing agent being preferred. Intermediate II-5 and different R 1 The substituted phenylhydrazine hydrochloride was synthesized by Fischer indole under acidic conditions to give intermediate II-6; the acid used was selected from acetic acid, phosphoric acid, sulfuric acid, and hydrochloric acid, with acetic acid being preferred; Intermediate II-6 was deprotected and epoxidized with a pentyl lactone to prepare compound (II); the deprotecting agent used was selected from pyridine hydrogen fluoride, tetrabutylammonium fluoride, trifluoroacetic acid, preferably pyridine hydrogen fluoride; the oxidizing agent used was selected from alumina, Des Martin oxidant, 2-iodobenzoic acid, preferably alumina; Synthesis Route 2: Intermediate II-5 was brominated to give intermediate III-1; the brominating reagents used were pyridinium tribromide and bromine water. N - Bromosuccinimide, preferably pyridinium tribromide; Intermediate III-1 reacts with thiourea via cyclization and deprotection to yield aminothiazole intermediate III-2; the solvents used in the cyclization reaction are selected from ethanol, n-butanol, and acetonitrile. N , N - Dimethylformamide, preferably ethanol; the deprotecting agent used is selected from pyridine hydrogen fluoride, tetrabutylammonium fluoride, trifluoroacetic acid, preferably pyridine hydrogen fluoride; Intermediate III-2 was prepared by epoxidation of a five-membered lactone to obtain compound (III); the oxidant used was selected from alumina, Des Martin oxidant, 2-iodobenzoic acid, peracetic acid, and preferably alumina. Intermediate III-2 was prepared into compound (IV) by rearrangement addition reaction under acidic conditions; the acid used was selected from hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, hydrobromic acid, with hydrochloric acid being preferred; Synthesis Route 3: Brominated intermediate III-1 reacts with o-phenylenediamine via an elimination cyclization reaction to yield quinoxaline intermediate IV-1; the solvent used in the cyclization reaction is selected from... N , N -Dimethylformamide, n-butanol, acetonitrile, preferred N , N -Dimethylformamide; Intermediate IV-1 was deprotected and epoxidized with a pentyl lactone to prepare compound (IV); the deprotecting agent used was selected from pyridine hydrogen fluoride, trifluoroacetic acid, tetrabutylammonium fluoride, preferably pyridine hydrogen fluoride; the oxidizing agent used was selected from alumina, Des Martin oxidant, 2-iodobenzoic acid, preferably alumina; Synthesis Route 4: Intermediate II-2 reacts with tert-butyldiphenylchlorosilane under alkaline conditions via a nucleophilic substitution reaction followed by acid hydrolysis to yield intermediate V-1; the base used is selected from imidazole. N , N -Diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, potassium carbonate, preferably imidazole; the acid used is selected from acetic acid, hydrobromic acid, hydrochloric acid, preferably acetic acid; Intermediate V-1 was subjected to nucleophilic substitution of tert-butyldiphenylchlorosilane and oxidation with a secondary alcohol to obtain intermediate V-2; the oxidant used was selected from Dys-Martin oxidant, 2-iodobenzoic acid, peracetic acid, manganese dioxide, with Dys-Martin oxidant being preferred; Intermediate V-2 reacts with aminourea hydrochloride via an addition-elimination reaction to yield intermediate V-3; the reaction solvents used are selected from ethanol, n-butanol, tert-butanol, and acetonitrile. N , N -Dimethylformamide, preferably ethanol; Intermediate V-3 was deprotected and epoxidized with a pentyl lactone to prepare compound (V); the deprotecting agent used was selected from pyridine hydrogen fluoride, trifluoroacetic acid, tetrabutylammonium fluoride, preferably pyridine hydrogen fluoride; the oxidizing agent used was selected from alumina, Des Martin oxidant, 2-iodobenzoic acid, preferably alumina; Synthesis Route 5: Intermediate V-3 is reacted with a thiodiazole reagent via an elimination cyclization reaction to yield 1,2,3-thiadiazole intermediate VII-1; the thiodiazole reagent includes thionyl chloride, phenyl thiochloroformate, elemental sulfur, preferably thionyl chloride. Intermediate VII-1 was deprotected and epoxidized with a pentyl lactone to obtain intermediate VII-2; the deprotecting agent used was selected from pyridine hydrogen fluoride, trifluoroacetic acid, tetrabutylammonium fluoride, preferably pyridine hydrogen fluoride; the oxidizing agent used was selected from alumina, Des Martin oxidant, 2-iodobenzoic acid, preferably alumina; Intermediate VII-2 was esterified with different alkyl acids in the presence of a coupling agent to prepare compound (VII); the coupling agent used was selected from 2-(7-azabenzotriazole)- N , N , N' , N' -Tetramethylurea hexafluorophosphate (HATU), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), preferably EDCI; Intermediate VII-2 undergoes an oxidation reaction under the action of an oxidizing agent to give aldehyde intermediate VII-3; the oxidizing agent used is selected from 2,2,6,6-tetramethylpiperidine oxide, pyridinium chlorochromate, Jones reagent, Des Martin oxidizing agent, preferably 2,2,6,6-tetramethylpiperidine oxide; Intermediate VII-3 is further oxidized under the action of an oxidant to obtain carboxylic acid intermediate VII-4; the oxidant used is selected from sodium hypochlorite, potassium permanganate, and m-chloroperoxybenzoic acid, with sodium hypochlorite being preferred; The intermediate VII-4 was reacted with different aliphatic or aromatic amines via amide condensation to prepare compounds of formula (VII); the reaction solvents used were selected from tetrahydrofuran, dichloromethane, acetonitrile, ethyl acetate, chloroform, acetone, and preferably tetrahydrofuran; The definitions of each group in the above synthetic route are the same as those in claim 1.

6. A pharmaceutical composition comprising a diterpenoid natural product derivative of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, polymorph, isotope label, metabolite, enantiomer, diastereomer or tautomer thereof, and at least one pharmaceutically acceptable carrier, excipient, stabilizer, excipient, solubilizer, diluent or sustained-release material.

7. A pharmaceutical formulation comprising a diterpenoid natural product derivative of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, polymorph, isotope label, metabolite, enantiomer, diastereomer, or tautomer thereof, or a pharmaceutical dosage form of a pharmaceutical composition according to claim 6, characterized in that, It is selected from at least one of the following: tablets, capsules, granules, powders, pills, drop pills, oral solutions, oral suspensions, syrups, injections, powder for injection, large-volume infusions, lyophilized powder for injection, aerosols, sprays, inhalers, powder mists, gels, ointments, creams, patches, transdermal patches, lotions, liniments, suppositories, films, sublingual tablets, orally disintegrating tablets, emulsions, nanoformulations, liposome formulations, sustained-release formulations, or controlled-release formulations.

8. A diterpenoid natural product derivative of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, metabolite, polymorph, or isotope label thereof, Use of the pharmaceutical composition according to claim 6 or the pharmaceutical formulation according to claim 7 in the preparation of a medicament for treating neuroinflammatory-related neurological diseases; wherein the neuroinflammatory-related neurological diseases include high-altitude cerebral edema, high-altitude brain injury, hypoxic-ischemic encephalopathy of newborns, ischemic / hemorrhagic stroke, traumatic brain injury, Alzheimer's disease, Huntington's disease, Parkinson's disease, delayed encephalopathy after carbon monoxide poisoning, epilepsy, and post-traumatic stress disorder.

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