Oridonin derivatives, preparation method thereof, pharmaceutical composition and application thereof

Abstract

The application discloses oripramine derivatives, a preparation method and pharmaceutical compositions and application thereof, wherein the oripramine derivative is a compound with the shown structure or a medicinal salt thereof, wherein R is selected from any one of hydrogen, deuterium and substituted or unsubstituted alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl. Experiments prove that the oripramine derivative has higher anti-inflammatory activity and lower toxicity compared with existing oripramine, can be applied as an active ingredient in the preparation of an anti-inflammatory disease, a nervous system disease or an antitumor drug, provides a new thought and method for preparing a novel oripramine derivative drug with better curative effect and lower toxicity, and has a wide application prospect.

Description

TECHNICAL FIELD

[0001] The present application relates to a derivative of oridonin, a preparation method thereof, a pharmaceutical composition and application thereof, and belongs to the technical field of production and application of medical products. BACKGROUND

[0002] Oridonin (English name: Oridonin, for short: Ori) is a type of kopsanoid tetracyclic diterpenoid compound extracted from Rabdosia rubescens (Hsuan Kuo) Hara, and its chemical formula is C 20 H 28 O6, the molecular weight is 364.44, the CAS registration number is 28957-04-2, and has the following chemical structure:

[0003]

[0004] Studies have shown that oridonin has moderate anti-inflammatory activity, and can inhibit the release of pro-inflammatory cytokines such as TNF-α and interleukin IL-6 by inhibiting NF-κB or activating MAPK. Further studies have shown that Ori can target inflammasome NLRP3 to exert its anti-inflammatory activity, and Ori can covalently bind to the Cys279 residue of the NLRP3 protein, block the NLRP3-NEK7 interaction and subsequent inflammasome assembly and activation of NLRP3, thereby effectively treating NLRP3-related diseases. Therefore, it is of great significance to synthesize oridonin derivatives, study their structure-activity relationship, and find oridonin derivatives with high efficiency and low toxicity.

[0005] Although oridonin has mild anti-inflammatory activity, its toxicity is relatively large and the therapeutic index is relatively narrow.

[0006] At present, the research on the structure modification of the anti-inflammatory activity of oridonin is relatively less, mainly focusing on the anti-cancer aspect. Although there have been studies such as introducing a carbamate structure on the C-14 hydroxyl group of oridonin, which can effectively improve the physicochemical properties of oridonin and improve its anti-inflammatory activity (European Journal of Medicinal Chemistry, 2023, 245, 114919), but overall, the research on the structure modification of the anti-inflammatory activity of oridonin is not deep enough, therefore, it is necessary to further modify the structure on the basis of the existing to enhance the activity of the compound, reduce the toxicity, and find new anti-inflammatory drugs from it. SUMMARY

[0007] Based on the above purpose, the present application first provides a new oridonin derivative which not only has excellent anti-inflammatory activity but also has relatively low toxicity and a preparation method thereof, and further provides a pharmaceutical composition of the oridonin derivative and its application in anti-inflammatory drugs on this basis.

[0008] A oribellulone derivative is a compound having a structure shown in formula (I) or (II) or a pharmaceutically acceptable salt thereof:

[0009]

[0010] wherein:

[0011] R is selected from any one of hydrogen, deuterium, and substituted or unsubstituted alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or heterocyclylalkyl.

[0012] Further:

[0013] The alkyl refers to a saturated straight chain or branched chain monovalent hydrocarbon radical of one to twelve carbon atoms, and the hydrogen atoms in the alkyl group can also be optionally substituted with one or more groups including methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl independently;

[0014] The alkenyl refers to a straight chain or branched chain monovalent hydrocarbon radical of two to twelve carbon atoms having at least one site of unsaturation, i.e., a carbon-carbon sp 2 The alkenyl refers to a straight chain or branched chain monovalent hydrocarbon radical of two to twelve carbon atoms having at least one site of unsaturation, i.e., a carbon-carbon sp

[0015] The cycloalkyl group refers to a monovalent non-aromatic saturated or group-saturated cyclic hydrocarbon radical having three to ten carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cycloundecyl, and also polycyclic cycloalkyl structures of bicyclic and tricyclic rings, wherein the polycyclic cycloalkyl structures also include saturated or group-unsaturated cycloalkyl or heterocyclyl or aryl or heteroaryl rings fused to the saturated or group-unsaturated cycloalkyl, and the bicyclic carbocyclic rings having 7 to 12 atoms can be arranged as [4,5], [5,5], [5,6] or [6,6] bicyclic systems, and also as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane bridging systems;

[0016] The heteroalkyl group, which includes alkoxy and heteroalkoxy, refers to a saturated straight-chain or branched-chain monovalent hydrocarbon radical having one to twelve carbon atoms, and wherein at least one carbon atom is replaced by any one atom selected from nitrogen, oxygen or sulfur, which nitrogen, oxygen or sulfur atom can occur in the middle or at the end of the heteroalkyl group to form a carbon radical or a heteroatom radical, and the hydrogen atoms in the heteroalkyl group can also be optionally independently substituted by one or more substituents;

[0017] The heteroalkenyl group refers to a straight-chain or branched-chain monovalent hydrocarbon radical having at least one double bond and two to twelve carbon atoms, including ethenyl and propenyl, and wherein at least one carbon atom is replaced by any one atom selected from nitrogen, oxygen or sulfur, and which nitrogen, oxygen or sulfur atom can occur in the middle or at the end of the heteroalkenyl group to form a carbon radical or a heteroatom radical, and the hydrogen atoms in the heteroalkenyl group can also be optionally independently substituted by one or more substituents including radicals having "cis" and "trans" or "E" and "Z" orientation;

[0018] The heteroalkynyl group refers to a straight-chain or branched-chain monovalent hydrocarbon radical having at least one triple bond and two to twelve carbon atoms, including ethynyl and propynyl, and wherein at least one carbon atom is replaced by any one atom selected from nitrogen, oxygen or sulfur, and which nitrogen, oxygen or sulfur atom can occur in the middle or at the end of the heteroalkynyl group to form a carbon radical or a heteroatom radical, and the hydrogen atoms in the heteroalkynyl group can also be optionally independently substituted by one or more substituents;

[0019] The heterocyclic group, often simply referred to as a heterocycle, includes heterocyclic alkoxy groups, which are saturated or unsaturated carbocyclic groups having 3 to 8 ring atoms, as well as groups fused with saturated, unsaturated, or fully unsaturated (i.e., aromatic) carbocyclic or heterocyclic groups. At least one ring atom is independently selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon atoms. Hydrogen atoms on one or more ring atoms may optionally be independently substituted by one or more substituents. The nitrogen, oxygen, or sulfur atoms may be... The groups appearing in the middle or at the end of the heterocyclic group that constitute a carbon group or heteroatom group include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, 4-thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, azacyclic butyl, oxacyclic butyl, thiocyclic butyl, homopiperidinyl, oxacyclic heptyl, thiepanyl, and oxacyclic heptyl. oxazepinyl (English: oxazepinyl), diazapyridine Basic, sulfur-nitrogen Thiazepinyl (English: thiazepinyl), 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxacyclopentyl, pyrazolinyl, dithiohexyl, dihydropyranyl, dihydrothiophenyl, dihydrofuranyl, pyrazolylalkyl, imidazolinyl, imidazolinyl, 3-azabicyclo[3.1.0]hexane, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolyl, quinazinyl or N-pyridylurea;

[0020] The heterocyclic group further includes a spirocyclic group, and the heterocyclic group can be C-linked or N-linked, including a C-linked pyrrolo-3-yl or an N-linked pyrrolo-1-yl, and an imidazole-1-yl or a C-linked imidazole-3-yl group derived from imidazole and linked via N-linking, including dihydroisoindole-1,3-diketone and 1,1-dioxothiomorpholino; and

[0021] The heterocyclic group may also be substituted at one or more substituted positions by a variety of substituents independently;

[0022] The aryl group refers to an optionally substituted monocyclic or polycyclic group or ring system containing at least one aromatic hydrocarbon ring, including phenyl, naphthyl, fluorenyl, azulel, anthraceneyl, phenanthryl, pyrene, biphenyl, or biphenylene.

[0023] The heteroaryl group refers to a substituted or unsubstituted monocyclic or polycyclic group or ring system containing at least one aromatic ring having one or more atoms independently selected from nitrogen, oxygen, or sulfur, wherein a monocyclic heteroaryl group includes furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, or triazolyl, a bicyclic heteroaryl group includes benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridinyl, imidazopyridinyl, imidazothiazolyl, indolizynyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridinyl, pyrrolopyridinyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidinyl, or thienopyridinyl, and a tricyclic heteroaryl group includes acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, phenarsenyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, or xanthenyl;

[0024] The arylalkyl group refers to an alkyl group substituted with an aryl group, wherein aryl-C 1-3 -alkyl includes benzyl, phenylethyl;

[0025] The heteroarylalkyl group refers to an alkyl group substituted with a heteroaryl group, wherein a five- or six-membered heteroaryl-C 1-3 -alkyl includes oxazolylmethyl, pyridylethyl;

[0026] The heterocyclylalkyl group refers to an alkyl group substituted with a heterocyclyl group, wherein a five- or six-membered heterocyclyl-C 1-3 -alkyl includes tetrahydropyranylmethyl;

[0027] The cycloalkylalkyl group refers to an alkyl group substituted with a cycloalkyl group, wherein a five- or six-membered cycloalkyl-C 1-3 -alkyl includes cyclopropylmethyl;

[0028] The substituted alkyl group refers to an alkyl group in which one or more hydrogen atoms are each independently replaced with a D substituent, wherein the D substituent includes F, Cl, Br, I, CN, CF3, OR1, R1, =O, =S, =NR1, =N + (O)(R1), =N + (O)(OR1), =N-NR1R2, -C(=O)R1, -C(=O)OR1, -C(=O)NR1R2, -NR1R2, -N +R1R2R3, -N(R1)C(=O)R2, -N(R1)C(=O)OR2, -N(R1)C(=O)NR2R3, -SR1, -OC(=O)R1, -OC(=O)OR1, -OC(=O)NR1R3, -OS(O)2OR1, -OP(=O)(OR1)2, -OP(OR1)2, -P(=O)(OR1)2, -P(=O)(OR)NR2R3, -S(O)R1, -S(O)2R1, -S(O)2NR1, -S(O)(OR1), -S(O)2(OR1), -SC(=O)R1, -SC(=O)OR1, =O, -SC(=O)NR2R3, alkenyl, alkynyl, allyl, cycloalkyl, heteroalkyl, heterocyclyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl, heteroaryl, and heteroaryl substituted with D substituents, wherein:

[0029] R1, R2, and R3 are each independently selected from the group consisting of hydrogen, deuterium, alkyl, alkenyl, alkynyl, aryl, and heterocyclyl, and each R1, R2, and R3 can also be independently substituted with any one element or group selected from the group consisting of hydrogen, deuterium, alkyl, alkenyl, alkynyl, aryl, or heterocyclyl.

[0030] Preferably:

[0031] The oripavine derivative having the structure of formula (I) or (II), wherein R is selected from the group consisting of substituted alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or heterocyclylalkyl; and

[0032] The substituted alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or heterocyclylalkyl can also optionally have one or more D1 groups independently selected from the group consisting of:

[0033] The D1 group is alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, CN, CF3, OR1, NR2R3, NR1OR2, NR1CO2R2, SO2NR1R2, SR1, SOR1, SO2R1, S-S-R1, C(=O)R1, OC(=O)R1, C(=O)OR1, C(=O)NR1R2, NR1C(=O)R2, NR1C(=O)NR2R3, OC(=O)NR1R2, or C(=O)CH2OR1, wherein:

[0034] R1, R2, and R3 are each independently selected from the group consisting of hydrogen, deuterium, alkyl, alkenyl, alkynyl, aryl, and heterocyclyl.

[0035] More preferred:

[0036] The oridonin derivative of formula (I) or (II) wherein R is selected from substituted alkyl, alkenyl, heteroalkyl, cycloalkylalkyl, heterocyclylalkyl, or aryl; and

[0037] The alkyl, alkenyl, heteroalkyl, cycloalkylalkyl, heterocyclylalkyl, or aryl group is optionally further substituted with one or more D2groups independently selected from:

[0038] The D2group is F, Cl, Br, I, CN, NH(CH3)2, OH, OCH3, OCH2CH3, SCH3, SCH2CH3, NHBoc, NHC(=O)CH3, NHC(=O)CH2CH3, C(=O)NH2, C(=O)OC(CH3)3, C(=O)OCH2CH3, CH2F, CHF2, or CF3.

[0039] Further preferred:

[0040] The oridonin derivative of formula (I) or (II) wherein R is selected from substituted C1-C8 alkyl, 3-8 membered cycloalkyl C1-C8 alkyl, 3-8 membered heterocyclyl C1-C8 alkyl, 3-8 membered alkyl containing an ether linkage, or 3-8 membered alkyl containing a thioether linkage; and

[0041] The C1-C8 alkyl, C1-C8 alkenyl, 3-8 membered cycloalkyl C1-C8 alkyl, 3-8 membered heterocyclyl C1-C8 alkyl, 3-8 membered alkyl containing an ether linkage, 3-8 membered alkyl containing a thioether linkage, or C6-C12 aryl group is optionally further substituted with one or more D3groups independently selected from:

[0042] The D3group is F, Cl, Br, I, CN, NH(CH3)2, OH, OCH3, OCH2CH3, SCH3, SCH2CH3, NHBoc, NHC(=O)CH3, NHC(=O)CH2CH3, C(=O)NH2, C(=O)OC(CH3)3, C(=O)OCH2CH3, CH2F, CHF2, or CF3.

[0043] Still further preferred:

[0044] The oridonin derivative is a compound having the following structure:

[0045]

[0046]

[0047] Further:

[0048] The pharmaceutically acceptable salt of the compound having the structure of formula (I) or (II) is a salt of the compound having the structure of formula (I) or (II) and a pharmaceutically acceptable inorganic acid or organic acid, wherein:

[0049] The inorganic acid is any one of hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid or sulfuric acid;

[0050] The organic acid is any one of formic acid, acetic acid, propionic acid, succinic acid, 1,5-naphthalene disulfonic acid, aspartic acid, carbenicillin, glycyrrhetinic acid, oleanolic acid, maslinic acid, ursolic acid, colosseum acid, betulinic acid, latic acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethylacetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methylsulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, citric acid or amino acid.

[0051] Further, a preparation method of the oripavine derivative is provided, comprising the following steps:

[0052]

[0053] That is:

[0054] Under the protection of inert gas, compound IV is dissolved in a second solvent and reacted with trifluoroacetic acid to obtain compound III; or;

[0055] Under the protection of inert gas, compound V is dissolved in a third solvent and reacted with Boc-glycine and a photocatalyst to obtain compound IV, and the obtained compound IV is dissolved in a second solvent and reacted with trifluoroacetic acid to obtain compound III;

[0056] Wherein:

[0057] The reaction b and the reaction c are respectively carried out at room temperature, and the reaction c is a photocatalytic reaction, and the photocatalyst is one or more of Ir[diF(Me)ppy]2(dtbpy)PF6, 4-CzIPN, tetraMeO-Acri-N-P or tetraMeO-Acri-N-diMeOPh;

[0058] The second solvent is a mixed solvent composed of dichloromethane and trifluoroacetic acid, and the third solvent is DMF or acetonitrile;

[0059] The molar ratio of the reactants of the reaction b and the reaction c is respectively:

[0060] Compound IV:dichloromethane:trifluoroacetic acid = 1:(1-4):1;

[0061] Compound V: Boc-glycine: photocatalyst: second solvent = 1:1.2:0.1:1.5.

[0062] Further, a medicine composition of the oridonin derivative:

[0063] The medicine composition comprises a therapeutically effective amount of the oridonin derivative according to any one of the above claims 1-8, and one or more of the pharmaceutically acceptable carriers, excipients and adjuvants.

[0064] Optionally,

[0065] The medicine composition is a liquid or solid preparation, including small-volume injection, medium-volume injection, large-volume injection, powder injection, injection emulsion, tablet, pill, capsule, paste, cream, patch, liniment, powder, spray, implant, drop, suppository, ointment and nano-preparation including liposome.

[0066] Further, an application of the oridonin derivative:

[0067] The application is to use a therapeutically effective amount of the above oridonin derivative as an active ingredient in the preparation of anti-inflammatory, inflammatory disease treatment, nervous system disease treatment or antitumor drugs.

[0068] Compared with the prior art, the present application has the following outstanding beneficial effects and significant progress:

[0069] 1) The oridonin derivative provided by the present application has anti-inflammatory activity, and can be used as an active ingredient in the preparation of anti-inflammatory drugs, inflammatory disease treatment, nervous system disease treatment or antitumor drugs, and can be in solid or liquid form when used as a medicine composition in the preparation of anti-inflammatory drugs, inflammatory disease treatment, nervous system disease treatment or antitumor drugs.

[0070] 2) The oridonin derivative, its preparation method and medicine composition provided by the present application provide a new idea and method for preparing new drugs with better efficacy and lower toxicity, have outstanding substantial characteristics and beneficial effects and significant progress, and have a broad application prospect. DETAILED DESCRIPTION

[0071] In order to make the purpose, technical scheme, beneficial effects and significant progress of the embodiments of the present application clearer, below, the technical scheme in the embodiments of the present application will be described clearly and completely in combination with the reaction formula provided in the embodiments of the present application. Obviously, all the described embodiments are only some embodiments of the present application, but not all the embodiments;

[0072] All other embodiments obtained by a person of ordinary skill in the art without creative labor based on the embodiments of the present application shall fall within the scope of the present application.

[0073] It should be noted that the terms "first", "second" and the like in the description of the specification and claims of the present application and in the embodiments of the present application are only used to distinguish different objects, and are not used to describe a specific sequence; in addition, the term "comprising" and any variations thereof are intended to cover non-exclusive inclusion, for example, a process, method, system, product or device including a series of steps or units and the listed steps or units without limitation, and optionally further including steps or units not listed, or optionally further including other operation steps or units inherent to the process, method, product or device.

[0074] It should be understood that in the description of the embodiments of the present application, some basic operation terms commonly used in the art are used, such as "heating", "stirring", "mixing", "dissolving", "washing", "filtering" and "drying", etc., which should be understood in a broad sense, i.e., it can be a conventional operation by using various conventional devices and instruments in the art, or it can be a program-controlled operation, unmanned automatic operation, etc. by using the latest devices, unless otherwise specified. A person of ordinary skill in the art can understand the specific meaning of the above terms in the present application and adopt specific operation methods to achieve the operation purpose according to the specific situation.

[0075] It should also be noted that the following specific embodiments can be combined with each other, and the same or similar concepts or processes may not be described again in some embodiments; in addition, the raw materials and reaction devices, facilities involved in the following specific embodiments are commercially available or prepared according to the prior art.

[0076] In the following, the technical solutions of the present application will be described in detail with specific embodiments.

[0077] Embodiment 1

[0078] The present embodiment provides a oripavine derivative.

[0079] The oripavine derivative is a compound having the structure shown in formula (I) or (II) or a pharmaceutically acceptable salt thereof:

[0080]

[0081] Among them:

[0082] R is selected from any one of hydrogen, deuterium, and substituted or unsubstituted alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or heterocyclylalkyl.

[0083] Further, the present embodiments provide the above orpiment derivatives, wherein:

[0084] The term "alkyl" refers to a saturated straight chain or branched chain monovalent hydrocarbon radical of one to twelve carbon atoms, and the hydrogen atoms in the alkyl group can also be optionally replaced by one or more groups including methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-methyl- 1 -propyl, 2-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl- 1 -butyl, 2-methyl- 1 -butyl, 1 -hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1 -heptyl, 1 -octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl independently;

[0085] The term "alkenyl" refers to a straight chain or branched chain monovalent hydrocarbon radical of two to twelve carbon atoms having at least one site of unsaturation, i.e., a carbon-carbon sp 2 The term "alkenyl" refers to a straight chain or branched chain monovalent hydrocarbon radical of two to twelve carbon atoms having at least one site of unsaturation, i.e., a carbon-carbon sp

[0086] The term "cycloalkyl" refers to a monovalent saturated or group saturated ring hydrocarbon radical of three to ten carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cycloundecyl, cyclododecyl, and also includes bicyclic and tricyclic polycyclic cycloalkyl structures, wherein the polycyclic cycloalkyl structures also include saturated or group unsaturated cycloalkyl or heterocyclyl or aryl or heteroaryl rings fused to the saturated or group unsaturated cycloalkyl, and bicyclic carbocyclic rings of 7 to 12 atoms can be arranged as [4,5], [5,5], [5,6], or [6,6] bicyclic systems, and also as bicyclo[2.2.1]heptane, bicyclo[2.2.2]heptoctane, and bicyclo[3.2.2]nonane bridging systems;

[0087] The term "heteroalkyl" includes alkoxy and heteroalkoxy and refers to saturated straight or branched chain monovalent hydrocarbon radicals of one to twelve carbon atoms wherein at least one carbon atom is replaced by any one of a nitrogen, oxygen, or sulfur atom, which can occur in the middle or at the end of the heteroalkyl group to form a carbon group or a heteroatom group, and wherein the hydrogen atoms in the heteroalkyl group are optionally substituted independently by one or more substituents;

[0088] The term "heteroalkenyl" refers to straight or branched chain monovalent hydrocarbon radicals containing at least one double bond and two to twelve carbon atoms, including vinyl and propenyl, and wherein at least one carbon atom is replaced by any one of a nitrogen, oxygen, or sulfur atom, which can occur in the middle or at the end of the heteroalkenyl group to form a carbon group or a heteroatom group, and wherein the hydrogen atoms in the heteroalkenyl group are optionally substituted independently by one or more substituents including groups having "cis" and "trans" or "E" and "Z" orientation;

[0089] The term "heteroalkynyl" refers to straight or branched chain monovalent hydrocarbon radicals containing at least one triple bond and two to twelve carbon atoms, including ethynyl and propynyl, and wherein at least one carbon atom is replaced by any one of a nitrogen, oxygen, or sulfur atom, which can occur in the middle or at the end of the heteroalkynyl group to form a carbon group or a heteroatom group, and wherein the hydrogen atoms in the heteroalkynyl group are optionally substituted independently by one or more substituents;

[0090] The term "heterocyclyl" which can be referred to as heterocycle, including heterocycloalkoxy, refers to saturated or group unsaturated carbocyclic radicals having 3 to 8 ring atoms, and including radicals fused to saturated, group unsaturated, or completely unsaturated, i.e., aromatic, carbocyclic or heterocyclic rings, and wherein at least one ring atom is any one of a nitrogen, oxygen, or sulfur atom, independently selected, and the remaining ring atoms are carbon atoms, and wherein the hydrogen atoms on one or more of the ring atoms are optionally substituted independently by one or more substituents, and the nitrogen, oxygen, or sulfur atom can occur in the middle or at the end of the heterocyclyl group to form a carbon group or a heteroatom group, including pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, 4-thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, and the like, and wherein the hydrogen atoms in the heterocyclyl group are optionally substituted independently by one or more substituents; ​​thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolizinyl, quinolizinyl, or N-pyridinylurea;

[0091] The term "heterocyclyl" also includes spirocyclic groups and the heterocyclyl group can be C-attached or N-attached, including C-attached pyrrol-3-yl or N-attached pyrrol-1-yl, as well as the group imidazol-1-yl derived from imidazole and attached through N or imidazol-3-yl attached through C, including dihydroisoindol-1,3-dionyl and 1,1-dioxidothiomorpholinyl; and

[0092] The term "heterocyclyl" can also be independently substituted at one or more of its substitution positions with a variety of substituents;

[0093] The term "aryl" refers to an optionally substituted monocyclic or polycyclic group or ring system containing at least one aromatic hydrocarbon ring, including phenyl, naphthyl, fluorenyl, azulenyl, anthracenyl, phenanthrenyl, pyrenyl, biphenyl, or terphenyl;

[0094] The term "heteroaryl" refers to an optionally substituted monocyclic or polycyclic group or ring system containing at least one aromatic ring having one or more of any one of the atoms independently selected from nitrogen, oxygen, or sulfur, including substituted monocyclic heteroaryl groups such as furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, or triazolyl, bicyclic heteroaryl groups such as benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridinyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridinyl, pyrrolopyridinyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidinyl, or thienopyridinyl, and tricyclic heteroaryl groups such as acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, phenarsenyl, phenazinyl, phenothiazinyl, phenoxazinyl, phenothiazinyl, or xanthenyl;

[0095] The term "arylalkyl" refers to an alkyl group substituted with one or more aryl groups, where aryl-C 1-3 -alkyl includes benzyl, phenylethyl;

[0096] The term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the five- or six-membered heteroaryl-C 1-3 -alkyl includes oxazolylmethyl, pyridylethyl;

[0097] The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl group, wherein the five- or six-membered heteroaryl-C 1-3 -alkyl includes tetrahydropyranylmethyl;

[0098] The term "cycloalkylalkyl" refers to an alkyl group substituted with a cycloalkyl group, wherein the five- or six-membered cycloalkyl-C 1-3 -alkyl includes cyclopropylmethyl;

[0099] The term "substituted alkyl" refers to an alkyl group wherein one or more hydrogen atoms are each independently replaced with a D substituent, which includes:

[0100] F, Cl, Br, I, CN, CF3, OR1, R1, =O, =S, =NR1, =N + (O)(R1), =N(OR1), =N + (O)(OR1),

[0101] =N-NR1R2, -C(=O)R1, -C(=O)OR1, -C(=O)NR1R2, -NR1R2, -N + R1R2R3, -N(R1)C(=O)R2, -N(R1)C(=O)OR2, -N(R1)C(=O)NR2R3, -SR1, -OC(=O)R1, -OC(=O)OR1, -OC(=O)NR1R3, -OS(O)2OR1, -OP(=O)(OR1)2, -OP(OR1)2, -P(=O)(OR1)2, -P(=O)(OR)NR2R3, -S(O)R1, -S(O)2R1, -S(O)2NR1, -S(O)(OR1), -S(O)2(OR1), -SC(=O)R1, -SC(=O)OR1, =O, -SC(=O)NR2R3, alkenyl, alkynyl, allyl, cycloalkyl, heteroalkyl, heterocyclyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl, heteroaryl, and heteroaryl similarly substituted with D substituents, wherein:

[0102] R1, R2, and R3are each independently selected from the group consisting of hydrogen, deuterium, alkyl, alkenyl, alkynyl, aryl, and heterocyclyl, and each R1, R2, and R3may also be independently substituted with any one element or group selected from the group consisting of hydrogen, deuterium, alkyl, alkenyl, alkynyl, aryl, or heterocyclyl.

[0103] Preferably, R is selected from substituted alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or heterocyclylalkyl; and

[0104] substituted alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or heterocyclylalkyl which hydrogen atoms are optionally further substituted by one or more D1groups independently selected from:

[0105] D1groups are alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, CN, CF3, OR1, NR2R3, NR1OR2, NR1CO2R2, SO2NR1R2, SR1, SOR1, SO2R1, S-S-R1, C(=O)R1, OC(=O)R1, C(=O)OR1, C(=O)NR1R2, NR1C(=O)R2, NR1C(=O)NR2R3, OC(=O)NR1R2, or C(=O)CH2OR1, wherein:

[0106] R1, R2, and R3are each independently selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, aryl, and heterocyclyl.

[0107] More preferably, R is selected from substituted alkyl, alkenyl, heteroalkyl, cycloalkylalkyl, heterocyclylalkyl, or aryl; and

[0108] alkyl, alkenyl, heteroalkyl, cycloalkylalkyl, heterocyclylalkyl, or aryl which hydrogen atoms are optionally further substituted by one or more D2groups independently selected from:

[0109] D2groups are F, Cl, Br, I, CN, NH(CH3)2, OH, OCH3, OCH2CH3, SCH3, SCH2CH3, NHBoc, NHC(=O)CH3, NHC(=O)CH2CH3, C(=O)NH2, C(=O)OC(CH3)3, C(=O)OCH2CH3, CH2F, CHF2, or CF.

[0110] Further preferred:

[0111] R is selected from substituted C1-C8 alkyl, 3-8 membered cycloalkyl C1-C8 alkyl, 3-8 membered heterocyclyl C1-C8 alkyl, ether-containing 3-8 membered alkyl, or thioether-containing 3-8 membered alkyl; and

[0112] C1-C8alkyl, C1-C8alkenyl, 3- to 8-membered cycloalkyl C1-C8alkyl, 3- to 8-membered heterocyclyl C1-C8alkyl, ether-containing 3- to 8-membered alkyl, thioether-containing 3- to 8-membered alkyl, or C6-C12aryl, the hydrogen atoms of which can optionally be substituted with one or more D3groups independently selected from:

[0113] D3groups are F, Cl, Br, I, CN, NH(CH3)2, OH, OCH3, OCH2CH3, SCH3, SCH2CH3, NHBoc, NHC(=O)CH3, NHC(=O)CH2CH3, C(=O)NH2, C(=O)OC(CH3)3, C(=O)OCH2CH3, CH2F, CHF2, or CF3.

[0114] Further preferred are:

[0115] The oripavine derivative provided by the present embodiment is a compound having the structure shown below or a pharmaceutically acceptable salt thereof:

[0116]

[0117]

[0118] Optionally:

[0119] The pharmaceutically acceptable salt of the compound having the structure shown in formula (I) or (II) is a salt of the compound having the structure shown in formula (I) or (II) and a pharmaceutically acceptable inorganic acid or organic acid, wherein:

[0120] The inorganic acid is any one of hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, or sulfuric acid;

[0121] The organic acid is any one of formic acid, acetic acid, propionic acid, succinic acid, 1,5-naphthalene disulfonic acid, aspartic acid, carpic acid, glycyrrhetinic acid, oleanolic acid, maslinic acid, ursolic acid, corosolic acid, betulinic acid, latic acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethylacetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, citric acid, or an amino acid.

[0122] Embodiment 2

[0123] The present embodiment provides a preparation method of the compound having the structure shown in formula (I) or (II) described in the above embodiment 1.

[0124]

[0125] i.e. under inert gas protection, reacting in a solvent at a molar ratio of compound III: sulfuryl isocyanate compound, i.e. RSO2NCO: basic catalyst = 1:1:(1-3) to obtain compound I; or

[0126] under inert gas protection, reacting in a second solvent at a molar ratio of compound III: sulfuryl chloride compound, i.e. RSO2Cl: basic catalyst = 1:1:(1-3) to obtain compound II;

[0127] wherein:

[0128] R in the sulfuryl isocyanate compound is a benzene ring, a substituted benzene ring or an aromatic heterocycle;

[0129] the sulfuryl chloride compound RSO2Cl is selected from benzene sulfonyl chloride, 4-cyanobenzene sulfonyl chloride, thiophene sulfonyl chloride, 1-methyl-1-pyrazole sulfonyl chloride, 3-pyridine sulfonyl chloride, 5-dimethylamino naphthalene sulfonyl chloride, 4-methoxy sulfonyl chloride, 4-trifluoromethyl sulfonyl chloride, trans-β-styrene sulfonyl chloride or 4-fluorobenzene sulfonyl chloride;

[0130] the basic catalyst is a nitrogen-containing compound, including any one or more of 4-dimethylamino pyridine, triethylamine or pyridine;

[0131] the solvent is any one or more of dichloromethane, DMF, toluene, tetrahydrofuran;

[0132] reaction a1 or reaction a2 is respectively carried out at room temperature, and in the reaction, compound III is first dissolved in a solvent, and then the basic catalyst and the sulfuryl isocyanate compound or the sulfuryl chloride compound are respectively added to carry out the reaction.

[0133] Further, the above compound III can be prepared by steps b or c-b:

[0134]

[0135] i.e.:

[0136] under inert gas protection, dissolving compound IV in a second solvent and reacting with trifluoroacetic acid to obtain compound III; or;

[0137] under inert gas protection, dissolving compound V in a third solvent and reacting with Boc-glycine and a photocatalyst to obtain compound IV, and then dissolving the obtained compound IV in a second solvent and reacting with trifluoroacetic acid to obtain compound III;

[0138] wherein:

[0139] Reaction b and reaction c are carried out at room temperature respectively, and reaction c is a photocatalytic reaction, and the photocatalyst thereof is one or more of Ir[diF(Me)ppy]2(dtbpy)PF6, 4-CzIPN, tetraMeO-Acri-N-P or tetraMeO-Acri-N-diMeOPh;

[0140] The second solvent is a mixed solvent of dichloromethane and trifluoroacetic acid, and the third solvent is DMF or acetonitrile;

[0141] The molar ratio of the reactants of reaction b and reaction c is respectively:

[0142] Compound IV:dichloromethane:trifluoroacetic acid = 1:(1-4):1;

[0143] Compound V:Boc-glycine:photocatalyst:second solvent = 1:1.2:0.1:1.5.

[0144] To further help understand the technical solutions provided by the present embodiment and the specific operation process and effects that can be obtained by the present embodiment, the following will further illustrate the preparation method and detection results provided by the present embodiment through specific examples.

[0145] Of course, those skilled in the art should understand that the examples specifically described below are only illustrative and not limiting, and should not limit the scope of protection claimed by the present application.

[0146] Example 1, preparation of compound Ia

[0147] 1.1) Preparation of intermediate compound IV

[0148] Reaction formula:

[0149]

[0150] Reaction process:

[0151] Oridonin (compound V) (473 mg, 1.20 mmol), N-Boc-glycine (252 mg, 1.44 mmol) and photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6(14 mg, 0.012 mmol) and DMF (6 mL) were added to a 10 mL glass bottle, then potassium phosphate dibasic (251 mg, 1.44 mmol) was added, the glass bottle was sealed, and the reaction was carried out at room temperature under the protection of nitrogen and under the irradiation of blue light LED lamp strip for 36 hours. After the reaction was completed, 10 mL of water was added, and ethyl acetate was extracted three times (10 mL x 3), the organic phase was combined, washed with water (10 mL), dried over anhydrous Na2SO4, and the solvent was evaporated under reduced pressure. Column chromatography purification gave 507 mg of yellow solid IV with a yield of 85%.

[0152] Detection results:

[0153] 1 H NMR (600 MHz, DMSO-d6) δ: 6.87 (t, J = 5.5 Hz, 1H), 6.78 (s, 1H), 6.08 (d, J = 2.1 Hz, 1H), 5.71 (d, J = 10.9 Hz, 1H), 4.80 (s, 1H), 4.35 (d, J = 5.0 Hz, 1H), 4.10 (d, J = 5.0 Hz, 1H), 4.07 (d, J = 10.1 Hz, 1H), 3.83 (d, J = 10.4 Hz, 1H), 3.42 (dd, J = 10.9, 6.2 Hz, 1H), 3.32 (dd, J = 11.0, 5.5 Hz, 1H), 2.97-2.93 (m, 1H), 2.82 (dd, J = 14.8, 6.8 Hz, 1H), 2.42 (t, J = 8.6 Hz, 1H), 2.00 (dt, J = 12.7, 9.3 Hz, 1H), 1.92-1.85 (m, 1H), 1.84-1.75 (m, 1H), 1.67-1.57 (m, 1H), 1.54-1.41 (m, 5H), 1.38 (s, 9H), 1.32 (d, J = 13.3 Hz, 1H), 1.24-1.16 (m, 1H), 1.09 (d, J = 6.2 Hz, 1H), 1.00 (s, 3H), 0.97 (s, 3H);

[0154] HRMS (ESI): m / z [M+H] + calculated for C 26 H 41 NO8: 518.2730; found: 518.2724.

[0155] 1.2) Preparation of intermediate compound III

[0156] Reaction scheme:

[0157]

[0158] Preparation process:

[0159] Compound IV (149 mg, 0.2 mmol) was added to a 25 mL single-neck flask, 2 mL of dichloromethane was added, then trifluoroacetic acid (1.5 mL, 19.5 mmol) was added, and the reaction was carried out at room temperature for 1.5 hours. After the reaction was completed, the solvent was removed under reduced pressure to obtain 122 mg of yellow crystalline compound III with a yield of 79.8%.

[0160] Detection results:

[0161] 1 H NMR (600 MHz, D20) δ 4.99 (d, J = 1.5 Hz, 1H), 4.16 (d, J = 10.2 Hz, 1H), 4.03 (d, J = 10.2 Hz, 1H), 3.57 (t, J = 7.3 Hz, 1H), 3.48-3.45 (m, 1H), 3.09-2.95 (m, 3H), 2.55 (t, J = 8.1 Hz, 1H), 2.05-1.95 (m, 3H), 1.87-1.84 (m, 1H), 1.74-1.69 (m, 1H), 1.63-1.56 (m, 1H), 1.56-1.47 (m, 1H), 1.47-1.35 (m, 3H), 1.27-1.25 (m, 1H), 1.22-1.18 (m, 1H), 1.00 (s, 3H), 0.93 (s, 3H).

[0162] 1.3) Preparation of compound la

[0163] Reaction scheme:

[0164]

[0165] Preparation process:

[0166] Into a 10 mL single necked flask, compound III (51 mg, 0.1 mmol), 2 mL of dichloromethane and triethylamine 25.9 uL (20 mg, 0.2 mmol) were added respectively, cooled to 0 °C, p-toluenesulfonyl isocyanate (19.7 mg, 0.1 mmol) was added slowly, slowly raised to room temperature, reacted overnight; after the reaction was completed, 5 mL of water was added, dichloromethane was extracted (5 mL x 3), and the organic phase was combined. The organic phase was washed with water (10 mL), dried over anhydrous Na2S04, and the solvent was evaporated under reduced pressure and purified by column chromatography to obtain 30 mg of white solid la with a yield of 25.9%.

[0167] Test results:

[0168] 1H NMR (600 MHz, DMSO) δ 10.59 (s, 1H), 7.77 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 6.77 (s, 1H), 6.57 (s, 1H), 6.07 (d, J = 2.2 Hz, 1H), 5.66 (d, J = 10.9 Hz, 1H), 4.77 (s, 1H), 4.34 (d, J = 5.0 Hz, 1H), 4.05 (d, J = 10.2 Hz, 1H), 3.82 (d, J = 10.8 Hz, 1H), 3.41 (dd, J = 11.0, 6.2 Hz, 1H), 3.29 (dd, J = 10.8, 5.2 Hz, 1H), 2.98 (dd, J = 13.3, 7.0 Hz, 2H), 2.73 (s, 1H), 2.39 (s, 3H), 2.36 - 2.32 (m, 1H), 1.96 (dd, J = 13.5, 7.9 Hz, 1H), 1.80 (dd, J = 19.6, 10.1 Hz, 1H), 1.72 (dd, J = 13.5, 6.5 Hz, 1H), 1.58 (dd, J = 13.2, 6.2 Hz, 1H), 1.53 - 1.37 (m, 4H), 1.33 (d, J = 11.9 Hz, 2H), 1.18 (dd, J = 15.2, 12.0 Hz, 1H), 1.06 (d, J = 5.0 Hz, 1H), 0.99 (s, 3H), 0.96 (s, 3H);

[0169] 13 C NMR (151 MHz, DMSO) δ 224.71, 129.23, 128.93, 128.51, 127.12, 97.02, 73.66, 73.52, 71.92, 63.23, 61.67, 60.54, 52.97, 48.52, 45.88, 40.58, 38.83, 38.14, 36.92, 33.80, 32.97, 29.73, 26.34, 21.91, 21.38, 19.62, 18.71;

[0170] HRMS (ESI): m / z [M + Na] calculated for C + calculated for C 29 H 40 N2O9S: 615.2353; found: 615.2347.

[0171] Example 2, Preparation of Compound Ib

[0172] Structure:

[0173]

[0174] Preparation process:

[0175] Following the preparation method of compound Ia in Example 1, p-toluenesulfonyl isocyanate was replaced with benzenesulfonyl isocyanate to obtain white solid compound Ib in yield of 17.3%.

[0176] Test results:

[0177] 1 H NMR (600MHz, DMSO) δ10.66 (s, 1H), 7.91-7.86 (m, 2H), 7.66 (t, J=7.3Hz, 1H), 7 .59(t, J=7.7Hz, 2H), 6.77(s, 1H), 6.56(s, 1H), 6.06(d, J=1.8Hz, 1H), 5.66(d, J=10.9Hz, 1H), 4.77 (s, 1H), 4.33 (d, J=5.0Hz, 1H), 4.05 (d, J=10.2Hz, 1H), 3.8 2 (dd, J=10.2, 1.3Hz, 1H), 3.41 (dd, J=11.0, 6.2Hz, 1H), 3.30-3.27 (m, 1H), 2.9 8(dd, J=13.2, 6.6Hz, 2H), 2.74 (dd, J=15.1, 6.5Hz, 1H), 2.35 (t, J=8.7Hz, 1H), 1.95 (td, J=13.2, 7.6Hz, 1H), 1.87-1.78 (m, 1H), 1.74 (td, J=13.3, 7.4Hz, 1H), 1.58 (dd, J=12.7, 6.2Hz, 1H), 1.52-1.33 (m, 5H), 1.30 (dd, J=10.1, 3.3Hz, 1H), 1.18 (td, J=13.6, 3.2Hz, 1H), 1.07 (d, J=6.1Hz, 1H), 0.99 (s, 3H), 0.96 (s, 3H);

[0178] 13 C NMR (151MHz, DMSO) δ224.45, 152.19, 141.13, 133.38, 129.40, 127.51, 97.03, 73.62, 73.55, 71.93, 63.24, 61.65, 60.53, 52.94, 49.06, 48.43, 38.84, 38.18, 37.04, 33.80, 32.98, 29.74, 26.01, 21.92, 19.61, 18.70;

[0179] HRMS(ESI): m / z[M+Na] + Calculated for C28 H 38 N2O9S: 601.2196; found: 601.2190.

[0180] Example 3, Preparation of compound Ila

[0181] Reaction scheme:

[0182]

[0183] Preparation procedure:

[0184] Into a 10 ml single necked flask was added compound 3 (51 mg, 0.1 mmol), 2 mL of dichloromethane, triethylamine 25.9 uL (20 mg, 0.2 mmol) respectively. Cooled to 0 °C, trans-β-styrene sulfonyl chloride (18.2 mg, 0.1 mmol) was added slowly. Slowly raised to room temperature, the reaction was left overnight. After the reaction was completed, 5 mL of water was added, dichloromethane extraction (5 mL x 3), the combined organic phase was washed with water (10 mL), dried over anhydrous Na2S04, the solvent was evaporated under reduced pressure and purified by column chromatography to give 30 mg of white solid Ila, yield 26.7%.

[0185] Test results:

[0186] 1 H NMR (600 MHz, DMSO) δ 7.73 - 7.69 (m, 2H), 7.45 - 7.42 (m, 3H), 7.38 - 7.32 (m, 2H), 7.17 (d, J = 15.5 Hz, 1H), 6.76 (s, 1H), 6.10 (d, J = 2.2 Hz, 1H), 5.65 (d, J = 10.9 Hz, 1H), 4.79 (s, 1H), 4.33 (d, J = 5.0 Hz, 1H), 4.04 (d, J = 10.4 Hz, 1H), 3.81 (d, J = 10.4 Hz, 1H), 3.40 (dd, J = 10.9, 6.2 Hz, 1H), 3.27 (dt, J = 10.8, 5.3 Hz, 1H), 2.97 - 2.89 (m, 3H), 2.45 - 2.37 (m, 1H), 2.02 - 1.93 (m, 1H), 1.88 (qd, J = 13.8, 8.2 Hz, 2H), 1.59 - 1.28 (m, 7H), 1.18 (td, J = 10.7, 4.9 Hz, 1H), 1.05 (d, J = 6.2 Hz, 1H), 0.99 (s, 3H), 0.96 (s, 3H);

[0187] 13C NMR (151 MHz, DMSO) δ 224.64, 139.69, 133.34, 130.89, 129.42, 128.87, 127.23, 97.01, 73.60, 73.51, 71.92, 63.23, 61.75, 60.56, 52.98, 48.03, 40.99, 40.57, 38.83, 36.91, 33.80, 32.97, 29.71, 26.46, 21.90, 19.65, 18.71;

[0188] HRMS (ESI): m / z [M + Na] 584.2289; found: 584.2289. + calculated for C 29 H 39 NO8S:584.2294;found:584.2289。

[0189] Example 4, Preparation of compound IIb

[0190] Structure:

[0191]

[0192] Preparation process:

[0193] Referring to the preparation method of compound IIa in Example 3, 4-cyanobenzenesulfonyl chloride is replaced by trans-β-styrenesulfonyl chloride to obtain white solid IIb with a yield of 35.7%.

[0194] Test results:

[0195] 1H NMR (600 MHz, DMSO) δ 8.10 - 8.08 (m, 2H), 8.00 (t, J = 5.8 Hz, 1H), 7.95 (d, J = 8.5 Hz, 2H), 6.67 (s, 1H), 6.39 - 5.89 (m, 1H), 5.65 (s, 1H), 4.78 (s, 1H), 4.25 (s, 1H), 4.05 (d, J = 10.0 Hz, 1H), 3.82 (d, J = 10.2 Hz, 1H), 3.40 (d, J = 6.1 Hz, 1H), 3.30 (dd, J = 11.2, 5.6 Hz, 1H), 2.91 - 2.85 (m, 1H), 2.86 - 2.79 (m, 2H), 2.34 (t, J = 8.6 Hz, 1H), 2.04 - 1.92 (m, 1H), 1.90 - 1.82 (m, 1H), 1.82 - 1.73 (m, 1H), 1.58 (dd, J = 12.6, 6.0 Hz, 1H), 1.54 - 1.37 (m, 4H), 1.33 - 1.23 (m, 2H), 1.18 (dd, J = 15.1, 11.7 Hz, 1H), 1.06 (d, J = 6.0 Hz, 1H), 0.99 (s, 3H), 0.96 (s, 3H);

[0196] 13 C NMR (151 MHz, DMSO) δ 224.49, 145.03, 133.94, 127.71, 118.22, 115.33, 97.00, 73.53, 73.51, 71.93, 63.24, 61.73, 60.58, 52.98, 49.06, 47.90, 41.22, 38.83, 36.88, 33.80, 32.96, 29.71, 26.11, 21.89, 19.62, 18.69;

[0197] HRMS (ESI): m / z [M+H] + calculated for C 28 H 36 N2O8S: 561.2270; found: 561.2265.

[0198] Example 5, Preparation of compound IIc

[0199] Structure:

[0200]

[0201] Preparation process:

[0202] The procedure of Example 3 was followed for the preparation of compound Ila using 4- trifluoromethylbenzenesulfonyl chloride instead of trans- -stilbene sulfonyl chloride to give IIc as a white solid in 23.2% yield.

[0203] Results of the assay:

[0204] 1 H NMR (600 MHz, DMSO) δ 8.03 - 7.98 (m, 4H), 7.96 (t, J = 5.8 Hz, 1H), 6.76 (s, 1H), 6.09 (d, J = 2.3 Hz, 1H), 5.63 (d, J = 11.0 Hz, 1H), 4.78 (s, 1H), 4.34 (d, J = 5.0 Hz, 1H), 4.05 (d, J = 10.1 Hz, 1H), 3.82 (d, J = 9.4 Hz, 1H), 3.40 (dd, J = 11.0, 6.2 Hz, 1H), 3.29 (dt, J = 10.8, 5.2 Hz, 1H), 2.88 (dd, J = 15.3, 6.7 Hz, 1H), 2.84 (dt, J = 14.9, 7.5 Hz, 2H), 2.36 (t, J = 8.8 Hz, 1H), 1.98 (qd, J = 13.1, 7.8 Hz, 1H), 1.92 - 1.70 (m, 2H), 1.57 (dd, J = 12.4, 6.2 Hz, 1H), 1.53 - 1.36 (m, 4H), 1.28 (dt, J = 13.7, 9.9 Hz, 2H), 1.18 (td, J = 13.3, 3.1 Hz, 1H), 1.06 (d, J = 6.1 Hz, 1H), 0.99 (s, 3H), 0.96 (s, 3H);

[0205] 13 C NMR (151 MHz, DMSO) δ 224.50, 144.81, 132.74, 132.53, 127.94, 126.96, 124.89, 123.09, 97.00, 73.54, 73.51, 71.94, 63.23, 61.73, 60.58, 53.00, 49.06, 47.91, 41.23, 38.83, 36.88, 33.79, 32.96, 29.71, 26.11, 21.89, 19.62, 18.68;

[0206] HRMS (ESI): m / z [M + H] calculated for C + calculated for C 28 H 36 F3N1O8S: 604.2192; found: 604.2186.

[0207] Example 6, Preparation of compound IId

[0208] Structure:

[0209]

[0210] Preparation process:

[0211] Referring to the preparation method of compound Ila in Example 3, trans-β-styrenesulfonyl chloride was replaced by 5-dimethylaminonaphthalene sulfonyl chloride to obtain white solid IId with a yield of 25%.

[0212] Detection results:

[0213] 1 H NMR (600 MHz, DMSO) δ 8.46 (d, J = 8.5 Hz, 1H), 8.29 (d, J = 8.6 Hz, 1H), 8.17 - 8.04 (m, 1H), 7.96 (t, J = 5.4 Hz, 1H), 7.65 - 7.55 (m, 2H), 7.26 (d, J = 7.6 Hz, 1H), 6.74 (s, 1H), 6.04 (s, 1H), 5.61 (d, J = 10.9 Hz, 1H), 4.74 (s, 1H), 4.33 (d, J = 4.9 Hz, 1H), 4.03 (d, J = 10.1 Hz, 1H), 3.80 (d, J = 10.2 Hz, 1H), 3.39 (dd, J = 11.0, 6.2 Hz, 1H), 3.27 (dt, J = 10.7, 5.3 Hz, 1H), 2.84 (s, 1H), 2.83 (s, 6H), 2.80 (dd, J = 12.9, 6.2 Hz, 2H), 2.29 (t, J = 8.7 Hz, 1H), 1.98 - 1.87 (m, 1H), 1.81 - 1.65 (m, 2H), 1.53 - 1.27 (m, 6H), 1.16 (dt, J = 13.8, 10.2 Hz, 2H), 1.03 (d, J = 6.2 Hz, 1H), 0.98 (s, 3H), 0.95 (s, 3H);

[0214] 13 C NMR (151 MHz, DMSO) δ 224.47, 151.84, 136.36, 129.88, 129.54, 128.83, 128.34, 124.03, 119.53, 115.60, 96.97, 73.53, 73.50, 71.95, 63.20, 61.70, 60.53, 52.94, 49.06, 47.81, 45.53, 41.08, 38.83, 36.80, 33.78, 32.97, 29.71, 26.34, 21.89, 19.49, 18.64;

[0215] HRMS (ESI): m / z [M + H] calculated for C + calculated for C 33 H 44 N2O8S:629.2896;found:629.2891.

[0216] Example 7, Preparation of compound IIe

[0217] Structure:

[0218]

[0219] Preparation procedure:

[0220] Referring to the preparation procedure of compound IIa in Example 3, 1-methyl-1H-pyrazole sulfonyl chloride was used to replace trans-β-styrene sulfonyl chloride to obtain compound IIe as a white solid with a yield of 28%.

[0221] Detection results:

[0222] 1 H NMR (600 MHz, DMSO) δ 7.86 (d, J = 2.2 Hz, 1H), 7.67 (s, 1H), 6.76 (s, 1H), 6.59 (d, J = 2.3 Hz, 1H), 6.10 (s, 1H), 5.66 (d, J = 11.0 Hz, 1H), 4.79 (s, 1H), 4.34 (d, J = 4.7 Hz, 1H), 4.05 (d, J = 10.1 Hz, 1H), 3.91 (s, 3H), 3.82 (d, J = 10.7 Hz, 1H), 3.40 (dd, J = 11.0, 6.2 Hz, 1H), 3.31 - 3.28 (m, 1H), 2.94 - 2.83 (m, 3H), 2.41 - 2.32 (m, 1H), 2.03 - 1.93 (m, 1H), 1.90 - 1.78 (m, 2H), 1.59 (dd, J = 12.5, 6.1 Hz, 1H), 1.53 - 1.38 (m, 4H), 1.32 (ddd, J = 13.4, 12.1, 5.0 Hz, 2H), 1.22 - 1.14 (m, 1H), 1.07 (d, J = 6.1 Hz, 1H), 0.99 (s, 3H), 0.96 (s, 3H);

[0223] 13C NMR (151 MHz, DMSO) δ 224.64, 150.75, 133.23, 106.50, 97.01, 73.59, 73.52, 71.94, 63.23, 61.75, 60.57, 52.97, 49.06, 47.98, 41.25, 40.60, 38.83, 36.84, 33.80, 32.97, 29.73, 26.01, 21.90, 19.60, 18.72;

[0224] HRMS (ESI): m / z [M-H] - calculated for C 25 H 37 N3O8S: 538.2223; found: 538.2218.

[0225] Example 8, Preparation of compound II

[0226] Structure:

[0227]

[0228] Preparation process:

[0229] Referring to the preparation method of compound IIa in Example 3, 3-pyridine sulfonyl chloride is replaced by trans-β-styrene sulfonyl chloride to obtain white solid IIf with a yield of 24.9%.

[0230] Test results:

[0231] 1H NMR (600 MHz, DMSO) δ 8.95 (d, J = 2.3 Hz, 1H), 8.83 (dd, J = 4.8, 1.5 Hz, 1H), 8.18 (ddd, J = 8.0, 2.3, 1.6 Hz, 1H), 7.94 (t, J = 5.8 Hz, 1H), 7.66 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 6.76 (s, 1H), 6.10 (s, 1H), 5.62 (s, 1H), 4.79 (s, 1H), 4.35 (s, 1H), 4.07 - 4.04 (m, 1H), 3.82 (d, J = 10.1 Hz, 1H), 3.40 (s, 1H), 3.31 - 3.28 (m, 1H), 2.89 (dd, J = 14.3, 7.5 Hz, 1H), 2.84 (dd, J = 13.7, 7.3 Hz, 2H), 2.39 - 2.34 (m, 1H), 2.03 - 1.92 (m, 1H), 1.90 - 1.76 (m, 2H), 1.59 (dd, J = 12.5, 6.2 Hz, 1H), 1.45 (ddt, J = 21.3, 13.8, 5.3 Hz, 4H), 1.33 - 1.25 (m, 2H), 1.22 - 1.16 (m, 1H), 1.07 (d, J = 6.1 Hz, 1H), 0.99 (s, 3H), 0.96 (s, 3H);

[0232] 13 C NMR (151 MHz, DMSO) δ 224.49, 153.50, 147.48, 137.24, 134.99, 124.80, 97.01, 73.56, 73.53, 71.94, 63.25, 61.74, 60.57, 55.37, 52.99, 47.95, 41.20, 38.85, 36.88, 33.81, 32.97, 29.73, 26.12, 21.90, 19.64, 18.70;

[0233] HRMS (ESI): m / z [M+H] + calculated for C 26 H 36 N2O8S: 537.2270; found: 537.2265.

[0234] Example 9, Preparation of compound IIg

[0235] Structure:

[0236]

[0237] Preparation procedure:

[0238] The procedure of Example 3 was followed for the preparation of compound Ila using phenylsulfonyl chloride instead of trans- -stilbene sulfonyl chloride to give IIg as a white solid in 32.2% yield.

[0239] Results of the assay:

[0240] 1 H NMR (600 MHz, DMSO) δ 7.81 - 7.78 (m, 2H), 7.67 (t, J = 5.7 Hz, 1H), 7.64 (d, J = 7.0 Hz, 1H), 7.60 (t, J = 7.4 Hz, 2H), 6.75 (s, 1H), 6.09 (s, 1H), 5.62 (s, 1H), 4.78 (s, 1H), 4.33 (s, 1H), 4.05 (d, J = 10.1 Hz, 1H), 3.82 (d, J = 10.0 Hz, 1H), 3.40 (s, 1H), 3.30 (dd, J = 11.1, 5.5 Hz, 1H), 2.88 (dd, J = 14.9, 6.8 Hz, 1H), 2.77 (dd, J = 13.3, 6.9 Hz, 2H), 2.35 (t, J = 8.6 Hz, 1H), 1.97 (qd, J = 13.4, 7.9 Hz, 1H), 1.88 - 1.76 (m, 2H), 1.57 (dd, J = 12.4, 6.4 Hz, 1H), 1.53 - 1.34 (m, 4H), 1.33 - 1.23 (m, 2H), 1.18 (dd, J = 13.5, 10.6 Hz, 1H), 1.06 (d, J = 6.2 Hz, 1H), 0.99 (s, 3H), 0.96 (s, 3H);

[0241] 13 C NMR (151 MHz, DMSO) δ 224.54, 140.82, 132.84, 129.70, 126.92, 97.00, 73.56, 73.51, 71.93, 63.23, 61.74, 60.56, 55.36, 52.97, 47.96, 41.19, 38.83, 36.85, 33.80, 32.96, 29.72, 26.06, 21.90, 19.60, 18.69;

[0242] HRMS (ESI): m / z [M + Na] calculated for C + calculated for C 27 H 37 NO8S: 558.2138; found: 558.2132.

[0243] Example 10, Preparation of compound IIh

[0244] Structure:

[0245]

[0246] Preparation process:

[0247] Referring to the preparation method of compound Ila in Example 3, trans-β-styrenesulfonyl chloride was replaced by 4-fluorobenzenesulfonyl chloride to obtain white solid Ih with a yield of 27.1%.

[0248] Detection results:

[0249] 1 H NMR (600 MHz, DMSO) δ 7.90-7.79 (m, 2H), 7.71 (t, J = 5.8 Hz, 1H), 7.44 (t, J = 8.8 Hz, 2H), 6.75 (s, 1H), 6.09 (s, 1H), 5.63 (s, 1H), 4.78 (s, 1H), 4.32 (s, 1H), 4.05 (d, J = 10.1 Hz, 1H), 3.82 (d, J = 10.0 Hz, 1H), 3.40 (d, J = 5.9 Hz, 1H), 3.30 (dd, J = 11.2, 5.5 Hz, 1H), 2.88 (dd, J = 15.1, 6.6 Hz, 1H), 2.78 (dd, J = 13.4, 7.0 Hz, 2H), 2.35 (t, J = 8.7 Hz, 1H), 1.98 (qd, J = 13.1, 7.8 Hz, 1H), 1.88-1.81 (m, 1H), 1.78 (dt, J = 13.5, 6.8 Hz, 1H), 1.58 (dd, J = 12.6, 6.4 Hz, 1H), 1.54-1.36 (m, 4H), 1.29 (ddd, J = 20.6, 12.1, 5.2 Hz, 2H), 1.18 (td, J = 13.4, 2.9 Hz, 1H), 1.06 (d, J = 6.1 Hz, 1H), 0.99 (s, 3H), 0.96 (s, 3H);

[0250] 13 C NMR (151 MHz, DMSO) δ 224.53, 165.38, 137.22, 129.99, 129.92, 116.91, 116.76, 97.00, 73.55, 73.51, 71.93, 63.23, 61.74, 60.56, 55.36, 52.97, 47.95, 41.18, 38.83, 36.86, 33.80, 32.96, 29.72, 26.03, 21.89, 19.61, 18.70;

[0251] HRMS (ESI): m / z [M+NH 4 ]+ Calcd for C 27 H 36 FNO8S: 571.2489; found: 571.2484.

[0252] Example 11, Preparation of compound IIi

[0253] Structural formula:

[0254]

[0255] Preparation procedure:

[0256] Referring to the preparation procedure of compound IIa in Example 3, 4-methoxybenzenesulfonyl chloride was used to replace trans-β-styrenesulfonyl chloride to obtain compound IIi as a white solid with a yield of 29.3%.

[0257] Test results:

[0258] 1 H NMR (600 MHz, DMSO) δ 7.75-7.66 (m, 2H), 7.49 (t, J = 5.9 Hz, 1H), 7.18-7.06 (m, 2H), 6.75 (s, 1H), 6.09 (s, 1H), 5.63 (s, 1H), 4.78 (s, 1H), 4.32 (s, 1H), 4.05 (d, J = 10.1 Hz, 1H), 3.84 (s, 3H), 3.82 (d, J = 10.2 Hz, 1H), 3.40 (d, J = 5.9 Hz, 1H), 3.30 (dd, J = 11.2, 5.5 Hz, 1H), 2.88 (dd, J = 15.2, 6.6 Hz, 1H), 2.73 (dd, J = 13.4, 6.8 Hz, 2H), 2.35 (t, J = 8.7 Hz, 1H), 1.98 (qd, J = 13.3, 7.7 Hz, 1H), 1.89-1.81 (m, 1H), 1.82-1.74 (m, 1H), 1.57 (dd, J = 12.5, 6.1 Hz, 1H), 1.53-1.37 (m, 4H), 1.29 (ddd, J = 20.4, 12.1, 5.1 Hz, 2H), 1.23-1.14 (m, 1H), 1.06 (d, J = 6.1 Hz, 1H), 0.99 (s, 3H), 0.96 (s, 3H);

[0259] 13C NMR (151 MHz, DMSO) δ 224.56, 162.57, 132.47, 129.12, 114.81, 97.00, 73.57, 73.51, 71.94, 63.23, 61.74, 60.57, 56.10, 55.36, 52.98, 47.99, 41.16, 38.83, 36.86, 33.80, 32.97, 29.72, 26.01, 21.89, 19.61, 18.70;

[0260] HRMS (ESI): m / z [M + Na] 588.2244; found: 588.2238. + calculated for C 28 H 39 NO9S:588.2244;found:588.2238。

[0261] Example 12, Preparation of compound IIj

[0262] Structure:

[0263]

[0264] Preparation procedure:

[0265] Referring to the preparation procedure of compound IIa in Example 3, trans-β-styrenesulfonyl chloride was replaced by 2-thiophenesulfonyl chloride to obtain compound IIj as a white solid in 31% yield.

[0266] Test results:

[0267] 1H NMR (600 MHz, DMSO) δ 7.93 (dd, J = 5.0, 1.1 Hz, 1H), 7.86 (t, J = 5.7 Hz, 1H), 7.58 (dd, J = 3.6, 1.1 Hz, 1H), 7.19 (dd, J = 4.9, 3.8 Hz, 1H), 6.75 (s, 1H), 6.10 (s, 1H), 5.63 (s, 1H), 4.79 (s, 1H), 4.34 (s, 1H), 4.05 (d, J = 10.0 Hz, 1H), 3.82 (d, J = 10.5 Hz, 1H), 3.30 (dd, J = 11.1, 5.5 Hz, 2H), 2.92 - 2.88 (m, 1H), 2.86 (dd, J = 13.2, 6.7 Hz, 2H), 2.39 - 2.29 (m, 1H), 1.98 (ddd, J = 27.3, 17.1, 10.6 Hz, 1H), 1.84 (ddd, J = 21.2, 14.0, 8.5 Hz, 2H), 1.59 (dd, J = 12.3, 6.0 Hz, 1H), 1.53 - 1.38 (m, 4H), 1.34 - 1.28 (m, 2H), 1.18 (t, J = 12.1 Hz, 1H), 1.07 (d, J = 6.1 Hz, 1H), 0.99 (s, 3H), 0.95 (s, 3H);

[0268] 13 C NMR (151 MHz, DMSO) δ 224.52, 141.73, 132.88, 131.95, 128.16, 97.01, 73.57, 73.52, 71.93, 63.24, 61.74, 60.57, 55.36, 52.98, 48.02, 41.43, 38.83, 36.87, 33.80, 32.97, 29.72, 25.90, 21.90, 19.63, 18.71;

[0269] HRMS (ESI): m / z [M+H] + calculated for C 25 H 35 NO8S2: 542.1882; found: 542.1877.

[0270] Example 13, Preparation of compound IIk

[0271] Structure:

[0272]

[0273] Preparation process:

[0274] The procedure of Example 3 was followed for the preparation of compound IIa, using trans- -4-fluorostyrene sulfonyl chloride instead of trans- -styrene sulfonyl chloride to give IIk as a white solid.

[0275] Results of the assay:

[0276] 1 H NMR (600 MHz, DMSO) δ 7.80 (dd, J = 8.6, 5.6 Hz, 2H), 7.36 (d, J = 5.1 Hz, 1H), 7.34 (d, J = 10.7 Hz, 1H), 7.27 (t, J = 8.8 Hz, 2H), 7.15 (d, J = 15.5 Hz, 1H), 6.75 (s, 1H), 6.09 (d, J = 2.1 Hz, 1H), 5.64 (d, J = 11.0 Hz, 1H), 4.79 (s, 1H), 4.33 (d, J = 5.0 Hz, 1H), 4.05 (d, J = 10.0 Hz, 1H), 3.81 (d, J = 11.0 Hz, 1H), 3.40 (dd, J = 10.9, 6.2 Hz, 1H), 3.27 (dd, J = 10.9, 5.2 Hz, 1H), 2.98 - 2.88 (m, 3H), 2.43 - 2.36 (m, 1H), 1.98 (dd, J = 23.0, 10.1 Hz, 1H), 1.89 (dd, J = 13.8, 6.2 Hz, 2H), 1.69 - 1.58 (m, 1H), 1.58 - 1.46 (m, 4H), 1.38 - 1.31 (m, 2H), 1.18 (t, J = 12.4 Hz, 1H), 1.04 (d, J = 6.3 Hz, 1H), 0.99 (s, 3H), 0.96 (s, 3H);

[0277] 13 C NMR (151 MHz, DMSO) δ 224.62, 138.52, 131.28, 130.03, 127.14, 116.49, 116.35, 97.01, 73.60, 73.52, 71.94, 63.23, 61.76, 60.58, 55.36, 53.01, 48.03, 40.99, 38.83, 36.93, 33.80, 32.97, 29.71, 26.48, 21.90, 19.67, 18.71;

[0278] HRMS (ESI): m / z [M + H] + calculated for C 29 H 38 FNO8S: 580.2381; found: 580.2375.

[0279] Example 14, Preparation of compound III

[0280] Structure:

[0281]

[0282] Preparation procedure:

[0283] Referring to the preparation procedure of compound IIa in Example 3, trans-β-4- chlorostyrene sulfonyl chloride was used to replace trans-β-styrene sulfonyl chloride to obtain compound III as a white solid.

[0284] Detection results:

[0285] 1 H NMR (600 MHz, DMSO) δ 7.76 (d, J = 8.5 Hz, 2H), 7.49 (dd, J = 8.5, 1.7 Hz, 2H), 7.39 (dd, J = 10.8, 5.3 Hz, 1H), 7.34 (dd, J = 15.5, 6.0 Hz, 1H), 7.22 (d, J = 15.5 Hz, 1H), 6.76 (s, 1H), 6.10 (s, 1H), 5.65 (d, J = 10.9 Hz, 1H), 4.79 (s, 1H), 4.33 (d, J = 5.0 Hz, 1H), 4.05 (d, J = 10.3 Hz, 1H), 3.81 (d, J = 10.5 Hz, 1H), 3.40 (dd, J = 11.0, 6.2 Hz, 1H), 3.26 (dd, J = 11.0, 5.3 Hz, 1H), 2.99 - 2.89 (m, 3H), 2.44 - 2.37 (m, 1H), 1.98 - 1.94 (m, 1H), 1.88 (dd, J = 13.7, 8.0 Hz, 2H), 1.65 - 1.60 (m, 1H), 1.56 - 1.48 (m, 4H), 1.44 (d, J = 13.8 Hz, 1H), 1.18 (td, J = 10.7, 5.1 Hz, 2H), 1.04 (d, J = 6.5 Hz, 1H), 0.99 (s, 3H), 0.96 (s, 3H);

[0286] 13 C NMR (151 MHz, DMSO) δ 224.63, 138.29, 135.41, 132.36, 130.62, 129.44, 128.12, 97.01, 73.60, 73.52, 71.94, 63.23, 61.76, 60.58, 56.49, 53.02, 48.01, 40.99, 38.83, 36.93, 33.79, 32.97, 29.71, 26.51, 21.89, 19.67, 18.71;

[0287] HRMS (ESI): m / z [M + H] calculated for C + calculated for C 29 H 38 ClNO8S:596.2085;found:596.2079.

[0288] Example 15, Preparation of compound Ilm

[0289] Structure:

[0290]

[0291] Preparation procedure:

[0292] Referring to the preparation procedure of compound Ilia in Example 3, trans- -3- bromostyrene sulfonyl chloride was used to replace trans- -styrene sulfonyl chloride to obtain compound Ilm as a white solid.

[0293] Test results:

[0294] 1 H NMR (600 MHz, DMSO) δ 8.01 (t, J = 1.6 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.61 (dd, J = 8.0, 1.1 Hz, 1H), 7.42 (t, J = 5.8 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.32 (d, J = 2.5 Hz, 2H), 6.76 (s, 1H), 6.10 (d, J = 2.2 Hz, 1H), 5.65 (d, J = 11.0 Hz, 1H), 4.79 (s, 1H), 4.32 (d, J = 4.9 Hz, 1H), 4.05 (s, 1H), 3.81 (d, J = 10.3 Hz, 1H), 3.40 (dd, J = 11.0, 6.2 Hz, 1H), 3.27 (dt, J = 10.7, 5.3 Hz, 1H), 2.96 - 2.90 (m, 3H), 2.42 - 2.37 (m, 1H), 1.96 (dd, J = 12.5, 5.7 Hz, 1H), 1.91 - 1.85 (m, 2H), 1.63 (dd, J = 12.3, 6.7 Hz, 1H), 1.58 - 1.47 (m, 4H), 1.44 (d, J = 13.8 Hz, 1H), 1.18 (dd, J = 13.2, 10.0 Hz, 2H), 1.05 (d, J = 6.1 Hz, 1H), 0.99 (s, 3H), 0.96 (s, 3H).

[0295] Example 16, Preparation of compound Ilm

[0296] Structure:

[0297] Preparation procedure:

[0298] Referring to the preparation procedure of compound Ha of Example 3, trans-β-2- bromostyrene sulfonyl chloride was used instead of trans-β-styrene sulfonyl chloride to give compound In as a white solid.

[0299] Test results:

[0300] 1 H NMR (600 MHz, DMSO) δ 7.91 (dd, J = 7.8, 1.6 Hz, 1H), 7.73 (dd, J = 8.0, 1.1 Hz, 1H), 7.58 (dd, J = 15.4, 3.1 Hz, 1H), 7.52 (t, J = 5.8 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.38 (td, J = 7.8, 1.6 Hz, 1H), 7.28 (dd, J = 15.4, 10.4 Hz, 1H), 6.76 (s, 1H), 6.10 (d, J = 2.2 Hz, 1H), 5.64 (d, J = 11.0 Hz, 1H), 4.79 (s, 1H), 4.33 (d, J = 5.0 Hz, 1H), 4.05 (s, 1H), 3.81 (d, J = 10.1 Hz, 1H), 3.40 (dd, J = 11.0, 6.2 Hz, 1H), 3.28 - 3.24 (m, 1H), 2.97 (dd, J = 13.4, 7.0 Hz, 2H), 2.91 (dt, J = 12.8, 6.3 Hz, 1H), 2.42 - 2.38 (m, 1H), 1.97 (dd, J = 13.2, 6.9 Hz, 1H), 1.91 - 1.85 (m, 2H), 1.66 - 1.58 (m, 1H), 1.47 (dddd, J = 46.1, 32.5, 12.4, 5.5 Hz, 6H), 1.18 (dd, J = 13.4, 10.3 Hz, 1H), 1.04 (d, J = 6.1 Hz, 1H), 0.99 (s, 3H), 0.96 (s, 3H).

[0301] Example 17, Preparation of compound IIo

[0302] Structure:

[0303] Preparation procedure:

[0304] Referring to the preparation procedure of compound Ha of Example 3, trans-β-2- bromostyrene sulfonyl chloride was used instead of trans-β-styrene sulfonyl chloride to give compound In as a white solid.

[0305] Test results:

[0306] 1H NMR (600 MHz, DMSO) δ 8.22 (s, 1H), 7.95 (t, J = 8.4 Hz, 3H), 7.89 (dd, J = 8.6, 1.5 Hz, 1H), 7.59 - 7.56 (m, 2H), 7.50 (d, J = 15.5 Hz, 1H), 7.41 (t, J = 5.9 Hz, 1H), 7.30 (d, J = 15.5 Hz, 1H), 6.76 (s, 1H), 6.10 (d, J = 2.2 Hz, 1H), 5.65 (d, J = 10.9 Hz, 1H), 4.79 (s, 1H), 4.29 (d, J = 5.0 Hz, 1H), 4.01 (s, 1H), 3.80 (d, J = 12.5 Hz, 1H), 3.39 (dd, J = 11.0, 6.2 Hz, 1H), 3.30 (d, J = 5.3 Hz, 1H), 3.01 - 2.90 (m, 3H), 2.42 (t, J = 8.6 Hz, 1H), 1.98 (d, J = 6.8 Hz, 1H), 1.90 - 1.86 (m, 2H), 1.61 (d, J = 3.0 Hz, 1H), 1.57 - 1.48 (m, 5H), 1.10 (d, J = 4.8 Hz, 2H), 1.01 (d, J = 5.9 Hz, 1H), 0.98 (s, 3H), 0.93 (s, 3H).

[0307] Example 18, Preparation of compound IIp

[0308] Structure:

[0309]

[0310] Preparation procedure:

[0311] Referring to the preparation procedure of compound IIa in Example 3, trans-β-4- bromostyrene sulfonyl chloride was used to replace trans-β-styrene sulfonyl chloride to obtain compound IIp as a white solid.

[0312] Test results:

[0313] 1H NMR (600 MHz, DMSO) δ 7.70-7.67 (m, 2H), 7.64-7.61 (m, 2H), 7.40 (t, J = 5.8 Hz, 1H), 7.33 (d, J = 15.5 Hz, 1H), 7.23 (d, J = 15.5 Hz, 1H), 6.76 (s, 1H), 6.09 (d, J = 2.3 Hz, 1H), 5.64 (d, J = 10.9 Hz, 1H), 4.79 (s, 1H), 4.32 (d, J = 5.0 Hz, 1H), 4.04 (d, J = 10.0 Hz, 1H), 3.81 (d, J = 10.0 Hz, 1H), 3.40 (dd, J = 11.0, 6.2 Hz, 1H), 3.25 (dd, J = 10.9, 5.5 Hz, 1H), 2.97-2.89 (m, 3H), 2.43-2.36 (m, 1H), 1.96 (dd, J = 12.3, 5.5 Hz, 1H), 1.90-1.85 (m, 2H), 1.61 (dd, J = 11.6, 8.7 Hz, 1H), 1.52 (ddd, J = 13.4, 9.5, 3.2 Hz, 4H), 1.46 (d, J = 10.5 Hz, 1H), 1.21-1.14 (m, 2H), 1.03 (d, J = 6.2 Hz, 1H), 0.98 (s, 3H), 0.96 (s, 3H).

[0314] It should be noted that:

[0315] Although the present embodiment only provides 18 kinds of oridonin derivative compounds having the structure shown in formula (I) or (II) through Examples 1-18, it can be understood by those skilled in the art that other specific oridonin derivatives having the structure shown in formula (I) or (II) can also be obtained by the methods given in Examples 1-18, and therefore, the preparation of other oridonin derivatives having the structure shown in formula (I) or (II) will not be described in detail.

[0316] Example 3

[0317] The present embodiment provides a preparation method of the compound having the structure shown in formula (I) or (II) or its pharmaceutically acceptable salt as described in the above Example 1.

[0318] First, using the 18 kinds of oridonin derivatives obtained in each of the above Examples 2, the 18 kinds of oridonin derivative pharmaceutically acceptable salts corresponding to the 18 kinds of oridonin derivatives can be obtained by reacting with pharmaceutically acceptable inorganic or organic acids, respectively.

[0319] Since the related reactions are basic reactions commonly used in the art, the related salt formation reactions will not be described in detail.

[0320] Secondly, other various oroticum derivatives pharmaceutical salts with the structure shown in formula (I) or (II) can be obtained by imitating the above-mentioned method for obtaining 18 kinds of oroticum derivatives pharmaceutical salts. Since the process is also a basic reaction commonly used in the art, the present specification will not be described in further detail.

[0321] In the preparation process of the above-mentioned oroticum derivatives pharmaceutical salts:

[0322] The inorganic acid can be any one of hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid or sulfuric acid;

[0323] The organic acid can be any one of formic acid, acetic acid, propionic acid, succinic acid, 1,5-naphthalene disulfonic acid, aspartic acid, carbenicillin, glycyrrhizic acid, oleanolic acid, maslinic acid, ursolic acid, colosseum acid, white birch acid, olibanic acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethylacetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methylsulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, citric acid or amino acid.

[0324] Example 4

[0325] The present example is used to provide a pharmaceutical composition of oroticum derivatives.

[0326] A therapeutically effective amount of the oroticum derivatives provided in the above-mentioned example 1 is mixed or dissolved with one or more of the pharmaceutically acceptable carriers, excipients and adjuvants to obtain the pharmaceutical composition corresponding to each oroticum derivative.

[0327] Since the related operations are basic operations commonly used in the art, the present example will not be described in detail.

[0328] The pharmaceutical composition provided in the present example can be a liquid or solid preparation, including small volume injection, medium volume injection, large volume injection, powder injection, injection emulsion, tablet, pill, capsule, ointment, cream, patch, liniment, powder, spray, implant, drop, suppository, ointment and nanometer preparation including liposome.

[0329] Since the preparation operation of the related preparation is a basic operation commonly used in the art, the present example will not be described in detail.

[0330] Example 5

[0331] The present example provides an application of oroticum derivatives.

[0332] The application provided by the embodiment is that a therapeutically effective amount of the oridonin derivative provided by the embodiment 1 is used in anti-inflammatory, inflammatory disease treatment, nervous system disease treatment or antitumor drug preparation as an active ingredient.

[0333] To further help understand the technical effects that can be obtained by the technical solutions provided by the embodiment, the application effects of the oridonin derivative provided by the embodiment are further described below through specific effect examples.

[0334] Effect example 1, the cytotoxicity experiment and in-vitro anti-inflammatory activity experiment of part of the oridonin derivatives provided by the embodiment 2 of the present application

[0335] In this effect example, the cytotoxicity experiment of part of the oridonin derivatives provided by the embodiment 2 of the present application is carried out by using the conventional CCK-8 method, in which:

[0336] The THP-1 (human monocytic leukemia cell line) cell strain used in the experiment is provided by Wuhan Punsense Life Science Technology Co., Ltd., and the culture solution is RPMI1640 culture medium containing 10% fetal bovine serum, 1% penicillin-streptomycin mixture and 0.05mM β-mercaptoethanol.

[0337] The test method is as follows: THP-1 cells are placed in a 96-well plate, stimulated with 100ng / mL PMA for 48 hours, and the supernatant is taken out and replaced with fresh culture medium containing Ori or different concentrations of test samples, and then the cells are treated with Ori or different concentrations of test samples for 24 hours, and the culture supernatant is replaced with fresh culture medium containing CCK8 (10μL), and incubated at 37℃ for 3 hours, and then the absorbance (OD) is read at 450nm on a full-function microplate detector Biotek Synergy H2, and the drug concentration causing 50% cell death (CC50) is calculated by simulating the GraphPad Prism software.

[0338] In this effect example, the in-vitro anti-inflammatory activity experiment of part of the oridonin derivatives provided by the embodiment 2 of the present application is carried out by detecting the secretion level of human interleukin IL-1β by using the ELISA method, in which:

[0339] THP-1 cell culture: the cells are cultured in complete culture medium (RPMI1640 culture medium) containing 10% fetal bovine serum, 1% penicillin-streptomycin mixture and 0.05mM β-mercaptoethanol, and the culture environment is a sterile environment containing 5% carbon dioxide and 95% air at 37℃;

[0340] THP-1 cell induction differentiation: the culture medium containing THP-1 cells in the culture bottle is aspirated, centrifuged at 1000rmp for 3min, the cells are resuspended with complete culture medium, and the cell concentration is adjusted to 5×105 THP-1 cells were seeded in 24-well plates at 1x105 cells / ml in 1ml of cell culture medium, PMA was added at a concentration of 100 ng / ml, and the THP-1 cells were stimulated for 48 hours to differentiate into macrophages (THPM cells);

[0341] NLRP3 inflammasome activation: PMA-differentiated THP-1 cells were washed with phosphate buffered saline and treated with 100 μg / ml of LPS for 3 hours in basal medium, the medium was removed, and the compound medium was added to the 24-well plate at different concentrations, mixed, and incubated in the incubator for 24 hours, the original medium was not removed, and the cells were stimulated with ATP (5 mM) for 1 hour;

[0342] ELISA: the cell culture supernatant was collected, centrifuged at 12000 rpm for 5 min, and dead cells were removed, and IL-1β in the cell supernatant was analyzed using an ELISA kit according to the manufacturer's instructions.

[0343] The test results are shown in Table 1, in which 15 oridonin derivatives prepared in Example 2 and commercially available oridonin are detected samples.

[0344] Table 1

[0345]

[0346] As can be seen from the data listed in Table 1:

[0347] The 15 oridonin derivatives provided in Example 2 of the present application have anti-inflammatory activity comparable to oridonin, and more importantly, the toxicity of the 15 oridonin derivatives provided in Example 2 of the present application is much lower than that of oridonin. Except for compounds III and II, the CC 50 values of all other compounds are greater than or equivalent to 100 uM, wherein the anti-inflammatory activity of compounds Ia, IIa, IIc, IId, IIg, Iii, IIj, IIk, and IIl at 20 uM is better than that of oridonin, the anti-inflammatory activity of compounds Ib and IIe is comparable to that of oridonin, the anti-inflammatory activity of compounds IIc and IIk at a concentration of 50 uM is better than that of oridonin, and the anti-inflammatory activity of multiple compounds is comparable to or slightly weaker than that of oridonin.

[0348] It should be noted that:

[0349] Although, the present effect example only provides the cytotoxicity experiment and in vitro anti-inflammatory activity test data of the 15 oripavine derivatives provided by the present application embodiment 2, but those skilled in the art can obtain the test data of the compounds having the structure shown in formula (I) or (II) provided by the present application embodiment 1 and embodiment 3 and the present effect example basically the same, so it can be considered that the oripavine derivatives provided by the present application have higher anti-inflammatory activity and lower cytotoxicity than the existing oripavine, and can be used for preparing anti-inflammatory drugs.

[0350] Effect example 2, in vitro anti-tumor activity test of some oripavine derivatives provided by the present application embodiment 2

[0351] The present effect example adopts tumor cell proliferation inhibition test, that is, the commonly used CCK-8 method to carry out the in vitro anti-tumor activity test of some oripavine derivatives provided by the present application embodiment 2, wherein the cell strain is HCT-116 (human intestinal cancer cells), the culture solution is DMEM+10%FBS+double antibody, and the operation method is carried out according to the CCK-8 method in "New Drug Pharmacology Research Method" (2007: 242-243) edited by Lv Qiujun, including:

[0352] In vitro activity test process: take the cells in logarithmic growth phase, inoculate them into 96-well plates at a density of 7×10 3 / well, and incubate them at 37℃ in a 5% CO2 environment for 24 hours to maintain normal physiological pH value; after cell adhesion, add different concentrations of test compounds, that is, the compounds prepared in the present application embodiment, into three wells, and add 0.1% DMSO as a control; after 72 hours, add 10 μL of CCK-8 cell counting kit into each well, and incubate the plate at 37℃ for 0.5-1 hour, read the absorbance (OD) at 450 nm on a full-function microplate detector Biotek Synergy H2, and simulate and calculate the concentration causing 50% cell growth inhibition (IC 50 ) by GraphPad Prism software, so as to characterize the in vitro anti-tumor activity of oripavine derivatives.

[0353] The in vitro anti-tumor activity test results data of some oripavine derivatives provided by the present application embodiment 2 and the commercially available oripavine are shown in Table 2, wherein IC 50 is the half-inhibitory concentration of the test sample to HCT-116 cell proliferation.

[0354] Table 2

[0355] Test sample HCT-116(IC 50 , μM) III 6.81±2.35 IIm 18.8±17.1 IIn 8.98±5.69 IIo 5.77±6.95 IIp 15.22±11.71 Oridonin 12.5±10.5 From the data listed in Table 2, it can be seen that:

[0356] The partial ormodiolin derivatives provided in Embodiment 2 have better inhibitory activity on human intestinal cancer cell line HCT116, and the IC50 values are all lower than 20 μM, wherein the antitumor activity of compounds III, IIn and IIo is better than that of ormodiolin, indicating that the partial ormodiolin derivatives provided in Embodiment 2 have the potential of developing into antitumor drugs. 50 The partial ormodiolin derivatives provided in Embodiment 2 have better inhibitory activity on human intestinal cancer cell line HCT116, and the IC50 values are all lower than 20 μM, wherein the antitumor activity of compounds III, IIn and IIo is better than that of ormodiolin, indicating that the partial ormodiolin derivatives provided in Embodiment 2 have the potential of developing into antitumor drugs.

[0357] It should be noted that:

[0358] Although the effect example only provides the in-vitro antitumor activity test data of the five ormodiolin derivatives provided in Embodiment 2 of the present application, the person skilled in the art can obtain the basically same test data of the compounds having the structure shown in formula (I) or (II) or the pharmaceutical salts thereof provided in Embodiment 1 and Embodiment 3 of the present application by using the above-mentioned test method, and thus it can be considered that the ormodiolin derivatives provided in the present application have the potential of developing into antitumor drugs.

[0359] In summary, it can be seen that:

[0360] Firstly, the ormodiolin derivatives provided in the present application have higher anti-inflammatory activity and lower toxicity than the existing ormodiolin, and can be applied as active ingredients in the preparation of anti-inflammatory drugs, nervous system diseases or antitumor drugs.

[0361] Secondly, the ormodiolin derivatives, the preparation method and the pharmaceutical composition and application thereof provided in the present application provide a new idea and method for preparing new drugs with better curative effect and lower toxicity, have outstanding substantial characteristics and beneficial effects and significant progress, and have a broad application prospect.

[0362] In the description process of the above specification:

[0363] The description of the terms "the present embodiment", "the present embodiment of the present application", "as shown", "further" and the like means that the specific features, structures, materials or characteristics described in the embodiment or example are contained in at least one embodiment or example of the present application, and the illustrative description of the above terms in the specification is not necessarily for the same embodiment or example, and the specific features, structures, materials or characteristics described can be combined or combined in any one or more embodiments or examples in a suitable manner.

[0364] In addition, the person skilled in the art can combine or combine the different embodiments or examples and the features of the different embodiments or examples described in the specification without contradiction.

[0365] It should be pointed out finally that the above embodiments are only used to illustrate the technical solutions of the present application, but are not a limitation thereof. Although the present application has been described in detail with reference to the above embodiments or examples, it should be understood by those skilled in the art that the technical solutions recorded in the above embodiments or examples can still be modified, or the groups or all technical features thereof can be replaced equivalently, and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments or examples of the present application. The non-essential improvements, adjustments or replacements made by those skilled in the art according to the content of the present application are all within the scope of the present application.

Claims

1. An oridonin derivative, characterized in that, A compound having the structure shown below or a pharmaceutically acceptable salt thereof:

2. The oridonin derivative according to claim 1, characterized in that: The pharmaceutically acceptable salt is a salt of a compound having the structure shown in any one of the preceding claims with a pharmaceutically acceptable inorganic or organic acid, wherein: The inorganic acid is any one of hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid or sulfuric acid; The organic acid is any one of formic acid, acetic acid, propionic acid, succinic acid, 1,5-naphthalene disulfonic acid, aspartic acid, carbenicillin, glycyrrhetinic acid, oleanolic acid, maslinic acid, ursolic acid, colosolic acid, betulinic acid, laticic acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethylacetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, citric acid or an amino acid.

3. A method for preparing the oridonin derivative of claim 1, characterized in that, The method comprises the following steps: That is, under inert gas protection, a reaction is carried out in a solvent at a molar ratio of compound III: sulfuryl isocyanate compound RSO2NCO: basic catalyst = 1:1:(1-3) to obtain compound I; or Under inert gas protection, a reaction is carried out in a second solvent at a molar ratio of compound III: sulfuryl chloride compound RSO2Cl: basic catalyst = 1:1:(1-3) to obtain compound II; Wherein: R in the sulfuryl isocyanate compound is phenyl or 4-methylphenyl; The sulfuryl chloride compound RSO2Cl is selected from benzene sulfonyl chloride, 4-cyanobenzene sulfonyl chloride, thiophene sulfonyl chloride, 1-methyl-1-pyrazole sulfonyl chloride, 3-pyridine sulfonyl chloride, 5-dimethylaminonaphthalene sulfonyl chloride, 4-methoxy sulfonyl chloride, 4-trifluoromethyl sulfonyl chloride, trans-β-styrene sulfonyl chloride or 4-fluorobenzene sulfonyl chloride; The reaction a1 or the reaction a2 is respectively carried out at room temperature, and during the reaction, compound III is first dissolved in a solvent, and then a basic catalyst and a sulfuryl isocyanate compound or a sulfuryl chloride compound are respectively added to carry out the reaction, wherein the basic catalyst is any one or more of 4-dimethylaminopyridine, triethylamine or pyridine, and the solvent is any one or more of dichloromethane, DMF, toluene or tetrahydrofuran.

4. The production method according to claim 3, characterized by, The compound III can be prepared by step b or steps c-b: That is, Under inert gas protection, compound IV is dissolved in a second solvent to react with trifluoroacetic acid to obtain compound III; or Under inert gas protection, compound V is dissolved in a third solvent to react with Boc-glycine and a photocatalyst to obtain compound IV, and the obtained compound IV is dissolved in a second solvent to react with trifluoroacetic acid to obtain compound III; Wherein: The reaction b and the reaction c are respectively carried out at normal temperature, and the reaction c is a photocatalytic reaction, and the photocatalyst thereof is one or more of Ir[diF(Me)ppy]2(dtbpy)PF6, 4-CzIPN, tetraMeO-Acri-N-P or tetraMeO-Acri-N-diMeOPh; The second solvent is a mixed solvent of dichloromethane and trifluoroacetic acid, and the third solvent is DMF or acetonitrile; The molar ratio of the reactants of the reaction b and the reaction c is respectively: Compound IV:dichloromethane:trifluoroacetic acid = 1:(1-4):1; Compound V:Boc-glycine:photocatalyst:third solvent = 1:1.2:0.1:1.

5. 5.A pharmaceutical composition of oridonin derivative, characterized in that: The pharmaceutical composition comprises a therapeutically effective amount of the oridonin derivative of claim 1, and one or more of pharmaceutically acceptable carriers, excipients and adjuvants. 6.The pharmaceutical composition of claim 5, characterized in that: The pharmaceutical composition is a small-volume injection, a medium-volume injection, a large-volume injection, a powder injection, an injection emulsion, a tablet, a pill, a capsule, a paste, a cream, a patch, a liniment, a powder, a spray, an implant, a drop, a suppository, an ointment and a liposome nano-preparation. 7.The use of the oridonin derivative of claim 1 in the preparation of an anti-inflammatory drug, a drug for treating nervous system diseases or an anti-tumor drug.

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