7a-substituted phenyltetrahydrothebaine derivatives, processes for their preparation and uses thereof

Abstract

This application relates to a 7α-substituted phenyltetrahydrothebaine derivative, its preparation method, and its uses. Specifically, it relates to a 7α-substituted phenyltetrahydrothebaine derivative as shown in general formula (I) or a pharmaceutically acceptable salt thereof, and its preparation method, and to the use of such derivatives in the preparation of analgesic, anti-anxiety, anti-addiction, and antidepressant drugs. The derivatives of this invention exhibit significantly enhanced agonist activity and subtype selectivity of δ-opioid receptors.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field and relates to 7α-substituted phenyl tetrahydrothebaine derivatives, their preparation methods and uses, specifically to 7α-substituted phenyl tetrahydrothebaine derivatives as shown in general formula (I) or pharmaceutically acceptable salts thereof and their preparation methods, and to the use of such derivatives in the preparation of analgesic, anti-addiction, anti-anxiety and antidepressant drugs. Background Technology

[0002] Opioids are widely used clinically as potent analgesics; however, they primarily act on μ-opioid receptors, potentially leading to serious side effects such as addiction, respiratory depression, and constipation. In contrast, delta-opioid receptors, another subtype of opioid receptors, not only possess potent analgesic activity similar to μ-opioid receptors but also enhance the analgesic effect of μ-receptors while mitigating adverse reactions such as constipation, respiratory depression, addiction, and dependence. Furthermore, preclinical studies have shown that activating delta-opioid receptors may also alleviate symptoms of anxiety, depression, and alcohol dependence. In the early 21st century, some delta-receptor agonists, such as ADL5859, ADL5747, and AZD2327, entered phase II clinical trials to evaluate their efficacy in treating acute or chronic pain and conditions like depression. These agonists are all based on the classic highly selective delta-receptor agonists SNC80 and SNC86. However, the SNC series compounds induced severe seizures in rodents, and AZD2327 also showed convulsant-promoting effects, limiting further development of these compounds. Similar trends exist in the study of κ receptors. Therefore, developing other opioid receptor agonists with novel structures and exploring the mechanisms underlying the isolating δ / κ opioid receptors to mediate analgesia, antidepressant effects, and seizure side effects are of great significance for improving the pharmacological properties of δ / κ opioid receptor agonists. Summary of the Invention

[0003] The object of this invention is to provide 7α-substituted phenyl tetrahydrothebaine derivatives as shown in general formula (I) or pharmaceutically acceptable salts thereof and methods for their preparation, and such derivatives have potential use in the preparation of drugs for indications such as analgesia, addiction, anxiety, and depression.

[0004] According to one aspect of the invention, a 7α-substituted phenyl tetrahydrothebaine derivative as shown in general formula (I) or a pharmaceutically acceptable salt thereof is provided.

[0005]

[0006] in,

[0007] R 1Selected from H and C1-C6 alkyl groups; particularly, selected from H and C1-C4 alkyl groups; for example, methyl, ethyl, n-propyl or isopropyl;

[0008] R 2 Selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C5-C7 cycloalkenyl, C3-C6 cycloalkylC1-C6 alkyl, C5-C7 cycloalkenylC1-C6 alkyl, C6-C 12 Aryl, 5-7 heteroaryl, C6-C 12 aryl C1-C6 alkyl, 5-7-membered heteroaryl C1-C6 alkyl; particularly, selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 ynyl, C3-C6 cycloalkyl, C5-C7 cycloalkenyl, C3-C6 cycloalkyl C1-C4 alkyl, C5-C7 cycloalkenyl C1-C4 alkyl, C6-C 12 Aryl, 5-6 quinone heteroaryl, C6-C 12 Aryl C1-C6 alkyl, 5-6-membered heteroaryl C1-C6 alkyl; more particularly, selected from H and C3-C6 cycloalkyl C1-C4 alkyl; for example, cyclopropylmethyl, cyclobutylmethyl or phenethyl;

[0009] R 3 Selected from H and C1-C6 alkyl groups; particularly, selected from H and C1-C4 alkyl groups; for example, methyl, ethyl, n-propyl or isopropyl;

[0010] R 4 Selected from C1-C6 alkylene and C2-C6 alkenylene; particularly, selected from C1-C4 alkylene and C2-C4 alkenylene; for example, vinylene;

[0011] R 5 Selected from H, halogens, C1-C6 alkyl, C3-C6 cycloalkyl, C5-C7 cycloalkenyl, unsubstituted or substituted by substituents selected from group A, C6-C 12 aryl, 5-9 membered heteroaryl, unsubstituted or substituted with a substituent selected from group A, and an amino group, unsubstituted or substituted with a substituent selected from group A; particularly, R 5 Selected from H, halogen, unsubstituted or substituted C6-C groups selected from group A 12 aryl, 5-9 membered heteroaryl, unsubstituted or substituted with a substituent selected from group A, and an amino group, unsubstituted or substituted with a substituent selected from group A; more particularly, R 5 Selected from H, halogen, unsubstituted or substituted C6-C groups selected from group A 10 aryl, 5-6 membered heteroaryl, unsubstituted or substituted by a substituent selected from group A, and amino group, unsubstituted or substituted by a substituent selected from group A;

[0012] Wherein, the substituents selected from group A are each independently selected from unsubstituted or halogen-substituted C1-C6 alkyl groups, unsubstituted or halogen-substituted C1-C6 alkoxy groups, C1-C6 alkoxyacyl groups, C1-C6 alkanoyloxy groups, and unsubstituted or substituted C6-C6 groups selected from group B. 12 The group consists of an aryl group, an unsubstituted or substituted 5-9 member heteroaryl group, a carboxyl group, a cyano group, a hydroxyl group, a halogen, or an amino group; particularly, the substituents selected from group A are each independently selected from unsubstituted or arbitrarily substituted C1-C6 alkyl groups, unsubstituted or arbitrarily substituted C1-C6 alkoxy groups, and unsubstituted or substituted C6-C6 alkoxy groups. 12 aryl, halogen; more particularly, the substituents selected from group A are each independently selected from unsubstituted or halogen-substituted C1-C4 alkyl groups, unsubstituted or halogen-substituted C1-C4 alkoxy groups, and unsubstituted or substituted C6-C groups. 10 Aryl, halogen; for example, substituents selected from group A are each independently methyl, ethyl, CF3, methoxy, unsubstituted or substituted phenyl or Cl selected from group B;

[0013] The substituents selected from group B are each independently selected from unsubstituted or arbitrarily substituted C1-C6 alkyl groups, unsubstituted or arbitrarily substituted C1-C6 alkoxy groups, C1-C6 alkoxyacyl groups, C1-C6 alkanoyloxy groups, carboxyl groups, cyano groups, hydroxyl groups, halogens, and unsubstituted or arbitrarily substituted amino groups; in particular, the substituents selected from group B are each independently selected from unsubstituted or arbitrarily substituted C1-C6 alkyl groups, unsubstituted or arbitrarily substituted C1-C6 alkyl groups, and unsubstituted or arbitrarily substituted C1-C6 alkyl groups. 6. Alkoxy, halogen; more particularly, each substituent selected from group B is independently selected from unsubstituted or arbitrarily substituted C1-C4 alkyl, unsubstituted or arbitrarily substituted C1-C4 alkoxy, halogen; for example, each substituent selected from group B is independently selected from methyl, methyl substituted with F and / or hydroxyl (such as CF3), ethyl, ethyl substituted with F and / or hydroxyl, n-propyl, isopropyl, n-propyl substituted with F and / or hydroxyl, isopropyl substituted with F and / or hydroxyl, methoxy, Cl;

[0014] For example, R 5 The group is selected from Br, phenyl, phenyl substituted with a substituent selected from methyl, ethyl, CF3, methoxy and Cl, furanyl, thiophene, amino substituted with an unsubstituted or substituted phenyl group, wherein the substituent on the substituted phenyl group is selected from methyl, methyl substituted with F and / or hydroxyl, ethyl, ethyl substituted with F and / or hydroxyl, n-propyl, isopropyl, n-propyl substituted with F and / or hydroxyl, isopropyl substituted with F and / or hydroxyl, CF3, methoxy, and Cl.

[0015] According to one embodiment of the present invention, a derivative of formula (I) or a pharmaceutically acceptable salt thereof, wherein...

[0016] R 1 Selected from C1-C6 alkyl groups;

[0017] R 2 Selected from C3-C6 cycloalkyl and C1-C6 alkyl groups;

[0018] R 3 Selected from C1-C6 alkyl groups;

[0019] R 4 Selected from C2-C6 alkenyl groups;

[0020] R 5 As described above.

[0021] According to one embodiment of the present invention, a derivative of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 It is H or methyl, and other substituents are as described above.

[0022] According to one embodiment of the present invention, a derivative of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 2 It is cyclopropylmethyl, cyclobutylmethyl, or phenethyl, and other substituents are as described above.

[0023] According to one embodiment of the present invention, a derivative of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3 It is H or methyl, and other substituents are as described above.

[0024] According to one embodiment of the present invention, a derivative of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 It is vinylidene or ethylidene, and other substituents are as described above.

[0025] According to the present invention, the derivatives represented by general formula (I) are as shown in the following formula (I-1):

[0026]

[0027] Among them, R 5 As described above. In some embodiments, R 5 Selected from H, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, unsubstituted or optionally substituted with groups selected from halogen, C1-C6 alkyl, C3-C6 cycloalkyl, amino, hydroxyl, nitro, cyano, etc., C6-C 12Aryl, 5-9 membered heteroaryl, and C6-C6 groups optionally substituted with halogen, C1-C6 alkyl, C3-C6 cycloalkyl, amino, hydroxyl, nitro, cyano, etc. 12 A aryl or 5-9 heteroaryl substituted amino group.

[0028] Specifically, according to the present invention, compounds selected from or pharmaceutically acceptable salts thereof are provided:

[0029]

[0030]

[0031]

[0032] According to another aspect of the present invention, a method for preparing a derivative of general formula (I) or a pharmaceutically acceptable salt thereof is provided, comprising:

[0033] In the formula, R1 = H or other alkyl derivatives can be prepared by conversion of R1 = CH3 derivatives in formula (I) under certain conditions. The conversion preparation conditions refer to BBr3 / CH2Cl2, different concentrations of H2SO4, different concentrations of HBr, methanesulfonic acid or KOH / diethylene glycol (DEG), sodium propanethiolate / HMPA, preferably BBr3 / CH2Cl2.

[0034] In the formula, R2 = H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C5-C7 cycloalkenyl, C3-C6 cycloalkyl C1-C6 alkyl, C5-C7 cycloalkenyl C1-C6 alkyl, C6-C 12 Aryl, 5-7 heteroaryl, C6-C 12Aromatic C1-C6 alkyl or 5-7 heteroaryl C1-C6 alkyl derivatives can be prepared by conversion of the derivative of formula (I) where R2 = CH3 under certain conditions. The conversion conditions are: reaction with brominated nitriles, ethyl chloroformate, phenyl chloroformate, vinyl chloroformate, diisopropyl azodicarbonate, or ethyl azoformate (Kauer JC, Organic Synthesis, 1963, 4, 411) in an inert solvent, followed by acid hydrolysis to obtain the derivative of formula (I) where R2 = H. The inert solvent is selected from acetonitrile, tetrahydrofuran (THF), diethyl ether, chloroform, dichloromethane, benzene, toluene, N,N-dimethylformamide (DMF), or a mixture of the above solvents, preferably acetonitrile; the preferred conversion condition is ethyl azoformate; the acidic conditions are selected from different concentrations of H2SO4, HCl, or HBr. The intermediate product (II, R2 = H) reacts with a monohalogenated hydrocarbon in an inert solvent to yield the product in formula (I), where R2 = C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C5-C7 cycloalkenyl, C3-C6 cycloalkyl, C1-C6 alkyl, C5-C7 cycloalkenyl, C1-C6 alkyl, C6-C 12 Aryl, 5-7 heteroaryl, C6-C 12 An intermediate of aryl C1-C6 alkyl, or a derivative of a 5-7 membered heteroaryl C1-C6 alkyl. The monohalogenated hydrocarbon is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C5-C7 cycloalkenyl, C3-C6 cycloalkylC1-C6 alkyl, C5-C7 cycloalkenylC1-C6 alkyl, C6-C 12 Aryl, 5-7 heteroaryl, C6-C 12 The aryl C1-C6 alkyl chlorine, bromine, or iodide, wherein the inert reagent is selected from THF, diethyl ether, chloroform, dichloromethane, benzene, toluene, N,N-dimethylformamide (DMF), or a mixture of the above solvents.

[0035] It is well known in the art that derivatives of R3 = H or other alkyl groups in formula (I) can be obtained by conversion of derivatives of R3 = CH3 in formula (I) under certain conditions, namely, different concentrations of H2SO4, different concentrations of HBr, methanesulfonic acid or KOH / diethylene glycol (DEG).

[0036] This is also well known in the art; derivatives in formula (I) where R4 is -CH2CH2- can be prepared by conversion of derivatives in formula (I) where R4 is -CH=CH- under certain reducing conditions. These reducing conditions are selected from reduction under Pd / C catalytic hydrogenation.

[0037] The derivative of R5 = Br can be obtained by a series of transformation reactions of the derivative of formula (II). The transformation conditions are: reacting the derivative of formula (II) with p-bromostyrene in an inert solvent to obtain intermediate (III). The inert solvent is selected from benzene, toluene, xylene or a mixture of the above solvents, preferably xylene.

[0038] In the formula, R5 = aryl (phenyl) or a substituted aryl (phenyl) or heteroaryl derivative can be obtained by reacting the derivative of formula (III) with aryl (phenyl)boronic acid or a substituted aryl (phenyl)boronic acid or heteroarylboronic acid in an inert solvent. The inert solvent is selected from THF, diethyl ether, chloroform, dichloromethane, benzene, toluene, N,N-dimethylformamide (DMF) or a mixture of the above solvents.

[0039] In the formula, R5 = derivatives of substituted amino groups can be obtained by reacting derivatives of formula (III) with amines in the presence of a base, Xantphos and dioxane.

[0040]

[0041] According to an embodiment of the present invention, the method includes:

[0042]

[0043] Reagents and reaction conditions: (a) DIAD, pyridine hydrochloride and acetonitrile; (b) bromocyclopropane, Na2CO3 and DMF, room temperature; (c) 2-nitrostyrene and xylene, reflux; (d) base, inert solvent, inert atmosphere, Xantphos, dioxane;

[0044] The definitions of R5 are as described above.

[0045] Terminology Explanation

[0046] In this invention, unless otherwise expressly stated, the terminology used herein has the meanings defined below. Terms not explicitly defined in this invention have their general meanings as commonly understood by those skilled in the art.

[0047] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable, non-toxic acid, including both inorganic and organic acids. Suitable non-toxic acids include, but are not limited to, acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, borneol sulfonic acid, citric acid, vinyl sulfonic acid, formic acid, fumaric acid, furanoic acid, gluconic acid, glutamic acid, glucuronic acid, galacturonic acid, epoxypropionic acid, hydrobromic acid, hydrochloric acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, galactobionic acid, nitric acid, papoic acid, pantothenic acid, phenylacetic acid, propionic acid, phosphoric acid, salicylic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, etc., with hydrochloride salts being preferred.

[0048] "Heteroatom" refers to a nitrogen (N), oxygen (O), or sulfur (S) atom, particularly nitrogen or oxygen, which may be substituted or unsubstituted, including their oxidized forms. Examples of heteroatoms include, but are not limited to, -O-, -N=, -NR-, -S-, -S(O)-, and -S(O)2-, where R is hydrogen, a C1-C4 alkyl group, or a nitrogen-protecting group (e.g., benzyloxycarbonyl, p-methoxybenzylcarbonyl, tert-butoxycarbonyl, acetyl, benzoyl, benzyl, p-methoxy-benzyl, p-methoxy-phenyl, 3,4-dimethoxybenzyl, etc.). Any heteroatom with an unsatisfied valence bond is considered to have a hydrogen atom sufficient to satisfy the valence bond, unless otherwise indicated.

[0049] "Halogen" or "halogenated" refers to fluorine, chlorine, bromine, and iodine. Fluorine and chlorine are preferred halogens as substituents.

[0050] "alkyl" refers to a fully saturated, straight-chain or branched monovalent hydrocarbon group. The number preceding the alkyl group indicates the number of carbon atoms. For example, "C1-C6 alkyl" indicates an alkyl group with 1-6 carbon atoms, and "C1-C4 alkyl" indicates an alkyl group with 1-4 carbon atoms. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, etc. This definition applies whether the term "alkyl" appears alone or as part of other groups such as haloalkyl, alkoxy, etc.

[0051] "alkylene" refers to a fully saturated straight-chain or branched divalent hydrocarbon group. The number before alkylene indicates the number of carbon atoms. For example, "C1-C6 alkylene" indicates alkylene groups with 1-6 carbon atoms, such as methylene-CH2- and ethylene-CH2CH2-.

[0052] "Alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group containing at least one double bond. The number before the alkenyl group indicates the number of carbon atoms. Representative examples of alkenyl groups include, but are not limited to, vinyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, heptenyl, octenyl, etc.

[0053] "Alkenyl" refers to a straight-chain or branched divalent hydrocarbon group containing at least one double bond. The number preceding the alkenyl group indicates the number of carbon atoms. Representative examples of alkenyl groups include, but are not limited to, vinylene-CHCH-.

[0054] "Alkoxy" refers to an alkyl group as defined herein, connected by an oxygen bridge, i.e., an alkyl-O- group. The number before the alkoxy group indicates the number of carbon atoms. For example, "C1-C6 alkoxy" indicates an alkoxy group having 1-6 carbon atoms, i.e., -O-C1-6 alkyl. Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentoxy, and hexoxy.

[0055] "Cycloalkyl" refers to a saturated non-aromatic carbon ring. For example, "C3-C6 cycloalkyl" indicates a cycloalkyl group including C3, C4, C5, and C6. Exemplary monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0056] "Cycloalkenyl" refers to a non-aromatic carbon ring having at least one double bond. For example, "C3-C6 cycloalkenyl" means that it includes C3, C4, C5 and C6 cycloalkenyl groups.

[0057] "Halogenated alkyl" refers to an alkyl group in which one or more hydrogen atoms, for example, one, two, or three hydrogen atoms are replaced by a halogen, as defined herein, and when more than one hydrogen atom is replaced by a halogen atom, the halogen atoms may be the same or different from each other. For example, "C1-C4 halogenated alkyl" means including C1, C2, C3, and C4 halogenated alkyl groups. Examples of halogenated alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, 1,1-difluoroethyl, 1,1,-difluoropropyl, and 1,1,1-trifluoropropyl.

[0058] "Aryl" is a monocyclic, bicyclic, or tricyclic carbocyclic hydrocarbon group consisting of one or more fused rings having, for example, 6-12 ring carbon atoms, wherein at least one ring is an aromatic ring, and the other rings (if present) can be aromatic or non-aromatic, including: monocyclic aryl (e.g., phenyl); or fused bicyclic systems, where one ring is an aromatic ring and the other ring is aromatic (e.g., in naphthalene, biphenyl), etc. Non-limiting examples of aryl groups include phenyl, biphenyl, naphthyl, tetrahydronaphthyl, etc.

[0059] "Heteroaryl" refers to a 5-9 membered aromatic ring system containing one or two cyclic heteroatoms selected from N, O or S, with the remaining cyclic atoms being carbon atoms. It includes monocyclic, bicyclic or fused polycyclic rings, preferably 5-7 membered aromatic heterocycles, and more preferably 5-6 membered. Examples of heteroaryl groups include, but are not limited to: pyrrole, furanyl, thiophene, pyrazolyl, imidazole, triazolyl, thiazolyl, isothiazolyl, oxazolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, oxazinyl, oxadiazinyl, quinolinyl, isoquinolinyl, cyclolinyl, quinazolinyl, quinoxolinyl, benzoxazinyl, 2H-chromene, benzopyranyl, benzothiophene, indoleyl, inazolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, 7-azaindoleyl, 6-azaindoleyl, 5-azaindoleyl, 4-azaindoleyl, 1H-benzo[d][1,2,3]triazolyl, etc.

[0060] "Acyl" refers to a group containing RC (=O)-, where R represents an alkyl group with a single bond attached to C=O.

[0061] As used herein, the terms “substituted,” “substituted,” or “replaced by” mean that one or more hydrogen atoms on a given atom or group are replaced by one or more substituents selected from a given group of substituents, provided that the replacement does not exceed the normal valence of the given atom.

[0062] In this invention, the complex substituent AB indicates that B is connected to the parent nucleus and is simultaneously replaced by group A. For example, "C3-C6 cycloalkyl C1-C6 alkyl" indicates that the parent nucleus is connected through C1-C6 alkyl, while C1-C6 alkyl is replaced by C3-C6 cycloalkyl.

[0063] In this invention, "substituted or unsubstituted" or "unsubstituted or substituted by..." means that the defined group is unsubstituted or substituted by... For example, in "unsubstituted or substituted by substituents selected from group A of C3-C6 cycloalkyl C1-C6 alkyl", "unsubstituted or substituted by substituents selected from group A" is used to define C3-C6 cycloalkyl.

[0064] According to another aspect of the invention, a composition is provided comprising a therapeutically effective amount of a derivative of general formula (I) or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutical excipient.

[0065] According to another aspect of the invention, a derivative of general formula (I) or a pharmaceutically acceptable salt thereof is provided, or the use of said composition in the preparation of an opioid receptor-mediated therapeutic agent is provided.

[0066] According to another aspect of the invention, a derivative of general formula (I) or a pharmaceutically acceptable salt thereof is provided, or the use of said composition in the preparation of a medicament for treating and / or preventing pain, addiction, depression, or anxiety.

[0067] According to the present invention, the pain includes pain during surgery, chronic pain, neuropathic pain, and cancer pain.

[0068] Beneficial effects

[0069] Compared with the prior art, the derivatives of general formula (I) provided by the present invention have significantly improved the agonistic activity and subtype selectivity of δ / κ opioid receptors, which is non-obvious. Attached Figure Description

[0070] Figure 1 The DOR agonist activity exhibited by compounds 14 and 18 of the present invention in a cAMP inhibition assay is shown. Detailed Implementation

[0071] The 7α-substituted phenyltetrahydrothebaine derivatives involved in this invention can be used to determine the affinity and selectivity of the ligand for three opioid receptors by radioreceptor ligand binding assays, and the receptor agonist activity of the compound can be determined by cAMP inhibition assays.

[0072] Referring to the following specific embodiments will make it easier to understand the features, technical solutions, and advantages described in this invention.

[0073] Unless otherwise specified, the raw materials, reagents, equipment, and methods used in this application are all conventional or commercially available in the field.

[0074] Mass spectrometry data for all relevant compounds were obtained using an Agilent 1100 Series LC / MSD1946D mass spectrometer and expressed as mass-to-nucleus ratio (m / z). High-resolution mass spectrometry (ESI-HRMS) was performed using an AB SCIEX TRIPLE TOF 5600+ mass spectrometer. Melting points of solids were determined using a capillary method on a WRS-1B digital melting point apparatus. 1 H NMR was measured on a Varian Mercury plus 400MHz NMR spectrometer. 13 CNMR measurements were performed on a Bruker 600 MHz NMR spectrometer. All chemical shift values ​​are expressed as δ in ppm, and coupling constants are expressed in J in Hz. Peak types are s for singlet, d for doublet, t for triplet, q for quartet, m for multiplet, and br for broad peak.

[0075] The solvents used in the reaction were purchased from Sinopharm Shanghai Chemical Reagent Co., Ltd., and were of analytical grade. Chemical reagents were purchased from companies such as Tansuo Chemical, Sinopharm, Bailingwei, Maclean's, Acros, and Aldrich. Other solvents, including petroleum ether, ethyl acetate, dichloromethane, and methanol, were purchased from Sinopharm Group and were all of synthetic grade. The column chromatography silica gel used was reagent-grade ZCXII type silica gel from Rushan Taiyang Desiccant Co., Ltd., with a particle size of 200-300 mesh; the analytical thin-layer chromatography silica gel plates used were GF254 type silica gel plates (0.15mm-0.2mm) from Rushan Taiyang Desiccant Co., Ltd.; and the preparative thin-layer chromatography plates used were GF254 type silica gel plates (0.5mm) from Rushan Taiyang Desiccant Co., Ltd. This invention will be illustrated through the following examples.

[0076] Example 1: Synthesis of N-cyclopropylmethyl-desmethylthebaine (compound ii)

[0077]

[0078] Thebaine (2.0 g, 6.4 mmol, 1.0 equivalent) was dissolved in 40 mL of anhydrous acetonitrile. A solution of diisopropyl azodicarbonate (DIAD) (1.8 mL, 8.3 mL, 1.3 equivalent) dissolved in 2 mL of anhydrous acetonitrile was slowly added dropwise. The mixture was purged with argon, and the system was heated to 90 °C and refluxed for 5 h. The mixture was then cooled to room temperature, and the solvent was removed by concentration under reduced pressure. 20 mL of methanol was added to the residue to dissolve it, followed by the addition of pyridine hydrochloride (PyHCl) (2.2 g, 19.2 mmol, 3 equivalent). The mixture was stirred at room temperature and reacted overnight. The solution was filtered under reduced pressure to obtain 1.3 g of a white solid, with a yield of 61%.

[0079]

[0080] Compound i (800 mg, 2.4 mmol, 1.0 equivalent), anhydrous sodium carbonate (763 mg, 7.2 mmol, 3 equivalent), and DMF (10 mL) were added to a 50 mL round-bottom flask and stirred. Bromomethylcyclopropane (430 mg, 3.12 mmol, 1.3 equivalent) was then added dropwise to the system to replace the argon atmosphere. The mixture was heated to 90 °C and reacted for 2 h. The reaction was monitored by TLC until complete. EA (30 mL × 2) and water (20 mL) were added to the reaction solution for extraction. The mixture was separated, and the organic phases were combined. The organic phases were washed with saturated brine (50 mL × 4), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by silica gel column chromatography (PE / EA = 5 / 1) to obtain 610 mg of a yellow oily liquid ii, with a yield of 72%. ESI-MS [M+H] + 352.2.

[0081] Example 2: Synthesis of N-cyclopropylmethyl-7α-4′-bromobenzene-6,14-neinethylenetetrahydrodestybaine (compound iii)

[0082]

[0083] Compound ii (400 mg, 1.1 mmol, 1.0 equivalent) and p-bromostyrene (421 mg, 2.3 mmol, 2.0 equivalent) were dissolved in 5 mL of xylene, purged with argon, and the mixture was heated to 140 °C and refluxed overnight. The reaction was monitored by TLC until completion. The solvent was removed by concentration under reduced pressure, and the residue was separated by silica gel column chromatography (PE / EA = 10 / 1) to give 244 mg of yellow oily liquid iii, in 38% yield. 1 H NMR (400MHz, CDCl3) δ7.35(d,J=8.3Hz,2H),7.09(d,J=8.3Hz,2H),6.64(d,J=7.9Hz,1H),6.54(d,J=7.8 Hz,1H),5.91(d,J=8.4Hz,1H),5.63(d,J=8.6Hz,1H),4.73(s,1H),3.82(s,3H),3.56(d,J=15.9Hz,1H), 3.34(s,3H),3.13(d,J=18.5Hz,1H),3.01(s,1H),2.71(s,1H),2.49–2.37(m,3H),2.33(s,1H),2.09(s, 1H),1.92(d,J=12.1Hz,1H),1.27(d,J=12.4Hz,2H),0.80(s,1H),0.49(s,2H),0.12(s,2H).ESI-MS[M+H] + 534.2.

[0084] Example 3: Synthesis of N-cyclopropylmethyl-7α-4′-biphenyl-6,14-neinylvinyltetrahydrodestybaine (Compound 1)

[0085]

[0086] Compound iii (60 mg, 0.11 mmol, 1.0 equivalent), anhydrous potassium carbonate (51 mg, 0.33 mmol, 3.0 equivalent), phenylboronic acid (15 mg, 0.12 mmol, 1.1 equivalent), and toluene (4 mL) were added to a 15 mL sealed tube. After stirring and purging with argon, Pd(PPh3)4 (6.9 mg, 10% equivalent) was added to the reaction solution. The mixture was heated to 110 °C and refluxed for 5 h. The reaction was monitored by TLC until it ended. The reaction solution was diluted with ethyl acetate (10 mL), washed with saturated NH4Cl solution (5 mL × 3), washed with saturated Na2CO3 solution (5 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was then separated by preparative thin-layer chromatography (DCM / MeOH = 20 / 1) to give 35 mg of pale yellow oily liquid 1, yield: 59%. 1 H NMR (400MHz, CDCl3) δ7.56(d,J=7.4Hz,2H),7.47(d,J=7.9Hz,2H),7.41(t,J=7.4Hz,2H),7.30(t,J=8.3Hz,3H ),6.64(d,J=8.1Hz,1H),6.54(d,J=8.0Hz,1H),5.98(t,J=7.6Hz,1H),5.65(d,J=8.7Hz,1H),4.75(d,J=24.4H z, 1H), 3.83(s, 3H), 3.57(s, 1H), 3.37(s, 3H), 3.12(t, J = 14.1 Hz, 2H), 2.73(s, 1H), 2.43(t, J = 27.9 Hz, 4H), 2.14(s, 1H), 1.94(d, J = 11.6 Hz, 1H), 1.43–1.19(m, 2H), 0.81(s, 1H), 0.54–0.42(m, 2H), 0.13(s, 2H). HMRS: Calculated values: C 36 H 37 NO3([M+H)) + 532.2846, Measured value: 532.2845.

[0087] Example 4: Synthesis of N-cyclopropylmethyl-7α-4′-(2″-methylbiphenyl)-6,14-neinethylenetetrahydrodestybaine (Compound 2)

[0088]

[0089] Following the synthetic method of compound 1, phenylboronic acid was replaced with o-methylphenylboronic acid to synthesize yellow oily compound 2, with a yield of 34%. 1H NMR (400MHz, CDCl3) δ7.27–7.18(m,8H),6.64(s,1H),6.55(s,1H),5.99(s,1H), 5.65(d,J=5.1Hz,1H),4.78(s,1H),3.83(s,3H),3.56(s,1H),3.43(s,1H),3.37( s,3H),3.14(d,J=20.3Hz,2H),2.73(s,1H),2.44(s,3H),2.34(s,1H),2.27(s,3H ),2.14(s,1H),1.96(s,1H),1.40(s,1H),0.81(s,1H),0.49(s,2H),0.13(s,2H). 13 C NMR (151MHz, CDCl3) δ148.36,141.82,141.38,139.73,136.17,135.39,1 34.70,130.25,129.86,128.86,128.60,128.36,127.75,127.01,125.68 ,119.17,113.36,94.36,81.78,59.85,57.21,56.61,51.85,48.03,44.2 5,43.51,43.47,37.41,34.11,23.23,20.55,9.53,4.20,3.35.ESIMS: m / z 546.3([M+H + ],100).HMRS: Calculated value: C 37 H 39 NO3([M+H)) + 546.3003, Measured value: 546.3003.

[0090] Example 5: Synthesis of N-cyclopropylmethyl-7α-4′-(3″-methylbiphenyl)-6,14-neinethylenetetrahydrodestybaine (compound 3)

[0091]

[0092] Following the synthetic method of compound 1, but replacing phenylboronic acid with m-methylphenylboronic acid, a yellow oily compound 3 was synthesized in a yield of 34%. 1H NMR (400MHz, CDCl3) δ7.46(d,J=8.0Hz,2H),7.37(d,J=8.5Hz,2H),7.28(dt,J=7.3,6.5Hz,3H),7.13(d,J=7.2Hz,1H), 6.65(d,J=8.2Hz,1H),6.55(d,J=7.9Hz,1H),5.97(d,J=8.4Hz,1H),5.65(d,J=8.7Hz,1H),4.78(s,1H),3.83(s,3H),3 0.57(s, 1H), 3.40(s, 1H), 3.37(s, 3H), 3.14(d, J = 18.3Hz, 2H), 2.74(s, 1H), 2.51–2.37(m, 6H), 2.34(d, J = 5.6Hz, 1H), 2.14(s, 1H), 1.94(d, J = 11.9Hz, 1H), 1.40(d, J = 6.2Hz, 1H), 0.81(s, 1H), 0.50(d, J = 8.0Hz, 2H), 0.13(s, 2H). HMRS: Calculated value: C 37 H 39 NO3([M+H)) + 546.3003, Measured value: 546.3003.

[0093] Example 6: Synthesis of N-cyclopropylmethyl-7α-4′-(4″-methylbiphenyl)-6,14-neinethylenetetrahydrodestybaine (compound 4)

[0094]

[0095] Following the synthetic method of compound 1, but replacing phenylboronic acid with p-methylphenylboronic acid, a pale yellow oily compound 4 was synthesized in a yield of 57%. 1H NMR (400MHz, CDCl3) δ7.45(d,J=3.6Hz,4H),7.25(d,J=20.2Hz,4H),6.66–6.61(m,1H),6.53(d,J=4 .4Hz,1H),5.96(d,J=5.6Hz,1H),5.64(d,J=5.0Hz,1H),4.78(s,1H),3.82(s,3H),3.56(s,1H),3.4 1(s,1H),3.37(s,3H),3.13(d,J=18.8Hz,2H),2.71(s,1H),2.45(s,3H),2.37(s,3H),2.33(s,1H), 2.13(s,1H),1.93(d,J=12.6Hz,1H),1.38(d,J=6.5Hz,1H),0.80(s,1H),0.48(s,2H),0.12(s,2H). 13 C NMR (151MHz, CDCl3) δ 148.32, 141.84, 141.74, 138.99, 138.16, 136.67, 136.13, 134.66, 129.38, 129.26, 128.32, 127.88, 126.79, 126.56, 119.17, 113.32, 94.22, 81.75, 59.79, 57.13, 56.56, 51.77, 48.03, 44.25, 43.43, 43.32, 37.35, 34.09, 23.20, 21.07, 9.50, 4.23, 3.30. HMRS: Calculated values: C 37 H 39 NO3([M+H)) + 546.3003, Measured value: 546.3005.

[0096] Example 7: Synthesis of N-cyclopropylmethyl-7α-4′-(4″-trifluoromethylbiphenyl)-6,14-neinethylenetetrahydrodestybaine (compound 5)

[0097]

[0098] Following the synthetic method of compound 1, phenylboronic acid was replaced with p-trifluoromethylphenylboronic acid to synthesize colorless and transparent liquid 5, with a yield of 24%. 1H NMR (400MHz, CDCl3) δ7.66(s,4H),7.48(d,J=7.6Hz,2H),7.33(d,J=7.7Hz,2H),6.65(d,J=7.8Hz,1 H),6.55(d,J=7.4Hz,1H),5.97(d,J=8.0Hz,1H),5.67(d,J=8.6Hz,1H),4.79(s,1H),3.83(s,3H),3. 57(s,1H),3.44(s,1H),3.39(s,3H),3.15(d,J=17.7Hz,2H),2.73(s,1H),2.47(d,J=13.1Hz,3H),2. 34(s,1H),2.14(s,1H),1.95(d,J=12.7Hz,1H),1.38(s,1H),0.81(s,1H),0.49(s,2H),0.13(s,2H). 13 C NMR (151MHz, CDCl3) δ 148.31, 144.56, 143.26, 141.87, 137.59, 136.31, 134.59, 129.56, 129.05 (q, J = 32.3Hz), 128.31, 127.80, 127.20, 126.91, 125.63 (d, J = 3.2Hz), 119.24, 113.35, 94.27, 81.75, 59.82, 57.15, 56.59, 51.88, 48.10, 44.26, 43.47, 43.43, 37.32, 34.11, 23.22, 9.51, 4.23, 3.32. HMRS: Calculated values: C 37 H 36 F3NO3([M+H) + 600.2720, Measured value: 600.2712.

[0099] Example 8: Synthesis of N-cyclopropylmethyl-7α-4′-(4″-methoxybiphenyl)-6,14-neinethylenetetrahydrodestybaine (compound 6)

[0100]

[0101] Following the synthetic method of compound 1, phenylboronic acid was replaced with p-methoxyphenylboronic acid to synthesize colorless and transparent liquid 6, with a yield of 28%. 1H NMR(400MHz, CDCl3)δ7.50(dd,J=7.1,3.9Hz,2H),7.43(s,2H),7.27(s,2H),7.00–6.94(m ,2H),6.65(s,1H),6.56(s,1H),5.97(s,1H),5.66(d,J=3.1Hz,1H),4.79(s,1H),3.85–3.8 2(m,6H),3.57(s,1H),3.45–3.35(m,4H),3.14(d,J=19.1Hz,2H),2.72(s,1H),2.39(d,J=4 1.4Hz,4H),2.14(s,1H),1.96(s,1H),1.38(s,1H),0.80(s,1H),0.49(s,2H),0.13(s,2H). 13 C NMR (151MHz, CDCl3) δ 158.95, 148.35, 141.85, 141.41, 138.70, 136.14, 134.68, 133.64, 129.28, 128.34, 127.97, 126.36, 119.18, 114.13, 113.31, 94.23, 81.75, 59.80, 57.12, 56.58, 55.32, 51.78, 48.05, 44.28, 43.44, 43.29, 37.36, 34.11, 23.21, 9.51, 4.24, 3.30. HMRS: Calculated values: C 37 H 39 NO4([M+H)) + 562.2952, Measured value: 562.2948.

[0102] Example 9: Synthesis of N-cyclopropylmethyl-7α-4′-(4″-chlorobiphenyl)-6,14-neinethylenetetrahydrodestybaine (compound 7)

[0103]

[0104] Following the synthetic method of compound 1, phenylboronic acid was replaced with p-chlorophenylboronic acid to synthesize a yellow oily liquid 7, with a yield of 28%. 1H NMR (400MHz, CDCl3) δ7.48(d,J=7.8Hz,2H),7.43(d,J=7.5Hz,2H),7.37(d,J=7.2Hz,2H),7.29(d,J=7.3Hz,2H),6.64( d,J=7.7Hz,1H),6.55(d,J=7.8Hz,1H),5.96(d,J=8.3Hz,1H),5.66(d,J=8.6Hz,1H),4.78(s,1H),3.83(s,3H),3.57(s, 1H),3.43(d,J=9.7Hz,1H),3.38(s,3H),3.14(d,J=18.5Hz,2H),2.73(d,J=6.9Hz,1H),2.45(t,J=12.5Hz,3H),2.34(d, J=5.9Hz,1H),2.14(s,1H),1.94(d,J=12.7Hz,1H),1.42–1.32(m,1H),0.80(s,1H),0.49(d,J=7.8Hz,2H),0.13(s,2H). 13 C NMR (151MHz, CDCl3) δ 148.31, 142.53, 141.87, 139.49, 137.83, 136.25, 134.61, 133.05, 129.45, 128.82, 128.31, 128.20, 127.83, 126.60, 119.23, 113.34, 94.22, 81.73, 59.79, 57.13, 56.58, 51.83, 48.06, 44.26, 43.44, 43.34, 37.30, 34.09, 23.22, 9.50, 4.24, 3.31. HMRS: Calculated values: C 36 H 36 ClNO3([M+H)) + 566.2456, Measured value: 566.2454.

[0105] Example 10: Synthesis of N-cyclopropylmethyl-7α-4′-(2″-ethylbiphenyl)-6,14-neinethylenetetrahydrodestybaine (Compound 8)

[0106]

[0107] Following the synthetic method of compound 1, o-ethylphenylboronic acid was replaced with phenylboronic acid to synthesize a yellow oily liquid 8 with a yield of 46%. 1H NMR (400MHz, CDCl3) δ7.29(s,2H),7.24(d,J=6.6Hz,2H),7.21–7.15(m,4H),6.65(d,J=8.0Hz,1H),6.55(d,J=8.1Hz,1H) ,5.99(d,J=8.6Hz,1H),5.65(d,J=8.7Hz,1H),4.78(s,1H),3.83(s,3H),3.56(d,J=5.0Hz,1H),3.44(t,J=10.9Hz,1H),3. 37(s,3H),3.16(s,0.5H),3.12(s,1.5H),2.79–2.70(m,1H),2.59(q,J=7.5Hz,2H),2.51–2.40(m,3H),2.34(d,J=6.2Hz,1 H),2.15(s,1H),1.95(d,J=12.1Hz,1H),1.45–1.34(m,1H),1.09(t,J=7.5Hz,3H),0.81(s,1H),0.49(s,2H),0.13(s,2H). 13 C NMR (151MHz, CDCl3) δ148.37,141.85,141.65,141.54,141.33,139.75,136. 18,134.70,130.07,128.87,128.55,128.48,128.36,127.70,127.25,125.48 ,119.17,113.37,94.39,81.78,59.86,57.24,56.61,51.86,48.03,44.23,43.55,43.47,37.40,34.11,26.10,23.23,15.62,9.53,4.18,3.37.HMRS: Calculated value: C 38 H 41 NO3([M+H)) + 560.3159, Measured value: 560.3154.

[0108] Example 11: Synthesis of N-cyclopropylmethyl-7α-4′-(3″,4″-dimethylbiphenyl)-6,14-neinylvinyltetrahydrodestybaine (compound 9)

[0109]

[0110] Following the synthetic method of compound 1, phenylboronic acid was replaced with 3,4-dimethylphenylboronic acid to synthesize a yellow oily liquid 9, with a yield of 17%. 1H NMR (400MHz, CDCl3) δ7.46(d,J=7.7Hz,2H),7.36(s,1H),7.30(dd,J=13.5,6.7Hz,3H),7.19(d,J=7.6Hz,1H), 6.66(d,J=8.3Hz,1H),6.56(d,J=7.5Hz,1H),5.99(d,J=7.8Hz,1H),5.67(d,J=8.7Hz,1H),4.80(s,1H),3.85(s ,3H), 3.59(s,1H), 3.43(s,1H), 3.39(s,3H), 3.16(d,J=18.6Hz,2H), 2.75(s,1H), 2.46(s,3H), 2.31(d,J=8.9Hz,6H), 2.16(s,1H), 1.98(s,1H), 1.41(s,1H), 1.27(s,1H), 0.83(s,1H), 0.51(s,2H), 0.15(s,2H). HMRS: Calculated value: C 38 H 41 NO3([M+H)) + 560.3159, Measured value: 560.3156.

[0111] Example 12: Synthesis of N-cyclopropylmethyl-7α-4′-(2″,4″-dimethylbiphenyl)-6,14-neinylvinyltetrahydrodestybaine (Compound 10)

[0112]

[0113] Following the synthetic method of compound 1, phenylboronic acid was replaced with 2,4-dimethylphenylboronic acid to synthesize a yellow oily liquid 10, with a yield of 34%. 1H NMR (400MHz, CDCl3) δ7.26(s,1H),7.23(s,1H),7.18(d,J=7.7Hz,2H),7.13(d,J=7.7Hz,1H),7.09–7.02(m,2H),6.65(d,J =8.0Hz,1H),6.55(d,J=7.9Hz,1H),5.98(d,J=8.5Hz,1H),5.65(d,J=8.8Hz,1H),4.78(s,1H),3.83(s,3H),3.57(s,1H),3 .44(d,J=12.5Hz,1H),3.37(s,3H),3.14(d,J=18.6Hz,2H),2.73(s,1H),2.46(d,J=11.7Hz,2H),2.35(s,3H),2.24(s,3H) ,2.15(s,1H),1.94(d,J=11.1Hz,1H),1.69(s,1H),1.45–1.36(m,1H),1.26(s,1H),0.81(s,1H),0.49(s,2H),0.13(s,2H). 13 C NMR (151MHz, CDCl3) δ 148.36, 141.85, 141.17, 139.69, 138.97, 136.61, 136.14, 135.17, 134.70, 131.04, 129.81, 128.94, 128.56, 128.35, 127.77, 126.40, 119.17, 113.35, 94.34, 81.77, 59.83, 57.19, 56.60, 51.82, 48.02, 44.25, 43.46, 37.40, 34.10, 23.22, 21.02, 20.46, 9.52, 4.21, 3.34. HMRS: Calculated values: C 38 H 41 NO3([M+H)) + 560.3159, Measured value: 560.3158.

[0114] Example 13: Synthesis of N-cyclopropylmethyl-7α-4′-(2″,6″-dimethylbiphenyl)-6,14-neinylvinyltetrahydrodestybaine (compound 11)

[0115]

[0116] Following the synthetic method of compound 1, phenylboronic acid was replaced with 2,6-dimethylphenylboronic acid to synthesize a yellow oily liquid 11, with a yield of 17%. 1H NMR (400MHz, CDCl3) δ7.26(d,J=4.1Hz,2H),7.14(d,J=6.3Hz,1H),7.09(d,J=7.1Hz,2H),7.00(d,J=7.5Hz,2H),6.65(d,J= 8.1Hz,1H),6.54(d,J=8.1Hz,1H),6.00(d,J=8.6Hz,1H),5.66(d,J=8.8Hz,1H),4.76(s,1H),3.84(s,3H),3.56(d,J=6.2Hz ,1H), 3.42(s,1H), 3.32(s,3H), 3.12(dd,J=20.9,12.8Hz,2H), 2.75(s,1H), 2.51–2.39(m,3H), 2.38–2.30(m,1H), 2.16(d,J=11.9Hz,1H), 2.01(s,6H), 1.95(d,J=11.9Hz,1H), 1.45–1.37(m,1H), 0.82(s,1H), 0.50(s,2H), 0.14(s,2H). HMRS: Calculated values: C 38 H 41 NO3([M+H)) + 560.3159, Measured value: 560.3153.

[0117] Example 14: Synthesis of N-cyclopropylmethyl-7α-4′-(3″-furan)-phenyl-6,14-neinethylenetetrahydrodestybaine (compound 12)

[0118]

[0119] Following the synthetic method of compound 1, phenylboronic acid was replaced with 3-furanboronic acid to synthesize a yellow oily liquid 12, with a yield of 43%. 1H NMR (400MHz, CDCl3) δ7.69(s,1H),7.45(s,1H),7.36(d,J=6.7Hz,2H),7.24(s,2H),6.65(d,J=1 2.3Hz,2H),6.55(s,1H),5.95(d,J=7.0Hz,1H),5.64(d,J=8.2Hz,1H),4.77(s,1H),3.83(s,3H), 3.56(s,1H),3.40(s,1H),3.35(s,3H),3.17–3.05(m,2H),2.78–2.69(m,1H),2.44(s,3H),2.35( s,1H),2.13(s,1H),1.94(d,J=11.4Hz,1H),1.34(s,1H),0.80(s,1H),0.49(s,2H),0.13(s,2H). 13 C NMR (151MHz, CDCl3) δ 148.34, 143.51, 141.87, 138.25, 136.16, 134.64, 130.40, 129.34, 128.31, 127.83, 126.34, 125.59, 119.21, 113.34, 108.86, 94.22, 81.70, 59.79, 57.13, 56.58, 51.77, 48.02, 44.26, 43.41, 37.23, 34.08, 30.91, 23.22, 9.49, 4.22, 3.32. HMRS: Calculated values: C 34 H 35 NO4([M+H)) + 522.2639, Measured value: 522.2634.

[0120] Example 15: Synthesis of N-cyclopropylmethyl-7α-4′-(3″-thiophene)-phenyl-6,14-neinylethenetetrahydrodestybaine (compound 13)

[0121]

[0122] Following the synthetic method of compound 1, phenylboronic acid was replaced with 3-thiopheneboronic acid to synthesize a pale yellow oily liquid 13, with a yield of 44%. 1H NMR (400MHz, CDCl3) δ7.47 (s, 2H), 7.37 (d, J = 15.9Hz, 3H), 7.25 (s, 2H), 6.64 (s, 1H) ),6.55(s,1H),5.96(s,1H),5.65(s,1H),4.77(s,1H),3.82(s,3H),3.56(s,1H),3. 40(s,1H),3.36(s,3H),3.13(d,J=21.0Hz,2H),2.72(s,1H),2.44(s,3H),2.34(s, 1H),2.12(s,1H),1.95(s,1H),1.36(s,1H),0.80(s,1H),0.49(s,2H),0.12(s,2H). 13 C NMR (151MHz, CDCl3) δ148.35,142.26,141.87,136.17,134.64,133.90,129.35,128.33,127.83,126.32,126.13,125.99,119.80,119 .21,113.32,94.24,81.72,59.80,57.13,56.59,51.79,48.04,44.26,43.40,37.25,34.08,30.92,23.22,9.51,4.22,3.32.ESIMS: m / z 538.2([M+H + ],100).HMRS: Calculated value: C 34 H 35 NO3S([M+H)) + 538.2410, Measured value: 538.2408.

[0123] Example 16: Synthesis of N-cyclopropylmethyl-7α-4′-(N′-phenylamine)-phenyl-6,14-neinethylenetetrahydrodestybaine (compound 14)

[0124]

[0125] Compound iii (100 mg, 0.19 mmol, 1.0 equivalent), anhydrous cesium carbonate (124 mg, 0.38 mmol, 2.0 equivalent), Xantphos (23 mg, 0.04 mmol, 0.2 equivalent), and dioxane (4 mL) were added to a 15 mL sealed tube. Aniline (92 mg, 0.19 mmol, 1.0 equivalent) and Pd2(dba)3 (10 mg, 10% equivalent) were then added. The mixture was purged with argon, heated to 110 °C, and refluxed for 2 h. The reaction was monitored by TLC until complete. After the reaction solution was evaporated to dryness, EA (10 mL × 3) and saturated NH4Cl (15 mL) were added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was separated by silica gel column chromatography (PE / EA = 5 / 1) to give a pale yellow oily compound 14, yield: 40%. 1 H NMR (400MHz, CDCl3) δ7.22(d,J=7.8Hz,2H),7.11(d,J=8.1Hz,2H),7.03(d,J=8.0Hz,2H),6.96(d,J=8.2Hz,2H),6 .88(t,J=7.2Hz,1H),6.64(d,J=7.8Hz,1H),6.54(d,J=7.5Hz,1H),5.93(d,J=7.9Hz,1H),5.68(s,1H),5.62(d,J= 8.7Hz,1H),4.76(s,1H),3.82(s,3H),3.55(s,1H),3.34(d,J=12.3Hz,4H),3.13(d,J=18.7Hz,1H),3.01(s,1H),2 .70(s,1H),2.38(d,J=35.7Hz,4H),2.12(s,1H),1.94(s,1H),1.33(s,1H),0.81(s,1H),0.49(s,2H),0.14(s,2H). 13 C NMR (151MHz, CDCl3) δ 148.35, 143.48, 141.84, 141.23, 136.04, 135.58, 134.72, 129.74, 129.25, 128.34, 127.85, 120.50, 119.14, 117.85, 117.35, 113.29, 94.26, 81.72, 59.80, 57.15, 56.58, 51.71, 47.99, 44.26, 43.39, 42.92, 37.26, 34.07, 23.20, 9.52, 4.22, 3.32. HMRS: Calculated values: C 36 H 38 N₂O₃([M+H)) +547.2955, Measured value: 547.2969.

[0126] Example 17: Synthesis of N-cyclopropylmethyl-7α-4′-(N′-4″-methylphenylamine)-phenyl-6,14-neinethylenetetrahydrodestybaine (compound 15)

[0127]

[0128] Following the synthetic method of compound 14, aniline was replaced with p-methylaniline to synthesize a pale yellow oily liquid 15, with a yield of 38%. 1 H NMR (400MHz, CDCl3) δ7.06(dd,J=12.1,8.3Hz,4H),6.95(d,J=8.1Hz,2H),6.90(d,J=8.2Hz,2H),6.63(d,J=8.0Hz,1 H),6.53(d,J=8.1Hz,1H),5.91(d,J=8.6Hz,1H),5.63–5.53(m,2H),4.75(s,1H),3.82(s,3H),3.53(s,1H),3.37(d,J =17.2Hz,4H),3.12(d,J=18.3Hz,1H),2.99(s,1H),2.70(s,1H),2.41(dd,J=24.9,16.2Hz,3H),2.33(d,J=6.0Hz,1H ),2.28(s,3H),2.10(s,1H),1.91(d,J=12.0Hz,1H),1.36–1.30(m,1H),0.80(s,1H),0.53–0.43(m,2H),0.12(s,2H). 13 C NMR (151MHz, CDCl3) δ 148.34, 142.04, 141.82, 140.67, 135.99, 134.80, 134.73, 130.32, 129.75, 129.68, 128.33, 127.87, 119.11, 118.36, 116.88, 113.28, 94.25, 81.72, 59.79, 57.15, 56.56, 51.68, 47.96, 44.25, 43.38, 42.86, 37.26, 34.06, 23.19, 20.64, 9.51, 4.21, 3.32. HMRS: Calculated values: C 37 H 40 N₂O₃([M+H)) + 561.3112, Measured value: 561.3128.

[0129] Example 18: Synthesis of N-cyclopropylmethyl-7α-4′-(N′-4″-methylphenylamine)-phenyl-6,14-neinethylenetetrahydrodestybaine (compound 16)

[0130]

[0131] Following the synthetic method of compound 14, aniline was replaced with p-trifluoromethylaniline to synthesize yellow powder solid 16, with a yield of 41%. 1 H NMR (400MHz, CDCl3) δ7.42 (s, 2H), 7.16 (s, 2H), 7.00 (s, 4H), 6.59 (d, J = 32.8Hz, 2 H),5.96(d,J=35.6Hz,2H),5.62(s,1H),4.76(s,1H),3.82(s,3H),3.55(s,1H),3. 36(s,4H),3.13(d,J=18.5Hz,1H),3.04(s,1H),2.72(s,1H),2.38(d,J=36.2Hz,4 H),2.11(s,1H),1.94(s,1H),1.34(s,1H),0.81(s,1H),0.49(s,2H),0.13(s,2H). 13 C NMR (151MHz, CDCl3) δ148.37,147.15,141.92,139.36,137.65,136.30,134.69,129.9 8,128.39,127.79,126.66(d,J=3.2Hz),125.65,123.85,121.18(q,J=32.7Hz),120.0 2,119.30,115.05,113.39,94.30,81.81,59.88,57.24,56.63,51.81,48.09,44.29,43.48,43.09,37.30,34.13,31.57,30.21,29.76,23.27,9.57,4.26,3.41.HMRS: Calculated value: C 37 H 37 F3N2O3([M+H) + 615.2829, Measured value: 615.2840.

[0132] Example 19: Synthesis of N-cyclopropylmethyl-7α-4′-(N′-4″-methoxyphenylamine)-phenyl-6,14-neinethylenetetrahydrodestybaine (Compound 17)

[0133]

[0134] Following the synthetic method of compound 14, aniline was replaced with p-methoxyaniline to synthesize a pale yellow powdery solid 17, with a yield of 24%. 1 H NMR (400MHz, CDCl3) δ7.04 (s, 4H), 6.82 (d, J = 6.3Hz, 4H), 6.64 (s, 1H), 6.55 (s, 1H), 5.92 ( s,1H),5.60(d,J=8.2Hz,1H),5.48(s,1H),4.75(s,1H),3.80(d,J=14.3Hz,6H),3.55(s,1 H),3.36(d,J=10.8Hz,4H),3.13(d,J=17.0Hz,1H),2.99(s,1H),2.72(s,1H),2.43(s,4H) ,2.11(s,1H),1.93(s,1H),1.31(d,J=15.4Hz,1H),0.82(s,1H),0.49(s,2H),0.13(s,2H). 13 C NMR (151MHz, CDCl3) δ 154.98, 148.44, 143.37, 141.93, 136.26, 136.03, 134.06, 129.77, 128.40, 127.99, 121.62, 119.23, 115.74, 114.85, 114.69, 113.37, 94.25, 81.76, 59.82, 57.18, 56.65, 55.66, 51.71, 48.00, 44.36, 43.41, 42.81, 37.29, 34.12, 23.29, 9.56, 4.31, 3.38. HMRS: Calculated values: C 37 H 40 N₂O₄([M+H)) + 577.3061, Measured value: 577.3047.

[0135] Example 20: Synthesis of N-cyclopropylmethyl-7α-4′-(N′-4″-chlorophenylamine)-phenyl-6,14-neinethylenetetrahydrodestybaine (compound 18)

[0136]

[0137] Following the synthetic method of compound 14, aniline was replaced with p-chloroaniline to synthesize a white powdery solid 18, with a yield of 31%. 1H NMR (400MHz, CDCl3) δ7.14(dd,J=19.4,7.9Hz,4H),6.93(t,J=7.0Hz,4H),6.64(d,J=7.9Hz,1H),6 .54(d,J=7.8Hz,1H),5.91(d,J=8.2Hz,1H),5.71(s,1H),5.61(d,J=8.6Hz,1H),4.75(s,1H),3.82( s,3H),3.54(s,1H),3.35(s,4H),3.13(d,J=18.4Hz,1H),3.01(s,1H),2.71(s,1H),2.38(d,J=39. 1Hz,4H),2.11(s,1H),1.92(d,J=12.1Hz,1H),1.33(s,1H),0.81(s,1H),0.49(s,2H),0.13(s,2H). 13 C NMR (151MHz, CDCl3) δ 148.32, 142.24, 141.83, 140.75, 136.11, 134.66, 129.82, 129.15, 128.32, 127.79, 124.87, 119.17, 118.30, 118.10, 113.30, 94.22, 81.72, 72.78, 59.79, 57.16, 56.56, 51.70, 47.99, 44.23, 43.39, 42.91, 37.23, 34.06, 23.19, 9.51, 4.20, 3.33. HMRS: Calculated values: C 36 H 37 ClN2O3([M+H) + 581.2565, Measured value: 581.2578.

[0138] Example 21: Synthesis of N-cyclopropylmethyl-7α-4′-[N′-4″-(hexafluoro-2″′-hydroxyisopropyl)phenylamine]-phenyl-6,14-neinethylenetetrahydrodestybaine (compound 19)

[0139]

[0140] Following the synthetic method of compound 14, aniline was replaced with 4-(hexafluoro-2-hydroxyisopropyl)aniline to synthesize a pale yellow oily liquid 19, with a yield of 25%. 1H NMR (400MHz, CDCl3) δ7.51(d,J=8.2Hz,2H),7.14(s,2H),7.01(d,J=8.1Hz,4H),6.64(d,J=7.3Hz,1H ),6.55(s,1H),5.96–5.83(m,2H),5.63(d,J=8.6Hz,1H),4.76(s,1H),3.82(s,3H),3.75(s,1H),3.5 6(s,1H),3.35(s,4H),3.13(d,J=18.0Hz,1H),3.03(s,1H),2.72(s,1H),2.43(s,3H),2.33(s,1H),2 .12(s,1H),1.93(d,J=11.3Hz,1H),1.33(s,1H),0.81(s,1H),0.49(s,2H),0.13(s,2H).ESI-MS[M+H] + 712.3.

[0141] Example 22: Synthesis of N-cyclopropylmethyl-7α-4′-(N′-3″,4″-dimethylphenylamine)-phenyl-6,14-neinethylenetetrahydrodestybaine (compound 20)

[0142]

[0143] Following the synthetic method of compound 14, aniline was replaced with 3,4-dimethylaniline to synthesize a yellow oily liquid 20, with a yield of 23%. 1 H NMR (400MHz, CDCl3) δ7.08(d,J=6.9Hz,2H),7.00(d,J=7.7Hz,1H),6.94–6.80(m,4H),6.64(d,J=7.8Hz,1H) ,6.55(s,1H),5.93(s,1H),5.61(d,J=8.8Hz,1H),5.53(s,1H),4.75(s,1H),3.82(s,3H),3.55(s,1H),3.37( d,J=11.9Hz,3H),3.13(d,J=18.0Hz,1H),3.00(s,1H),2.71(s,1H),2.39(d,J=34.7Hz,4H),2.20(d,J=4.7Hz ,6H),2.15–2.06(m,1H),1.94(s,1H),1.31(dd,J=32.2,12.2Hz,2H),0.82(s,1H),0.49(s,2H),0.13(s,2H). 13C NMR (151MHz, CDCl3) δ 148.36, 142.13, 140.97, 137.41, 135.98, 134.70, 130.25, 129.68, 129.10, 128.34, 127.89, 119.83, 119.13, 116.89, 115.73, 113.29, 94.26, 81.72, 72.78, 59.79, 57.14, 56.57, 51.69, 47.96, 44.27, 43.37, 42.86, 37.27, 34.07, 23.20, 19.92, 18.93, 9.51, 4.22, 3.31. HMRS: Calculated values: C 38 H 42 N₂O₃([M+H)) + 575.3268, Measured value: 575.3287.

[0144] Example 23: Synthesis of N-cyclopropylmethyl-7α-4′-(N′-2″,6″-dimethylphenylamine)-phenyl-6,14-neinethylenetetrahydrodestybaine (compound 21)

[0145]

[0146] Following the synthetic method of compound 14, aniline was replaced with 2,6-dimethylaniline to synthesize a yellow oily liquid 21, with a yield of 23%. 1 H NMR (400MHz, CDCl3) δ7.04 (s, 4H), 6.82 (d, J = 6.3Hz, 4H), 6.64 (s, 1H), 6.55 (s, 1H), 5.92 ( s,1H),5.60(d,J=8.2Hz,1H),5.48(s,1H),4.75(s,1H),3.80(d,J=14.3Hz,6H),3.55(s,1 H),3.36(d,J=10.8Hz,4H),3.13(d,J=17.0Hz,1H),2.99(s,1H),2.72(s,1H),2.43(s,4H) ,2.11(s,1H),1.93(s,1H),1.31(d,J=15.4Hz,1H),0.82(s,1H),0.49(s,2H),0.13(s,2H). 13C NMR (151MHz, CDCl3) δ 154.98, 148.44, 143.37, 141.93, 136.26, 136.03, 134.06, 129.77, 128.40, 127.99, 121.62, 119.23, 115.74, 114.85, 114.69, 113.37, 94.25, 81.76, 59.82, 57.18, 56.65, 55.66, 51.71, 48.00, 44.36, 43.41, 42.81, 37.29, 34.12, 23.29, 9.56, 4.31, 3.38. HMRS: Calculated values: C 38 H 42 N₂O₃([M+H)) + 575.3268, Measured value: 575.3270.

[0147] Example 24: Synthesis of N-cyclopropylmethyl-7α-4′-(N′-3″,4″-dichlorophenylamine)-phenyl-6,14-neinethylenetetrahydrodestybaine (compound 22)

[0148]

[0149] Following the synthetic method of compound 14, aniline was replaced with 3,4-dichloroaniline to synthesize a yellow oily liquid 22, with a yield of 44%. 1 H NMR (400MHz, CDCl3) δ7.20(t,J=8.9Hz,1H),7.14(d,J=7.4Hz,2H),7.08(s,1H),6.93(d,J=7.5Hz,2H),6.80(d,J=8 .5Hz,1H),6.64(d,J=7.9Hz,1H),6.54(d,J=8.1Hz,1H),5.91(d,J=8.5Hz,1H),5.81(s,1H),5.62(d,J=8.6Hz,1H), 4.75(s,1H),3.81(s,3H),3.54(s,1H),3.36(s,4H),3.13(d,J=18.3Hz,1H),3.02(s,1H),2.71(s,1H),2.41(dd,J= 30.8, 23.4Hz, 4H), 2.11 (s, 1H), 1.92 (d, J = 11.5Hz, 1H), 1.38–1.28 (m, 1H), 0.80 (s, 1H), 0.49 (s, 2H), 0.12 (s, 2H). 13C NMR (151MHz, CDCl3) δ 148.28, 143.63, 141.81, 139.71, 137.07, 136.21, 134.63, 132.79, 130.66, 129.91, 128.32, 127.69, 122.33, 119.20, 119.08, 117.52, 115.98, 113.31, 94.26, 81.73, 59.80, 57.16, 56.56, 51.75, 48.01, 44.20, 43.40, 42.99, 37.22, 34.05, 23.19, 9.51, 4.18, 3.35. HMRS: Calculated values: C 36 H 36 Cl2N2O3([M+H) + 615.2176, Measured value: 615.2190.

[0150] Performance Test 1: Radioligand binding experiment

[0151] Compounds used in pharmacological binding affinity screening All samples were in free base form. The experiment included total binding tubes, non-specific binding tubes, and sample tubes containing the analyte. Each tube contained 50 μL of a Tris-HCl buffer solution of appropriate concentration containing MOR, KOR, and DOR membrane proteins, and 10 μL of the corresponding radioactive ligand. 3 H]DAMGO、[ 3 H]U69,593 and [ 3 In the non-specific binding tubes, 10 μL of the corresponding positive compounds DAMGO, U69, 593, and DPDPE were added. In the sample tubes, 10 μL of different concentrations of the test compound were added, and the final volume of each tube was adjusted to 100 μL with 50 mM Tris HCl buffer (pH = 7.4). The samples in the test tubes were mixed thoroughly and incubated in a 37°C water bath for 30 min, then transferred to an ice bath to terminate the incubation. The samples were then filtered under negative pressure using Whatman GF / C glass fiber filter paper on a Millipore sample collector, and the test tubes were rinsed three times with ice-cold 50 mM Tris HCl buffer (pH = 7.4). The filter paper was collected, dried, and placed in a 0.5 mL EP tube. 0.5 mL of toluene scintillation solution was added, and the radioactivity intensity was measured using an LS-6500 multi-functional liquid scintillation counter (Beckman Laboratories, USA). The experiment was independently repeated at least three times, and the percentage inhibition rate and K0 were calculated. i The average value and SEM value.

[0152] Calculate the percentage inhibition rate: Inhibition rate = (Total binding tube dpm - Sample tube dpm) / (Total binding tube dpm - Non-specific binding tube dpm) × 100%. Calculate K. i IC50 value: Based on the percentage inhibition rate at each concentration, the IC50 value of the compound competitively binding to the opioid receptor was calculated using Prism 5.0 software. 50 According to formula [K] i =IC 50 / (1+[L] / K d )]Calculate K i Value, where [L] is the concentration of the added labeled ligand, K d The equilibrium dissociation parameters for the labeled ligands are given.

[0153] Table 1. Inhibitory rates of compounds against opioid receptors at concentrations of 10 μM and 100 nM

[0154]

[0155] a The mean ± SEM of the data obtained from three independent experiments. b and[ 3 H]DAMGO competitively binds to MOR expressed on the CHO cell membrane. c and[ 3 H]U69593 competitively binds to KOR expressed on the CHO cell membrane. d and[ 3 H]DPDPE competitively binds to DOR expressed on the CHO cell membrane.

[0156] Table 2. Affinity activity data of compounds for various opioid receptor subtypes

[0157]

[0158]

[0159]

[0160] a The mean ± SEM of the data obtained from three independent experiments. b and[ 3 H]DAMGO competitively binds to MOR expressed on the CHO cell membrane. c and[ 3 H]U69593 competitively binds to KOR expressed on the CHO cell membrane. d and[ 3 H]DPDPE competitively binds to DOR expressed on the CHO cell membrane.

[0161] Performance Test 2:cAMP inhibition assay

[0162] 200 μL of HEK293-hKOR-Glosensor cells (density: 60,000 cells / 200 μL) were added to each well of a white 96-well plate and incubated at 37°C with 5% CO2 for 16 h. The culture medium was then discarded, and 40 μL of 2% Glo-Sensor cAMP reagent (Buffer: 20 mM HEPES, 1×HBSS, pH 7.4) was added to each well, and the plate was incubated at room temperature in the dark for 15 min. Then, 20 μL of different concentrations of the target compound (Buffer: 20 mM HEPES, 1×HBSS, 0.1% BSA, pH 7.4) were added to each well and incubated at room temperature for 15 min. Chemiluminescence detection was performed using a microplate reader to calculate the cAMP inhibition at different concentrations. The test results for compounds 14 and 18 are shown below. Figure 1 As shown in Table 3. Figure 1 The concentration-response curves of compounds 14 and 18 to hDOR agonistic activity are shown. The agonistic activity is reflected by the inhibitory effect of the compounds on cAMP production.

[0163] Calculate the percentage inhibition rate: Inhibition rate = (sample group - background group) / (blank group - background group) × 100%. In Graphpad Prism 9.5, plot the drug concentration (logarithmic form) on the horizontal axis and the relative luminescent unit (RLU) on the vertical axis using log(agonist) vs. response(three parameters).

[0164] Table 3. IC50 values ​​of compounds 14, 18, and DPDPE in hDOR in cAMP Glosensor experiments. 50 value

[0165]

[0166] Although exemplary embodiments have been presented in the foregoing embodiments, it should be understood that numerous variations of the invention are possible. It should also be understood that the embodiments described herein are not intended to limit the scope or use of the claimed application in any way, and those skilled in the art can make various changes to the function and arrangement of the elements without departing from the scope defined by the claims of this application, which include known equivalents and all foreseeable equivalents at the time of filing of this patent application.

Claims

1. A 7α-substituted phenyl tetrahydrothebaine derivative of general formula (I) or a pharmaceutically acceptable salt thereof, in R 1 Selected from H and C1-C6 alkyl groups; R 2 Selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C5-C7 cycloalkenyl, C3-C6 cycloalkylC1-C6 alkyl, C5-C7 cycloalkenylC1-C6 alkyl, C6-C 12 Aryl, 5-7 heteroaryl, C6-C 12 Aryl C1-C6 alkyl, 5-7 membered heteroaryl C1-C6 alkyl; R 3 Selected from H and C1-C6 alkyl groups; R 4 Selected from C1-C6 alkylene and C2-C6 alkenylene groups; R 5 Selected from H, halogens, C1-C6 alkyl, C3-C6 cycloalkyl, C5-C7 cycloalkenyl, unsubstituted or substituted by substituents selected from group A, C6-C 12 aryl, 5-9 membered heteroaryl, unsubstituted or substituted with a substituent selected from group A, amino group, unsubstituted or substituted with a substituent selected from group A, in, The substituents selected from Group A are each independently selected from unsubstituted or halogen-substituted C1-C6 alkyl groups, unsubstituted or halogen-substituted C1-C6 alkoxy groups, C1-C6 alkoxyacyl groups, C1-C6 alkanoyloxy groups, and unsubstituted or substituted C6-C6 groups selected from Group B. 12 Aryl, 5-9 membered heteroaryl, unsubstituted or substituted by substituents selected from group B, carboxyl, cyano, hydroxyl, halogen, amino; The substituents selected from group B are each independently selected from unsubstituted or arbitrarily substituted C1-C6 alkyl groups, unsubstituted or arbitrarily substituted C1-C6 alkoxy groups, C1-C6 alkoxyacyl groups, C1-C6 alkanoyloxy groups, carboxyl groups, cyano groups, hydroxyl groups, halogens, and unsubstituted or arbitrarily substituted amino groups.

2. The derivative of claim 1 or a pharmaceutically acceptable salt thereof, wherein, R 1 Selected from H and C1-C4 alkyl groups; and / or R 2 Selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C5-C7 cycloalkenyl, C3-C6 cycloalkylC1-C4 alkyl, C5-C7 cycloalkenylC1-C4 alkyl, C6-C 12 Aryl, 5-6 quinone heteroaryl, C6-C 12 aryl C1-C6 alkyl, 5-6 heteroaryl C1-C6 alkyl; and / or R 3 Selected from H and C1-C4 alkyl groups; and / or R 4 Selected from C1-C4 alkylene and C2-C4 alkenylene.

3. The derivative of claim 1 or a pharmaceutically acceptable salt thereof, wherein, R 1 H or methyl; and / or R 2 Cyclopropylmethyl, cyclobutylmethyl, or phenethyl; and / or R 3 H or methyl; and / or R 4 It is vinylene or ethylene.

4. The derivative of claim 1 or a pharmaceutically acceptable salt thereof, wherein, in R 1 Selected from C1-C6 alkyl groups; R 2 Selected from C3-C6 cycloalkyl and C1-C6 alkyl groups; R 3 Selected from C1-C6 alkyl groups; R 4 Selected from C2-C6 alkenyl groups.

5. The derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein, R 5 Selected from H, halogen, unsubstituted or substituted C6-C groups selected from group A 12 aryl, 5-9 membered heteroaryl groups (unsubstituted or substituted with groups selected from group A), amino groups (unsubstituted or substituted with groups selected from group A), and / or The substituents selected from Group A are each independently selected from unsubstituted or halogen-substituted C1-C6 alkyl groups, unsubstituted or halogen-substituted C1-C6 alkoxy groups, and unsubstituted or substituted C6-C6 alkyl groups selected from Group B. 12 Aryl, halogen, and / or The substituents selected from group B are each independently selected from unsubstituted or arbitrarily substituted C1-C6 alkyl groups, unsubstituted or arbitrarily substituted C1-C6 alkoxy groups, and halogens.

6. The derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein, R 5 Selected from H, halogen, unsubstituted or substituted C6-C groups selected from group A 10 aryl, 5-6 membered heteroaryl, unsubstituted or substituted with a substituent selected from group A, unsubstituted or substituted amino group, and / or The substituents selected from Group A are each independently selected from unsubstituted or halogen-substituted C1-C4 alkyl groups, unsubstituted or halogen-substituted C1-C4 alkoxy groups, and unsubstituted or substituted C6-C6 alkyl groups selected from Group B. 10 Aryl, halogen, and / or The substituents selected from group B are each independently selected from unsubstituted or arbitrarily substituted C1-C4 alkyl groups, unsubstituted or arbitrarily substituted C1-C4 alkoxy groups, and halogens. In particular, R 5 The group is selected from Br, phenyl, phenyl substituted with a substituent selected from methyl, ethyl, CF3, methoxy and Cl, furanyl, thiophene, amino substituted with an unsubstituted or substituted phenyl group, wherein the substituent on the substituted phenyl group is selected from methyl, methyl substituted with F and / or hydroxyl, ethyl, ethyl substituted with F and / or hydroxyl, n-propyl, isopropyl, n-propyl substituted with F and / or hydroxyl, isopropyl substituted with F and / or hydroxyl, methoxy, and Cl.

7. The derivative or a pharmaceutically acceptable salt thereof according to claim 1, 5 or 6, wherein, Derivatives represented by general formula (I) are shown in the following formula (I-1): Among them, R 5 As described in claims 1, 5, or 6 respectively, In particular, the derivative is selected from compounds including:

8. A composition comprising a therapeutically effective amount of the derivative of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutical excipient.

9. Use of the derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, or the composition according to claim 8, in the preparation of an opioid receptor-mediated therapeutic agent.

10. Use of the derivatives or pharmaceutically acceptable salts thereof according to any one of claims 1 to 7, or the composition according to claim 8, in the preparation of medicaments for treating and / or preventing pain, addiction, anxiety, and depression; particularly, the pain includes pain during surgery, chronic pain, neuropathic pain, and cancer pain.

Images