3-(dimethylaminomethyl) piperidine derivative as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention belongs to the field of biological medicine, and particularly relates to a 3-(dimethylaminomethyl) piperidine compound and a preparation method, a pharmaceutical composition and application thereof. The invention provides a compound as shown in a formula (I) or a stereoisomer, a geometric isomer, a tautomer, a deuterated compound, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or prodrugs of the stereoisomer, the geometric isomer, the tautomer, the deuterated compound, the nitrogen oxide, the solvate, the metabolite and the pharmaceutically acceptable salt of the compound as shown in the formula (I), and also provides a preparation method of the compound. The invention also relates to application in preparation of medicines for treating pain diseases. According to the compound, the selectivity to KOR and DOR and the druggability of the compound are improved while good MOR agonistic activity is maintained, and certain activity is shown in an in-vivo pharmacological experiment.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and specifically relates to 3-(dimethylaminomethyl)piperidine derivatives, preparation methods, pharmaceutical compositions and uses thereof. Background Art

[0002] Pain is one of the common symptoms in the course of many diseases and one of the main problems faced by patients. It is called the "fifth vital sign" after body temperature, pulse, respiration, and blood pressure. At present, opioid analgesics (such as morphine and fentanyl) play an irreplaceable role in pain treatment. However, long-term use of such drugs may lead to adverse reactions such as drug tolerance, addiction, withdrawal reactions and respiratory depression. Tramadol (trade name: Tramal) is a synthetic opioid central analgesic developed by Grünenthal in 1977. As a relatively weak μ opioid receptor agonist (K for μ opioid receptors), it has a strong inhibitory effect on the analgesic effect. i =2400nM, EC 50 Tramadol also inhibits the reuptake of serotonin and norepinephrine (>1000nM). Its metabolism occurs primarily in the liver, with excretion almost entirely through the kidneys. Unlike traditional opioids, tramadol possesses unique pharmacological properties, resulting in significant analgesic effects and minimal adverse reactions, making it widely used in pain management.

[0003] However, clinical studies have shown that tramadol's analgesic effect is slightly weaker than that of stronger analgesics such as morphine and fentanyl. Furthermore, tramadol may still cause side effects such as respiratory depression, addiction, nausea, diarrhea, headache, dizziness, drowsiness, and constipation. Long-term use may also lead to withdrawal symptoms such as sweating, anxiety, sleep disorders, pain, and body tremors. Other studies have shown that tramadol use may increase the risk of hyponatremia and hypoglycemia requiring hospitalization. Therefore, the development of new analgesics with stronger analgesic effects and fewer side effects remains an urgent issue. Summary of the Invention

[0004] In order to achieve the above object, the present invention provides the following technical solutions:

[0005] The first aspect of the present invention discloses a compound having a structure represented by formula (I), or a stereoisomer, deuterated compound, solvate, metabolite, pharmaceutically acceptable salt, cocrystal or prodrug thereof:

[0006]

[0007] wherein R1 is selected from hydrogen, C1-6 alkyl, fluoroalkyl, cycloalkyl, chain alkenyl, cycloalkenyl, substituted or unsubstituted aryl C1-6 alkyl;

[0008] R2 is selected from substituted or unsubstituted aroyl, substituted or unsubstituted aryl, wherein the substituted group in R2 is selected from aryl, halogen, C1-6 alkyl, cyano, alkoxy, amino, nitro, alkylsulfonyl, ester, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, fluorine, nitro or phenolic hydroxyl;

[0009] R3 is selected from hydrogen, deuterium, tritium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, C5-C7 heteroaryl, C5-C6 substituted heteroaryl;

[0010] R4 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein the substituted group in R4 is selected from aryl, halogen, C1-6 alkyl, cyano, alkoxy, amino, nitro, alkylsulfonyl, ester, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, fluorine, nitro, phenolic hydroxyl;

[0011] X is selected from N, O, and C;

[0012] Y is selected from C0-C6 alkyl, O, and N.

[0013] Preferably, the compound of formula I has the structure shown in the following formula Ia:

[0014]

[0015] Preferably, the compound of formula I also has the structure shown in the following formula Ib:

[0016]

[0017] Preferably, the compound of formula I also has the structure shown in the following formula Ic:

[0018]

[0019] The second aspect of the present invention discloses the use of the above-mentioned compound or its stereoisomers, geometric isomers, tautomers, deuterated compounds, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs in the preparation of drugs for preventing, treating or alleviating diseases.

[0020] The disease is an opioid receptor-related indication, including pain, irritable bowel syndrome, pruritus, addiction, and depression; the disease can be selected from, but not limited to, pain, gastrointestinal diseases, and depression. For example, the pain can be selected from, but not limited to, centrally mediated pain, peripherally mediated pain, pain associated with structural or soft tissue damage, pain associated with inflammation, pain associated with progressive diseases, neuropathic pain, acute pain, and chronic pain.

[0021] The third aspect of the present invention discloses a pharmaceutical composition comprising the above-mentioned compound or its stereoisomers, geometric isomers, tautomers, deuterated compounds, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs as active ingredients.

[0022] The pharmaceutical composition further comprises a pharmaceutically acceptable carrier and / or adjuvant.

[0023] The treatment of diseases by the above-mentioned pharmaceutical composition is achieved by administering to a subject an effective therapeutic amount of a compound of formula (I) or its stereoisomers, deuterated compounds, solvates, metabolites, pharmaceutically acceptable salts, cocrystals or prodrugs.

[0024] The fourth aspect of the present invention discloses a method for synthesizing a compound of formula (I), wherein the preparation method comprises the steps of Mannich reaction, nucleophilic addition of a Grignard reagent, resolution with a resolving agent, deprotection of the Boc protecting group, condensation, and salt formation.

[0025] In the case of substituted or unsubstituted aromatic acyl, substituted or unsubstituted aryl, or substituted or unsubstituted fatty acyl:

[0026]

[0027] Compared with the prior art, the present invention has the following technical effects:

[0028] The present invention provides a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, deuterated compound, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (I). While maintaining good MOR agonist activity, the compound improves the selectivity for KOR and DOR and the drugability of the compound, and shows certain activity in in vivo efficacy experiments. The compound prepared by the present invention has a latency period of 60 seconds after administration, indicating that mice have basically no response to stimulation, and has good analgesic activity. DETAILED DESCRIPTION

[0029] As used throughout this application, including the claims, unless specifically stated otherwise, the following terms have the meanings defined below as used herein.

[0030] The term "C0-C6 alkyl" refers to a saturated branched or straight chain alkyl group containing 0 to 6 carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

[0031] The term "C1-C6 alkoxy" refers to -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyloxy, and cyclobutyloxy.

[0032] The term "C1-C6 alkylthio" refers to -S-alkyl. Non-limiting examples include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio, n-pentylthio, n-hexylthio, cyclopropylthio, and cyclobutylthio.

[0033] The term "C1-C6 haloalkoxy" refers to an alkoxy group substituted with one or more halogens. Non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, and the like.

[0034] The term "C1-C6 monosubstituted or polysubstituted alkyl" means that one or more hydrogen atoms in the C1-C6 alkyl group as defined above are replaced by substituents selected from the following: OH, halogen, alkyl, dialkylamino or heterocyclic groups, such as morpholinyl, piperidinyl, etc.

[0035] The term "C2-C6 alkenyl" refers to a linear or branched monovalent unsaturated hydrocarbon group containing 2 to 6 carbon atoms and one or more carbon-carbon double bonds, preferably containing 2-4 carbon atoms. Non-limiting examples include ethenyl, propenyl, allyl, 2-butenyl, 1-butenyl, etc.

[0036] The term "C2-C6 alkynyl" refers to a linear or branched monovalent unsaturated hydrocarbon group containing 2 to 6 carbon atoms and one or more carbon-carbon triple bonds, preferably containing 2-4 carbon atoms. Non-limiting examples include ethynyl, propynyl, propargyl, etc.

[0037] The term "C3-C8 cycloalkyl" refers to a cyclic, saturated, monovalent, monocyclic or bicyclic hydrocarbon radical containing 3 to 8 carbon atoms, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like. The cycloalkyl radical may be optionally substituted with one, two, or three substituents selected from halogen atoms, hydroxyl groups, and aryl groups.

[0038] The term "3-8 membered heterocycloalkyl" refers to a saturated or partially unsaturated, non-aromatic monocyclic, bicyclic or tricyclic ring system containing 3-12 atoms, wherein at least one ring atom is selected from nitrogen, sulfur, oxygen and phosphorus atoms, wherein the heterocyclic group is non-aromatic and does not contain any aromatic rings, and the ring system has one or more points of attachment to the rest of the molecule. Non-limiting examples include oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4-pyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, thioxanyl, etc. The heterocycloalkyl radical may be optionally substituted with one, two or three substituents selected from halogen atoms, hydroxyl groups and aryl groups.

[0039] The term "aryl" refers to all carbon monocyclic or fused-ring polycyclic aromatic groups containing from 6 to 10 carbon atoms and having a conjugated electron system, non-limiting examples of which are phenyl or theanyl.

[0040] The term "substituted or unsubstituted aryl" means that 0 to 3 hydrogen atoms on the aryl group are replaced by substituents selected from the group consisting of aryl, halogen, C1-6 alkyl, nitrile, alkyl, amino, nitro, alkylsulfonyl, ester, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, fluorine, nitro, and phenolic hydroxyl.

[0041] The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic heterocyclic group in which one or more heteroatom ring members (ring atoms) in at least one ring are independently selected from oxygen (O), sulfur (S) and nitrogen (N). Examples of heteroaryl groups include, but are not limited to, 6-membered ring substituents, non-limiting examples of which are pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl; 5-membered heteroaryl groups such as triazolyl, imidazolyl, furanyl, isoxazolyl, isothiazolyl, 1,2,3-, 1,2,4, 1,2,5- or 1,3,4-oxadiazolyl, oxazolyl, thienyl, thiazolyl, isothiazolyl and pyrazolyl; 6 / 5-membered fused ring substituents such as indolyl, indazolyl, benzofuranyl, benzimidazolyl, benzothienyl, benzoxadiazolyl, benzothiazolyl, isobenzothienyl, benzo pyridinyl, thienopyridinyl, triazolopyrimidinyl, triazolopyridinyl (e.g., 5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-2-yl), and o-aminobenzoyl; and 6 / 6-membered fused ring substituents such as quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, oxochromanyl, and 1,4-benzoxazinyl.

[0042] The term "substituted or unsubstituted heteroaryl" means that 0 to 3 hydrogen atoms on the heteroaryl group are replaced by substituents selected from the group consisting of aryl, halogen, C1-6 alkyl, methyl, alkyl, amino, nitro, alkylsulfonyl, ester, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, fluorine, nitro, and phenolic hydroxyl.

[0043] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0044] The term "optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "alkyl optionally substituted with F" means that it may but need not be substituted with F, and the description includes instances where it is substituted with F and instances where it is not substituted with F.

[0045] The term "solvate" refers to a substance formed by a compound of the present invention or a salt thereof and a stoichiometric or non-stoichiometric amount of a solvent bound to the compound or salt thereof by non-covalent forces between the molecules. When the solvent is water, the solvate is a hydrate.

[0046] The term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammal to be treated therewith. Preferably, the "pharmaceutically acceptable" herein means approved by U.S. federal regulatory agencies or national governments or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopeia for use in animals, particularly humans.

[0047] The term "cocrystal" refers to a crystal formed by the active pharmaceutical ingredient (API) and cocrystal former (CCF) bound together by hydrogen bonds or other non-covalent bonds, where both API and CCF are solid in their pure form at room temperature and the components exist in a fixed stoichiometric ratio. A cocrystal is a multi-component crystalline solid, encompassing both binary crystalline solids formed between two neutral solids and multi-component crystalline solids formed with salts or solvates.

[0048] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically / pharmaceutically acceptable carriers, excipients, diluents, binders, fillers, and other excipients, as well as additional therapeutic agents such as antidiabetic, antihyperglycemic, antiobesity, antihypertensive, antiplatelet, antiatherosclerotic, or lipid-lowering agents. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism.

[0049] The term "therapeutically effective amount" refers to that amount of the compound being administered which relieves to some extent one or more of the symptoms of the condition being treated.

[0050] The term "pharmaceutically acceptable carrier" refers to a carrier that can be used to prepare a pharmaceutical composition, is generally safe, non-toxic, not biologically or otherwise undesirable, and includes carriers that are pharmaceutically acceptable to animals and humans. As used in the specification and claims, "pharmaceutically acceptable carrier" includes one or more such carriers.

[0051] The term "carrier" refers to a system that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound, and can change the way the drug enters the human body and its distribution in the body, control the release rate of the drug and deliver the drug to the target organ. Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0052] The term "excipient" refers to a substance that is not itself a therapeutic agent and is used as a diluent, adjuvant, binder and / or vehicle to be added to a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate the formation of a compound or pharmaceutical composition into a unit dosage form for administration. As known to those skilled in the art, pharmaceutical excipients can provide various functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents and sweeteners. Examples of pharmaceutical excipients include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose and cross-linked carboxymethylcellulose (e.g., sodium cross-linked carboxymethylcellulose); (4) tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) pH buffer solutions; (21) polyesters, polycarbonates, and / or polyanhydrides; and (22) other nontoxic compatible substances used in pharmaceutical preparations.

[0053] The present invention is further illustrated by way of examples, but the invention is not limited to the scope of the examples. The experimental methods in the following examples, unless otherwise specified, are conventional methods and were performed according to the techniques or conditions described in literature in the field or according to product specifications. The materials and reagents used in the following examples, unless otherwise specified, are commercially available.

[0054]

[0055] Example 1, tert-Butyl 3-((dimethylamino)methyl)-4-oxopiperidine-1-carboxylate (2)

[0056] Boc-piperidin-4-one (5 g, 25.20 mmol, 1 eq.) was dissolved in acetonitrile. N-methyl-N-methylenecarbammonium chloride (1.75 g, 30.12 mmol, 1.2 eq.) and acetyl chloride (0.18 mL, 5.02 mmol, 0.1 eq.) were added. Stirring was continued at room temperature for 2 hours. The acetonitrile was then removed by distillation under reduced pressure, and the mixture was extracted with DCM and saturated aqueous sodium bicarbonate. The solvent was then removed by distillation under reduced pressure from the oil phase to obtain a light yellow liquid, which was directly used in the next reaction.

[0057] Example 2, tert-Butyl 3-((dimethylamino)methyl)-4-hydroxy-4-(3-benzyloxyphenyl)piperidine-1-carboxylate (3a)

[0058] A solution of magnesium turnings (2.81 g, 115.47 mmol, 2.3 eq.), tetrahydrofuran (THF, 20 mL), and one iodine pellet was added to a small amount of 3-benzyloxybromobenzene (23.22 g, 115.47 mmol, 2.3 eq.) dissolved in THF (50 mL). The mixture was heated to 56°C with stirring under nitrogen. When the yellow color faded, the remaining 3-benzylbromobenzene was added dropwise at room temperature. The mixture was refluxed for 30 minutes and then cooled to room temperature. A solution of Intermediate 2 in THF (50 mL) was added dropwise. After stirring at room temperature for 5 hours, the mixture was extracted with saturated aqueous ammonium chloride and EA. The resulting oil phase was dried and the solvent was removed by distillation under reduced pressure to yield a yellow liquid. Finally, the product was purified by column chromatography (eluent system: DCM to DCM:MeOH = 150:1 to 100:1 to 30:1 gradient) to obtain 5.54 g of a light yellow viscous liquid. The yield of the two-step reaction was calculated to be 30.27% (based on Boc-piperidin-4-one).

[0059] Example 3, tert-Butyl 4-(3-(methoxy)phenyl)-3-((dimethylamino)methyl)-4-hydroxypiperidine-1-carboxylate (3b)

[0060] Refer to the synthesis of 3a, the yield was 29.23%.

[0061] Example 4, 3-((dimethylamino)methyl)-4-(3-benzyloxyphenyl)piperidin-4-ol dihydrochloride (4a)

[0062] Intermediate 3a (5.54 g, 12.57 mmol, 1 eq.) was dissolved in methanol (20 mL). HCl / dioxane (16.3 mL, 37.72 mmol, 2.5 eq.) was slowly added dropwise at room temperature. The temperature was raised to 40°C and stirred for 5 hours. Methyl tert-butyl ether (MTBE, 150 mL) was added to the reaction system and stirred. After overnight, the mixture was filtered and the filter cake was rinsed with MTBE (20 mL). The mixture was then spin-dried to obtain 4.10 g of an off-white solid in a yield of 95.85%.

[0063] Example 5, 3-((dimethylamino)methyl)-4-(3-methoxyphenyl)piperidin-4-ol dihydrochloride (4b)

[0064] Refer to the synthesis of 4a, the yield is 97.33%.

[0065] Example 6, 1-(4-(3-(benzyloxy)phenyl)-3-((dimethylamino)methyl)-4-hydroxypiperidin-1-yl)-2-(2,4,5-trifluorophenyl)ethan-1-one (5a)

[0066] To a 100 mL single-necked flask were added intermediate 4a (4.1 g, 12.04 mmol, 1 eq), DMF (40 mL), 2,4,5-trifluorophenylacetic acid (2.29 g, 12.04 mmol, 1 eq.), 1-hydroxybenzotriazole (HOBT, 2.44 g, 18.06 mmol, 1.5 eq.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI-HCl, 3.46 g, 18.06 mmol, 1.5 eq.), and N-methylmorpholine (NMM, 5.35 mL, 48.17 mmol, 4 eq.), followed by stirring at room temperature for 19 hours. The reaction mixture was extracted with DCM and water, and the organic phases were combined, dried, and then spin-dried to afford a light brown liquid. Finally, the product was purified by column chromatography (eluent system gradually transitioned from DCM to DCM:MeOH=50:1) to obtain 1.57 g of colorless oil with a yield of 25.52%.

[0067] Example 7, 1-(4-(3-(benzyloxy)phenyl)-3-((dimethylamino)methyl)-4-hydroxypiperidin-1-yl)-2-(2,4,5-trifluorophenyl)ethan-1-one (5b)

[0068] Refer to the synthesis of 5a, the yield was 38.17%.

[0069] Example 8, 4-(3-(benzyloxy)phenyl)-3-((dimethylamino)methyl)-1-(2-(2,4,5-trifluorophenyl)acetyl)piperidin-4-yl benzoate (6a)

[0070] 5a (200mg, 0.39mmol, 1eq), dichloromethane (20mL), triethylamine (0.14mL, 0.98mmol, 2.5eq) are added to the flask and cooled to 0 ℃. Benzoyl chloride (0.09mL, 0.78mmol, 2eq) is dissolved in dichloromethane (5mL), added dropwise, and then the reaction mixture is stirred at room temperature for 12 hours. After the reaction is complete, water (50mL) is added, and then extracted with dichloromethane (50mL, 50mL, 30mL, 30mL). The organic phase is combined and a light yellow viscous oil is obtained after evaporation. Finally, 168mg of colorless oil is obtained by column chromatography purification, and the yield is 69.82%.

[0071] Examples 9, 6b-6l

[0072] Refer to the synthesis of 6a, which is a colorless oil or light yellow oil with a yield of 53.29%-80.66%.

[0073] Example 10, 3-((dimethylamino)methyl)-4-(3-hydroxyphenyl)-1-(2-(2,4,5-trifluorophenyl)acetyl)piperidin-4-yl benzoate (7a)

[0074] To a 100 mL flask equipped with a hydrogen balloon was added 6a (168 mg, 0.27 mmol, 1 eq), methanol, and 10% Pd / C (17 mg). The reaction mixture was then stirred at room temperature for 12 hours. After completion of the reaction, the Pd / C was removed by filtration, and the filtrate was concentrated under reduced pressure to yield a pale yellow oil. This oil was then chromatographed on a silica gel column to yield 83 mg of a pale yellow syrup (57.86% yield).

[0075] Examples 11, 7b-7f

[0076] Refer to the synthesis of 7a, which is a colorless to light yellow viscous oil with a yield of 48.81%-67.93%.

[0077] Example 12, 3-((dimethylamino)methyl)-4-(3-hydroxyphenyl)-1-(2-(2,4,5-trifluorophenyl)acetyl)piperidin-4-yl phenyl carbonate (7c)

[0078] Refer to the synthesis of 7a, the yield was 55.98%.

[0079] Example 13, 3-((dimethylamino)methyl)-4-(3-hydroxyphenyl)-1-(2-(2,4,5-trifluorophenyl)acetyl)piperidin-4-ylphenylcarbamate (7d)

[0080] Refer to the synthesis of 7a, the yield was 48.81%.

[0081] Example 14, 3-((dimethylamino)methyl)-4-(3-hydroxyphenyl)-1-(2-(2,4,5-trifluorophenyl)acetyl)piperidin-4-yl 2-phenylacetate (7e)

[0082] Refer to the synthesis of 7a, the yield was 59.72%.

[0083] Example 15, 3-((dimethylamino)methyl)-4-(3-hydroxyphenyl)-1-(2-(2,4,5-trifluorophenyl)acetyl)piperidin-4-yl 3-phenylpropanoate (7f)

[0084] Refer to the synthesis of 7a, the yield was 63.12%.

[0085] Example 16, 3-((dimethylamino)methyl)-4-(3-hydroxyphenyl)-1-(2-(2,4,5-trifluorophenyl)acetyl)piperidin-4-yl benzoate hydrochloride (FW-XXD-AP-A1)

[0086] 7a (83 mg, 0.16 mmol, 1 eq) was dissolved in DCM (1.5 mL) and MeOH (0.2 mL). HCl / dioxane solution (0.05 mL, 0.19 mmol, 1.2 eq) was slowly added dropwise, followed by the dropwise addition of MTBE (6 mL), resulting in the precipitation of a solid. After stirring for 1 hour, the mixture was filtered, the filter cake washed with MTBE (2 mL), and finally oven-dried at 60°C for 1 hour to afford 50 mg of a pale yellow solid (56.34% yield). 1 H NMR(400MHz,DMSO-d6)δ9.58(s,1H),8.20–8.12(m,2H),7.78(s,1H),7.63(s,2H),7.57–7.35(m,2H ),7.23(t,J=7.9Hz,1H),6.84(d,J=7.3Hz,1H),6.76(dd,J=7.9,2.2Hz,1H),6.74–6.69(m,1H),4.7 8(d,J=12.6Hz,1H),4.20(d,J=16.8Hz,1H),3.94–3.77(m,1H),3.50(dd,J=13.8,11.2Hz,1H),3.36 (s,6H),3.23–3.01(m,2H),2.70(dd,J=20.7,4.6Hz,2H),2.43–2.31(m,2H),2.24(d,J=4.6Hz,2H). 13C NMR (101MHz, DMSO) δ168.32,168.16,164.55,157.85,155.37,147.30,141.44,141.31,134.32,130.26,130.17,129.46,121.59,120.36 ,116.51,115.15,113.33,106.10,85.22,55.65,46.24,44.92,43.56,37.50,33.78,32.57.LC-MS-ESI+:[M+H]+527.2.HRMS(ESI),calcd for C 29 H 29 F3N2O4[M+H]+,527.2152; found,527.2152.Mp:142.01-147.22℃.

[0087] Example 17, 3-((dimethylamino)methyl)-4-(3-methoxyphenyl)-1-(2-(2,4,5-trifluorophenyl)acetyl)piperidin-4-yl benzoate hydrochloride (FW-XXD-AP-A2)

[0088] Referring to the synthesis of A1, a white solid was obtained with a yield of 73.82%. 1 HNMR(400MHz,DMSO-d6)δ8.15(d,J=7.5Hz,2H),7.77(s,1H),7.62(t,J=7.7Hz,2 H),7.52(dq,J=9.6,4.9Hz,2H),7.34(t,J=8.1Hz,1H),6.94(m,J=9.1Hz,3H),3.9 6–3.83(m,2H),3.77(s,2H),3.54(s,6H),3.06(d,J=14.4Hz,1H),2.71(d,J=4.7 Hz, 2H), 2.64 (q, J = 5.1, 4.3Hz, 2H), 2.20 (d, J = 4.6Hz, 2H), 1.26 (d, J = 8.5Hz, 3H). 13C NMR (101MHz, DMSO) δ168.23,164.67,160.12,159.86,157.77,147.18,141. 56,134.37,130.12,129.74,129.49,129.07,120.24,118.33,114.21,113. 36,112.26,105.55,85.31,72.62,71.00,60.64,55.71,46.27,44.93,43.2 6,37.45,33.83,32.52,29.46.LC-MS-ESI+:[M+H]+541.2.HRMS(ESI),calcd for C 30 H 31 F3N2O4[M+H]+,541.2309; found,541.2313.Mp:145.29-148.31℃.

[0089] Example 18, 3-((dimethylamino)methyl)-4-(3-hydroxyphenyl)-1-(2-(2,4,5-trifluorophenyl)acetyl)piperidin-4-yl acetate hydrochloride (FW-XXD-AP-A3)

[0090] Referring to the synthesis of A1, a light yellow solid was obtained with a yield of 62.18%. 1 HNMR(400MHz, DMSO-d6)δ9.60(d,J=7.5Hz,1H),7.58–7.47(m,1H),7.46–7.36(m,1H),7.21(t,J=7 .9Hz,1H),6.83–6.73(m,2H),6.70(dt,J=4.4,2.1Hz,1H),4.58(t,J=16.6Hz,1H),4.07(dd,J=49.3 ,15.3Hz,1H),3.87(d,J=3.6Hz,1H),3.37(s,6H),2.91–2.82(m,1H),2.73(t,J=12.2Hz,1H),2.65 (d,J=4.6Hz,2H),2.60(d,J=4.3Hz,1H),2.38(d,J=4.8Hz,2H),2.24(s,3H),2.22(d,J=4.6Hz,3H). 13C NMR (101MHz, DMSO) δ169.72,168.18,167.94,157.87,157.83,155.45,147.28,141.66,129.97,120.20,116.57,114.99,113.3 3,105.93,84.03,83.70,55.71,45.93,44.84,43.08,37.42,33.64,32.40,22.13.LC-MS-ESI+:[M+H]+465.3.HRMS(ESI),calcd for C 24 H 27 F3N2O4[M+H]+,465.1996; found,465.1999.Mp:169.73-172.64℃.

[0091] Example 19, 3-((dimethylamino)methyl)-4-(3-methoxyphenyl)-1-(2-(2,4,5-trifluorophenyl)acetyl)piperidin-4-yl acetate hydrochloride (FW-XXD-AP-A4)

[0092] Referring to the synthesis of A1, a light yellow solid was obtained with a yield of 78.92%. 1 HNMR(400MHz,DMSO-d6)δ7.53(m,6.3Hz,1H),7.43(m,1H),7.35(t,J=8.0Hz,1H ),6.93(m,2H),6.90(s,1H),4.75–4.36(m,1H),4.13(d,J=16.8Hz,1H),3.87(t ,J=8.4Hz,1H),3.80(s,3H),3.59(s,2H),3.36(s,6H),2.66(d,J=4.7Hz,2H),2 .61(d,J=4.5Hz,1H),2.38(d,J=4.4Hz,1H),2.26(s,3H),2.21(d,J=4.6Hz,2H). 13 C NMR (101MHz, DMSO) δ169.83,169.78,168.13,167.99,159.84,157.89,147.30,141.86,129.93,120.13,118.41,113.29,112.26 ,105.92,84.09,66.86,55.73,45.98,44.84,42.84,37.38,33.77,32.32,22.07.LC-MS-ESI+:[M+Na]+501.2.HRMS(ESI),calcd for C 25 H 29F3N2O4[M+H]+,479.2152; found,479.2148.Mp:159.19-163.28℃.

[0093] Example 20, phenyl carbonate 3-((dimethylamino)methyl)-4-(3-hydroxyphenyl)-1-(2-(2,4,5-trifluorophenyl)acetyl)piperidin-4-yl ester hydrochloride (FW-XXD-AP-A5)

[0094] Referring to the synthesis of A1, a pale white solid was obtained with a yield of 64.38%. 1 HNMR(400MHz,DMSO-d6)δ7.59–7.41(m,4H),7.41–7.32(m,3H),7.29(t,J=7 .9Hz,1H),6.92(d,J=7.7Hz,1H),6.88–6.77(m,2H),4.74–4.39(m,1H),4.2 9–4.02(m,1H),3.90(s,1H),3.42(s,6H),2.90–2.84(m,1H),2.67(d,J=4.7 Hz,2H),2.61(d,J=4.5Hz,1H),2.41(d,J=4.8Hz,1H),2.22(d,J=4.6Hz,2H). 13 C NMR (101MHz, DMSO) δ168.30,168.09,158.07,155.47,151.02,147.33,140.91,140.74,130.38,130.24,126.94,121.95,121.90,120.40,116. 31,115.50,112.91,105.92,86.76,66.86,55.45,46.04,44.79,42.87,37.32,33.68,32.38.LC-MS-ESI+:[M+H]+543.3.HRMS(ESI),calcdfor C 29 H 29 F3N2O5[M+H]+,543.2102,found,543.2101Mp:132.47-137.92℃.

[0095] Example 21, phenyl carbonate 3-((dimethylamino)methyl)-4-(3-methoxyphenyl)-1-(2-(2,4,5-trifluorophenyl)acetyl)piperidin-4-yl ester hydrochloride (FW-XXD-AP-A6)

[0096] Referring to the synthesis of A1, a light yellow solid was obtained with a yield of 80.19%. 1HNMR(400MHz,Chloroform-d)δ7.42(t,J=7.8Hz,2H),7.36(t,J=8.0Hz,1H),7.32–7.25(m, 1H),7.19(p,J=9.6,8.9Hz,3H),6.97(dt,J=9.6,4.8Hz,1H),6.94–6.79(m,3H),4.47(d,J= 13.8Hz,1H),4.20–4.03(m,1H),3.86(s,3H),3.82–3.73(m,2H),3.43(dd,J=13.9,10.3Hz, 1H),3.24–2.89(m,2H),2.48–2.27(m,2H),2.04(s,6H),1.95(td,J=10.5,9.1,2.9Hz,2H). 13 C NMR (151MHz, DMSO) δ168.07,166.23,160.01,151.05,150.94,146.71,141.08,130.31,130.26,129.25,126.93,121.85,120.27,118.00,11 3.98,111.74,105.89,86.81,66.82,55.79,55.45,45.96,44.77,42.57,37.25,33.67,32.30.LC-MS-ESI+:[M+H]+557.4.HRMS(ESI),calcd forC 30 H 31 F3N2O5[M+H]+,557.2258,found 557.2258.Mp:139.88-142.20℃.

[0097] Example 22, 3-((dimethylamino)methyl)-4-(3-hydroxyphenyl)-1-(2-(2,4,5-trifluorophenyl)acetyl)piperidin-4-ylphenylcarbamate hydrochloride (FW-XXD-AP-A7)

[0098] Referring to the synthesis of A1, a light yellow solid was obtained with a yield of 73.01%. 1HNMR(400MHz,DMSO-d6)δ9.07(s,1H),7.07–6.90(m,4H),6.82(t,J=7.8Hz,2H),6.72(t,J=7.9Hz,1H ),6.53(t,J=7.5Hz,1H),6.35(d,J=7.9Hz,1H),6.31–6.27(m,1H),6.24(dd,J=8.0,2.3Hz,1H),3.98( d,J=8.5Hz,1H),3.40–3.34(m,1H),3.24–3.15(m,1H),2.99(dd,J=11.8,4.5Hz,1H),2.87(s,6H),2. 16(m,3H),1.93(d,J=4.7Hz,2H),1.80(d,J=4.6Hz,2H).LC-MS-ESI+:[M+H]+542.2.HRMS(ESI),calcd for C 29 H 30 F3N3O4[M+H]+,542.2261,found,542.2260.Mp:149.65-156.28℃.

[0099] Example 23, 3-((dimethylamino)methyl)-4-(3-methoxyphenyl)-1-(2-(2,4,5-trifluorophenyl)acetyl)piperidin-4-ylphenylcarbamate hydrochloride (FW-XXD-AP-A8)

[0100] Referring to the synthesis of A1, a light yellow solid was obtained with a yield of 88.48%. 1 HNMR(400MHz,DMSO-d6)δ7.49(m,5.8Hz,11H),7.44(s,1H),7.32(m,3H),6.99(m,3H),6.91(d,2H),4.71(s,1H),4.41(d,J=13.2Hz,1H ),3.87(d,J=8.5Hz,1H),3.76(s,3H),3.56(s,6H),2.97(d,J=14.2Hz,1H),2.85–2.71(m,2H),2.63(m,3H),2.45(s,1H),2.26(s,2H). 13C NMR (101MHz, DMSO) δ167.73,167.52,159.29,154.85,151.61,151.55,146.85,142.43,138.96,129.50,128.83,122.62,119.88,118.14,11 7.80,112.61,111.84,105.39,82.51,55.18,45.39,44.51,42.52,37.16,33.21,32.50,26.82.LC-MS-ESI+:[M+H]+556.2.HRMS(ESI),calcd for C 30 H 32 F3N3O4[M+H]+,556.2418,found,556.2426.Mp:163.46-165.02℃.

[0101] Example 24, 3-((dimethylamino)methyl)-4-(3-hydroxyphenyl)-1-(2-(2,4,5-trifluorophenyl)acetyl)piperidin-4-yl 2-phenylacetate hydrochloride (FW-XXD-AP-A9)

[0102] Referring to the synthesis of A1, a light yellow solid was obtained with a yield of 60.96%. 1 HNMR(400MHz,DMSO-d6)δ9.59(s,1H),7.58–7.49(m,1H),7.47–7.36(m,5H),7.36–7.29(m,1H),7.18(t,J=7.9Hz,1H ),6.74(dd,J=7.8,2.2Hz,1H),6.73–6.65(m,2H),4.53(d,J=12.2Hz,1H),4.31(d,J=13.3Hz,1H),3.99–3.90(m,2H) ,3.89–3.78(m,1H),3.71(d,J=8.2Hz,1H),3.07(dt,J=44.9,12.6Hz,1H),2.93–2.68(m,2H),2.59(dd,J=18.2,4.7H z,4H),2.36(d,J=4.8Hz,2H),2.20(d,J=4.6Hz,2H),2.18–2.09(m,1H).LC-MS-ESI+:[M+H]+541.3.HRMS(ESI),calcd forC 30 H 31 F3N2O4[M+H]+,541.2309,found,541.2312.Mp:200.87-202.98℃.

[0103] Example 25, 3-((dimethylamino)methyl)-4-(3-methoxyphenyl)-1-(2-(2,4,5-trifluorophenyl)acetyl)piperidin-4-yl 2-phenylacetate hydrochloride (FW-XXD-AP-A10)

[0104] Referring to the synthesis of A1, a light yellow solid was obtained with a yield of 74.52%. 1 HNMR(400MHz, DMSO-d6)δ7.54–7.45(m,1H),7.43(q,J=2.7,1.9Hz,1H),7.42–7.39(m,3H),7.37(d,J=7.5Hz,1H),7.30(d t,J=7.1,2.0Hz,1H),7.27(d,J=3.1Hz,1H),6.87(dd,J=8.3,2.3Hz,1H),6.82(d,J=7.7Hz,1H),6.77(s,1H),4.73–4.50( m,1H),4.23(dd,J=68.3,15.2Hz,1H),3.96–3.86(m,3H),3.82(d,J=12.3Hz,1H),3.70(d,J=2.2Hz,4H),3.22–3.00(m,1H ),2.86–2.74(m,2H),2.63–2.52(m,4H),2.44(s,1H),2.34(d,J=4.4Hz,1H),2.23(d,J=4.4Hz,1H),2.14(d,J=4.5Hz,2H). 13 C NMR (101MHz, DMSO) δ170.03,169.98,167.94,159.77,157.76,147.32,141.56,141.42,134.92,130.19,129.96,129.02,127.55,120.35,118.2 1,113.60,111.87,105.93,84.47,55.65,45.87,44.88,42.87,41.95,37.18,33.74,33.00,32.27.LC-MS-ESI+:[M+H]+555.2.HRMS(ESI),calcd for C 31 H 33 F3N2O4[M+H]+,555.2465,found,555.2473.Mp:179.39-183.71℃.

[0105] Example 26, 3-((dimethylamino)methyl)-4-(3-hydroxyphenyl)-1-(2-(2,4,5-trifluorophenyl)acetyl)piperidin-4-yl 3-phenylpropanoate hydrochloride (FW-XXD-AP-A11)

[0106] Referring to the synthesis of A1, an off-white solid was obtained with a yield of 79.50%. 13 C NMR (101MHz, DMSO) δ174.24,171.35,167.87,157.88,155.35,147.27,141.55,141.39,140.92,129.88,128.88,128.78,126.70,120.37,11 6.59,114.99,113.26,105.92,84.24,66.86,45.87,44.86,43.12,37.18,36.05,35.75,33.69,30.58.LC-MS-ESI+:[M+H]+HRMS(ESI),calcd for C 31 H 33 F3N2O4[M+H]+,555.2465,found 555.2475.Mp:159.33-162.74℃.

[0107] Example 27, 3-((dimethylamino)methyl)-4-(3-methoxyphenyl)-1-(2-(2,4,5-trifluorophenyl)acetyl)piperidin-4-yl 3-phenylpropanoate hydrochloride (FW-XXD-AP-A12)

[0108] Referring to the synthesis of A1, a light yellow solid was obtained with a yield of 52.72%. 1 HNMR(400MHz,DMSO-d6)δ7.49(m,1H),7.40(m,1H),7.31(m,4H),7.23(m,2H) ,6.91–6.80(m,2H),6.73(d,J=7.7Hz,1H),4.72–4.51(m,1H),4.22(dd,J=47. 4,15.0Hz,1H),3.88–3.78(m,1H),3.74(s,3H),3.30–3.21(m,1H),3.07–2.7 5(m,8H),2.60(s,3H),2.47–2.29(m,3H),2.23(d,J=4.3Hz,1H),2.14(s,2H). 13C NMR(101MHz,DMSO)δ171.45,171.41,167.92,159.82,155.35,147.24,14 1.72,141.56,140.91,129.84,128.87,128.81,126.71,120.33,118.39,1 13.41,112.05,105.93,84.31,55.71,45.86,44.87,42.84,37.16,35.92,33.77,33.03,32.30,30.54.LC-MS-ESI+:[M+H]+569.4.HRMS(ESI),calcd for C 32 H 35 F3N2O4[M+H]+,569.2622,found569.2626.Mp:145.18-148.29℃.

[0109]

[0110] Example 28, 1-[3-((dimethylamino)methyl)-4-hydroxy-4-(3-hydroxyphenyl)piperidin-1-yl]-3-(3-fluorophenyl)propan-1-one hydrochloride (FW-XXD-AP-C1)

[0111] Refer to the condensation of 5a, yield 56.06%

[0112] Refer to the removal of A1, the yield is 83.98%

[0113] The salt formation method of A1 was used as a reference to obtain a light yellow solid with a yield of 63.11%. 1 HNMR(400MHz,DMSO-d6)δ7.35–7.25(m,2H),7.24–7.15(m,1H),7.15–6.96(m,3H),6.82(dd,J= 8.1,2.5Hz,1H),4.60(dd,J=49.0,12.2Hz,1H),4.29(d,J=11.9Hz,1H),3.69(s,3H),3.16(s,1 H),3.07(s,1H),3.04–2.93(m,1H),2.93–2.67(m,6H),2.58(t,J=5.1Hz,3H),2.45–2.37(m,1H ),2.32(d,J=4.7Hz,2H),1.86(dtd,J=40.2,13.3,4.6Hz,1H),1.65–1.54(m,1H),1.10(s,3H). 13C NMR (101MHz, DMSO) δ170.49,163.90,159.75,148.70,145.07,130.43,129.75,125.30,117.91,115.96,115.76,113.10,112.6 1,111.79,73.42,56.85,55.57,49.24,45.51,45.05,37.56,33.96,31.00,27.34.LC-MS-ESI+:[M+H]+401.4.HRMS(ESI),calcd for C 23 H 29 FN2O3[M+H]+,401.2235,found401.2235.Mp:173.62-175.03℃.

[0114] Example 29, 1-[3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)piperidin-1-yl]-3-(3-fluorophenyl)propan-1-one hydrochloride (FW-XXD-AP-C2)

[0115] Refer to the condensation of 5a, yield 63.89%

[0116] The salt formation method of A1 was used as a reference to obtain a light yellow solid with a yield of 73.62%. 1 HNMR(400MHz, DMSO-d6)δ7.18–7.07(m,2H),6.99(t,J=2.1Hz,1H),6.91(d,J=7.6Hz,1H),6.78–6.59(m, 3H),6.43–6.36(m,1H),4.70–4.57(m,1H),4.33(dd,J=30.5,14.6Hz,1H),4.02(t,J=15.1Hz,1H),3.24( dd,J=13.5,11.3Hz,1H),3.18(s,2H),3.09(s,1H),2.95(ddd,J=29.3,13.5,10.2Hz,2H),2.62(dd,J=20 .1,4.6Hz,3H),2.39(d,J=4.6Hz,2H),1.86(td,J=13.4,4.8Hz,1H),1.65(d,J=13.7Hz,1H),1.12(s,2H). 13C NMR (101MHz, DMSO) δ167.79,165.05,162.67,157.82,149.83,148.47,129.60,116.14,114.18,113.08,110.39,103. 48,100.54,73.32,56.96,49.08,46.79,45.16,44.88,38.00,27.34.LC-MS-ESI+:[M+H]+415.4.HRMS(ESI),calcdfor C 24 H 31 FN2O3[M+H]+,415.2392,found415.2387.Mp:164.59-168.74℃.

[0117] Example 30, 1-[3-((dimethylamino)methyl)-4-hydroxy-4-(3-hydroxyphenyl)piperidin-1-yl]-2-((3-fluorophenyl)amino)ethan-1-one hydrochloride (FW-XXD-AP-C3)

[0118] Refer to the condensation of 5a, yield 49.54%

[0119] Refer to the debenzylation of A1, yield 51.47%

[0120] The salt formation method of A1 was used as a reference to obtain a light yellow solid with a yield of 61.30%. 1 HNMR(400MHz, DMSO-d6)δ7.18–7.07(m,2H),6.99(t,J=2.1Hz,1H),6.91(d,J=7.6Hz,1H),6.78–6.59(m, 3H),6.43–6.36(m,1H),4.70–4.57(m,1H),4.33(dd,J=30.5,14.6Hz,1H),4.02(t,J=15.1Hz,1H),3.24( dd,J=13.5,11.3Hz,1H),3.18(s,2H),3.09(s,1H),2.95(ddd,J=29.3,13.5,10.2Hz,2H),2.62(dd,J=20 .1,4.6Hz,3H),2.39(d,J=4.6Hz,2H),1.86(td,J=13.4,4.8Hz,1H),1.65(d,J=13.7Hz,1H),1.12(s,2H). 13C NMR (101MHz, DMSO) δ167.79,165.05,162.67,157.82,149.83,148.47,129.60,116.14,114.18,113.08,110.39,103. 48,100.54,73.32,56.96,49.08,46.79,45.16,44.88,38.00,27.34.LC-MS-ESI+:[M+H]+402.3.HRMS(ESI),calcdfor C 22 H 28 FN3O3[M+H]+,402.2188,found 402.2183.Mp:173.94-176.13℃.

[0121] Example 31, 1-[3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)piperidin-1-yl]-2-((3-fluorophenyl)amino)ethan-1-one hydrochloride (FW-XXD-AP-C4)

[0122] Refer to the condensation of 5a, yield 39.84%

[0123] The salt formation method of A1 was used as a reference to obtain a light yellow solid with a yield of 83.01%. 1HNMR(400MHz,DMSO-d6)δ7.53(d,J=5.4Hz,2H),7.47(q,J=3.5Hz,4H),7.29(q,J=7.9Hz, 2H),7.17(dd,J=14.9,7.7Hz,3H),7.12–7.03(m,2H),6.92(d,J=8.0Hz,1H),6.86–6.80( m,2H),6.72–6.64(m,1H),4.41–4.25(m,1H),4.20(d,J=16.8Hz,1H),3.98(s,7H),3.81– 3.71(m,10H),3.51–3.32(m,2H),3.16(s,4H),3.07(s,2H),3.02–2.92(m,2H),2.68–2.57 (m,6H),2.46–2.25(m,6H),2.17–1.95(m,2H),1.72–1.58(m,1H),1.39–1.26(m,1H),1.2 3(d,J=4.0Hz,3H),1.10(s,6H).13CNMR(101MHz,DMSO)δ169.72,168.00,159.78,148.37, 136.64,130.01,129.79,128.91,127.72,127.49,117.98,112.69,111.66,85.12,73.39 ,55.59,49.24,49.09,45.17,29.52,27.35.LC-MS-ESI+:[M+H]+416.2.HRMS(ESI),calcd for C 23 H 30 FN3O3[M+H]+,416.2344,found,416.2351.Mp:173.83-178.44℃.

[0124] Example 32, 1-[3-((dimethylamino)methyl)-4-hydroxy-4-(3-hydroxyphenyl)piperidin-1-yl]-2-((3-fluorophenyl)amino)propan-1-one hydrochloride (FW-XXD-AP-C5)

[0125] Refer to the condensation of 5a, yield 49.29%

[0126] Refer to the debenzylation of A1, yield 82.74%

[0127] The salt formation was carried out by referring to A1 to obtain a white solid with a yield of 85.93%. 1HNMR(400MHz,DMSO-d6)δ7.20(d,J=11.5Hz,1H),7.13(dt,J=8.3,4.2Hz,2H),6.97(s,1H ),6.85–6.76(m,3H),6.71–6.67(m,2H),3.35–3.21(m,1H),2.95(dd,J=24.1,13.0Hz,3H) ,2.64(d,J=4.5Hz,3H),2.48(d,J=4.5Hz,1H),2.35(dd,J=20.8,4.6Hz,4H),1.80(dd,J=1 5.1,10.6Hz,1H),1.69–1.57(m,2H),1.41(d,J=6.5Hz,1H),1.30(dd,J=12.1,6.5Hz,3H). 13 C NMR (101MHz, DMSO) δ171.57,170.13,164.89,162.01,157.85,157.81,148.25,131.01,129.62,116.11,114.22,113.14 ,113.02,73.43,73.09,56.85,49.07,45.82,45.27,45.11,18.75,16.99.LC-MS-ESI+:[M+H]+416.4.HRMS(ESI),calcd for C 23 H 30 FN3O3[M+H]+,416.2344; found,416.2338.Mp:128.97-132.37℃.

[0128] Example 33, 1-[3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)piperidin-1-yl]-2-((3-fluorophenyl)amino)propan-1-one hydrochloride (FW-XXD-AP-C6)

[0129] Refer to the condensation of 5a, yield 55.72%

[0130] The salt formation was carried out according to the method of A1 to obtain a white solid with a yield of 81.02%. 1HNMR(400MHz, DMSO-d6)δ7.28(td,J=7.9,2.3Hz,2H),7.14(d,J=2.2Hz,1H),7.05(dt,J=23.5, 6.7Hz,3H),6.84(dt,J=8.0,2.5Hz,1H),6.65(t,J=10.3Hz,2H),3.78(d,J=2.8Hz,5H),3.09(s ,1H),3.05–2.87(m,3H),2.65(dd,J=4.9,2.4Hz,3H),2.59(d,J=4.5Hz,2H),2.37(dd,J=13.5, 4.7Hz,4H),1.69–1.61(m,1H),1.42(d,J=6.6Hz,1H),1.27(q,J=6.6,5.0Hz,3H),1.12(s,3H). 13 C NMR (101MHz, DMSO) δ171.94,170.71,164.96,162.61,159.77,148.55,148.47,130.92,129.80,117.85,113.86,112.87,11 1.80,73.64,73.25,56.86,55.55,49.08,45.27,45.13,27.34,18.90,17.38.LC-MS-ESI+:[M+H]+430.2.HRMS(ESI),calcd for C 24 H 32 FN3O3[M+H]+,430.2501; found,430.2515.Mp:175.32-180.39℃.

[0131] Example 34, tert-Butyl 4-(benzoyloxy)-3-((dimethylamino)methyl)-4-(3-benzyloxyphenyl)piperidine-1-carboxylate (10a)

[0132] A flask was charged with 3a (4.0 g, 9.08 mmol, 1 eq), dichloromethane (40 mL), and triethylamine (1.84 g, 18.16 mmol, 2 eq), followed by cooling in an ice-water bath. Benzoyl chloride (2.55 g, 18.16 mmol, 2 eq) was added dropwise. After the addition was complete, the ice-water bath was removed and the mixture was stirred. The reaction was allowed to proceed overnight, and thin-layer chromatography indicated that the reaction was complete. Water (50 mL) was added and stirred for 10 minutes. The mixture was extracted with DCM and water, and the oil phase was dried and evaporated to dryness under reduced pressure to obtain 7.45 g of a yellow liquid. Purification by silica gel column chromatography (DCM to DCM:MeOH = 200:1, with 0.5‰ triethylamine) gave 4.5 g of a colorless liquid with a yield of 91.0%.

[0133] Example 35, tert-Butyl 4-(benzoyloxy)-3-((dimethylamino)methyl)-4-(3-methoxyoxyphenyl)piperidine-1-carboxylate (10b)

[0134] Synthesized according to 10a with a yield of 89.06%.

[0135] Example 36, 4-(3-(Benzyloxy)phenyl)-3-((dimethylamino)methyl)-4-hydroxypiperidine-1-carboxylic acid phenyl ester (13a)

[0136] The Boc protecting group of 4a was removed to give 11a in 93.22% yield.

[0137] To a 100 ml single-necked flask, 11a (250 mg, 0.56 mmol, 1 eq), dichloromethane (20 mL), and triethylamine (114 mg, 1.12 mmol, 2 eq) were added, followed by cooling in an ice-water bath. Benzoyl chloride (176 mg, 1.12 mmol, 2 eq) was added dropwise. The mixture was allowed to react overnight, followed by extraction with water and DCM. The oil phase was dried and spin-dried. Purification by silica gel column chromatography (DCM to DCM:MeOH = 100:1) afforded 287 mg of 12a as a colorless liquid in a 93.38% yield.

[0138] 12a (287 mg, 0.51 mmol, 1 eq.), ethanol (20 mL), and sodium hydroxide (45 mg, 1.02 mmol, 2 eq.) were added to a flask and stirred at 78°C for 2 h. The ethanol was dried by rotary evaporation, and the mixture was extracted with water and EA. The oil phase was evaporated under reduced pressure to obtain 3.82 g of a yellow oil. Purification by silica gel column chromatography afforded 149 mg of a colorless, transparent oil (yield: 63.65%).

[0139] Example 37, phenyl 3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)piperidine-1-carboxylate (13b)

[0140] Refer to the synthesis method of 13a to remove the Boc protecting group (yield 96.81%), add the phenyl carbonate group (yield 81.74%) and remove the benzoyl group (yield 89.38%).

[0141] Example 38, 3-((dimethylamino)methyl)-4-hydroxy-4-(3-hydroxyphenyl)piperidine-1-carboxylic acid phenyl ester hydrochloride (FW-XXD-AP-C7)

[0142] Refer to the debenzylation of 7a, yield 87.34%

[0143] The salt formation was carried out by referring to A1 to obtain a white solid with a yield of 73.07%. 1HNMR (400MHz, DMSO-d6) δ8.16–8.09(m,2H),7.76(t,J=7.4Hz,1H),7.61(t,J=7.7Hz,2H),7. 20(t,J=7.9Hz,1H),6.82(d,J=7.8Hz,1H),6.75(dd,J=8.0,2.4Hz,1H),6.70(d,J=2.1Hz,1H ),4.15–4.01(m,3H),3.77–3.64(m,1H),3.55–3.45(m,1H),3.21(t,J=12.1Hz,1H),3.01(dt ,J=14.5,2.7Hz,1H),2.81(dd,J=13.4,8.3Hz,2H),2.63(d,J=4.4Hz,3H),2.48–2.31(m,6H). 13 C NMR (101MHz, DMSO) δ163.97,157.29,154.71,140.90,133.77,129.77,129.57,128.93,115.99,114.60, 112.80,84.34,60.95,60.17,44.07,41.95,32.16,14.58.LC-MS-ESI+:[M+H]+389.2.HRMS(ESI),calcd for C 21 H 25 N2O4[M+H]+,389.1871; found,389.1874.Mp:159.65-163.96℃.

[0144] Example 39, phenyl 3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)piperidine-1-carboxylate hydrochloride (FW-XXD-AP-C8)

[0145] The salt formation was carried out according to the method of A1 to obtain a white solid with a yield of 65.59%. 1 HNMR(400MHz,DMSO-d6)δ8.16–8.09(m,2H),7.79–7.72(m,1H),7.61(t,J=7 .7Hz,2H),7.35–7.28(m,1H),6.94–6.87(m,3H),4.09(p,J=6.4,5.8Hz,3H), 3.74–3.66(m,1H),3.59–3.45(m,2H),3.39–3.19(m,2H),3.00(dt,J=14.4,2 .6Hz,1H),2.79(dd,J=13.5,8.3Hz,1H),2.61(d,J=4.5Hz,3H),2.33(s,3H). 13CNMR(101MHz,DMSO)δ164.59,159.87,155.19,141.60,134.33,130.23,130.08,129.47,118.35,113.39,11 2.26,85.01,61.45,55.69,55.16,44.56,42.23,32.67,15.09.LC-MS-ESI+:[M+H]+403.2.HRMS(ESI),calcd for C 22 H 27 N2O4[M+H]+,403.2028; found,403.2029.Mp:173.03-177.37℃.

[0146] Example 40, R-(3-fluorophenyl)alanine (R-FW-XXD-AP-15)

[0147] To a 100 mL single-necked flask, add D-alanine (2 g, 22.45 mmol, 1 eq), m-bromofluorobenzene (4.71 g, 26.94 mmol, 1.2 eq), 2-isobutyrylcyclohexanone (755 mg, 0.449 mmol, 0.2 eq), Cs2CO3 (14.63 g, 44.90 mmol, 2 eq), CuI (214 mg, 22.45 mmol, 0.05 eq), and DMF (50 mL). The mixture was heated to 50°C and stirred for 24 h. Water (80 mL) was added, and the mixture was extracted with ethyl acetate (80 + 80 mL). The aqueous phases were combined, and the pH of the aqueous phase was adjusted to weak acidity with 2 M dilute hydrochloric acid. The mixture was extracted with ethyl acetate (100 mL + 100 mL + 100 mL + 100 mL), and distilled under reduced pressure to obtain 2.94 g of a brown oil with a yield of 71.50%.

[0148] Example 41, R-1-[3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)piperidin-1-yl]-2-((3-fluorophenyl)amino)propan-1-one hydrochloride (R-FW-XXD-AP-C6)

[0149] Condensation and salt formation were carried out according to the synthetic method of A1 to obtain a light yellow solid with a two-step yield of 48.63%. 1HNMR(400MHz,Methanol-d4)δ7.61–7.49(m,1H),7.33–7.17(m,2H),7.16–7.03(m,2H),7.03–6 .90(m,1H),6.83(dd,J=8.2,2.4Hz,1H),5.56(q,J=6.7Hz,1H),4.64–4.36(m,1H),3.81–3.76( m,3H),3.64–3.42(m,1H),3.27(p,J=1.7Hz,1H),3.15–2.88(m,2H),2.70(d,J=4.1Hz,4H),2.6 3–2.43(m,2H),2.33(s,2H),2.25–1.86(m,1H),1.75–1.54(m,2H),1.50(dd,J=6.8,2.1Hz,2H). 13 C NMR(101MHz,MeOD)δ167.59,161.64,160.20,147.05,146.76,136.46,131.51,129.52,119.75,117.12,115.66,112.38, 111.13,73.15,57.58,54.55,45.87,44.55,42.00,40.99,38.56,14.46.LC-MS-ESI+:[M+H]+430.2.HRMS(ESI),calcdfor C 24 H 32 FN3O3[M+H]+,430.2501; found,430.2514.Mp:163.54-165.82℃.[α] 25.0℃ D =-3.000°(c=0.1,MeOH)

[0150] Example 42, S-1-[3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)piperidin-1-yl]-2-((3-fluorophenyl)amino)propan-1-one hydrochloride (S-FW-XXD-AP-C6)

[0151] The synthesis method of S-15 refers to the synthesis method of R-15, with a yield of 87.34%.

[0152] Condensation and salt formation were carried out according to the method of A1 to obtain a light yellow solid with a two-step yield of 32.28%. 1HNMR(400MHz,Methanol-d4)δ7.48(m,2H),7.26(t,J=7.9Hz,2H),7.03(m,2H),7.01–6.8 9(m,1H),6.80(dd,J=8.1,2.5Hz,1H),4.49(d,J=457.2Hz,2H),3.89(d,J=13.7Hz,1H),3. 76(d,J=2.1Hz,3H),3.70–3.39(m,1H),3.25(p,J=1.6Hz,1H),3.16–2.86(m,2H),2.74–2 .42(m,6H),2.32(s,2H),1.95(d,J=4.9Hz,0H),1.80–1.52(m,2H),1.46(d,J=6.6Hz,2H). 13 CNMR(101MHz,MeOD)δ168.68,167.70,161.64,160.18,158.30,147.08,146.79,131.50,129.53,119.74,117.15,112.43,1 11.13,73.21,57.49,54.59,48.13,45.87,44.59,41.94,41.01,38.59,14.45.LC-MS-ESI+:[M+H]+430.2.HRMS(ESI),calcd for C 24 H 32 FN3O3[M+H]+,430.2501,found,430.2515.Mp:167.27-170.89℃.[α] 25.0℃ D = +3.000° (c = 0.1, MeOH)

[0153] Example 43, tert-butyl (3R,4S)-4-(3-(methoxy)phenyl)-3-((dimethylamino)methyl)-4-hydroxypiperidine-1-carboxylate ((3R,4S)-3b)

[0154] 3b (3.8 g) was added to isopropanol (25 mL), and L-tartaric acid (L-DBTA, 3.29 g, 9.17 mmol, 0.8 eq) was added. The mixture was stirred at 83°C to dissolve. Seed crystals (5 mg) were added at room temperature. After overnight, a solid precipitated. Stirring was continued at -10-0°C for 1.5 hours. The mixture was filtered, rinsed with isopropanol (3 mL), and evaporated to dryness to obtain an off-white solid. The off-white solid was added to isopropanol (30 mL), heated to 73°C to dissolve, stirred at room temperature for 2 hours, filtered, rinsed with isopropanol (5 mL), and evaporated to dryness under reduced pressure to obtain an off-white solid.

[0155] The off-white solid was then added to isopropanol (15 mL), refluxed at 83°C to dissolve it, and stirred at room temperature for 1 hour. The mixture was filtered with suction, and the filter cake was rinsed with isopropanol (4 mL). The mixture was evaporated to dryness under reduced pressure to obtain some white solid. The solid was then added to isopropanol (15 mL), heated to 73°C to dissolve it, and then stirred at room temperature for 1 hour. The mixture was filtered with suction, rinsed with isopropanol (4 mL), and evaporated to dryness under reduced pressure to obtain a white solid. The mixture was then extracted with saturated sodium bicarbonate aqueous solution and EA. The resulting oil phase was dried and evaporated under reduced pressure to obtain 591 mg of a colorless oil with a yield of 15.55%.

[0156] All mother liquors were combined, the solvent was evaporated under reduced pressure, extracted with saturated sodium bicarbonate aqueous solution and EA, and the obtained organic phase was dried and evaporated to dryness to obtain a yellow oil, which was directly used for the resolution of D-tartaric acid.

[0157] Example 44, tert-butyl (3S,4R)-4-(3-(methoxy)phenyl)-3-((dimethylamino)methyl)-4-hydroxypiperidine-1-carboxylate ((3S,4R)-3b)

[0158] Referring to the synthesis of (3R,4S)-3b, 752 mg of a transparent oil was obtained with a yield of 19.79%.

[0159] Example 45, R, (3R, 4S) -1- [3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl] -2- ((3-fluorophenyl) amino) propan-1-one hydrochloride (R, (3R, 4S) -FW-XXD-AP-C6)

[0160] Refer to the A1 synthesis method to obtain a light yellow solid. 1 HNMR (400MHz, Methanol-d4) δ7.52(dtd,J=22.5,8.1,5.8Hz,1H),7.42(d,J=8.1Hz,1H),7.31(td,J=8.5,2.1Hz,1H ),7.27–7.12(m,2H),7.07–6.88(m,2H),6.78(dd,J=8.1,2.3Hz,1H),4.63–4.28(m,1H),3.73(d,J=4.9Hz,3H),3.62

[0161] –3.48(m,1H),3.22(p,J=1.7Hz,1H),3.13–2.92(m,2H),2.66(d,J=1.6Hz,3H),2.64–2.55(m ,1H),2.52(s,2H),2.45(s,1H),2.22–1.97(m,2H),1.71–1.57(m,2H),1.46(d,J=6.5Hz,2H). 13 C NMR(101MHz,MeOD)δ168.92,164.42,161.98,160.21,147.01,146.77,131.33,129.58,117.00,112.33,112.27,111.12,73.01,57.22,56.8 3,54.53,54.43,45.16,44.78,44.46,41.87,41.38,40.84,39.88,38.49,38.09,16.48,14.88.LC-MS-ESI+:[M+H]+430.2.HRMS(ESI),calcd for C 24 H 32 FN3O3[M+H]+430.2501,found,430.2515.177.14-184.19℃.[α] 25.0℃ D =-11.000° (c=0.1, MeOH).

[0162] Example 46, R, (3S, 4R) -1- [3- ((dimethylamino) methyl) -4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl] -2- ((3-fluorophenyl) amino) propan-1-one hydrochloride (R, (3S, 4R) -FW-XXD-AP-C6)

[0163] Refer to the A1 synthesis method to obtain a light yellow solid. 1HNMR(400MHz, Methanol-d4)δ7.69–7.58(m,2H),7.34(q,J=8.4,7.9Hz,2H),7.29–7.10( m,1H),7.06(s,1H),6.94(d,J=7.5Hz,1H),6.87(dd,J=8.2,2.4Hz,1H),5.65(q,J=6.6Hz, 1H),4.47(d,J=12.8Hz,1H),3.82(s,3H),3.35(s,1H),3.21(s,1H),3.20–2.89(m,1H),2 .74(d,J=5.8Hz,4H),2.34(s,3H),1.75–1.62(m,1H),1.55(d,J=6.5Hz,2H),1.19(s,4H). 13 C NMR(101MHz,MeOD)δ167.21,160.20,147.00,131.63,129.53,120.23,117 .08,116.54,116.33,112.31,111.91,111.65,111.27,73.07,58.07,57.1 8,54.52,48.30,48.09,47.88,47.67,47.45,47.24,47.03,44.52,42.09,41.02,38.50,25.86,14.39.LC-MS-ESI+:[M+H]+430.2.HRMS(ESI),calcd forC 24 H 32 FN3O3[M+H]+430.2501,found,430.2515.163.09-169.73℃.[α] 25.0℃ D =-1.000°(c=0.1,MeOH)

[0164] Example 47, 1-[3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)piperidin-1-yl]-2-((2,4,5-trifluorophenyl)amino)propan-1-one hydrochloride (FW-XXD-AP-D1)

[0165] Refer to the A1 synthesis method to obtain a light yellow solid. 1HNMR(600MHz,Methanol-d4)δ7.32(ddd,J=12.7,7.9,5.6Hz,1H),7.13–6.98(m,3H),6.87(qd ,J=5.2,2.5Hz,1H),4.72–4.56(m,2H),4.15–4.08(m,1H),3.85–3.78(m,3H),3.72–3.59(m,1 H),3.55–3.44(m,1H),3.18–3.01(m,2H),2.83–2.66(m,5H),2.65–2.54(m,2H),2.42(s,1H), 2.33–2.06(m,2H),1.88–1.72(m,1H),1.49(t,J=6.4Hz,1H),1.45–1.37(m,2H),1.19(s,1H). 13 C NMR(151MHz,MeOD)δ172.60,172.56,172.38,160.19,147.22,146.81,129.59,129.57,116.84,112.22,111.07,104.64,1 01.12,72.97,57.30,57.05,56.98,54.33,41.73,41.61,41.42,25.81,17.28,16.94LC-MS-ESI+:466.2.HRMS(ESI),calcd for C 24 H 29 F3N3O3[M+H]+,466.2312,found,466.2332.Mp:167.27-170.89℃.

[0166] Example 48, 1-[3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)piperidin-1-yl]-2-((3-(trifluoromethyl)phenyl)amino)propan-1-one hydrochloride (FW-XXD-AP-D2)

[0167] Refer to the synthesis method A1 to obtain a white solid. 1HNMR(600MHz, Methanol-d4)δ8.04–7.99(m,1H),7.80(dd,J=28.3,7.8Hz,1H),7.73–7.62(m,2H),7.30(td,J=7.9, 4.7Hz,1H),7.09–6.87(m,2H),6.85(dt,J=8.2,2.3Hz,1H),3.80(d,J=4.6Hz,3H),3.74–3.71(m,1H),3.67–3.63(m, 1H),3.57(dd,J=5.5,4.2Hz,1H),3.19(s,2H),2.71(d,J=6.2Hz,3H),2.62–2.47(m,2H),2.31–2.27(m,2H),1.54(dd ,J=12.3,6.6Hz,2H),1.36(s,1H),1.17(s,5H),0.88(t,J=7.0Hz,1H).LC-MS-ESI+:[M+H]+480.2.HRMS(ESI),calcd for C 25 H31F3N3O3[M+H]+,480.2469; found,480.2475.Mp:173.91-179.72℃.

[0168] Example 49, 1-[3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)piperidin-1-yl]-2-((3-nitrophenyl)amino)propan-1-one hydrochloride (FW-XXD-AP-D3)

[0169] Refer to the synthesis method of A1 to obtain a yellow solid. 1HNMR (400MHz, Methanol-d4) δ8.18–7.80 (m, 1H), 7.83–7.37 (m, 3H), 7.27 (dq, J=8.0, 4.0Hz, 1H), 7.10–6.90 (m, 2H), 6.81 (dt, J=8.3, 2.3Hz, 1H), 4.72–4.36 (m, 1H), 3.76 (dd, J=7 .6,2.5Hz,3H),3.25(p,J=1.6Hz,1H),3.17–2.90(m,3H),2.79–2.62(m,4H),2.54(d,J=2 7.0Hz,1H),2.36(s,1H),1.83–1.52(m,2H),1.47(dd,J=6.8,5.0Hz,2H),1.13(s,3H).13C NMR(101MHz,MeOD)δ170.95,169.34,160.20,149.18,147.08,130.51,129.60,126.67,123.53,119.24,117.19,115.75,11 4.16,73.17,66.78,56.94,54.51,44.49,40.97,38.61,25.87,15.78,15.19.LC-MS-ESI+:[M+H]+456.2.HRMS(ESI),calcd for C 24 H 31 N4O5[M+H]+,457.2446; found,457.2449.Mp:201.78-213.32℃.

[0170] Example 50, Biological Test Experiment MOR In Vitro Affinity Experiment:

[0171] 1. Reagent Preparation

[0172]

[0173] 2. Experimental steps

[0174] 1) Pre-incubate the UNIFILTER-96GF / B filter plate with 0.5% PEI solution for 3 hours;

[0175] 2) Dilute the compound in assay buffer in a 96-well deep-well plate, 50 μL per well;

[0176] 3) Add 3 μL of membrane protein and 97 μL of detection buffer to each well;

[0177] 4) Dilute [3H]-DAMGO 4-fold with 50 μL assay buffer, transfer to the assay plate (final concentration 2 nM), and incubate at 27°C for 90 minutes;

[0178] 5) Prewash the UNIFILTER-96GF / B filter plate twice with 1 mL / well wash buffer, transfer the membrane to the filter plate using a vacuum pump, and then wash four times with 1 mL / well buffer.

[0179] 6) Dry the filter plate at 55°C for 10 minutes;

[0180] 7) Add 40 μL of ULTIMAGOLD scintillation fluid to each well and count using a Microbeta 2 instrument.

[0181] 3. Data Analysis

[0182] The inhibition rate was calculated as follows: inhibition rate % = 100 - (test compound signal - low control) / (high control - low control) × 100;

[0183] IC 50 Calculation and dose-effect curve fitting: Y = baseline value + (maximum value - baseline value) / (1 + 10^((logIC 50 -X)*Hill slope))(X: logarithmic value of concentration; Y: inhibition rate %);

[0184]

[0185]

[0186]

[0187] NT: Not tested.

[0188] Example 51: Evaluation of agonist activity at the in vitro cell level

[0189] CHO-μ-PKAcatEGFP, CHO-κ-PKAcatEGFP, and CHO-δ-PKAcatEGFP cells were seeded in 60 mm culture dishes, harvested using Versene dissociation buffer (Gibco, Invitrogen), and subsequently washed with Hank's balanced salt solution buffer. 6 / ml density was resuspended in stimulation buffer (containing 5mM HEPES, 0.1% BSA and 0.05mM 3-isobutyl-1-methylxanthine). Forskolin and thienorphine (3×10 -12 -10 -5 M)Alexa 647-labeled antibody (PerkinElmer, Waltham, MA), orskolin and thienorphine (3 × 10 -12 -10 -5 M) were added sequentially to the cell suspension. DAMGO, U50488, and MORPHINE were used as positive controls. After incubation at 37°C for 15 minutes, the detection mixture was added and the signal was read using a VICTOR instrument (PerkinElmer). Subsequently, the LANCE signal was measured after 1 hour of incubation. The cAMP inhibition rate (%) was calculated using the following formula: LANCE signal (compound - forskolin) / forskolin × 100%.

[0190]

[0191]

[0192] Example 52: Analgesic activity in animals in vivo

[0193] Kunming mice (female) weighing 20±2g were selected and placed in a constant temperature hot plate apparatus at 55±0.5℃. The pain threshold of the mice was determined by observing their behavior of shaking or licking their hind paws and jumping. The average of three measurement results at each time point was taken, with an interval of at least 1 hour between each measurement. Mice with a basal threshold of 5 to 30 seconds were screened and randomly divided into groups. The drug was administered by intraperitoneal injection. The pain threshold of the mice was measured at 15 minutes, 30 minutes, 60 minutes, 90 minutes and 120 minutes after administration. In order to avoid scalding of the mouse's feet, the maximum time for a single observation was set to 60 seconds, and the timeout was recorded as 60 seconds. %MPE was calculated according to this formula: (latency after administration - latency before administration) / (60-latency before administration)*100%.

[0194]

[0195]

[0196]

[0197] From the above calculation results, it can be seen that the compounds prepared by the present invention, such as FW-XXD-AP-C6, R-FW-XXD-AP-C6, and R,(3R,4S)-FW-XXD-AP-C6, have significant analgesic effects, with a latency period of 60 seconds after administration, indicating that mice have basically no response to the stimulus.

[0198] The above description is only a preferred specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any technician familiar with the technical field, within the technical scope disclosed by the present invention, who makes equivalent replacements or changes based on the technical solution and inventive concept of the present invention, should be covered by the scope of protection of the present invention.

Claims

1. A compound having a structure represented by formula (I), or a stereoisomer, deuterated compound, solvate, metabolite, pharmaceutically acceptable salt, cocrystal or prodrug thereof: in, R1 is selected from hydrogen, C1-6 alkyl, fluoroalkyl, cycloalkyl, chain alkenyl, cycloalkenyl, substituted or unsubstituted aryl C1-6 alkyl; R2 is selected from substituted or unsubstituted aroyl, substituted or unsubstituted aryl, and the substituted group is selected from aryl, halogen, C1-6 alkyl, cyano, alkoxy, amino, nitro, alkylsulfonyl, ester, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, fluorine, nitro or phenolic hydroxyl; R3 is selected from hydrogen, deuterium, tritium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, C5-C7 heteroaryl, C5-C6 substituted heteroaryl; R4 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and the substituted group is selected from aryl, halogen, C1-6 alkyl, cyano, alkoxy, amino, nitro, alkylsulfonyl, ester, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, fluorine, nitro, and phenolic hydroxyl; X is selected from N, O, and C; Y is selected from C0-C6 alkyl, O, and N.

2. The compound of claim 1, or a stereoisomer, deuterated compound, solvate, metabolite, pharmaceutically acceptable salt, cocrystal or prodrug thereof, wherein: The compound of formula I has the structure shown in the following formula Ia:

3. The compound of claim 1, or a stereoisomer, deuterated compound, solvate, metabolite, pharmaceutically acceptable salt, cocrystal or prodrug thereof, wherein: The compound of formula I also has the structure shown in the following formula Ib:

4. The compound of claim 1, or a stereoisomer, deuterated compound, solvate, metabolite, pharmaceutically acceptable salt, cocrystal or prodrug thereof, wherein: The compound of formula I also has the structure shown in the following formula Ic:

5. The compound of claim 1, including its stereoisomers, deuterated compounds, solvates, metabolites, pharmaceutically acceptable salts, cocrystals or prodrugs, characterized in that: The specific compounds of the structure shown in formula (I) are as follows:

6. Use of the compound according to any one of claims 1 to 5, or its stereoisomers, geometric isomers, tautomers, deuterated compounds, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, in the preparation of a medicament for preventing, treating or alleviating a disease.

7. The use according to claim 6, characterized in that The diseases are opioid receptor-related indications, including pain, irritable bowel syndrome, pruritus, addiction, and depression; The pain includes treating or alleviating pain during surgery, chronic pain, neuropathic pain, and cancer pain.

8. A pharmaceutical composition, characterized in that The active ingredient is a compound according to any one of claims 1 to 5 or a stereoisomer, geometric isomer, tautomer, deuterated compound, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof.

9. The pharmaceutical composition according to claim 8, wherein The pharmaceutical composition further comprises a pharmaceutically acceptable carrier and / or adjuvant.

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