A fused ring morphine derivative, process for its preparation and use thereof

Abstract

The application belongs to the field of pharmacy, discloses a fused ring morphine derivative and a preparation method and application thereof, and relates to N-cyclopropylmethyl-4'-substituted aminonalepotem series derivatives with formula (I) and pharmaceutically acceptable salts. The derivative with formula (I) is prepared by reacting thebaine with a substituted phenyl vinyl ketone reagent and through a series of conversion methods. Among them, N-cyclopropylmethyl-(4'-benzoyl amino) nalepotem (SLL-1062) is a typical high selectivity mu opioid receptor antagonist, and can be applied to the research and development in the fields of diagnosis and treatment of opioid and other narcotic analgesic dependence, opioid drug-induced intestinal dysfunction, sedative hypnotics and acute alcohol poisoning, opioid and other narcotic analgesic poisoning and the like.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field and relates to N-cyclopropylmethyl-4'-substituted aminonapetone derivatives having formula (I) and methods for their preparation, as well as the use of these derivatives in the field of opioid receptor therapy. Background Technology

[0002] Drug addiction is a chronic, relapsing brain disorder resulting from repeated exposure to specific drugs. Its core characteristic is compulsive drug use: the addict loses control over seeking and consuming the drug. Furthermore, withdrawal symptoms such as restlessness and anxiety after cessation of drug use mean that even after long-term treatment and years of drug abstinence, patients still face a significant risk of relapse. In recent years, drug addiction has gradually become a global public health and social problem.

[0003] The occurrence and development of addiction are closely related to the dopamine-mediated reward pathway in the mesolimbic dopamine system. Addictive drugs induce positive emotions such as euphoria and pleasure in addicts by directly or indirectly upregulating dopamine levels, thereby inducing patients to actively seek drugs and gradually develop physical and psychological dependence on them. Numerous studies have shown that opioid receptors play an important role in the occurrence and development of addiction. Among them, μ-opioid receptors, as an important subtype of opioid receptors, are widely distributed in the central nervous system. The μ-receptor-mediated signaling pathway can indirectly regulate the level of dopamine in the central nervous system; therefore, μ-receptors are an important driving factor in drug addiction. Modulating the μ-receptor-mediated signaling pathway through exogenous opioid receptor ligands has been proven to be an important strategy for treating addiction: selective μ-receptor antagonists can inhibit the activation of μ-receptor-mediated signaling pathways, thereby suppressing the euphoric and pleasant emotional experiences produced by patients, reducing their active drug-seeking behavior, and alleviating their dependence on addictive drugs.

[0004] Morphine structural analogs and derivatives have always been a focus of opioid receptor modulator research and development. Among them, naltrexone and naloxone, although non-selective μ receptor antagonists, have been used clinically for many years as addiction treatment drugs. The clinical success of these drugs has provided theoretical support for the development of μ receptor antagonists with better activity and selectivity. Numerous studies have shown that octyl morphine structural derivatives have good affinity activity for opioid receptors and have variable subtype selectivity. Therefore, derivatives based on the octyl structure with μ receptor antagonistic activity have good development value and potential clinical application prospects. Summary of the Invention

[0005] To address the aforementioned problems, the present invention aims to provide an N-cyclopropylmethyl-4'-substituted aminonapezone derivative with opioid receptor binding activity. This type of compound can be used in the treatment of analgesia, pruritus, antidepressant, opioid addiction withdrawal, opioid-induced intestinal dysfunction, sedative-hypnotic drug and acute alcohol poisoning, opioid and other narcotic analgesic poisoning, and other treatments.

[0006] Another object of the present invention is to provide selective μ-ligands and μ / κ dual-ligands as potential analgesics, antipruritics, antidepressants, opioid withdrawal agents, and opioid-induced bowel dysfunction treatments.

[0007] Another object of the present invention is to provide N-cyclopropylmethyl-4'-substituted aminonapetone derivatives, stereoisomers or pharmaceutically acceptable salts thereof as represented by formula (I) and methods for their preparation.

[0008]

[0009] This invention provides compounds, stereoisomers, or pharmaceutically acceptable salts thereof as ligands for opioid receptors, as shown in formula (I), wherein:

[0010] R 1 Selected from H or CH3;

[0011] R 2 Selected from H, C 1-6 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-7 cycloalkyl, C 5-7 Cycloalkenyl, -(CH2) m -C 6-10 Aryl, -(CH2) m- 5-7 quinone heteroaryl groups; the C 1-6 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-7 cycloalkyl, C 5-7 Cycloalkenyl, aryl, and heteroaryl groups are bonded to 1-3 halogens, amino groups, hydroxyl groups, or C atoms. 1-6 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-7 Cycloalkyl groups may be optionally substituted;

[0012] R 3 Selected from H or CH3;

[0013] R 4 Selected from -CH=CH- or -CH2-CH2-;

[0014] R5 Selected from H or C 1-6 Alkyl, C 3-7 cycloalkyl, C 5-7 Cycloalkenyl, -(CH2) m -C 6-10 Aryl, -(CH2) m- 5-10 heteroaryl, -C(O)-C 1-6 Alkyl group, -C(O)-C 3-7 Cycloalkyl, -C(O)-(CH2) m -C 6-10 Aryl, -C(O)-(CH2) m -5-10 heteroaryl groups, -C(O)OC 1-6 Alkyl, -C(O)OC 3-7 Cycloalkyl, -C(O)O-(CH2) n -C 6-10 Aryl, -C(O)O-(CH2) n -5-10 heteroaryl groups; the C 1-6 Alkyl, C 3-7 cycloalkyl, C 5-7 Cycloalkenyl, aryl, and heteroaryl groups are surrounded by 1-3 halogens, nitro groups, amino groups, hydroxyl groups, or C groups. 1-6 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-7 cycloalkyl, -OC 1-6 Alkyl, -OC 3-7 Cycloalkyl, -OCF3, -C(O)OC 1-6 Alkyl groups and -SO2CH3 may be optionally substituted;

[0015] m is selected from 0, 1, 2, or 3;

[0016] n can be selected from 1, 2, or 3.

[0017] Preferably, formula (I) in this invention has the following structure:

[0018]

[0019] in,

[0020] R 1 and R 3 Each is independently selected from H or CH3;

[0021] R 4 Selected from -CH=CH- or -CH2-CH2-;

[0022] R 5 Selected from H or C 1-6 Alkyl, C3-7 cycloalkyl, C 5-7 Cycloalkenyl, -(CH2) m -C 6-10 Aryl, -(CH2) m- 5-10 heteroaryl, -C(O)-C 1-6 Alkyl, -C(O)-C 3-7 Cycloalkyl, -C(O)-(CH2) m -C 6-10 Aryl, -C(O)-(CH2) m -5-10 heteroaryl groups, -C(O)OC 1-6 Alkyl, -C(O)OC 3-7 Cycloalkyl, -C(O)O-(CH2) n -C 6-10 Aryl, -C(O)O-(CH2) n -5-10 heteroaryl groups; the C 1-6 Alkyl, C 3-7 cycloalkyl, C 5-7 Cycloalkenyl, aryl, and heteroaryl groups are surrounded by 1-3 halogens, nitro groups, amino groups, hydroxyl groups, or C groups. 1-6 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-7 cycloalkyl, -OC 1-6 Alkyl, -OC 3-7 Cycloalkyl, -OCF3, -C(O)OC 1-6 Alkyl groups and -SO2CH3 may be optionally substituted;

[0023] m is selected from 0, 1, 2, or 3;

[0024] n can be selected from 1, 2, or 3.

[0025] In this invention, 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, inorganic and organic acids, such as 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., preferably hydrochloride salts.

[0026] The beneficial effects of this invention: The compound represented by formula (I) involved in this invention belongs to opioid receptor ligands. Using a radioactive receptor ligand binding experiment, the affinity and selectivity of the ligand for three types of receptors can be determined. 35 The S]GTPγS binding assay can determine the agonist or antagonist activity of a compound on three receptors.

[0027] The present invention also provides the potential use of the compound represented by formula (I) in the preparation of analgesics, antipruritics, antidepressants, diagnoses and treatments of opioid and other narcotic analgesic dependence, opioid-induced bowel dysfunction, sedative-hypnotic drugs and acute alcohol poisoning, and remedies for opioid and other narcotic analgesic poisoning. Attached Figure Description

[0028] Figure 1 This diagram illustrates how SLL-1062 (10 mg / kg) can inhibit the analgesic effect of the classic opioid drug morphine (8 mg / kg) in the hot plate experiment of this invention. Detailed Implementation

[0029] This invention will be illustrated by the following embodiments, which are described by way of example only. It is obvious that those skilled in the art can make various modifications and variations to this invention within its scope and spirit. It should be understood that this invention is intended to cover all modifications and variations included in the appended claims.

[0030] Instruments used in experiments and sample analysis: 1 H NMR was measured on a Varian Mercury plus 400 NMR spectrometer. 13 CNMR was performed on a Bruker 600MHz NMR spectrometer. LS-MS was performed using an Agilent 1100 Series LC / MSD1946D mass spectrometer. Specialty chemical reagents were purchased from companies such as Tansun, Bide, Anengji, Sigma, Alfa, Acros, and Adamas. General chemical reagents were purchased from Sinopharm Shanghai Chemical Reagent Company. Major solvents, including petroleum ether, ethyl acetate, dichloromethane, and methanol, were purchased from Sinopharm and were all synthetic grade. Column chromatography silica gel was chemically pure silica gel from Huanghai Chemical Plant, typically 200-300 mesh. Reagent processing methods followed the Purification of Laboratory Chemicals (1988 edition).

[0031] Example 1: Preparation of N-cyclopropylmethyl-desmethylthebaine (compound 2)

[0032]

[0033] 10.0 g thebaine (32.12 mmol, 1.0 eq), 100 mL acetonitrile, and 7.79 g diisopropyl azodicarbonate (38.54 mmol, 1.2 eq) were added sequentially to a 250 mL single-necked flask. The mixture was heated to reflux for 4 h under nitrogen protection. The reaction was stopped after TLC monitoring showed complete reaction. The reaction solution was cooled to room temperature, and the solvent was removed by vacuum distillation. The remaining oily substance was dissolved in 100 mL methanol, and pyridine hydrochloride was added. The mixture was stirred overnight at room temperature, and the reaction was stopped after TLC monitoring showed complete reaction. The reaction solution was directly filtered, and the filter cake was washed successively with small amounts of methanol and ethyl acetate. After removing some solvent from the filtrate by vacuum distillation, a solid precipitated again. The filtrate was filtered again, and the filter cakes were combined and dried to give 5.0 g of white solid compound 1, yield: 46.6%.

[0034]

[0035] 3.0 g of compound 1 (8.99 mmol, 1.0 eq), 2.86 g of anhydrous sodium carbonate (26.96 mmol, 3.0 eq), 30 mL of DMF, and 1.58 g of bromomethylcyclopropane (11.68 mmol, 1.3 eq) were added sequentially to a 100 mL single-necked flask. The mixture was heated in an oil bath to 90 °C (outer temperature) and reacted for 3 h. The reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature, dissolved in water and ethyl acetate, and separated. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The solution was purified by silica gel column chromatography (PE:EA = 3:1) to give 2.26 g of yellow oily liquid compound 2, yield: 71.5%. ESI-MS: m / z 362.2 (M+H) + ,100). 1 H NMR (400MHz, CDCl3) δ6.68(d,J=8.2Hz,1H),6.61(d,J=8.1Hz,1H),5.60(d,J=6.4Hz,1H),5. 06(d,J=6.4Hz,1H),3.98(d,J=6.9Hz,1H),3.86(s,3H),3.61(s,3H),3.31(d,J=17.7Hz,1H) ,3.01–2.80(m,2H),2.75(dd,J=18.0,6.7Hz,1H),2.53(d,J=6.1Hz,2H),2.22(td,J=12.5,5 .3Hz,1H),1.75(d,J=11.9Hz,1H),0.96(s,1H),0.58(d,J=6.9Hz,2H),0.19(d,J=3.9Hz,2H).

[0036] Example 2: Preparation of p-nitrophenyl ketene (compound 3)

[0037]

[0038] 6.0 g of nitrobenzaldehyde (39.70 mmol, 1.0 eq) was dissolved in 90 mL of anhydrous tetrahydrofuran. The solution was cooled to -78 °C, and 55.6 mL of a 1 mol / L tetrahydrofuran solution of vinyl magnesium bromide (55.6 mmol, 1.4 eq) was slowly added. The reaction was carried out at this temperature for 4 h, and the reaction was monitored by TLC until complete. The reaction was quenched by adding 60 mL of an aqueous solution containing 12 g of ammonium chloride. The solution was filtered, and the filtrate was extracted several times with ethyl acetate. The organic phases were combined, and the solvent was removed by vacuum distillation. The remaining brown oily substance was dissolved in 60 mL of acetone. An excess of freshly prepared Jones reagent was added to the solution under ice bath conditions, and the reaction was stirred under ice bath conditions for 0.5 h. The reaction was monitored by TLC until complete. The reaction solution was quenched by slowly adding 30 mL of an aqueous solution containing 9 g of sodium bisulfite. The aqueous phase was extracted three times with diethyl ether. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The solution was purified by silica gel column chromatography (PE:EA = 5:1) to give 3.1 g of white solid compound 3, yield: 44.3%.

[0039] Example 3: Preparation of N-cyclopropylmethyl p-nitronapetone (compound 4)

[0040]

[0041] 1.2 g of compound 2 (3.41 mmol, 1.0 eq), 1.5 g of compound 3 (8.54 mmol, 2.5 eq), and 24 mL of toluene were added sequentially to a 100 mL single-necked flask. The mixture was heated to reflux for 2 h, and the reaction was monitored by TLC until complete. The solvent was removed by vacuum distillation, and the mixture was purified by silica gel column chromatography (PE:EA = 8:1). The resulting cross-component was recrystallized from the PE / EA system to give 1.3 g of pale yellow solid compound 4, yield: 72.2%. ESI-MS: m / z 529.2 (M+H) + ,100).

[0042] Example 4: Preparation of N-cyclopropylmethyl p-aminonaphthalene (compound 5)

[0043]

[0044] 0.2 g of compound 4 (0.378 mmol, 1.0 eq), 0.85 g of stannous chloride dihydrate (37.8 mmol, 10.0 eq), and 8 mL of ethanol were added sequentially to a 50 mL single-necked flask. The mixture was heated to reflux for 2 h, and the reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature, and the pH was adjusted to 7-8 by adding an appropriate amount of saturated sodium carbonate. The mixture was then filtered under reduced pressure (with diatomaceous earth as a filter aid). The filtrate was distilled under reduced pressure to remove some of the solvent, extracted several times with ethyl acetate, and the organic phases were combined. The mixture was washed once with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to give 140 mg of a pale yellow, foamy solid, compound 5, yield: 74.1%. ESI-MS: m / z 499.3 (M+H) + ,100). 1 H NMR (400MHz, DMSO-d6) δ7.74(d,J=8.61Hz,2H),6.58(d,J=8.22Hz,1H),6.56(d,J=9.00Hz,2H),6.46(d,J=7.82Hz,1H),6.00(s,2H,this peak is diminished when treated with D2O),5.72(d,J=9.00Hz,1H),5.37(d,J=8.61Hz,1H),4.77(s,1H),3.94-3.90(m,1H),3 .68(s,3H),3.44(d,J=6.26,1H),3.22(s,3H),3.02-2.94(m,2H),2.67(brd,J=7.04Hz,1 H),2.41(dd,J1=6.26Hz,J2=18.58Hz,1H),2.29-2.20(m,4H),1.68(brd,J=9.78,1H),1. 07(dd,J1=6.65Hz,J2=12.12Hz,1H),0.76(brs,1H),0.45-0.39(m,2H),0.051(brs,2H).

[0045] Example 5: Preparation of N-cyclopropylmethyl-(4'-benzoylamino)napetone (compound 6a)

[0046]

[0047] 50 mg of compound 5 (0.10 mmol, 1.0 eq) was dissolved in 1.5 mL of dichloromethane. Then, 30 mg of triethylamine (0.30 mmol, 3.0 eq) and 28 mg of benzoyl chloride (0.20 mmol, 2.0 eq) were added sequentially at room temperature. The mixture was stirred at room temperature for 2.5 h, and the reaction was monitored by TLC until complete. The solvent was removed by vacuum distillation, and the mixture was dissolved in dichloromethane. The solution was washed successively with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The solution was purified by silica gel column chromatography (DCM:MeOH = 100:1) to give 37.4 mg of a white solid, compound 6a, in 61.8% yield. 1 H NMR (400MHz, CDCl3) δ8.03(d,J=7.5Hz,3H),7.90(d,J=6.7Hz,2H),7.77(d,J=7.9Hz,2H),7.58(d,J=6.7Hz,1H) ,7.53(d,J=6.8Hz,2H),6.64(d,J=7.7Hz,1H),6.54(d,J=8.0Hz,1H),6.09(d,J=8.3Hz,1H),5.59(d,J=8.7Hz,1H ),4.70(s,1H),3.83(s,4H),3.58(s,1H),3.48(s,3H),3.12(d,J=16.6Hz,2H),2.74(s,1H),2.53–2.38(m,3H), 2.34(d,J=6.0Hz,1H),2.12(s,1H),1.93(d,J=12.5Hz,1H),1.48(s,1H),0.81(s,1H),0.49(s,2H),0.12(s,2H). 13 C NMR (151MHz, CDCl3) δ199.19,170.33,165.85,148.13,142.09,141.92,134.54,134 .26,133.12,132.22,130.07,130.00,128.90,128.38,127.15,126.30,119.39,119 .21,113.68,96.08,82.06,59.70,57.00,56.68,53.99,47.99,44.58,44.25,43.26 ,33.46,32.05,30.30,29.70,23.34,14.13,9.21,4.35,3.34.HRMS(ESI):m / z[M+H] + calcd for C 38 H 38 N₂O₅ + H₂ + :603.2853; found:603.2849.

[0048] Example 6: Preparation of N-cyclopropylmethyl-(4'-acetylamino)naperidone (compound 6b)

[0049]

[0050] Referring to the synthesis of compound 6a in Example 5, acetyl chloride was substituted for benzoyl chloride to give white solid compound 6b, yield: 37.1%. 1 H NMR (400MHz, CDCl3) δ7.95(d,J=8.3Hz,2H),7.62(d,J=8.1Hz,2H),6.59(d,J=38 .4Hz,2H),6.09(s,1H),5.58(d,J=8.6Hz,1H),4.69(s,1H),3.83(s,4H),3.47(d, J=8.2Hz,3H),3.11(s,2H),2.74(s,1H),2.42(s,3H),2.23(d,J=8.0Hz,3H),2.0 9(s,1H),1.94(s,1H),1.63(s,4H),0.83(s,1H),0.49(s,2H),0.18–0.05(m,2H). 13 C NMR (151MHz, CDCl3) δ168.65,148.18,141.94,134.37,129.92,126.20,119.44,118.74,113.54,96.10,82.01,56.98 ,56.71,53.98,48.09,44.47,43.26,32.07,29.70,24.81,23.20,14.13,9.38,4.20,3.33,1.02.HRMS(ESI):m / z[M+H] + calcd for C 33 H 36 N₂O₅ + H₂ + :541.2697; found:541.2699.

[0051] Example 7: Preparation of N-cyclopropylmethyl-(4'-(3,4-dimethylbenzoyl)amino)napetone (compound 6c)

[0052]

[0053] 20 mg of 3,4-dimethylbenzoic acid (0.13 mmol, 1.3 eq) was dissolved in 1.5 mL of dichloromethane. 26 mg of DIPEA (0.20 mmol, 2.0 eq) and 57 mg of HATU (0.15 mmol, 1.5 eq) were added sequentially at room temperature. After thorough mixing, 50 mg of compound 5 (0.10 mmol, 1.0 eq) was added, and the reaction was allowed to proceed for 9 h at room temperature. The reaction was monitored for completeness by TLC. The solvent was removed by vacuum distillation of the reaction solution, which was then dissolved in dichloromethane and washed successively with saturated sodium bicarbonate and saturated brine. The solution was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The solution was purified by silica gel column chromatography (DCM:MeOH = 100:1) to give 18.8 mg of a white oily compound 6c, yield: 29.7%. 1 H NMR (400MHz, CDCl3) δ8.02(d,J=8.3Hz,2H),7.98(s,1H),7.76(d,J=8.2Hz,2H),7.67(s,1H),7.61(d ,J=7.6Hz,1H),6.63(s,1H),6.55(s,1H),6.10(d,J=8.0Hz,1H),5.58(d,J=8.6Hz,1H),4.70(s,1H),3 .83(s,4H),3.58(s,1H),3.47(s,3H),3.13(d,J=17.4Hz,2H),2.75(s,1H),2.43(s,2H),2.34(s,8H) ,2.11(d,J=17.0Hz,1H),1.95(s,1H),1.45(d,J=24.5Hz,1H),0.82(s,1H),0.49(s,2H),0.12(s,2H). 13 C NMR (151MHz, CDCl3) δ199.23,165.97,148.13,142.34,141.88,141.52,137.35,134.88,1 34.06,131.98,130.01,129.96,128.42,126.27,124.51,119.38,119.13,113.64,96.10,8 2.07,59.74,57.04,56.67,53.96,48.01,44.51,44.20,43.26,33.67,32.09,31.92,29.70 ,23.33,22.69,19.91,19.82,19.18,14.13,13.73,9.32,4.31,3.35.HRMS(ESI):m / z[M+H] + calcd for C 40 H 42 N₂O₅ + H₂ +:631.3166; found:631.3165.

[0054] Example 8: Preparation of N-cyclopropylmethyl-(4'-(1-methylpyrazole-4-formyl)amino)napeston (compound 6d)

[0055]

[0056] Referring to the synthesis of compound 6c in Example 7, 3,4-dimethylbenzoic acid was replaced with 1-methylpyrazole-4-carboxylic acid to obtain colorless oily compound 6d, yield: 23.8%. 1 H NMR (400MHz, CDCl3) δ7.98 (s, 3H), 7.90 (s, 1H), 7.72 (d, J = 8.0Hz, 3H), 6.59 (d, J = 3 3.4Hz,2H),6.10(s,1H),5.57(d,J=8.9Hz,1H),4.69(s,1H),3.96(s,3H),3.83(s,3 H),3.46(s,3H),3.11(s,2H),2.74(s,1H),2.43(s,3H),1.94(s,1H),1.67(d,J=33 .0Hz,4H),1.46(d,J=7.5Hz,1H),0.82(s,1H),0.49(s,2H),0.09(d,J=20.2Hz,2H). 13 C NMR (151MHz, CDCl3) δ199.33,160.68,148.11,142.22,138.26,132.43,130.9 5,129.92,128.83,126.22,119.41,119.14,118.81,113.59,96.00,82.06,65. 61,59.74,57.04,56.66,53.93,48.05,44.49,43.25,39.45,33.67,32.12,30. 56,29.70,23.29,19.18,14.13,13.73,9.36,4.25,3.36.HRMS(ESI):m / z[M+H] + calcd for C 36 H 38 N4O5+H + :607.2915; found:607.2915.

[0057] Example 9: Preparation of N-cyclopropylmethyl-(4'-(2-propylpentanoyl)amino)naperidone (compound 6e)

[0058]

[0059] Referring to the synthesis of compound 6c in Example 7, 3,4-dimethylbenzoic acid was replaced with 2-propylvaleric acid to obtain colorless oily compound 6e, yield: 13.4%. 1 H NMR (400MHz, CDCl3) δ7.96(d,J=8.6Hz,2H),7.65(d,J=8.5Hz,2H),7.41(s,1H),6.64(d,J=8.0Hz,1H),6.53(d,J=8.0Hz ,1H),6.08(d,J=8.6Hz,1H),5.57(d,J=8.9Hz,1H),4.69(s,1H),3.82(s,4H),3.58(s,1H),3.46(s,3H),3.13(d,J=18.6 Hz,2H),2.80(s,1H),2.79–2.67(m,1H),2.43(s,3H),2.23(dd,J=13.4,5.4Hz,2H),1.95(s,1H),1.70(ddd,J=14.1,12. 1,7.3Hz,6H),1.46(dt,J=11.2,7.9Hz,4H),1.39–1.29(m,5H),0.84–0.74(m,1H),0.50(s,2H),0.10(d,J=24.4Hz,2H). 13 C NMR (151MHz, CDCl3) δ174.21,147.54,141.38,134.71,134.32,133.78,133.37,12 9.31,125.55,118.75,118.19,113.00,95.54,81.44,64.96,63.81,59.14,56.41,5 6.09,53.34,48.35,47.41,43.85,43.54,42.63,38.00,34.66,33.07,31.44,29.07 ,28.70,22.66,22.06,20.24,18.56,13.53,8.78,3.58,2.71.HRMS(ESI):m / z[M+H] + calcd for C 39 H 48 N₂O₅ + H₂ + :625.3636; found:625.3635.

[0060] Example 10: Preparation of N-cyclopropylmethyl-(4'-p-trifluoromethylbenzoylamino)naperidone (compound 6f)

[0061]

[0062] Referring to the synthesis of compound 6c in Example 7, 3,4-dimethylbenzoic acid was replaced with p-trifluoromethylbenzoic acid to obtain colorless oily compound 6f, yield: 31.4%. 1 H NMR (400MHz, CDCl3) δ8.13(s,1H),8.02(s,3H),7.78(t,J=8.5Hz,5H),6.60(d,J=3 7.9Hz,2H),6.12(d,J=30.5Hz,1H),5.59(d,J=8.8Hz,1H),4.76(d,J=51.2Hz,1H), 3.83(s,4H),3.47(s,4H),3.12(s,2H),2.74(s,1H),2.42(s,2H),1.99(d,J=39.1H z,2H),1.62(s,2H),1.49(s,1H),0.84(d,J=28.5Hz,2H),0.49(s,2H),0.12(s,1H). 13 C NMR (151MHz, CDCl3) δ164.75,148.17,141.98,137.82,133.76,133.54,129.91,127.95,125.80,124.50,122.69,119.62,113.90,95.9 2,82.00,59.58,57.02,56.69,54.00,48.03,44.48,43.17,31.99,29.70,29.32,23.29,22.69,14.13,9.30,3.35.HRMS(ESI):m / z[M+H] + calcd for C 39 H 37 F3N2O5+H + :671.2727; found:671.2726.

[0063] Example 11: Preparation of N-cyclopropylmethyl-(4'-p-methoxybenzoylamino)napetone (compound 6g)

[0064]

[0065] Referring to the synthesis of compound 6a in Example 5, benzoyl chloride was replaced with p-methoxybenzoyl chloride to give 6g of white solid compound, yield: 29.6%. 1H NMR (400MHz, CDCl3) δ8.01(d,J=8.2Hz,2H),7.96(s,1H),7.87(d,J=7.6Hz,2H),7.76(d,J=8.3Hz,2H),6. 99(d,J=8.4Hz,2H),6.63(s,1H),6.54(s,1H),6.09(d,J=8.7Hz,1H),5.58(d,J=8.8Hz,1H),4.69(s,1H),3 .88(s,3H),3.83(s,4H),3.58(s,1H),3.47(s,3H),3.12(d,J=16.9Hz,2H),2.74(s,1H),2.42(t,J=24.5H z,3H),2.11(d,J=9.4Hz,1H),1.93(d,J=12.2Hz,1H),1.47(s,1H),0.81(s,1H),0.49(s,2H),0.12(s,2H). 13 C NMR (151MHz, CDCl3) δ199.34,165.40,162.75,148.14,142.44,141.83,135.0 0,134.42,134.03,129.94,129.15,128.41,126.65,126.18,119.37,119.18, 114.03,113.62,96.14,82.11,59.79,57.06,56.69,55.50,53.95,48.07,44. 53,44.13,43.28,33.69,32.11,23.26,9.44,4.21,3.37.HRMS(ESI):m / z[M+H] + calcd for C 39 H 40 N₂O₆ + H⁺ + :633.2959; found:633.2960.

[0066] Example 12: Preparation of N-cyclopropylmethyl-(4'-cyclopropylcarboxymethylamino)napetone (compound 6h)

[0067]

[0068] Referring to the synthesis of compound 6a in Example 5, benzoyl chloride was replaced with cyclopropionyl chloride to obtain white solid compound 6h, yield: 39.8%. 1H NMR(400MHz, CDCl3) δ7.95(d,J=6.3Hz,2H),7.63(d,J=8.0Hz,3H),6.63(s,1H),6.54(s,1H) ,6.09(s,1H),5.58(d,J=8.6Hz,1H),4.68(s,1H),3.83(s,4H),3.57(s,1H),3.46(s,3H),3. 12(d,J=15.8Hz,2H),2.74(s,1H),2.39(d,J=30.7Hz,3H),2.10(d,J=1.7Hz,1H),1.94(s,1H ),1.60(s,3H),1.42(s,2H),1.12(s,2H),0.81(s,1H),0.49(s,2H),0.09(d,J=18.3Hz,2H). 13 C NMR (151MHz, CDCl3) δ198.72,171.74,147.51,141.81,141.22,134.32,133.78,1 33.09,129.29,127.84,125.58,118.77,118.05,112.99,95.42,81.48,59.14,56. 42,56.07,53.26,47.45,43.81,43.51,42.65,33.09,31.52,31.30,29.69,29.07 ,28.74,22.64,22.07,15.23,13.50,8.80,7.77,3.62,2.72.HRMS(ESI):m / z[M+H] + calcd for C 35 H 38 N₂O₅ + H₂ + :567.2853; found:567.2850.

[0069] Example 13: Preparation of N-cyclopropylmethyl-(4'-phenylacetylamino)naperidone (compound 6i)

[0070]

[0071] Referring to the synthesis of compound 6a in Example 5, benzoyl chloride was replaced with phenylacetyl chloride to obtain colorless oily compound 6i, yield: 27.5%. 1H NMR (400MHz, CDCl3) δ7.92(d,J=7.7Hz,2H),7.52(d,J=8.1Hz,2H),7.41(d,J=6.7Hz,2H),7.35(d,J=6.7 Hz,3H),6.61(t,J=32.7Hz,2H),6.11(d,J=33.7Hz,1H),5.57(d,J=8.7Hz,1H),4.71(d,J=41.4Hz,1H),3. 82(s,3H),3.78(s,3H),3.56(s,1H),3.44(s,3H),3.11(d,J=16.6Hz,2H),2.74(s,1H),2.37(d,J=35.2Hz ,3H),2.09(d,J=1.7Hz,1H),1.93(s,1H),1.42(s,1H),0.75(d,J=29.9Hz,2H),0.48(s,2H),0.10(s,1H). 13 C NMR (151MHz, CDCl3) δ199.28,169.27,148.13,141.69,135.04,134.42,134 .05,129.85,129.52,129.33,128.41,127.85,126.06,119.35,118.76,113 .61,96.27,82.11,59.79,57.04,56.70,53.99,48.09,44.93,44.55,44.10 ,43.28,33.72,32.05,29.70,23.25,9.45,4.19,3.33.HRMS(ESI):m / z[M+H] + calcd for C 39 H 40 N₂O₅ + H₂ + :617.3010; found:617.3010.

[0072] Example 14: Preparation of N-cyclopropylmethyl-(4'-m-methoxybenzoylamino)naperidone (compound 6j)

[0073]

[0074] Referring to the synthesis of compound 6a in Example 5, benzoyl chloride was replaced with m-methoxybenzoyl chloride to obtain white solid compound 6j, yield: 17.6%. 1H NMR(400MHz, CDCl3)δ8.21(s,1H),8.01(d,J=8.0Hz,2H),7.83–7.74(m,2H),7.51–7.36(m,3H),7.11(d ,J=7.4Hz,1H),6.65(d,J=7.6Hz,1H),6.55(d,J=7.8Hz,1H),6.10(d,J=8.9Hz,1H),5.58(d,J=8.9Hz,1 H),4.71(s,1H),3.88(s,3H),3.83(s,4H),3.47(s,4H),3.14(d,J=18.6Hz,2H),2.48(s,3H),2.22(s,1 H),1.96(d,J=11.5Hz,2H),1.51(s,1H),1.31(s,1H),0.88(s,1H),0.54(s,2H),0.13(d,J=47.9Hz,2H). 13 C NMR (151MHz, CDCl3) δ165.65,160.05,148.21,142.14,140.18,136.02,130.04,129.88,119.24,118.85,118.44,113.76,112.57,96 .24,82.08,56.99,56.76,55.55,54.06,44.52,43.22,33.83,32.00,31.77,29.71,29.33,22.69,14.13,3.33.HRMS(ESI):m / z[M+H] + calcd for C 39 H 40 N₂O₆ + H⁺ + :633.2959; found:633.2959.

[0075] Example 15: Preparation of N-cyclopropylmethyl-(4'-neovalerylamino)naperidone (compound 6k)

[0076]

[0077] Referring to the synthesis of compound 6a in Example 5, benzoyl chloride was replaced with neopentanoyl chloride to obtain white solid compound 6k, yield: 44.7%. 1H NMR (400MHz, CDCl3) δ7.97(d,J=6.9Hz,2H),7.64(d,J=6.9Hz,2H),7.48(dd,J=2.4,1.8Hz,1H),6.6 3(s,1H),6.55(s,1H),6.08(d,J=7.9Hz,1H),5.58(d,J=9.0Hz,1H),4.69(s,1H),3.82(s,4H),3.58 (s,1H),3.46(s,3H),3.13(d,J=17.6Hz,2H),2.74(s,1H),2.43(s,2H),2.34(s,1H),2.12(s,1H),1 .95(s,1H),1.49(s,1H),1.34(d,J=2.0Hz,9H),1.28(s,1H),0.81(s,1H),0.49(s,2H),0.12(s,2H). 13 C NMR (151MHz, CDCl3) δ199.27,176.76,148.17,142.10,141.83,135.03,1 34.48,134.13,129.93,128.42,126.08,119.34,118.89,113.63,96.29, 82.13,59.80,57.04,56.73,54.01,48.09,44.52,44.11,43.28,39.88,3 3.72,32.04,29.71,27.59,23.23,9.44,4.18,3.33.HRMS(ESI):m / z[M+H] + calcd for C 36 H 42 N₂O₅ + H₂ + :583.3166; found:583.3162.

[0078] Example 16: Preparation of N-cyclopropylmethyl-(4'-(3,4-dimethylphenylacetyl)amino)naperidone (compound 6l)

[0079]

[0080] Referring to the synthesis of compound 6c in Example 7, 3,4-dimethylbenzoic acid was replaced with 3,4-dimethylphenylacetic acid to obtain white solid compound 6l, yield: 26.5%. 1H NMR (400MHz, CDCl3) δ7.92(d,J=7.4Hz,2H),7.52(d,J=7.4Hz,2H),7.30(s,1H),7.17(d,J=7.8Hz,1H),7.10( s,1H),7.06(d,J=7.6Hz,1H),6.63(s,1H),6.54(s,1H),6.08(s,1H),5.56(d,J=9.1Hz,1H),4.67(s,1H),3.8 2(s,3H),3.70(s,2H),3.59(s,1H),3.44(s,3H),3.10(s,2H),2.80(s,2H),2.41(s,2H),2.28(s,6H),2.24(s ,1H),2.08(s,1H),1.93(s,1H),1.45(s,1H),1.31(d,J=20.0Hz,1H),0.81(s,1H),0.49(s,2H),0.11(s,2H). 13 C NMR (151MHz, CDCl3) δ169.63,148.15,137.77,136.35,135.00,131.26,1 30.82,130.59,129.86,126.89,126.04,119.33,118.71,113.61,96.32, 82.07,59.82,57.01,56.73,54.00,44.59,44.12,43.28,38.62,33.68,3 2.04,29.71,23.22,19.80,19.46,9.46,4.18,3.32.HRMS(ESI):m / z[M+H] + calcd for C 41 H 44 N₂O₅ + H₂ + :645.3323; found:645.3321.

[0081] Example 17: Preparation of N-cyclopropylmethyl-(4'-p-methoxyphenylacetylamino)naperidone (compound 6m)

[0082]

[0083] Referring to the synthesis of compound 6c in Example 7, 3,4-dimethylbenzoic acid was replaced with p-methoxyphenylacetic acid to obtain white solid compound 6m, yield: 45.6%. 1H NMR (400MHz, CDCl3) δ7.92(d,J=8.6Hz,2H),7.53(d,J=8.7Hz,2H),7.31(s,1H),7.25(s,1H),6.94(d,J=8.5 Hz,2H),6.63(d,J=6.2Hz,1H),6.54(s,1H),6.08(s,1H),5.57(d,J=9.0Hz,1H),4.67(s,1H),3.84(s,3H),3. 82(s,3H),3.77(s,1H),3.71(s,2H),3.55(s,1H),3.44(s,3H),3.11(d,J=16.9Hz,2H),2.73(s,1H),2.38(d ,J=35.8Hz,3H),2.09(s,1H),1.93(s,1H),1.61(s,2H),1.45(s,1H),0.79(s,1H),0.48(s,2H),0.11(s,2H). 13 C NMR (151MHz, CDCl3) δ198.65,169.16,158.58,147.51,141.17,134.38,133.73,1 33.56,130.05,129.22,127.76,125.47,125.31,118.76,118.11,114.10,113.12 ,95.55,81.45,59.13,56.41,56.07,54.72,53.34,47.40,43.89,43.38,42.63,3 3.07,31.43,29.08,22.63,22.07,13.50,8.77,3.59,2.72.HRMS(ESI):m / z[M+H] + .calcdfor C 40 H 42 N₂O₆ + H⁺ + :647.3116; found:647.3109.

[0084] Example 18: Preparation of N-cyclopropylmethyl-4'-(3”-pyridyl)naperidone (compound 6n)

[0085]

[0086] Referring to the synthesis of compound 6c in Example 7, 3,4-dimethylbenzoic acid was replaced with 3-pyridinecarboxylic acid to obtain white solid compound 6n, yield: 40.3%. 1H NMR (400MHz, CDCl3) δ9.18(s,1H),8.76(s,1H),8.45(s,1H),8.28(s,1H),7.98(s,2H),7.81(d,J=8.7Hz,2H),7.49 –7.40(m,1H),6.61(d,J=61.3Hz,2H),6.09(s,1H),5.58(d,J=8.9Hz,1H),4.75(d,J=76.1Hz,1H),4.49(s,1H),3.8 8(s,1H),3.83(s,3H),3.62(dd,J=20.1,15.7Hz,1H),3.51–3.41(m,3H),3.14(s,3H),2.76(s,1H),2.37(dd,J=40. 4,32.8Hz,2H),2.02(dd,J=49.8,31.9Hz,2H),1.56(d,J=84.2Hz,2H),0.83(s,1H),0.49(s,2H),0.27–0.05(m,2H). 13 C NMR (151MHz, CDCl3) δ164.07,152.62,148.28,141.82,135.68,130.49,129.96,123.72,119.71,113.86,96.41,94.48,82.08,81.42,62 .84,62.14,57.11,56.84,54.06,48.07,46.64,44.14,43.28,33.76,31.94,31.45,30.22,29.71,25.12,23.31,9.54,6.15,4.27,3.41.

[0087] Example 19: Preparation of N-cyclopropylmethyl-4'-(4”-pyridyl)naperidone (compound 6o)

[0088]

[0089] Referring to the synthesis of compound 6c in Example 7, 3,4-dimethylbenzoic acid was replaced with 4-pyridinecarboxylic acid to obtain white solid compound 6o, yield: 44.0%. 1H NMR (400MHz, CDCl3) δ8.81(s,2H),8.00(s,2H),7.78(s,4H),6.65(s,1H),6.57(s,1H),6.09(s,1H),5.58(d,J=8.5Hz,1H),4.71(s,1H),3.82( s,4H),3.47(s,3H),3.14(d,J=18.2Hz,1H),2.48(s,2H),2.35(s,1H), 1.98(s,1H),1.39–1.27(m,7H),0.88(s,2H),0.53(s,2H),0.18(s,1H). 13 C NMR (151MHz, CDCl3) δ176.14,163.89,150.83,148.21,144.72,141.69,1 34.93,130.01,120.98,119.57,113.99,96.29,82.10,59.72,57.16,56. 77,54.13,47.95,44.74,43.26,34.99,34.45,33.61,31.94,31.52,31.4 5,30.22,30.17,29.70,29.61,29.36,29.13,24.84,22.70,14.12,3.36.

[0090] Example 20: Preparation of N-cyclopropylmethyl-4'-(3”-thienyl)naperidone (compound 6p)

[0091]

[0092] Referring to the synthesis of compound 6c in Example 7, 3,4-dimethylbenzoic acid was replaced with 3-thiophenecarboxylic acid to obtain colorless oily compound 6p, yield: 42.6%. 1H NMR (400MHz, CDCl3) δ8.05(s,1H),8.01(d,J=7.3Hz,2H),7.95(s,1H),7.75(d,J=8.3Hz,2H), 7.53(s,1H),7.42(s,1H),6.63(s,1H),6.55(s,1H),6.10(s,1H),5.58(d,J=8.7Hz,1H),4.70 (s,1H),3.83(s,4H),3.58(s,1H),3.47(s,3H),3.13(d,J=17.1Hz,2H),2.74(s,1H),2.39(d, J=35.4Hz,4H),2.13(s,1H),1.95(s,1H),1.48(s,1H),0.81(s,1H),0.49(s,2H),0.12(s,2H). 13 C NMR (151MHz, CDCl3) δ199.35,161.09,148.12,145.43,141.90,141.81,137.41,135.05,134.43,130.00,129.25,128.41,127.14,126.13,11 9.34,119.14,113.55,96.29,82.14,59.82,57.04,56.69,54.03,53.4 4,48.11,44.62,44.11,43.31,33.73,32.11,23.22,9.47,4.20,3.34.

[0093] Example 21: Preparation of N-cyclopropylmethyl-(4'-benzyloxyformylamino)naperidone (compound 7)

[0094]

[0095] 50 mg of compound 5 (0.10 mmol, 1.0 eq) was dissolved in 2 mL of ethyl acetate. 0.8 mL of saturated sodium carbonate aqueous solution and 19 mg of benzyl chloroformate (0.11 mmol, 1.1 eq) were added sequentially at room temperature. The mixture was stirred at room temperature for 5 h, and the reaction was monitored for completeness by TLC. The reaction solution was diluted with ethyl acetate and water, separated, and the organic phase was washed three times with water, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 3:1) to give 25.4 mg of a white oily compound 7, yield: 40.0%. 1H NMR (400MHz, CDCl3) δ7.96(d,J=8.6Hz,2H),7.49(d,J=8.4Hz,2H),7.38(dd,J=14.7,7.2Hz,5H),6.97(s,1H ),6.64(d,J=7.8Hz,1H),6.54(d,J=7.6Hz,1H),6.09(d,J=8.6Hz,1H),5.57(d,J=9.0Hz,1H),5.22(s,2H),4. 68(s,1H),3.83(s,4H),3.57(s,1H),3.46(s,3H),3.13(d,J=18.0Hz,2H),2.74(s,1H),2.42(s,2H),2.33(s ,1H),2.11(s,1H),1.94(s,1H),1.45(s,1H),1.31(d,J=20.0Hz,1H),0.83(s,1H),0.49(s,2H),0.12(s,2H). 13 C NMR (151MHz, CDCl3) δ199.15,152.86,148.18,142.04,135.71,133.45,130.0 9,128.68,128.52,128.40,126.18,119.40,117.59,113.68,96.26,82.04,67. 35,59.73,57.01,56.72,54.02,48.03,44.49,43.24,33.70,32.05,31.93,29. 70,29.36,23.18,22.70,19.19,14.13,9.37,4.22,3.33.HRMS(ESI):m / z[M+H] + .calcd for C 39 H 40 N₂O₆ + H⁺ + :633.2959; found:633.2958.

[0096] Example 22: Preparation of N-cyclopropylmethyl-(4'-p-methylsulfonylbenzylamino)napetone (compound 8a)

[0097]

[0098] 50 mg of compound 5 (0.10 mmol, 1.0 eq) was dissolved in 1.5 mL of DMF. 26 mg of anhydrous sodium carbonate (0.25 mmol, 2.5 eq) and 27 mg of 4-methylsulfonylbenzyl bromide (0.11 mmol, 1.1 eq) were added sequentially at room temperature. The mixture was heated to 80 °C and reacted overnight. The reaction was monitored by TLC until complete. Water was added to the reaction solution, resulting in the precipitation of a solid. The mixture was filtered, and the filter cake was washed twice with a small amount of water, then dissolved in ethyl acetate. The organic phase was washed three times sequentially with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (DCM:MeOH = 150:1) to give 20.7 mg of a white solid, compound 8a, in 30.9% yield. 1 H NMR (400MHz, CDCl3) δ7.90(d,J=8.2Hz,2H),7.85(d,J=8.6Hz,2H),7.53(d,J=8.1Hz,2H),6.62(d,J=8.1Hz,1H),6.54(dd,J =16.4,8.4Hz,3H),6.10(d,J=8.8Hz,1H),5.53(d,J=8.8Hz,1H),4.90(s,1H),4.64(s,1H),4.53(d,J=4.9Hz,2H),3.81(s,3 H),3.72(t,J=7.8Hz,1H),3.55(s,1H),3.46(s,3H),3.10(d,J=18.3Hz,2H),3.05(s,3H),2.71(s,1H),2.43(d,J=12.4Hz,3 H),2.32(s,1H),2.08(s,1H),1.90(d,J=12.2Hz,1H),1.40(dd,J=12.5,6.7Hz,1H),0.78(s,1H),0.47(s,2H),0.11(s,2H). 13 C NMR (151MHz, CDCl3) δ198.15,151.22,148.17,145.24,141.80,139.60,134.42, 130.98,128.44,127.90,127.81,126.54,119.29,113.48,111.82,96.10,81.91, 59.78,57.03,56.65,53.84,53.44,48.04,47.00,44.54,44.15,44.03,43.26,3 3.73,32.46,29.70,23.21,22.69,14.13,9.44,4.22,3.32.HRMS(ESI):m / z[M+H] + .calcdfor C 39 H 42N₂O₆S⁺H⁺ + :667.2836; found:667.2835.

[0099] Example 23: Preparation of N-cyclopropylmethyl-(4'-p-hydroxybenzylamino)napetone (compound 8b)

[0100]

[0101] 70 mg of compound 5 (0.14 mmol, 1.0 eq) was dissolved in 2 mL of 1,2-dichloroethane. 19 mg of p-hydroxybenzaldehyde (0.154 mmol, 1.1 eq) and 70 μL of glacial acetic acid were added at room temperature, and the mixture was stirred for 5 h at room temperature. The solvent was removed by vacuum distillation of the reaction solution. The solution was dissolved in ethyl acetate, washed several times with saturated sodium carbonate and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to obtain a pale yellow oil. The oil was dissolved in 2 mL of methanol, and 7 mg of sodium borohydride (0.182 mmol, 1.3 eq) was added. The mixture was stirred for 4 h at room temperature. The reaction solution was diluted with ethyl acetate, washed several times with saturated ammonium chloride and saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (DCM:MeOH = 150:1) to obtain 21 mg of a white solid, compound 8b, yield: 24.7%. 1 H NMR (400MHz, CDCl3) δ7.86(d,J=8.7Hz,2H),7.16(d,J=6.1Hz,2H),6.85–6.79(m,2H),6.63(d,J=8.1Hz,1H),6.57(d,J =7.1Hz,2H),6.52(d,J=8.1Hz,1H),6.12(d,J=8.8Hz,1H),5.52(d,J=8.8Hz,1H),4.67(s,1H),4.55(s,1H),4.27(s,2H ),3.81(d,J=3.0Hz,3H),3.74(s,1H),3.56(s,1H),3.47(d,J=3.0Hz,3H),3.11(d,J=17.9Hz,2H),2.74(s,1H),2.43(s ,3H),2.34(s,1H),2.11(s,1H),1.91(d,J=12.4Hz,1H),1.40(d,J=6.8Hz,1H),0.80(s,1H),0.48(s,2H),0.12(s,2H). 13C NMR (151MHz, CDCl3) δ198.19,155.56,152.01,148.22,141.88,134.39,131. 07,129.85,128.89,127.49,126.81,119.33,115.73,113.60,111.61,95.81, 81.87,59.74,57.05,56.68,53.72,47.96,47.12,44.27,43.88,43.23,33.5 6,32.53,29.70,23.29,22.69,14.13,9.30,4.31,3.33.HRMS(ESI):m / z[M+H] + .calcdfor C 38 H 40 N₂O₅S + H₂ + :605.3010; found:605.3013.

[0102] Example 24: Preparation of N-cyclopropylmethyl-(4'-benzylamino)naperidone (compound 8c)

[0103]

[0104] 50 mg of compound 5 (0.10 mmol, 1.0 eq) was added to a 10 mL single-necked flask and dissolved in 1.5 mL of DMF. Then, 26 mg of anhydrous sodium carbonate (0.25 mmol, 2.5 eq) and 22 mg of benzyl bromide (0.13 mmol, 1.3 eq) were added sequentially at room temperature. The reaction mixture was heated to 80 °C and reacted for 4 h, with TLC monitoring until complete. The reaction solution was poured into 10 mL of water and extracted with ethyl acetate (8 mL × 3). The organic phases were combined, washed once with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The solution was purified by silica gel column chromatography (DCM:MeOH = 100:1) to give 15.6 mg of a white, foamy solid, compound 8c, yield: 26.4%. 1H NMR (400MHz, CDCl3) δ7.87(d,J=7.3Hz,2H),7.35(s,4H),7.31(s,1H),6.60(d,J=8.5Hz,3H),6.53(s,1H ),6.12(d,J=8.3Hz,1H),5.53(d,J=8.5Hz,1H),4.66(s,1H),4.61(s,1H),4.40(s,2H),3.82(d,J=2.7Hz ,3H),3.74(s,1H),3.55(s,1H),3.47(d,J=2.7Hz,3H),3.10(d,J=17.8Hz,2H),2.72(s,1H),2.42(s,3H) ,2.33(s,1H),2.10(s,1H),1.91(d,J=11.2Hz,1H),1.41(s,1H),0.79(s,1H),0.48(s,2H),0.11(s,2H). 13 C NMR (151MHz, CDCl3) δ198.13,151.83,148.23,141.82,138.30,134.53,134.26,131.00,128. 81,127.88,127.57,127.41,126.75,119.24,113.50,111.64,96.01,81.87,77.24,77.03,76 .82,59.79,57.04,56.67,53.77,48.03,47.65,44.18,43.91,43.25,33.74,32.51,29.78,29 .70,29.61,29.32,29.25,27.22,23.22,22.69,14.13,9.45,4.23,3.31.HRMS(ESI):m / z[M+H] + ,calcd forC 38 H 40 N₂O₄ + H⁺ + :589.3061; found:589.3067.

[0105] Example 25: Radioligand binding experiment

[0106] The compounds used in the pharmacological binding affinity screening were all in free base form. The experiment consisted of total binding tubes and non-specific binding tubes, with several additional sample tubes containing the compounds to be screened. The total binding tubes contained 80 μL of cell suspension expressing opioid κ, μ, and δ receptors, and the three tubes contained […]. 3 H]U69593、[ 3 H]DAMGO、[ 3[H]10uL DPDPE (final concentration 0.35nM); corresponding nonspecific tubes were filled with U50488, DAMGO, and DPDPE respectively to a final concentration of 1uM; sample tubes were filled with the same concentration of drug 10ul (final concentration 1uM), and adjusted to a final volume of 100uL with 50mM Tris.HCl (pH 7.4). The reaction was incubated at 37℃ for 30 min, then terminated in an ice bath. The sample was filtered under negative pressure using a GF / C (Whatman) glass fiber filter on a Millipore sample collector. The sample was washed three times with 3mL of ice-cold 50mM Tris.HCl (pH 7.4), the filter paper was dried, and the sample was placed in a 0.5mL Eppendorf tube with 0.5mL of lipophilic scintillation solution. The radioactivity intensity was measured using a Beckman LS-6500 multifunction liquid scintillation counter. Each concentration was recorded in duplicate (two concentrations in total: 1×10⁻⁶). -5 M, 1×10 -7 M). Inhibition rate = (Total binding rate dpm - Sample tube dpm) / (Total binding tube dpm - Non-specific binding tube dpm) × 100%. IC50 was calculated using Prism 5.0 software. 50 Calculate K using the following formula i Value, K i =IC 50 / (1+[L] / K d [L] represents the concentration of the added labeled ligand, and K represents the concentration of the added ligand. d The equilibrium dissociation parameter for the labeled ligand. 1×10 -5 M and 1×10 -7 The initial screening results at M concentration are shown in Table 1. K values ​​for some compounds are also shown. i The data is shown in Table 2.

[0107] Table 1. Compounds at 1×10 -5 M and 1×10 -7 Inhibition rate of opioid receptors at M concentration

[0108]

[0109]

[0110] Table 2. Affinity and selectivity data of compounds for opioid receptor subtypes

[0111]

[0112]

[0113] Example 26: [ 35 S]GTPγS binding experiment

[0114] The Bradford Protein Assay Kit was used to determine protein concentration: Standard protein BSA at concentrations of 0, 50, 100, 200, and 250 μg / ml, along with the test sample, was added to each well of a 96-well plate, 20 μl per well. 200 μl of G250 staining solution was added to each well, and the plates were incubated at room temperature for 3-5 min. The absorbance at A595 wavelength was measured using a microplate reader. The protein concentration was calculated based on the standard curve. The prepared membrane receptor was diluted to the desired concentration with reaction buffer (RB), as shown in Table 3 (unit: μl). The reaction tubes were incubated in a 27°C water bath for 1 hour, filtered under reduced pressure through a glass fiber membrane, and liquid scintillation count was performed.

[0115] Table 3. 35 The volumes of each component in the NS binding tube, basal tube, and sample tube of the S]GTPγS binding assay.

[0116]

[0117] [ 35 The binding rate of S]GTPγS is calculated using the following formula: 35 S]GTPγS binding rate = 100 × (cpm) sample -cpm non-specific ) / (cpm basal -cpm non-specific )

[0118] The experimental results are shown in Table 4:

[0119] Table 4. 35 Results of S]GTPγS binding experiment

[0120]

[0121] Further testing was conducted on the antagonistic activity of compound 6a, and the results are shown in Table 5:

[0122] Table 5. Antagonistic activity of compound 6a (SLL-1062) against μ receptors

[0123]

[0124] Example 27: Pharmacological experiment on the antagonistic activity of SLL-1062 against morphine

[0125] Experimental animals: Male Kunming mice (approximately 27g) were used in the experiments and purchased from the Laboratory Animal Center, Chinese Academy of Sciences (Shanghai, China). All mice were housed in a temperature-controlled environment with a simulated 12-hour circadian rhythm (lights were turned on at 8:00 AM daily). Sufficient food was provided, and the mice had free access to food and water. All experiments were conducted in accordance with standard animal procedures (2021-12-LJG-56).

[0126] Hot Plate Test: The procedure for this test followed the group's previous work. Mice were placed on a smooth, uniformly heated surface (55°C), and the time interval between contact with the hot plate and licking the hind paw was observed; this was the pain latency. Before administration, the response time to heat pain was measured twice for each mouse, and the average value was taken as the basal latency. Mice that did not lick their paw within 30 seconds were excluded from subsequent tests. To avoid burning the mice, mice were removed if no pain response was observed after 60 seconds. The analgesic effect was calculated using the following formula: %antinociception = 100 × (test latency – pre-basal latency) / (cut-off time – basal latency).

[0127] Experimental results showed that, in the hot plate test, SLL-1062 (10 mg / kg) could inhibit the analgesic effect of the classic opioid morphine (8 mg / kg). Figure 1 ).

Claims

1. A fused ring morphinoid compound or a pharmaceutically acceptable salt thereof, characterized by, The compound has a structure of formula (Ia): ； wherein, R 1 and R 3 is selected from CH3; R 4 selected from -CH=CH-; R 5 selected from C 1-6 alkyl, C 3-7 cycloalkyl, -(CH2) m -C 6-10 aryl, -(CH2) m- 5-10 membered heteroaryl, -C(O)-(CH2) m -C 6-10 aryl, -C(O)-(CH2) m -5-10 membered heteroaryl, -C(O)O-C1-6alkyl, -C(O)O-C 3-7 cycloalkyl, -C(O)O-(CH2) n -C 6-10 aryl; said C 1-6 alkyl, C 3-7 cycloalkyl, C 5-7 cycloalkenyl, aryl, heteroaryl optionally substituted with 1-3 halogen, nitro, amino, hydroxy, C 1-6 alkyl, C 1-3 alkoxy, C 3-7 cycloalkyl, -O-C 1-6 alkyl, -O-C 3-7 cycloalkyl, -OCF3, -SO2CH3 optionally substituted; m is selected from 0, 1, 2 or 3; n is selected from 1, 2 or 3.

2. The fused ring morphinoid compound or pharmaceutically acceptable salt thereof according to claim 1, wherein m is selected from 0 or 1; n = 1.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein The compound has a structure as follows: 。 4. Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment of sedative-hypnotic or acute alcoholism; or for the manufacture of a medicament for the treatment of other narcotic analgesic intoxications, and for the manufacture of a medicament for the prevention of relapse in opiate addicts. ​

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