2-Amino-5-hydroxytetralin derivatives containing hydroxypyridone side chains and their preparation and application

Abstract

The present invention discloses a 2-amino-5-hydroxytetralin derivative containing a hydroxypyridone side chain, as well as its preparation and application. The target compound is obtained by using 2-amino-5-hydroxytetralin as the parent nucleus, and performing one-step condensation of a specific linker with a benzyl-protected hydroxypyridone and subsequent deprotection. Experiments have shown that at the cellular level, it has a significant anti-ferroptosis effect on RSL-3 or Erastin-induced related tumor cells (human fibrosarcoma cells HT-1080), and has a good protective effect on MPP+-induced damage-related nerve cells (human neuroblastoma cells SH-SY5Y). It also has a strong agonist effect on dopamine D2 receptors (HEK 293 cells stably transfected with human dopamine D2 receptors), and can be used to prepare corresponding anti-Parkinson's drugs. The structural formula I or II of the 2-amino-5-hydroxytetralin derivative containing a hydroxypyridone side chain is as follows: #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the pharmaceutical field, and in particular relates to a 2-amino-5-hydroxytetralin derivative containing a hydroxypyridone side chain, a preparation method, an intermediate, and applications thereof. Background Art

[0002] Parkinson's disease (PD) is a common neurodegenerative disorder affecting middle-aged and elderly patients. Its primary pathological change is the loss of dopamine (DA) neurons in the substantia nigra pars compacta of the midbrain, leading to a decrease in striatal DA content. Currently, pharmacological treatments for PD primarily focus on dopamine replacement drugs and drugs that affect dopaminergic function. Although levodopa (madopar) remains the "gold standard" for PD treatment, long-term treatment can lead to serious adverse reactions, such as dyskinesias, movement disorders, and motor fluctuations, and diminished efficacy in advanced patients. Another class of drugs that affect dopamine function is dopamine receptor agonists. These drugs mimic endogenous neurotransmitters, acting directly on dopamine receptors and activating them, mimicking dopamine's effects. Drugs such as rotigotine, pramipexole, and ropinirole have been shown to have a positive effect in alleviating symptoms.

[0003] In recent years, clinical pathology and imaging studies have revealed significant iron deposition in the substantia nigra of some patients with Parkinson's disease (PD). This excess iron may promote the production of lipid peroxides by catalyzing the Fenton reaction, leading to neuronal ferroptosis and accelerating PD progression. Therefore, maintaining iron homeostasis in the central nervous system plays a crucial role in PD treatment. Iron chelators, specifically targeted at the role of iron in PD, are a novel PD treatment approach. These chelators cross the blood-brain barrier and chelate iron deposits in the substantia nigra, clearing excess reactive iron from specific brain regions. This chelator blocks its ability to catalyze oxidative stress, interferes with the Fenton reaction, and directly blocks the generation of oxygen free radicals, thereby halting or alleviating PD progression. Related research reports suggest that dual-functional molecules with both dopamine receptor agonist activity and iron removal capabilities represent a promising PD treatment strategy, particularly for effectively improving symptoms while simultaneously alleviating or halting dopaminergic neuronal pathology. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a 2-amino-5-hydroxytetralin derivative containing a hydroxypyridone side chain, which has the following structural formula I or II:

[0005]

[0006] in:

[0007] R1 is an alkyl group, wherein the alkyl group is methyl, ethyl, etc.;

[0008] R2 is an alkyl group or a substituted alkyl group, wherein the alkyl group is a methyl group, an ethyl group, a propyl group, etc.; the substituted alkyl group is an arylalkyl group, a hydroxyalkyl group, etc.; the arylalkyl group is a phenethyl group, and the hydroxyalkyl group is a hydroxyethyl group.

[0009] The connecting chain is any of the following groups:

[0010]

[0011] wherein X is oxygen or hydrogen;

[0012] Y is carbon, nitrogen, oxygen or an amide bond;

[0013] n=1, 2, 3, 4, 5 or 6.

[0014] The 2-amino-5-hydroxytetralin derivative containing a hydroxypyridone side chain (Compounds I and II) of the present invention is any of the following compounds:

[0015] (S)-N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-2-(3-hydroxy-2-methyl-4-oxopyridin-1(4H)-yl)-N-propylacetamide (I-1),

[0016] (S)-N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-3-(3-hydroxy-2-methyl-4-oxopyridin-1(4H)-yl)-N-propylpropionamide (I-2),

[0017] (S)-N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-4-(3-hydroxy-2-methyl-4-oxopyridin-1(4H)-yl)-N-propylbutanamide (I-3),

[0018] (S)-N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-(3-hydroxy-2-methyl-4-oxopyridin-1(4H)-yl)-N-propylpentanamide (I-4),

[0019] (S)-N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-6-(3-hydroxy-2-methyl-4-oxopyridin-1(4H)-yl)-N-propylhexanamide (I-5),

[0020] (S)-N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-2-(3-hydroxy-2-ethyl-4-oxopyridin-1(4H)-yl)-N-propylacetamide (I-6),

[0021] (S)-N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-4-(3-hydroxy-2-ethyl-4-oxopyridin-1(4H)-yl)-N-propylbutanamide (I-7),

[0022] (S)-N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-(3-hydroxy-2-ethyl-4-oxopyridin-1(4H)-yl)-N-propylpentanamide (I-8),

[0023] (S)-N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-(3-hydroxy-2-ethyl-4-oxopyridin-1(4H)-yl)-N-propylpentanamide (I-9),

[0024] (S)-N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-6-(3-hydroxy-2-ethyl-4-oxopyridin-1(4H)-yl)-N-propylhexanamide (I-10),

[0025] (S)-3-Hydroxy-1-(2-(((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)-2-methyl-4(1H)-pyridone (I-11), (S)-3-Hydroxy-1-(2-(((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)propyl)-2-methyl-4(1H)-pyridone (I-12), (S)-3-Hydroxy-1-(2-(((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)butyl)-2-methyl-4(1H)-pyridone (I-13), (S)-3-Hydroxy-1-(2-(((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)butyl)-2-methyl-4(1H)-pyridone (I-14). -(2-(((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)pentyl)-2-methyl-4(1H)-pyridone (I-14), (S)-3-hydroxy-1-(2-(((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)hexyl)-2-methyl-4(1H)-pyridone (I-15), (S)-3-hydroxy-1-(2-(4-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazin-1-yl)-2-oxoethyl)-2-methyl-4(1H)-pyridone (I-16),

[0026] (S)-N-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)-3-(3-hydroxy-2-methyl-4-oxopyrido-1(4H)-yl)propanamide (I-17),

[0027] (S)-N-methyl-N-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)-3-(3-hydroxy-2-methyl-4-oxopyrido-1(4H)-yl)propanamide (I-18),

[0028] (S)-3-hydroxy-1-(3-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethoxy)propyl)-2-methyl-4(1H)-pyridinone (I-19),

[0029] (S)-3-hydroxy-2-(4-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazine-1-carbonyl)-4(1H)-pyridinone (II-1),

[0030] (S)-3-hydroxy-2-(4-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazine-1-carbonyl)-1-methyl-4(1H)-pyridinone (II-2),

[0031] (S)-3-hydroxy-2-(4-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazine-1-carbonyl)-1-ethyl-4(1H)-pyridinone (II-3),

[0032] (S)-3-hydroxy-2-(4-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazine-1-carbonyl)-1-propyl-4(1H)-pyridinone (II-4),

[0033] (S)-3-hydroxy-2-(4-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazine-1-carbonyl)-1-phenethyl-4(1H)-pyridinone (II-5),

[0034] (S)-3-hydroxy-2-(4-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazine-1-carbonyl)-1-benzyl-4(1H)-pyridinone (II-6),

[0035] (S)-3-Hydroxy-2-(4-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazine-1-carbonyl)-1-(2-hydroxyethyl)-4(1H)-pyridinone (II-7).

[0036] Another object of the present invention is to provide a method for preparing the compound I or II, which is achieved by the following steps: Preparation of 2-amino-5-hydroxytetralin intermediate:

[0037] 1,6-Dihydroxynaphthalene 1 was used as the starting material and reacted with dimethyl sulfate under water / sodium hydroxide conditions to obtain 1,6-dimethoxynaphthalene 2; 1,6-dimethoxynaphthalene 2 underwent Birch reduction with sodium metal under reflux conditions of anhydrous ethanol, and then the pH was adjusted to 2 to obtain 5-methoxy-2-tetralone 3; 5-methoxy-2-tetralone 3 was reacted with n-propylamine through reductive amination to produce 2-(N-propyl)-5-methoxytetrakisone. Hydronaphthalene 4; Using L-(-)-dibenzoyltartaric acid as a chiral resolving agent, 2-(N-n-propyl)-5-methoxytetralin 4 was subjected to chiral resolution to obtain (S)-2-(N-n-propyl)-5-methoxytetralin 5; (S)-2-(N-n-propyl)-5-methoxytetralin 5 was refluxed and demethylated in a hydrobromic acid and glacial acetic acid system to obtain (S)-2-N-propylamino-5-hydroxytetralin 6, (S)-2-N- Propylamino-5-hydroxytetralin 6 reacts with Boc anhydride under alkaline conditions to obtain N-Boc-protected intermediate 7; intermediate 7 reacts with benzyl chloride under alkaline conditions to obtain compound 8; compound 8 is de-Boced under concentrated hydrochloric acid to obtain (S)-2-N-propylamino-5-benzyloxytetralin 9; compound 9 reacts with bromohydrin under alkaline conditions to obtain intermediate 10; compound 9 is condensed with N-substituted Boc glycine to obtain amide intermediate 11; amide intermediate 11 is reduced under the action of lithium aluminum hydride to obtain the corresponding reduction product 12; compound 12 is de-tert-butyloxycarbonylated in concentrated hydrochloric acid to obtain compound 13; (S)-2-(N-n-propyl)-5-methoxytetralin 5 reacts with tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate under alkaline conditions to obtain intermediate 14, and intermediate 14 is deprotected under reflux in a hydrobromic acid and glacial acetic acid system to obtain intermediate 15. Reaction formula:

[0038]

[0039] The bromohydrin is N-substituted Boc glycine is The base used in the alkaline condition is one of potassium carbonate, sodium hydroxide, sodium hydride, DBU or DIPEA.

[0040] Preparation of hydroxypyridone intermediates:

[0041] 2-Alkyl-3-hydroxy-4-pyrone 16 is used as the starting material and reacted with benzyl chloride under alkaline conditions to generate 2-alkyl-3-benzyloxy-4-pyrone 17; 2-alkyl-3-benzyloxy-4-pyrone 17 and a substituted amine (R1-NH2) are heated under alkaline conditions to obtain 2-alkyl-3-benzyloxy-4-pyridone 18; 2-methyl-3-benzyloxy-4-pyridone 18 is oxidized to the corresponding aldehyde compound 19 under the action of selenium dioxide (SeO2); compound 19 is oxidized under the action of sodium chlorite to obtain 3-hydroxy-4-pyridone-2-carboxylic acid derivative 20. Reaction formula:

[0042]

[0043] Preparation of compound I or II:

[0044] (S)-2-amino-5-hydroxytetralin 6 is condensed with a 2-substituted 3-benzyloxy-4-pyridone-1-carboxylic acid derivative 18a to produce compound 21, which is then debenzylated under the action of Pd / C hydrogen to obtain target compounds I-1 to 10; intermediate 10 is chlorinated with thionyl chloride and reacted with 1-H-3-hydroxy-4-pyridone 18b or 3-(benzyloxy)-1-(3-hydroxypropyl)-2-methyl-4(1H)pyridine 18e under alkaline conditions to produce compounds 22 and 25, respectively, which are then debenzylated under the action of Pd / C hydrogen to obtain target compounds I-11 to 15 and I-19; intermediate 15 is condensed with 1-substituted 2-alkyl-3-benzyloxy-4-pyridone 18c to give compound 23, which is then debenzylated under Pd / C hydrogen to give the target compound I-16; intermediate 13 is condensed with 1-substituted 2-alkyl-3-benzyloxy-4-pyridone 18d to give compound 24, which is then debenzylated under Pd / C hydrogen to give the target compounds I-17-18; intermediate 15 is condensed with 3-hydroxy-4-pyridone-2-carboxylic acid derivative 20 to give compound 26, which is then debenzylated under Pd / C hydrogen to give the target compound II. Reaction formula:

[0045]

[0046] The definitions of the groups are the same as described above.

[0047] The raw materials or intermediates involved in the present invention can be purchased directly or prepared according to the literature methods mentioned in the examples.

[0048] Formula I or II compound described in preparation method of the present invention, can be prepared with the multiple method known to organic synthesis and medicinal chemistry field and technical personnel, can use the method described above to prepare compound of the present invention, it will be understood that when providing typical or preferred process conditions (i.e. reaction temperature, time, the mol ratio of reactant, solvent, pressure etc.), other process conditions can also be used, unless otherwise indicated.Optimum reaction conditions can change with used specific reactant or solvent, but these conditions can be determined by those skilled in the art by conventional optimization process.Usually, reaction scheme as above and process can be used to prepare the compounds of this invention, but are not limited to the reagent and solvent in reaction conditions.

[0049] Another object of the present invention is to provide the use of the 2-amino-5-hydroxytetralin derivative in the preparation of anti-Parkinson's drugs. The anti-Parkinson's effect is that the compound has a significant anti-ferroptosis effect on RSL-3 or Erastin-induced related tumor cells (human fibrosarcoma cells HT-1080) at the cellular level, has a good protective effect on MPP+-induced damaged related nerve cells (human neuroblastoma cells SH-SY5Y), and also has a strong agonist effect on dopamine D2 receptors (HEK 293 cells stably transfected with human dopamine D2 receptors).

[0050] The present invention provides a 2-amino-5-hydroxytetralin derivative containing a hydroxypyridone side chain. By combining the key pharmacophore of an iron chelator with a dopamine D2 receptor agonist, the compound achieves a dual-functional synergistic effect of stimulating dopamine receptors and removing iron. This achieves the goal of effectively improving symptoms while simultaneously alleviating or halting PD dopaminergic neuropathology, thereby discovering a new generation of dual-functional candidate compounds for the treatment of PD. In vitro activity evaluation results showed that the designed compound exhibited significant anti-ferroptosis effects on RSL-3 or Erastin-induced tumor cells (human fibrosarcoma cells HT-1080) at the cellular level, and had a good protective effect on MPP+-induced damaged neural cells (human neuroblastoma cells SH-SY5Y). Furthermore, the compound also had a strong agonist effect on dopamine D2 receptors. DETAILED DESCRIPTION

[0051] The present invention is further illustrated below by way of examples, but the present invention is not limited to the scope of the examples. Experimental methods without specific conditions specified in the following examples are carried out according to conventional methods and conditions, or selected according to the product instructions.

[0052] Example 1 (S) -N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-2-(3-hydroxy-2-methyl-4-oxopyridin-1(4H)-yl)-N-propylpropionamide;

[0053] step:

[0054] Raw material 1: (S)-2-(N-n-propyl)-5-hydroxytetralin was prepared according to the method reported in the literature (Zuo Hongjian, Du Hongguang, Li Ming, et al. Synthesis of (-)-2-(N-n-propylamino)-5-hydroxytetralin [J]. Journal of Beijing University of Chemical Technology: Natural Science Edition, 2007, 34(6): 4.).

[0055] Starting material 2: 2-(3(-(benzyloxy)-2-methyl-4-oxopyridin-1(4H)-yl)propanoic acid was prepared according to a reported method (Green DE, Ferreira CL, Stick RV, et al. Carbohydrate-bearing 3-hydroxy-4-pyridinonato complexes of gallium(III)and indium(III)[J]. Bioconjugate Chemistry, 2005, 16:1597-1609.).

[0056] Raw material 3: Preparation of (S)-N-(5-hydroxy-1,2,3,4-tetrahydronaphthalene-2-yl)-3-(3-benzyloxy-2-methyl-4-oxopyridin-1(4H)-yl)-N-propylpropionamide:

[0057]

[0058] (S)-2-(N-n-propyl)-5-hydroxytetralin (205 mg, 1 mmol) and 2-(3(-(benzyloxy)-2-methyl-4-oxopyridin-1(4H)-yl)propionic acid (287 mg, 1 mmol) were dissolved in 10 mL of DCM. To the mixture were added triethylamine (415 μL, 3 mmol), EDCI (286 mg, 1.5 mmol), and HOBt (203 mg, 1.5 mmol). The mixture was stirred at room temperature for 2 hours. After completion of the reaction, DCM was added, and the mixture was washed with saturated sodium bicarbonate solution and saturated brine. The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The mixture was separated by silica gel column chromatography (mobile phase: DCM:MeOH=50:1) to give a light yellow liquid.

[0059] 1H NMR(500MHz,Chloroform-d)δ7.44(d,J=7.5Hz,0.5H),7.42-7.38(m,1H),7.38-7.3 3(m,1.5H),7.33-7.30(m,1H),7.30-7.26(m,1H),7.25-7.19(m,1H),6.97-6.92(m, 1H),6.69(d,J=8.0Hz,0.5H),6.56(d,J=7.5Hz,0.5H),6.51(d,J=7.5Hz,1H),5.23( s,1H),5.17(s,1H),4.54-4.49(m,0.5H),4.23(t,J=6.5Hz,1H),4.20(t,J=7.0Hz,1 H),3.80-3.74(m,1H),3.27-3.21(m,0.5H),3.18-3.14(m,0.5H),3.13-3.07(m,0.5 H),3.06-3.01(m,1H),2.99-2.93(m,1H),2.90-2.88(m,0.5H),2.76-2.72(m,0.5H) ,2.58-2.70(m,3.5H),2.19(s,1.5H),2.13(s,1.5H),1.98-1.90(m,1H),1.89-1.85 (m,1H),1.63-1.57(m,1H),1.56-1.49(m,1H),0.89(q,J=7.0Hz,3H).HRMS(ESI):m / z calcd for C 29 H 34 N2O4[M+H] + :475.2592; found:475.2600.

[0060] Target compound: (S)-N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-3-(3-hydroxy-2-methyl-4-oxopyridin-1(4H)-yl)-N-propylpropionamide

[0061]

[0062] (S)-N-(5-Hydroxy-1,2,3,4-tetrahydronaphthalene-2-yl)-3-(3-benzyloxy-2-methyl-4-oxopyridin-1(4H)-yl)-N-propylpropionamide (237 mg, 0.5 mmol) was dissolved in 10 mL of methanol, 5% Pd / C (50 mg) was added, and the mixture was replaced with hydrogen three times and stirred at room temperature overnight. After the reaction was completed, the mixture was filtered using a suction filtration device with diatomaceous earth, the filtrate was collected, and dried under reduced pressure to obtain a white solid.

[0063] mp140.2-141.2℃. 1 H NMR(500MHz,DMSO-d6)δ7.66(dd,J=7.5,3.0Hz,1H),6.89(t,J=7.5Hz,1H),6.58(dd,J=8.0,3.5H z,1H),6.49(d,J=7.5Hz,1H),6.18(d,J=6.0Hz,0.5H),6.15(d,J=7.0Hz,0.5H),4.36-4.29(m,0.5 H),4.23-4.17(m,2H),3.97-3.92(m,1H),3.20-3.06(m,3H),2.95-2.70(m,4.5H),2.34(s,1.3H), 2.30(s,1.7H),1.92-1.77(m,2H),1.54-1.45(m,2H),0.83(td,J=7.5,2.0Hz,3H).HRMS(ESI):m / z calcd for C 22 H 28 N2O4[M+H] + :385.2122; found:385.2123.

[0064] Example 2 (S)-N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-2-(3-hydroxy-2-methyl-4-oxopyridin-1(4H)-yl)-N-propylacetamide

[0065] The method of Example 1 was followed, except that 2-(3(-(benzyloxy)-2-methyl-4-oxopyridin-1(4H)-yl)propionic acid was replaced with 2-(3(-(benzyloxy)-2-methyl-4-oxopyridin-1(4H)-yl)acetic acid. The resulting product was a white solid in a yield of 55%. mp 110.4-110.7°C. 1H NMR (500MHz, DMSO-d6) δ10.51 (s, 0.5H), 9.30 (s, 0.5H), 8.23 ​​(d, J = 7.0Hz, 0.5H), 8.1 9(d,J=7.0Hz,0.5H),7.20(d,J=7.0Hz,1H),6.94(t,J=7.5Hz,0.5H),6.89(t,J=7.5Hz ,0.5H),6.64(d,J=8.0Hz,0.5H),6.59(d,J=9.5Hz,0.5H),6.57-6.49(m,0.5H),5.68- 5.74(m,0.5H),5.64-5.60(m,0.5H),5.56(d,J=5.0Hz,0.5H),4.25-4.20(m,1H),3.97 -3.90(m,1H),3.77(s,0.5H),3.74(s,0.5H),3.33(t,J=8.0Hz,1H),3.23-3.19(m,1H ),3.03-3.00(m,1H),2.94-2.89(m,1H),2.88-2.78(m,1H),2.70-2.62(m,1H),2.39(s ,1.5H),2.37(s,1.5H),2.08-1.95(m,1H),1.90-1.87(s,1H),1.75-1.65(m,2H),1.55 -1.49(m,2H),0.95(t,J=7.5Hz,1.5H),0.82(t,J=7.5Hz,1.5H).HRMS(ESI):m / zcalcd for C 21 H 26 N2O4[M+H] + :371.1966; found:371.1965.

[0066] Example 3 (S)-N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-4-(3-hydroxy-2-methyl-4-oxopyridin-1(4H)-yl)-N-propylbutanamide

[0067] Referring to the method of Example 1, except that 2-(3(-(benzyloxy)-2-methyl-4-oxopyridin-1(4H)-yl)propanoic acid was replaced with 2-(3(-(benzyloxy)-2-methyl-4-oxopyridin-1(4H)-yl)butanoic acid, a white solid was obtained with a yield of 58%.

[0068] mp149.0-150.0℃. 1H NMR(500MHz,DMSO-d6)δ10.53(s,1H),9.29(s,1H),8.26(d,J=7.0Hz,0.5H),7 .23(d,J=7.0Hz,0.5H),7.24-7.20(m,1H),6.90(dt,J=14.0,8.0Hz,1H),6.62( d,J=7.5Hz,0.5H),6.60(d,J=8.0Hz,0.5H),6.53(d,J=7.5Hz,1H),4.38(t,J=7 .5Hz,1H),4.33(t,J=8.0Hz,1H),4.30-4.24(m,0.5H),3.98-3.94(m,0.5H),3. 19-3.14(m,1H),3.13-3.07(m,1H),2.93-2.88(m,1H),2.85-2.83(m,1H),2.57 (d,J=5.5Hz,4H),2.54-2.52(m,1H),2.46-2.40(m,2H),2.03-1.98(m,1H),1.9 8-1.94(m,1H),1.92-1.87(m,1H),1.86-1.79(m,1H),1.58-1.51(m,1H),1.50- 1.44(m,1H),0.87(t,J=7.5Hz,1.5H),0.82(t,J=7.5Hz,1.5H).HRMS(ESI):m / z calcd for C 23 H 30 N2O4[M+H] + :399.2279; found:399.2278.

[0069] Example 4 (S)-N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-(3-hydroxy-2-methyl-4-oxopyridin-1(4H)-yl)-N-propylpentanamide

[0070] Referring to the method of Example 1, except that 2-(3(-(benzyloxy)-2-methyl-4-oxopyridin-1(4H)-yl)propanoic acid was replaced with 2-(3(-(benzyloxy)-2-methyl-4-oxopyridin-1(4H)-yl)pentanoic acid, a white solid was obtained with a yield of 66%.

[0071] mp106.9-108.0℃. 1H NMR(500MHz,DMSO-d6)δ7.58(dd,J=14.5,7.0Hz,1H),6.89(q,J=8.0Hz,1H),6.59(t,J=7.5Hz,1H),6.5 0(dd,J=16.5,7.5Hz,1H),6.12(dd,J=11.5,7.5Hz,1H),4.34(tt,J=12.0,4.0Hz,1H),3.94(d,J=8.0Hz, 2H),3.16-3.05(m,2H),2.93-2.82(m,2H),2.72-2.50(m,2H),2.44-2.32(m,2H),2.28(d,J=12.5Hz,3H) ,1.92-1.79(m,2H),1.70-1.61(m,2H),1.54-1.45(m,2H),0.84(dt,J=23.5,7.5Hz,3H).HRMS(ESI):m / z calcd for C 24 H 32 N2O4[M+H] + :413.2435; found:413.2434.

[0072] Example 5 (S)-N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-6-(3-hydroxy-2-methyl-4-oxopyridin-1(4H)-yl)-N-propylhexanamide

[0073] Referring to the method of Example 1, except that 2-(3(-(benzyloxy)-2-methyl-4-oxopyridin-1(4H)-yl)propanoic acid was replaced with 2-(3(-(benzyloxy)-2-methyl-4-oxopyridin-1(4H)-yl)hexanoic acid, a white solid was obtained with a yield of 66%.

[0074] mp131.0-132.8℃. 1H NMR (500MHz, DMSO-d6) δ10.55(s,1H),9.30(s,1H),8.28(d,J=7.0Hz,0.5H),8.25(d,J=7.0Hz,0.5H),7.37(d,J=7.0Hz,0.5H),7.35(d, J=7.0Hz,0.5H),6.89(q,J=8.0Hz,1H),6.62(dd,J=10.0,7.5Hz,1H),6.52(d,J=7.5Hz,0.5H),6.48(d,J=7.5Hz,0.5H),4.35-4.29(m,4H ),3.18-3.08(m,2H),2.92-2.83(m,2H),2.70-2.66(m,0.5H),2.60-2.56(m,0.5H),2.55(s,1.5H),2.52(s,1.5H),2.40-2.28(m,2H),1 .90-1.71(m,4H),1.60-1.50(m,3H),1.49-1.43(m,1H),1.33-1.27(m,2H),0.87(t,J=7.5Hz,1H),0.81(t,J=7.5Hz,2H).HRMS(ESI):m / z calcd for C 25 H 34 N2O4[M+H] + :427.2592; found:427.2591.

[0075] Example 6 (S)-N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-2-(3-hydroxy-2-ethyl-4-oxopyridin-1(4H)-yl)-N-propylacetamide

[0076] Referring to the method of Example 1, except that 2-(3(-(benzyloxy)-2-methyl-4-oxopyridin-1(4H)-yl)propionic acid was replaced with 2-(3(-(benzyloxy)-2-ethyl-4-oxopyridin-1(4H)-yl)acetic acid, the product was a white solid with a yield of 64%.

[0077] mp121.5-122.5℃. 1H NMR(500MHz, Methanol-d4)δ7.58-7.40(m,1H),6.92(dt,J=27.5,8.0Hz,1H),6.64-6.59(m,1H),6.57-6.53(m,1H),6.39(d ,J=6.0Hz,1H),5.07(s,2H),4.32-4.27(m,0.5H),4.10-4.00(m,0.5H),3.37(t,J=8.0Hz,0.5H),3.27(t,J=8.0Hz,1H),3.15 -2.99(m,2H),2.98-2.84(m,1H),2.81-2.74(m,1H),2.73-2.65(m,2H),2.61-2.54(m,0.5H),2.18-1.96(m,2H),1.78(q,J=7 .5Hz,1H),1.64(q,J=7.5Hz,1H),1.23-1.15(m,3H),1.04(t,J=7.5Hz,1.5H),0.90(t,J=7.5Hz,1.5H).HRMS(ESI):m / zcalcd for C 22 H 28 N2O4[M+H] + :385.2122; found:385.2126.

[0078] Example 7 (S)-N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-4-(3-hydroxy-2-ethyl-4-oxopyridin-1(4H)-yl)-N-propylbutanamide

[0079] Refer to the method of Example 1, except that 2-(3(-(benzyloxy)-2-methyl-4-oxopyridin-1(4H)-yl)propanoic acid is replaced with 2-(3(-(benzyloxy)-2-ethyl-4-oxopyridin-1(4H)-yl)propanoic acid, white solid, with a yield of 57%.

[0080] mp99.8-101.3℃. 1H NMR(500MHz,Methanol-d4)δ7.65(dd,J=14.5,7.0Hz,1H),6.90(td,J=8.0,1.5Hz,1H),6.56(d,J=8.0Hz,1H),6 .53(dd,J=8.0,4.0Hz,1H),6.39(dd,J=20.0,7.5Hz,1H),4.42-4.6(m,0.5H),4.39(dt,J=12.0,6.5Hz,2H),3.95 -3.89(m,0.5H),3.29-3.18(m,1H),3.18-3.14(m,1H),3.01-2.86(m,6H),2.72-2.62(m,1H),2.60-2.53(m,1H), 1.96-1.81(m,2H),1.63-1.51(m,2H),1.23(dt,J=25.5,7.5Hz,3H),0.89(td,J=7.5,5.5Hz,3H).HRMS(ESI):m / z calcd for C 23 H 30 N2O4[M+H] + :399.2279; found:399.2285.

[0081] Example 8 (S)-N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-(3-hydroxy-2-ethyl-4-oxopyridin-1(4H)-yl)-N-propylpentanamide

[0082] Referring to the method of Example 1, except that 2-(3(-(benzyloxy)-2-methyl-4-oxopyridin-1(4H)-yl)propanoic acid was replaced with 2-(3(-(benzyloxy)-2-ethyl-4-oxopyridin-1(4H)-yl)butanoic acid, a white solid was obtained with a yield of 68%.

[0083] mp110.0-110.5℃. 1H NMR (500MHz, DMSO-d6) δ7.60(t,J=7.5Hz,1H),6.89(td,J=8.0,2.0Hz,1H),6.58(dd,J=8.0,4.0Hz,1H),6.49(d d,J=8.0,3.5Hz,1H),6.11(d,7.0Hz,1H),4.34(tt,J=12.0,4.0Hz,0.5H),4.14(dt,J=18.5,7.5Hz,2.5H),3.96 -3.90(m,2H),3.17-3.06(m,2H),2.95-2.77(m,4H),2.73-2.67(m,2H),2.63-2.52(m,1H),2.50-2.42(m,1H),1 .91-1.75(m,2H),1.56-1.44(m,2H),1.12(dt,J=15.0,7.5Hz,3H),0.82(t,J=7.5Hz,3H).HRMS(ESI):m / zcalcd for C 24 H 32 N2O4[M+H] + :413.2435; found:413.2439.

[0084] Example 9 (S)-N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-(3-hydroxy-2-ethyl-4-oxopyridin-1(4H)-yl)-N-propylpentanamide

[0085] Refer to the method of Example 1, except that 2-(3(-(benzyloxy)-2-methyl-4-oxopyridin-1(4H)-yl)propanoic acid is replaced with 2-(3(-(benzyloxy)-2-ethyl-4-oxopyridin-1(4H)-yl)pentanoic acid, resulting in a white solid with a yield of 70%.

[0086] mp161.0-161.5℃. 1H NMR (500MHz, DMSO-d6) δ7.56(dd,J=14.5,7.5Hz,1H),6.89(q,J=8.0Hz,1H),6.59(t,J=7.5Hz,1H),6.50(dd,J =17.0,7.5Hz,1H),6.12(dd,J=11.0,7.0Hz,1H),4.37-4.30(m,1H),3.93(d,J=7.5Hz,2H),3.17-3.06(m,2H), 2.92-2.82(m,2H),2.68(dd,J=12.5,7.5Hz,2H),2.61-2.53(m,1H),2.49-2.29(m,3H),1.92-1.78(m,2H),1.7 1-1.62(m,2H),1.57-1.47(m,4H),1.12(dt,J=10.5,7.5Hz,3H),0.84(dt,J=23.5,7.5Hz,3H).HRMS(ESI):m / z calcd for C 25 H 34 N2O4[M+H] + :427.2592; found:427.2600.

[0087] Example 10 (S)-N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-6-(3-hydroxy-2-ethyl-4-oxopyridin-1(4H)-yl)-N-propylhexanamide

[0088] Refer to the method of Example 1, except that 2-(3(-(benzyloxy)-2-methyl-4-oxopyridin-1(4H)-yl)propanoic acid is replaced with 2-(3(-(benzyloxy)-2-ethyl-4-oxopyridin-1(4H)-yl)hexanoic acid, a white solid, with a yield of 70%.

[0089] mp162.3-163.3℃. 1H NMR (500MHz, DMSO-d6) δ7.61(dd,J=15.0,7.5Hz,1H),6.89(dt,J=9.0,8.0Hz,1H),6.59(t,J=8.0Hz,1H),6.51(dd,J= 17.0,7.5Hz,1H),6.19(dd,J=10.0,7.0Hz,1H),4.38-4.32(m,1H),3.96-3.91(m,2H),3.34-3.31(m,1H),3.18-3.07( m,2H),2.92-2.84(m,2H),2.73-2.66(m,3H),2.60-2.53(m,1H),2.38-2.25(m,2H),1.89-1.77(m,2H),1.69-1.61(m, 2H),1.58-1.48(m,4H),1.33-1.25(m,2H),1.12(dt,J=11.0,7.5Hz,3H),0.84(dt,J=26.0,7.5Hz,3H).HRMS(ESI):m / z calcd for C 26 H 36 N2O4[M+H] + :441.2748; found:441.2754.

[0090] Example 11 (S)-3-(Benzyloxy)-1-(2-((5-(Benzyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)-2-methyl-4(1H)-pyridinone

[0091] step:

[0092] Raw material 1: (S)-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)carbamic acid tert-butyl ester

[0093]

[0094] (S)-2-(N-n-propyl)-5-hydroxytetralin (10 g, 32.8 mmol) and sodium bicarbonate (4.13 g, 49.2 mmol) were dissolved in a mixed solvent of 50 mL of THF and 50 mL of water. The reaction system was placed in an ice bath, and Boc anhydride (11.1 mL, 49.2 mmol) was added dropwise. After the addition was complete, the ice bath was removed, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, THF was removed under reduced pressure by TLC. The mixture was filtered, and the filter cake was washed with water and air-dried to obtain an off-white solid. The solid was directly used for the next step without further purification.

[0095] 1H NMR(500MHz,Chloroform-d)δ7.03-6.85(m,1H),6.73-6.47(m,2H),4.23-3.97(m,1H),3.12-3.06(m,2H),3.00-2.82(m,2H), 2.79-2.58(m,2H),2.05-1.93(m,1H),1.79(s,1H),1.59(q,J=7.5Hz,2H),1.48(s,9H),0.88(t,J=7.5Hz,3H).HRMS(ESI):m / z calcdfor C 18 H 27 NO3[M+Na] + :328.1883; found:328.1887.

[0096] Raw material 2: (S)-2-(N-propyl)-5-benzyloxytetralin

[0097]

[0098] The above-mentioned tert-butyl (S)-(5-hydroxy-1,2,3,4-tetrahydronaphthalene-2-yl)(propyl)carbamate, sodium hydroxide (1.97 g, 49.2 mmol), and benzyl chloride (5.67 mL, 150 mmol) were dissolved in a mixture of 50 mL of ethanol and 50 mL of water and stirred at 60°C for 12 hours. After completion of the reaction, the ethanol was removed under reduced pressure according to TLC. The reaction was then extracted three times with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, and the solvent was evaporated to obtain a crude product. The crude product was dissolved in 20 mL of ethanol, concentrated hydrochloric acid was added, and the reaction was continued at 60°C for 4 hours. After completion of the reaction, the reaction was cooled to room temperature and filtered to obtain (S)-2-(N-n-propyl)-5-benzyloxytetrahydronaphthalene hydrochloride. This was obtained as an off-white solid with a yield of 87%.

[0099] 1H NMR(500MHz,DMSO-d6)δ7.50-7.35(m,4H),7.33-7.31(m,1H),7.10(t,J=8.0Hz,1 H),6.87(d,J=7.0Hz,1H),6.72(d,J=7.0Hz,1H),5.09(s,2H),3.40(s,1H),3.17-3 .13(m,1H),2.98-2.94(m,3H),2.90-2.82(m,1H),2.61-2.56(m,1H),2.32-2.20(m ,1H),1.80-1.71(m,1H),1.71-1.62(m,2H),0.95(t,J=7.5Hz,3H).HRMS(ESI):m / z calcd forC 20 H 25 NO[M+H] + :296.2009; found:296.2018.

[0100] Raw material 3: (S)-2-(((5-(benzyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethanol

[0101]

[0102] (S)-2-(N-n-propyl)-5-benzyloxytetralin hydrochloride (1.02 g, 3 mmol), potassium carbonate (1.24 g, 9 mmol), and 2-bromoethanol (562.5 mg, 4.5 mmol) were added to 10 mL of anhydrous acetonitrile and refluxed with stirring for 24 hours. After completion of the reaction, the acetonitrile was removed under reduced pressure, and the mixture was extracted three times with saturated sodium bicarbonate solution and dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, and the solvent was evaporated to dryness to obtain a yellow oily liquid. The mixture was purified by column chromatography (dichloromethane:methanol=50:1) to obtain (S)-2-(((5-(benzyloxy)-1,2,3,4-tetralin-2-yl)(propyl)amino)ethanol as a yellow oily liquid with a yield of 34%.

[0103] 1H NMR(500MHz,Chloroform-d)δ7.45-7.42(m,2H),7.41-7.38(m,2H),7.35-7.30(m,1H),7.08( t,J=8.0Hz,1H),6.73(t,J=7.5Hz,2H),5.07(d,J=2.5Hz,2H),3.54(t,J=5.0Hz,2H),3.15-3. 10(m,1H),3.03-2.97(m,1H),2.86-2.78(m,2H),2.71(q,J=5.5Hz,2H),2.66-2.59(m,1H),2. 06-2.02(m,1H),1.65-1.56(m,1H),1.52-1.48(m,2H),,0.91(t,J=7.5Hz,3H).HRMS(ESI):m / z calcd for C 22 H 29 NO2[M+H] + :340.2271; found:340.2275.

[0104] Raw material 4: Preparation of (S)-3-(benzyloxy)-1-(2-((5-(benzyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)-2-methyl-4(1H)-pyridone

[0105]

[0106] (S)-2-(((5-(Benzyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethanol (340 mg, 1 mmol) was dissolved in 2 mL of dichloromethane, and then thionyl chloride (150 μL, 2 mmol) was added and stirred at room temperature for 2 hours. After TLC detection, the solvent was removed under reduced pressure. Acetonitrile was added and dissolved, and 3-benzyloxy-2-methyl-4(1H)-pyridone (215 mg, 1 mmol) and DABCO (224 mg, 2 mmol) were added and stirred at 60°C. After 12 hours, the solvent was removed under reduced pressure after TLC analysis, and the reaction mixture was washed three times with water, then with saturated brine. The mixture was dried over anhydrous Na2SO4, and the solvent was evaporated under reduced pressure to give a yellow oily liquid. The oily liquid was purified by column chromatography (mobile phase: DCM:MeOH = 60:1) to give (S)-3-(benzyloxy)-1-(2-((5-(benzyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)-2-methyl-4(1H)-pyridone as a light yellow oily liquid in a yield of 42%.

[0107] 1H NMR(500MHz,Chloroform-d)δ7.44-7.37(m,8H),7.33(dd,J=7.0,2.0Hz,1H),7.28(d,J=1.5Hz,1H),7.22(d,J=7 .5Hz,1H),7.07(t,J=8.0Hz,1H),6.72(s,t,J=8.0Hz,1H),6.69(d,J=8.0Hz,1H),6.44(d,J=7.5Hz,1H),5.20(s,2 H),5.06(s,2H),3.81-3.71(m,2H),3.09-3.04(m,1H),2.89-2.81(m,2H),2.72-2.68(m,2H),2.62-2.53(m,2H),2 .47-2.43(m,2H),2.10(s,3H),1.90-1.85(m,2H),1.51-1.41(m,2H),0.84(t,J=7.5Hz,3H).HRMS(ESI):m / zcalcd for C 35 H 40 N2O3[M+H] + :537.3112; found:537.3115.

[0108] Target compound: (S)-3-hydroxy-1-(2-(((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)-2-methyl-4(1H)-pyridinone

[0109]

[0110] (S)-3-(Benzyloxy)-1-(2-((5-(Benzyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)-2-methyl-4(1H)-pyridone (150 mg, 0.28 mmol) was dissolved in 10 mL of methanol, 5% Pd / C (50 mg) was added, and the mixture was replaced with hydrogen three times, followed by stirring at room temperature overnight. After the reaction, the palladium carbon was removed by filtration, and the solvent was removed under reduced pressure to obtain the product (S)-3-hydroxy-1-(2-(((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)-2-methyl-4(1H)-pyridone as a white solid in a yield of 95%.

[0111] mp110.4-110.7℃. 1H NMR(500MHz,Methanol-d4)δ7.51(d,J=7.5Hz,1H),6.85(t,J=7.5Hz,1H),6.50(t ,J=8.5Hz,2H),6.36(d,J=7.0Hz,1H),4.09-3.99(m,2H),2.91-2.81(m,4H),2.68 (dd,J=16.0,3.5Hz,1H),2.57-2.45(m,4H),2.43(s,3H),1.90-1.86(m,1H),1.52 -1.45(m,1H),1.31(qd,J=7.1,2.1Hz,2H),0.81(t,J=7.5Hz,3H).HRMS(ESI):m / z calcd for C 21 H 28 N2O3[M+H] + :357.2173; found:357.2186.

[0112] Example 12 (S)-3-Hydroxy-1-(2-(((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)propyl)-2-methyl-4(1H)-pyridinone

[0113] The method of Example 11 was followed, except that (S)-2-(((5-(benzyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethanol was replaced with (S)-2-(((5-(benzyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)propanol. The resulting product was a white solid in 39% yield. mp 87.5-87.8°C. 1 H NMR (500MHz, DMSO-d6) δ7.55(d,J=7.5Hz,1H),6.86(t,J=7.5Hz,1H),6.56(d,J=8.0Hz,1H),6.51(d,J=7.5 Hz,1H),6.11(d,J=7.0Hz,1H),5.76(s,1H),3.95(t,J=7.5Hz,2H),2.87-2.79(m,2H),2.72-2.60(m,2H),2 .53(d,J=7.0Hz,2H),2.44(t,J=7.4Hz,2H),2.41-2.35(m,1H),2.28(s,3H),1.94-1.89(m,1H),1.75(p,J= 6.9Hz,2H),1.48(dp,J=12.1,6.7,6.1Hz,1H),1.39(p,J=7.5Hz,2H),0.86(t,J=7.5Hz,3H).HRMS(ESI):m / z calcd for C22 H 30 N2O3[M+H] + :371.2329.; found:371.2336.

[0114] Example 13 (S)-3-Hydroxy-1-(2-(((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)butyl)-2-methyl-4(1H)-pyridinone

[0115] The method of Example 11 was followed, except that (S)-2-(((5-(benzyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethanol was replaced with (S)-2-(((5-(benzyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)butanol. The resulting product was a white solid in a yield of 39%. mp 52.9-53.9°C. 1 H NMR(500MHz,DMSO-d6)δ7.56(d,J=7.0Hz,1H),6.86(t,J=7.5Hz,1H),6.57(d,J=7.5Hz,1 H),6.50(d,J=7.5Hz,1H),6.11(d,J=7.0Hz,1H),3.93(t,J=7.5Hz,2H),2.86-2.79(m,2H) ,2.71-2.62(m,2H),2.52(d,J=12.0Hz,2H),2.45(t,J=8.0Hz,2H),2.41-2.36(m,1H),2.2 8(s,3H),1.65(t,J=7.5Hz,2H),1.55-1.32(m,6H),0.83(t,J=7.3Hz,3H).HRMS(ESI):m / z calcd for C 23 H 32 N2O3[M+H] + :385.2486; found:385.2496.

[0116] Example 14 (S)-3-Hydroxy-1-(2-(((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)pentyl)-2-methyl-4(1H)-pyridinone

[0117] The method of Example 11 was followed, except that (S)-2-(((5-(benzyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethanol was replaced with (S)-2-(((5-(benzyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)pentanol. The resulting product was a white solid in a yield of 41%. The mp was 71.7-72.7°C. 1H NMR(500MHz, Methanol-d4)δ7.60(d,J=7.5Hz,1H),6.89(t,J=8.0Hz,1H),6.55(t,J=7.0Hz,2H), 6.38(d,J=7.0Hz,1H),4.04(t,J=7.5Hz,2H),2.99-2.94(m,2H),2.85-2.80(m,1H),2.76-2.71(m ,1H),2.63(t,J=7.5Hz,2H),2.61-2.56(m,2H),2.53-2.46(m,1H),2.43(s,3H),2.10-2.06(m,1H ),1.81-1.75(m,2H),1.59-1.50(m,5H),1.42-1.36(m,2H),0.92(t,J=7.3Hz,3H).HRMS(ESI):m / z calcdfor C 24 H 34 N2O3[M+H] + :399.2642; found:399.2652.

[0118] Example 15 (S)-3-Hydroxy-1-(2-(((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)hexyl)-2-methyl-4(1H)-pyridinone

[0119] Refer to the method of Example 11, except that (S)-2-(((5-(benzyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethanol is replaced with (S)-2-(((5-(benzyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)hexanol, a white solid, with a yield of 46%.

[0120] mp62.5-63.5℃. 1H NMR(500MHz,Methanol-d4)δ7.60-7.57(d,J=7.0Hz,1H),6.89(t,J=8.0Hz,1H),6.55(dd,J=7.5,4.0Hz,2H) ,6.38(d,J=7.0Hz,1H),4.02(t,J=7.5Hz,2H),2.99-2.91(m,1H),2.85-2.81(m,1H),2.75-2.70(m,1H),2.61 -2.58(m,2H),2.58-2.53(m,2H),2.52-2.46(m,1H),2.42(s,3H),2.11-2.06(m,1H),1.74(q,J=7.5,7.0Hz, 2H),1.60-1.57(m,1H),1.52(p,J=7.5,6.0Hz,4H),1.42-1.37(m,4H),0.92(t,J=7.4Hz,3H).HRMS(ESI):m / z calcd for C 25 H 36 N2O3[M+H] + :413.2799; found:413.2806.

[0121] Example 16 (S)-3-hydroxy-1-(2-(4-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazin-1-yl)-2-oxoethyl)-2-methyl-4(1H)-pyridinone

[0122] step:

[0123] Raw material 1: (S)-4-(2-(((5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazine-1-carboxylic acid tert-butyl ester

[0124]

[0125] (S)-2-Amino-5-methoxytetralin (10 g, 45.6 mmol) was dissolved in 100 mL of acetonitrile, and tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate (17 g, 68.5 mmol) and potassium carbonate (9.5 g, 68.5 mmol) were added. The mixture was refluxed with stirring for 24 hours. After completion of the reaction as determined by TLC, the acetonitrile was removed under reduced pressure, and the mixture was extracted with water and dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and the solvent was evaporated to dryness to give a yellow oily liquid. The mixture was purified by column chromatography (dichloromethane:methanol=100:1) to give tert-butyl (S)-4-(2-(((5-methoxy-1,2,3,4-tetralin-2-yl)(propyl)amino)ethyl)piperazine-1-carboxylate as a light yellow oily liquid with a yield of 63%.

[0126] 1 H NMR(500MHz,Chloroform-d)δ7.08(t,J=8.0Hz,1H),6.70(d,J=7.5Hz,1H),6.64(d,J=8.0Hz ,1H),3.80(s,3H),3.42(t,J=5.0Hz,4H),3.01-2.95(m,1H),2.94-2.88(m,1H),2.86-2.80(m ,1H),2.77-2.72(m,1H),2.70-2.67(m,2H),2.54-2.46(m,5H),2.44-2.41(m,4H),2.06-2.0 2(m,1H),1.88(s,1H),1.60-1.47(m,2H),1.45(s,9H),0.88(t,J=7.5Hz,3H).HRMS(ESI):m / z calcd for C 25 H 41 N3O3[M+H] + :432.3221; found:432.3228.

[0127] Raw material 2: (S)-6-(((2-(piperazin-1-yl)ethyl)(propyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol

[0128]

[0129] Tert-butyl (S)-4-(2-(((5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazine-1-carboxylate (9 g, 21 mmol) was dissolved in 100 mL of aqueous hydrobromic acid solution and 50 mL of glacial acetic acid, and the mixture was refluxed with stirring for 16 hours. After completion of the reaction, the solvent was removed under reduced pressure by LC-MS to afford the hydrobromide salt of (S)-6-(((2-(piperazin-1-yl)ethyl)(propyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol without further purification as a brown oily liquid in a yield of 94%.

[0130] 1 H NMR (500MHz, DMSO-d6) δ9.46 (s, 2H), 9.01 (s, 3H), 6.96 (t, J = 7.5Hz, 1H), 6.65 (d, J = 8. 0Hz,1H),6.58(d,J=7.5Hz,1H),3.77-3.67(m,2H),3.60-3.54(m,2H),3.51-3.42(m,2H ),3.35(s,6H),3.24-3.17(m,4H),3.08-3.02(m,2H),2.93-2.89(m,1H),2.59-2.52(m, 1H),2.35-2.30(m,1H),1.81-1.77(m,2H),0.94(t,J=7.5Hz,3H).HRMS(ESI):m / zcalcd for C 19 H 31 N3O[M+H] + :318.2540; found:318.2544.

[0131] Target compound: (S)-3-hydroxy-1-(2-(4-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazin-1-yl)-2-oxoethyl)-2-methyl-4(1H)-pyridinone

[0132] Refer to the method of Example 2, except that (S)-2-(N-n-propyl)-5-hydroxytetralin is replaced with (S)-6-(((2-(piperazin-1-yl)ethyl)(propyl)amino)-5,6,7,8-tetralin-1-ol, a white solid is obtained in a yield of 70%.

[0133] mp176.3-177.3℃. 1H NMR (500MHz, DMSO-d6) δ7.42(d,J=7.5Hz,1H),6.87(t,J=7.5Hz,1H),6.57(d,J=8.0Hz,1H ),6.52(d,J=7.5Hz,1H),6.10(d,J=7.0Hz,1H),4.99(s,2H),3.43(t,J=5.0Hz,4H),2.90- 2.80(m,2H),2.74-2.64(m,4H),2.55-2.50(m,3H),2.43-2.39(m,6H),2.08(s,3H),1.98- 1.92(m,1H),1.55-1.50(m,1H),1.46-1.36(m,2H),0.86(t,J=7.5Hz,3H).HRMS(ESI):m / z calcd for C 27 H 38 N4O4[M+H] + :483.2973; found:483.2980.

[0134] Example 17 (S)-N-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)-3-(3-hydroxy-2-methyl-4-oxopyrido-1(4H)-yl)propanamide

[0135] Referring to the method of Example 1, except that (S)-2-(N-n-propyl)-5-hydroxytetralin was replaced with (S)-6-(((2-aminoethyl)(propyl)amino)-5,6,7,8-tetralin-1-ol, a white solid was obtained with a yield of 70%.

[0136] mp93.3-94.3℃. 1H NMR (500MHz, Methanol-d4) δ7.57(d,J=7.5Hz,1H),6.91(t,J=8.0Hz,1H),6.57(t,J=8.0Hz,2H),6.35(d ,J=7.0Hz,1H),4.33(t,J=6.5Hz,2H),3.32(s,1H),3.30(s,1H),3.09-3.14(m,1H),3.00-2.95(m,1H),2. 91-2.86(m,1H),2.82-2.74(m,3H),2.72(t,J=8.0Hz,2H),2.67(t,J=6.5Hz,2H),2.57-2.50(m,1H),2.4 5(s,3H),2.13-2.07(m,1H),1.67-1.59(m,1H),1.58-1.52(m,2H),0.94(t,J=7.5Hz,3H).HRMS(ESI):m / z calcd for C 24 H 33 N3O4[M+H] + :428.2573; found:428.2571.

[0137] Example 18 (S)-N-methyl-N-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)-3-(3-hydroxy-2-methyl-4-oxopyrido-1(4H)-yl)propanamide

[0138] Referring to the method of Example 1, except that (S)-2-(N-n-propyl)-5-hydroxytetralin was replaced with (S)-6-(((2-aminomethylethyl)(propyl)amino)-5,6,7,8-tetralin-1-ol, a white solid was obtained with a yield of 70%.

[0139] mp83.8-84.8℃. 1H NMR(500MHz,Methanol-d4)δ7.68(d,J=7.0Hz,1H),6.91(t,J=7.5Hz,1H),6.57(t,J=7.0Hz,2H), 6.37(d,J=7.5Hz,1H),4.33(d,J=7.0Hz,3H),3.52(t,J=7.0Hz,2H),3.22-3.10(m,1H),3.03(s,3 H),3.00(t,J=7.0Hz,1H),2.90-2.85(m,6H),2.81-2.76(m,1H),2.70-2.63(m,1H),2.46(s,3H), 2.12-2.04(m,1H),1.68-1.68(m,,1H),1.58-1.53(m,2H),0.94(t,J=7.3Hz,3H).HRMS(ESI):m / z calcd for C 25 H 35 N3O4[M+H] + :442.2701; found:442.2702.

[0140] Example 19 (S)-3-hydroxy-1-(3-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethoxy)propyl)-2-methyl-4(1H)-pyridinone

[0141] Refer to the method of Example 11, except that 3-benzyloxy-2-methyl-4(1H)-pyridone is replaced with 3-(benzyloxy)-1-(2-hydroxypropyl)-2-methyl-4(1H)-pyridone, and the result is a white solid with a yield of 62%.

[0142] mp114.0-115.0℃. 1H NMR (500MHz, Methanol-d4) δ7.50(d,J=7.5Hz,1H),6.89(t,J=8.0Hz,1H),6.57(d,J=7.5Hz,1H),6.54(d,J=8.0Hz,1H) ,6.35(d,J=7.0Hz,1H),4.09(t,J=7.5Hz,2H),3.55(t,J=6.0Hz,2H),3.45(t,J=6.0Hz,,2H),3.10-3.05(m,1H),3.00-2 .96(m,1H),2.92-2.89(m,1H),2.87(t,J=6.0Hz,2H),2.77-2.73(m,1H),2.67-2.63(m,2H),2.56-2.51(m,1H),2.39(s, 3H),2.13-2.09(m,1H),1.99-1.94(m,2H),1.63-1.59(m,1H),1.57-1.53(m,2H),0.94(t,J=7.5Hz,3H).HRMS(ESI):m / z calcd for C 24 H 34 N2O4[M+H] + :415.2592; found:415.2598.

[0143] Example 20 (S)-3-hydroxy-2-(4-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazine-1-carbonyl)-4(1H)-pyridinone

[0144] Referring to the method of Example 16, except that 2-(3-(benzyloxy)-2-methyl-4-oxopyridin-1(4H)-yl)acetic acid was replaced with 3-(benzyloxy)-1-benzyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid, a white solid was obtained with a yield of 73%.

[0145] mp170.7-171.7℃. 1H NMR(500MHz, Methanol-d4)δ7.63(d,J=6.5Hz,1H),6.90(t,J=8.0Hz,1H),6.59-6.54(m,2H),6. 50-6.48(m,1H),3.81-3.71(m,2H),3.46(s,2H),3.13-3.09(m,1H),3.01-2.97(m,1H),2.93-2.8 6(m,3H),2.81(t,J=6.0Hz,1H),2.75-2.69(m,2H),2.61(d,J=7.0Hz,6H),2.53(d,J=5.5Hz,1H) ,2.15-2.09(m,1H),1.68-1.62(m,1H),1.61-1.55(m,2H),0.95(t,J=7.5Hz,3H).HRMS(ESI):m / z calcd for C 25 H 34 N4O4[M+H] + :455.2653; found:455.2640.

[0146] Example 21 (S)-3-hydroxy-2-(4-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazine-1-carbonyl)-1-methyl-4(1H)-pyridinone

[0147] Referring to the method of Example 16, except that 2-(3-(benzyloxy)-2-methyl-4-oxopyridin-1(4H)-yl)acetic acid was replaced with 3-(benzyloxy)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid, a white solid was obtained with a yield of 73%.

[0148] mp79.1-80.1℃. 1H NMR (500MHz, Methanol-d4) δ7.65(d,J=7.0Hz,1H),6.97(t,J=8.0Hz,1H),6.65(d,J=8.0Hz,1H),6.20( d,J=8.0Hz,1H),6.41(d,J=7.2Hz,1H),3.91-3.72(m,3H),3.69(s,3H),3.51-3.46(m,2H),3.45-3.33(m ,2H),3.26(dd,J=11.0,6.0Hz,2H),3.18-3.05(m,3H),2.91-2.78(m,2H),2.72-2.67(m,3H),2.67-2.53 (m,2H),2.37-2.33(m,1H),1.97-1.86(m,1H),1.86-1.75(m,2H),1.06(t,J=7.5Hz,3H).HRMS(ESI):m / z calcd for C 26 H 36 N4O4[M+H] + :469.2810; found:469.2813.

[0149] Example 22 (S)-3-Hydroxy-2-(4-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazine-1-carbonyl)-1-ethyl-4(1H)-pyridinone

[0150] Referring to the method of Example 16, except that 2-(3-(benzyloxy)-2-methyl-4-oxopyridin-1(4H)-yl)acetic acid was replaced with 3-(benzyloxy)-1-ethyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid, a white solid was obtained with a yield of 53%.

[0151] mp36.5-37.5℃. 1H NMR(500MHz,Methanol-d4)δ7.72(d,J=7.0Hz,1H),6.95(d,J=7.0Hz,1H),6.64-3.10(m,2H),6.45(d,J=7.0Hz,1H),4 .15-4.07(m,1H),3.90-3.83(m,2H),3.78-3.73(m,2H),3.63-3.59(m,1H),3.51-3.41(m,2H),3.30-3.23(m,2H),3.15 -3.10(m,2H),3.09-3.03(m,2H),3.03-2.96(m,1H),2.78(t,J=6.0Hz,2H),2.71-2.62(m,4H),2.60-2.56(m,1H),2.3 1-2.28(m,1H),1.89-1.83(m,1H),1.77(p,J=7.5Hz,2H),1.40(t,J=7.0Hz,3H),1.02(t,J=7.5Hz,3H).HRMS(ESI):m / z calcd for C 27 H 38 N4O4[M+H] + :483.2966; found:483.2964.

[0152] Example 23 (S)-3-Hydroxy-2-(4-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazine-1-carbonyl)-1-propyl-4(1H)-pyridinone

[0153] Referring to the method of Example 16, except that 2-(3-(benzyloxy)-2-methyl-4-oxopyridin-1(4H)-yl)acetic acid was replaced with 3-(benzyloxy)-1-propyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid, a white solid was obtained with a yield of 52%.

[0154] mp52.9-53.9℃. 1H NMR (500MHz, Methanol-d4) δ7.76-7.70(m,1H),6.97(t,J=8.0Hz,1H),6.65(d,J=8.0Hz,1H),6.63(d,J=8.0Hz,1H),6.45( d,J=7.0Hz,1H),4.12-4.06(m,1H),3.93-3.90(m,1H),3.85-3.83(m,1H),3.80-3.73(m,2H),3.53-3.40(m,4H),3.30-3.2 8(m,1H),3.19-3.15(m,1H),3.13-3.08(m,2H),2.87-2.85(m,2H),2.72-2.67(m,4H),2.63-2.57(m,1H),2.43-2.40(m,1H ),1.99-1.92(m,1H),1.89-1.83(m,3H),1.82-1.68(m,2H),1.06(t,J=7.5Hz,3H),0.93(t,J=7.5,Hz,3H).HRMS(ESI):m / z calcd forC 28 H 40 N4O4[M+H] + :497.3123; found:497.3136.

[0155] Example 24 (S)-3-hydroxy-2-(4-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazine-1-carbonyl)-1-phenylethyl-4(1H)-pyridinone

[0156] Referring to the method of Example 16, except that 2-(3-(benzyloxy)-2-methyl-4-oxopyridin-1(4H)-yl)acetic acid was replaced with 3-(benzyloxy)-1-phenethyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid, a white solid was obtained with a yield of 68%.

[0157] mp120.2-121.2℃. 1H NMR(500MHz,Methanol-d4)δ7.47(dd,J=7.0,2.5Hz,1H),7.31-7.27(m,2H),7.26-7.21(m,1H),7.19-7.15(m,2H),6.98- 6.94(m,1H),6.66-6.59(m,2H),6.34-6.30(m,1H),4.32-4.25(m,1H),4.05-3.96(m,2H),3.82-3.64(m,2H),3.51-3.35( m,4H),3.22(dd,J=10.0,5.5Hz,2H),3.14(dd,J=15.0,5.0Hz,1H),3.07(t,J=7.5Hz,4H),2.87-2.75(m,2H),2.70-2.62( m,4H),2.60-2.52(m,1H),2.37-2.29(m,1H),1.94-1.86(m,1H),1.84-1.73(m,2H),1.05(t,J=7.5Hz,3H).HRMS(ESI):m / z calcd for C 33 H 42 N4O4[M+H] + :559.2379; found:559.2369.

[0158] Example 25 (S)-3-hydroxy-2-(4-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazine-1-carbonyl)-1-(2-hydroxyethyl)-4(1H)-pyridinone

[0159] Referring to the method of Example 16, except that 2-(3-(benzyloxy)-2-methyl-4-oxopyridin-1(4H)-yl)acetic acid was replaced with 3-(benzyloxy)-1-hydroxyethyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid, a white solid was obtained with a yield of 73%.

[0160] mp36.0-37.0℃. 1H NMR(500MHz, Methanol-d4)δ7.70(d,J=7.5Hz,1H),6.93(t,J=8.0Hz,1H),6.63-6.57(m,2H),6.44(d,J=7.0Hz, 1H),4.22-4.20(m,1H),3.95-3.91(m,1H),3.85-3.80(m,2H),3.78-3.71(m,2H),3.55-3.50(m,1H),3.47-4.43 (m,1H),3.08-3.04(m,2H),3.02-2.94(m,2H),2.93-2.89(m,1H),2.89-2.81(m,2H),2.69-2.64(m,6H),2.59-2 .51(m,2H),2.23-2.16(m,1H),1.76-1.70(m,1H),1.65(q,J=7.5Hz,2H),0.98(t,J=7.4Hz,3H).HRMS(ESI):m / z calcd for C 27 H 38 N4O5[M+H] + :499.2915; found:499.2909.

[0161] Example 26 Determination of the inhibitory activity of compounds on RSL-3 or Erastin-induced HT-1080 ferroptosis

[0162] This example is used to determine the inhibitory activity of the compounds of the present invention on ferroptosis in human fibrosarcoma cells HT-1080. The inhibitory activity of the compounds on ferroptosis is expressed as % of cell viability.

[0163] The experimental protocol is as follows: HT-1080 cells are seeded in a 96-well culture plate at an appropriate cell density (5000 cells / well); the cells are then cultured in a 37°C, 5% CO2 environment. After the cells grow to approximately 80%, the ferroptosis inducer RSL3 or Erastin is added to the HT-1080 cells, followed by a series of test compounds. The cells are then returned to the original culture environment and cultured for another 24 hours. The effects of the test compounds on cell viability are then determined using the MTT assay method to determine the inhibitory activity of different compounds against ferroptosis. Cell viability data for the test compounds of the present invention are shown in Table 1.

[0164] Table 1

[0165]

[0166]

[0167] Note: The cell viability of RSL-3-induced ferroptosis is <30%; the cell viability of Erastin-induced ferroptosis is <40%.

[0168] Conclusion: The compounds of this invention can inhibit RSL3-induced ferroptosis, restoring cell viability to over 30%, with the vast majority of compounds restoring cell viability to over 100%. They also have inhibitory activity against erastin-induced ferroptosis, restoring cell viability to over 40%, with some compounds showing significant effects, restoring cell viability to over 100%. This indicates that the compounds of this invention have significant anti-ferroptosis effects.

[0169] Example 27 Determination of the protective effect of the compound on MPP+-induced SH-SY5Y damage

[0170] This example is used to determine the anti-neuroinjury effect of the compound of the present invention on human neuroblastoma cells SH-SY5Y. The protective effect of the compound on the cells is expressed as % cell viability.

[0171] The experimental protocol was as follows: SH-SY5Y cells were seeded at an appropriate cell density (3000 cells / well) in a 96-well culture plate; the cells were then cultured at 37°C in a 5% CO2 environment. After the cells reached approximately 80% confluence, MPP+ was added to the SH-SY5Y cells, followed by a series of test compounds. The cells were then returned to the original culture environment and cultured for an additional 24 hours. The effects of the test compounds on cell viability were then determined using the MTT assay, assessing the protective effects of the various compounds against MPP+-induced damage. Cell viability data for the test compounds of the present invention are shown in Table 2.

[0172] Table 2

[0173]

[0174]

[0175] Note: The cell viability of MPP+-induced damage is <80%.

[0176] Conclusion: The compounds of the present invention showed a certain protective effect on MPP+-induced nerve cell damage, and some compounds showed significant protective effects, restoring cell viability to more than 100%. This shows that the compounds of the present invention have a good protective effect on MPP+-induced nerve cell damage.

[0177] Example 28 Determination of the agonist activity of the compound on dopamine D2 receptor

[0178] This example is used to determine the agonist activity of the compounds of the present invention on dopamine D2 receptors. The half effective concentration (EC) of the compounds on D2 receptors is used 50To express.

[0179] The experimental protocol is as follows: HEK-293 cells were seeded in 96-well culture plates at an appropriate cell density (2500 cells / well), a series of compound gradient concentrations were added, and the agonist activity of the compound at different concentrations on D2 receptors was measured using the LANCE Ultra cAMP kit. The agonist activity at different concentrations of the compound was then fitted. 50 See Table 3 for data.

[0180] Table 3

[0181]

[0182]

[0183] Note: Dopamine EC 50 :~10nM.

[0184] Conclusion: The compounds of the present invention can stimulate dopamine D2 receptors, and their EC 50 The values ​​were below 1 mM, and most of the compounds had EC 50 The concentration of the compounds reached below 100 nM, showing strong agonist activity. More than half of the compounds showed activity comparable to or stronger than that of dopamine. 50 The concentration of the compound of the present invention is less than 10 nM, indicating that the compound of the present invention has a strong agonist effect on dopamine D2 receptor.

[0185] Overall conclusion: The compounds of the present invention are novel in structure. At the same time, the results of in vitro biological activity evaluation show that the compounds of the present invention have significant anti-ferroptosis effects on RSL-3 and Erastin-induced related tumor cells (human fibrosarcoma cells HT-1080) at the cellular level, and have good protective effects on MPP+-induced damaged related nerve cells (human neuroblastoma cells SH-SY5Y). At the same time, they also have a strong agonist effect on dopamine D2 receptors.

Claims

1. A method for preparing a 2-amino-5-hydroxytetralin derivative containing a hydroxypyridone side chain, characterized in that: The 2-amino-5-hydroxytetralin derivatives are compounds I-1 to I-19 and II, and are prepared by the following steps: Step 1: Preparation of 2-amino-5-hydroxytetralin intermediate: 1,6-Dihydroxynaphthalene 1 was used as the starting material and reacted with dimethyl sulfate under water / sodium hydroxide conditions to obtain 1,6-dimethoxynaphthalene 2; 1,6-dimethoxynaphthalene 2 underwent Birch reduction with sodium metal under reflux conditions of anhydrous ethanol, and the pH was adjusted to 2 to obtain 5-methoxy-2-tetralone 3; 5-methoxy-2-tetralone 3 was reacted with n-propylamine through reductive amination to generate 2-(N-propyl)-5-methoxytetralin. 4; Using L-(-)-dibenzoyltartaric acid as a chiral resolving agent, 2-(N-n-propyl)-5-methoxytetralin 4 was subjected to chiral resolution to obtain (S)-2-(N-n-propyl)-5-methoxytetralin 5; (S)-2-(N-n-propyl)-5-methoxytetralin 5 was refluxed and demethylated in a hydrobromic acid and acetic acid system to obtain (S)-2-N-propylamino-5-hydroxytetralin 6, (S)-2-N-propylamino -5-Hydroxytetralin 6 reacts with Boc anhydride under alkaline conditions to obtain N-Boc-protected intermediate 7; intermediate 7 reacts with benzyl chloride under NaOH conditions to obtain compound 8; compound 8 is de-Bocated in concentrated hydrochloric acid to obtain (S)-2-N-propylamino-5-benzyloxytetralin 9; compound 9 reacts with bromohydrin under alkaline conditions to obtain intermediate 10; compound 9 is condensed with N-substituted Boc glycine to obtain amide intermediate 11; amide intermediate 11 is reduced under the action of lithium aluminum tetrahydride to obtain the corresponding reduction product 12; compound 12 is de-tert-butyloxycarbonylated in concentrated hydrochloric acid to obtain compound 13; (S)-2-(N-n-propyl)-5-methoxytetralin 5 reacts with tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate under alkaline conditions to obtain intermediate 14, and intermediate 14 is deprotected in hydrobromic acid and glacial acetic acid under reflux to obtain intermediate 15; reaction formula: The bromohydrin is n=1, 2, 3, 4, 5 or 6; N-substituted Boc glycine is The base used in the alkaline condition is one of potassium carbonate, sodium hydroxide, sodium hydride, DBU or DIPEA; R is hydrogen or methyl; Step 2: Preparation of hydroxypyridone intermediate: 2-Alkyl-3-hydroxy-4-pyrone 16 is used as the starting material and reacted with benzyl chloride under alkaline conditions to generate 2-alkyl-3-benzyloxy-4-pyrone 17; 2-alkyl-3-benzyloxy-4-pyrone 17 and R3-NH2 are heated under alkaline conditions to react to obtain 2-alkyl-3-benzyloxy-4-pyridone 18, intermediate 18 is 18a-18e, R3 is as defined in 18a-18e; wherein 2-methyl-3-benzyloxy-4-pyridone 18-1 is oxidized to the corresponding aldehyde compound 19 under the action of SeO2; compound 19 is oxidized to obtain 3-hydroxy-4-pyridone-2-carboxylic acid derivative 20 under the action of sodium chlorite; reaction formula: The base used in the alkaline condition is one of potassium carbonate, sodium hydroxide, sodium hydride, DBU or DIPEA; Step 3: Preparation of compound I-1 to I-19 or II: (S)-2-amino-5-hydroxytetralin 6 is condensed with a 2-substituted 3-benzyloxy-4-pyridone-1-carboxylic acid derivative 18a to produce compound 21, which is then debenzylated under the action of Pd / C hydrogen to obtain target compounds I-1 to 10; intermediate 10 is chlorinated with thionyl chloride and reacted with 1-H-3-hydroxy-4-pyridone 18b or 3-(benzyloxy)-1-(3-hydroxypropyl)-2-methyl-4(1H)pyridine 18e under alkaline conditions to produce compounds 22 and 25, respectively, which are then debenzylated under the action of Pd / C hydrogen to obtain target compounds I-11 to 15 and I-17. 19; intermediate 15 is condensed with 1-substituted 2-alkyl-3-benzyloxy-4-pyridone 18c to obtain compound 23, which is then debenzylated under the action of Pd / C hydrogen to obtain the target compound I-16; intermediate 13 is condensed with 1-substituted 2-alkyl-3-benzyloxy-4-pyridone 18d to obtain compound 24, which is then debenzylated under the action of Pd / C hydrogen to obtain target compounds I-17-18; intermediate 15 is condensed with 3-hydroxy-4-pyridone-2-carboxylic acid derivative 20 to obtain compound 26, which is then debenzylated under the action of Pd / C hydrogen to obtain the target compound II; reaction formula: The base used in the alkaline condition is one of potassium carbonate, sodium hydroxide, sodium hydride, DBU or DIPEA; in: R1 is methyl or ethyl; R2 is an alkyl group or a substituted alkyl group, wherein the alkyl group is a methyl group, an ethyl group, or a propyl group; the substituted alkyl group is an aryl alkyl group or a hydroxyalkyl group; the aryl alkyl group is a phenethyl group, and the hydroxyalkyl group is a hydroxyethyl group; n=1, 2, 3, 4, 5 or 6.

2. The 2-amino-5-hydroxytetralin derivative containing a hydroxypyridone side chain prepared by the method according to claim 1, characterized in that: The compound I-1 to I-19 or II is any of the following compounds: (S)-N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-2-(3-hydroxy-2-methyl-4-oxopyridin-1(4H)-yl)-N-propylacetamide (I-1), (S)-N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-3-(3-hydroxy-2-methyl-4-oxopyridin-1(4H)-yl)-N-propylpropionamide (I-2), (S)-N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-4-(3-hydroxy-2-methyl-4-oxopyridin-1(4H)-yl)-N-propylbutanamide (I-3), (S)-N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-(3-hydroxy-2-methyl-4-oxopyridin-1(4H)-yl)-N-propylpentanamide (I-4), (S)-N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-6-(3-hydroxy-2-methyl-4-oxopyridin-1(4H)-yl)-N-propylhexanamide (I-5), (S)-N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-2-(3-hydroxy-2-ethyl-4-oxopyridin-1(4H)-yl)-N-propylacetamide (I-6), (S)-N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-4-(3-hydroxy-2-ethyl-4-oxopyridin-1(4H)-yl)-N-propylbutanamide (I-7), (S)-N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-(3-hydroxy-2-ethyl-4-oxopyridin-1(4H)-yl)-N-propylpentanamide (I-8), (S)-N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-(3-hydroxy-2-ethyl-4-oxopyridin-1(4H)-yl)-N-propylpentanamide (I-9), (S)-N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-6-(3-hydroxy-2-ethyl-4-oxopyridin-1(4H)-yl)-N-propylhexanamide (I-10), (S)-3-Hydroxy-1-(2-(((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)-2-methyl-4(1H)-pyridone (I-11), (S)-3-Hydroxy-1-(2-(((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)propyl)-2-methyl-4(1H)-pyridone (I-12), (S)-3-Hydroxy-1-(2-(((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)butyl)-2-methyl-4(1H)-pyridone (I-13), (S)-3-Hydroxy-1-(2-(((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)butyl)-2-methyl-4(1H)-pyridone (I-14). -(2-(((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)pentyl)-2-methyl-4(1H)-pyridone (I-14), (S)-3-hydroxy-1-(2-(((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)hexyl)-2-methyl-4(1H)-pyridone (I-15), (S)-3-hydroxy-1-(2-(4-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazin-1-yl)-2-oxoethyl)-2-methyl-4(1H)-pyridone (I-16), (S)-N-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)-3-(3-hydroxy-2-methyl-4-oxopyrido-1(4H)-yl)propanamide (I-17), (S)-N-methyl-N-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)-3-(3-hydroxy-2-methyl-4-oxopyrido-1(4H)-yl)propanamide (I-18), (S)-3-hydroxy-1-(3-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethoxy)propyl)-2-methyl-4(1H)-pyridinone (I-19), (S)-3-hydroxy-2-(4-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazine-1-carbonyl)-4(1H)-pyridinone (II-1), (S)-3-hydroxy-2-(4-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazine-1-carbonyl)-1-methyl-4(1H)-pyridinone (II-2), (S)-3-hydroxy-2-(4-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazine-1-carbonyl)-1-ethyl-4(1H)-pyridinone (II-3), (S)-3-hydroxy-2-(4-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazine-1-carbonyl)-1-propyl-4(1H)-pyridinone (II-4), (S)-3-hydroxy-2-(4-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazine-1-carbonyl)-1-phenethyl-4(1H)-pyridinone (II-5), (S)-3-hydroxy-2-(4-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazine-1-carbonyl)-1-benzyl-4(1H)-pyridinone (II-6), (S)-3-Hydroxy-2-(4-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazine-1-carbonyl)-1-(2-hydroxyethyl)-4(1H)-pyridinone (II-7).

3. Use of the 2-amino-5-hydroxytetralin derivative containing a hydroxypyridone side chain in the preparation of an anti-Parkinson's drug according to claim 2, characterized in that: The anti-Parkinson's effect is that the compound has an anti-ferroptosis effect on human fibrosarcoma cells HT-1080 induced by RSL-3 or Erastin at the cellular level, a protective effect on human neuroblastoma cells SH-SY5Y induced by MPP+ damage, and an agonist effect on dopamine D2 receptors.

Images