2-((naphthalen-2-ylmethyl)amino)acetamide compounds and pharmaceutical uses thereof

Abstract

The application discloses a 2-((naphthalene-2-ylmethyl)amino)acetamide compound or a pharmaceutically acceptable salt thereof with a structure as shown in formula I: wherein R 1 is H or CH3; R 2 is H or CH3; X is O, S or NH; A ring is 3-6-membered cycloalkyl, 4-6-membered heterocyclyl, aryl or heteroaryl; R 3 is H, halogen, methyl, trifluoromethyl, methoxy, cyano, nitro, vinyl or ethynyl. The compound of the application has good reversible inhibitory effect on MAOs, especially, the MAO-B inhibitory activity is significantly better than that of the third generation MAO-B inhibitor safinamide, and has reversible inhibitory effect on MAO-B, and can be used for treating neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field and relates to the use of 2-((naphthyl-2-ylmethyl)amino)acetamide compounds or pharmaceutically acceptable salts thereof as inhibitors of monoamine oxidase A and / or monoamine oxidase B. Background Technology

[0002] Monoamine oxidases (MAOs) are flavin enzymes distributed on the outer membrane of mitochondria that catalyze the oxidative deamination of monoamines, accompanied by the production of toxic metabolites such as hydrogen peroxide and dihydroxyacetaldehyde, which are related to intracellular oxidative stress. Abnormal expression of MAOs in the body can cause neurotransmitter dysfunction, affecting the normal function of the nervous system and even causing neuronal damage, which is closely related to the occurrence and development of neurodegenerative diseases (Expert Opin TherPat. 2018, 28, 211).

[0003] MAOs exist in two subtypes, MAO-A and MAO-B. Although they share 80% sequence homology, they exhibit different substrate and inhibitor specificities. MAO-A is distributed in the central nervous system and peripheral tissues, primarily catalyzing the degradation of serotonin, tyramine, adrenaline, and noradrenaline. MAO-A inhibitors can increase serotonin and noradrenaline levels in the synaptic cleft of the brain, exerting an antidepressant effect. MAO-B mainly participates in catalyzing the oxidative degradation of dopamine in the central nervous system. With age, the number of glial cells gradually increases, and the expression and activity of MAO-B in glial cells gradually increase. This leads to the degradation of more dopamine and the production of high levels of hydrogen peroxide, resulting in oxidative stress and causing apoptosis of dopaminergic neurons in the substantia nigra (J Parkinsons Dis. 2022, 12, 477), which is considered one of the important events in the pathogenesis of Parkinson's disease. Therefore, MAO-B inhibitors can increase dopamine levels in the body, inhibit the formation of toxic metabolites, and exert neuroprotective effects.

[0004] Clinically, by inhibiting MAOs activity, the levels of neurotransmitters such as nopamine, norepinephrine, and serotonin are upregulated, thereby increasing the content of effective neurotransmitters in the synaptic cleft and achieving the goal of treating central nervous system diseases such as Parkinson's disease, Alzheimer's disease, and depression. It is worth noting that non-selective and irreversible MAOs inhibitors have a long-lasting inhibitory effect on enzymes, leading to potential immunogenicity and adverse reactions; while selective and reversible MAOs inhibitors restore enzyme activity upon discontinuation, have fewer toxic side effects, and can be used rationally for different indications. In particular, selective MAO-B inhibitors not only inhibit the degradation of dopamine in the central nervous system but also reduce the production of neurotoxic byproducts such as hydrogen peroxide and dihydroxyacetaldehyde, exerting a neuroprotective effect (Expert Opin Drug Discov. 2019, 14, 995). In addition, numerous preclinical studies have shown that selective MAO-B inhibitors have a certain effect on improving non-motor symptoms of Parkinson's disease (such as depression, cognitive impairment, sleep disorders, etc.), and have potential therapeutic effects on other neurological diseases, such as epilepsy, multiple sclerosis, Duchenne muscular dystrophy, ischemic brain injury, etc. (Neural Regen Res. 2024, 19, 16).

[0005] Therefore, MAOs inhibitors play an irreplaceable and crucial role in the treatment of central nervous system diseases such as Parkinson's disease, Alzheimer's disease, and depression. Developing novel, reversible, and selective MAOs inhibitors has significant research implications and promising application prospects. Summary of the Invention

[0006] The purpose of this invention is to provide a class of 2-((naphthyl-2-ylmethyl)amino)acetamide compounds or pharmaceutically acceptable salts thereof, wherein the 2-((naphthyl-2-ylmethyl)amino)acetamide compounds have good reversible inhibitory effects on MAOs, especially the MAO-B inhibitory activity of the 2-((naphthyl-2-ylmethyl)amino)acetamide compounds is significantly better than that of the third-generation MAO-B inhibitor safenamide, and has reversible inhibitory effects on MAO-B, which can be used to treat neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease.

[0007] The objective of this invention is achieved through the following technical solution:

[0008] 2-((naphthyl-2-ylmethyl)amino)acetamide compounds or pharmaceutically acceptable salts thereof with structures as shown in Formula I:

[0009] ;

[0010] Among them, R 1 For H or CH3; R 2H or CH3; X is O, S or NH; ring A is a 3-6 membered cycloalkyl, 4-6 membered heterocyclic, aryl or heteroaryl; R 3 It can be H, halogen, methyl, trifluoromethyl, methoxy, cyano, nitro, vinyl, or ethynyl.

[0011] Preferred, R 1 For H or CH3; R 2 H or CH3; X is O, S or NH; ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolyl, tetrahydropyranyl, piperidinyl, phenyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; when ring A is phenyl, R 3 It is H, F, Cl, Br, methyl, trifluoromethyl or methoxy substituted at the meta or para position.

[0012] Further preferred, R 1 For H or CH3, R 2 For H or CH3, X is O, and ring A is cyclobutyl, cyclopentyl, cyclohexyl, or phenyl; when ring A is phenyl, R 3 It is H, F, Cl, Br, methyl, trifluoromethyl or methoxy substituted at the meta or para position.

[0013] Further optimized, R 1 For H, R 2 For H or CH3, X is O, and ring A is cyclobutyl, cyclopentyl, cyclohexyl, or phenyl; when ring A is phenyl, R 3 It is H, F, Cl, Br, methyl, trifluoromethyl or methoxy substituted at the meta or para position.

[0014] The optimal choice, R 1 For H, R 2 It is H or CH3, X is O, ring A is phenyl, R 3 It is H, meta- or para-substituted F, Cl or Br, but does not include: (S)-2-((1-(6-((3-fluorobenzyl)oxy)naphth-2-yl)ethyl)amino)acetamide.

[0015] Specifically, the 2-((naphthyl-2-ylmethyl)amino)acetamide compounds are selected from the following compounds:

[0016]

[0017] The chemical names of the above compounds are:

[0018] 2-(((6-(benzyloxy)naphth-2-yl)methyl)amino)acetamide (compound I-1);

[0019] 2-(((6-((3-fluorobenzyl)oxy)naphth-2-yl)methyl)amino)acetamide (compound I-2);

[0020] 2-(((6-((3-chlorobenzyl)oxy)naphth-2-yl)methyl)amino)acetamide (compound I-3);

[0021] 2-(((6-((3-bromobenzyl)oxy)naphth-2-yl)methyl)amino)acetamide (compound I-4);

[0022] 2-(((6-((3-methylbenzyl)oxy)naphth-2-yl)methyl)amino)acetamide (compound I-5);

[0023] 2-(((6-((3-(trifluoromethyl)benzyl)oxy)naphth-2-yl)methyl)amino)acetamide (compound I-6);

[0024] 2-(((6-((3-methoxybenzyl)oxy)naphth-2-yl)methyl)amino)acetamide (compound I-7);

[0025] 2-(((6-((4-fluorobenzyl)oxy)naphth-2-yl)methyl)amino)acetamide (compound I-8);

[0026] 2-(((6-(cyclopropylmethoxy)naphth-2-yl)methyl)amino)acetamide (compound I-9);

[0027] 2-(((6-(cyclobutylmethoxy)naphth-2-yl)methyl)amino)acetamide (compound I-10);

[0028] 2-(((6-(cyclopentylmethoxy)naphth-2-yl)methyl)amino)acetamide (compound I-11);

[0029] 2-(((6-(cyclohexylmethoxy)naphth-2-yl)methyl)amino)acetamide (compound I-12);

[0030] 2-(((6-((tetrahydro-2H-pyran-4-yl)methoxy)naphth-2-yl)methyl)amino)acetamide (compound I-13);

[0031] 2-(((6-((3-fluorobenzyl)oxy)naphth-2-yl)methyl)amino)propionamide (compound I-14);

[0032] 2-((1-(6-((3-fluorobenzyl)oxy)naphth-2-yl)ethyl)amino)acetamide (compound I-15);

[0033] (R)-2-((1-(6-(((3-fluorobenzyl)oxy)naphth-2-yl)ethyl)amino)acetamide (compound I-16);

[0034] (S)-2-((1-(6-((3-fluorobenzyl)oxy)naphth-2-yl)ethyl)amino)acetamide (compound I-17).

[0035] The pharmaceutically acceptable salts of the 2-((naphthyl-2-ylmethyl)amino)acetamide compounds are hydrochloride, hydrobromide, sulfate, acetate, maleate, or methanesulfonate, preferably methanesulfonate.

[0036] Another object of the present invention is to provide the use of the 2-((naphthyl-2-ylmethyl)amino)acetamide compounds or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating and / or preventing monoamine oxidase A and / or monoamine oxidase B mediated diseases.

[0037] The diseases mediated by monoamine oxidase A and / or monoamine oxidase B are Parkinson's disease, Alzheimer's disease, depression, anxiety disorder, and panic disorder.

[0038] The diseases mediated by monoamine oxidase B are Parkinson's disease and Alzheimer's disease; the diseases mediated by monoamine oxidase A are depression, anxiety disorder, and panic disorder.

[0039] Another object of the present invention is to provide a pharmaceutical composition comprising tablets, capsules, granules, powders, microcapsules, drops, aerosols, suspensions or oral liquids prepared with the 2-((naphthyl-2-ylmethyl)amino)acetamide compound or a pharmaceutically acceptable salt thereof as the active ingredient and a pharmaceutically acceptable carrier. Attached Figure Description

[0040] Figure 1 The crystal structure of compound 14 is shown.

[0041] Figure 2 The crystal structure of compound 19 is shown.

[0042] Figure 3 The results are the high-performance liquid chromatography chiral analysis results for compounds I-16 and I-17.

[0043] Figure 4 The results are analyzed for the reversibility of the inhibition of recombinant human MAO-B enzyme activity by compounds I-2 and I-16 in vitro.

[0044] Figure 5 The results of the blood-brain barrier permeability test for compound I-16 are shown.

[0045] Figure 6This study investigated the effect of compound I-16 on motor function (grip test) in a Parkinson's disease model mouse. The left figure shows the pulling force level of mice in each group on day 0, and the right figure shows the changes in pulling force level in each group on days 0, 7, and 14 after drug administration. Compared with the model group, *p < 0.05, **p < 0.01; compared with the normal control group, ### p < 0.001; no statistically significant difference in ns.

[0046] Figure 7 This study investigated the effect of compound I-16 on motor function (rotarod test) in a mouse model of Parkinson's disease; compared with the model group, ***p < 0.001; compared with the normal control group, ### p < 0.001.

[0047] Figure 8 This study investigated the effect of compound I-16 on depressive symptoms in a Parkinson's disease model mouse; compared with the model group, *p < 0.05, **p < 0.01, ***p < 0.001; compared with the normal control group, ### p < 0.001; no statistically significant difference in ns. Detailed Implementation

[0048] To further illustrate the present invention, a series of embodiments are given below. These embodiments are intended to enable those skilled in the art to fully understand the present invention, but should not be considered as limiting the scope of the invention.

[0049] Example 1

[0050] Preparation of 2-(((6-(benzyloxy)naphth-2-yl)methyl)amino)acetamide (compound I-1)

[0051]

[0052] In a 100 mL round-bottom flask, 6-hydroxy-2-naphthaldehyde (compound 1, 600 mg, 3.48 mmol) was dissolved in 15 mL of anhydrous ethanol, and anhydrous potassium carbonate (530 mg, 3.83 mmol) was added. The mixture was stirred at room temperature for 30 min. Then, benzyl chloride (compound 2, 504 mg, 3.48 mmol) and potassium iodide (46 mg, 0.28 mmol) were added sequentially, and the mixture was stirred until dissolved. The mixture was stirred overnight at 80 °C until the reaction was complete (monitored by thin-layer chromatography). 30 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic layers were combined and washed with saturated brine and dried over anhydrous Na₂SO₄. The solvent was evaporated under reduced pressure to obtain the crude product, which was then purified by normal-phase silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 50:1 V / V) to give a white solid (compound 3, 621 mg, yield 68%).

[0053] In a 100 mL round-bottom flask, glycine aminohydrochloride (compound 4, 175 mg, 1.58 mmol) was dissolved in 10 mL of methanol, followed by the addition of triethylamine (1 mL). The mixture was stirred at room temperature for 20 min. Then, compound 3 (370 mg, 1.32 mmol) and NaBH3CN (166 mg, 3.16 mmol) were added sequentially and stirred until dissolved. The mixture was stirred overnight at 80 °C until the reaction was complete (monitored by thin-layer chromatography). 30 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic layers were combined and washed with saturated brine and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain the crude product, which was then purified by normal-phase silica gel column chromatography (eluent: dichloromethane:methanol = 250:1~100:1 V / V) to give a pale yellow solid (compound I-1, 170 mg, yield 47%).

[0054] 1 H NMR (400 MHz, DMSO-d6) δ 7.79 – 7.69 (m, 3H), 7.38 (m, 8H), 7.18(d, J = 8.8 Hz, 1H), 7.04 (s, 1H), 5.17 (s, 2H), 3.75 (s, 2H), 3.02 (s, 2H),2.75 (s, 1H); HRMS calcd for C 20 H 21 N₂O₂ [M + H] + m / z 321.15975, found321.16014.

[0055] Example 2

[0056] Preparation of 2-(((6-((3-fluorobenzyl)oxy)naphth-2-yl)methyl)amino)acetamide (compound I-2)

[0057]

[0058] Following the preparation method of compound I-1, the starting material benzyl chloride (compound 2) was replaced with an equal amount of 3-fluorobenzyl chloride, while all other steps remained the same, to obtain compound I-2.

[0059] 1 H NMR (400 MHz, DMSO-d6) δ 7.77 (d, J = 9.0 Hz, 1H), 7.71 (d, J = 7.2Hz, 2H), 7.45 – 7.39 (m, 2H), 7.36 (d, J = 2.8 Hz, 1H), 7.33 – 7.24 (m, HRMS calcd for C 20 H 20 FN2O2 [M + H] + m / z 339.15033, found339.15071.

[0060] Example 3

[0061] Preparation of 2-(((6-(((3-chlorobenzyl)oxy)naphth-2-yl)methyl)amino)acetamide (compound I-3)

[0062]

[0063] Following the preparation method of compound I-1, the starting material benzyl chloride (compound 2) was replaced with an equal amount of 3-chlorobenzyl chloride, while all other steps remained the same, to obtain compound I-3.

[0064] 1H NMR (400 MHz, DMSO-d6) δ 7.80 – 7.68 (m, 3H), 7.54 (s, 1H), 7.46 –7.34 (m, 5H), 7.28 (s, 1H), 7.19 (d, J = 9.0 Hz, 1H), 7.04 (s, 1H), 5.19 (s,2H), 3.75 (s, 2H), 3.01 (s, 2H), 2.71 (s, 1H); HRMS calcd for C 20 H 20 ClN2O2 [M +H] + m / z 355.12078, found 355.12121.

[0065] Example 4

[0066] Preparation of 2-(((6-((3-bromobenzyl)oxy)naphth-2-yl)methyl)amino)acetamide (compound I-4)

[0067]

[0068] Following the preparation method of compound I-1, the starting material benzyl chloride (compound 2) was replaced with an equal amount of 3-bromobenzyl chloride, while all other steps remained the same, to obtain compound I-4.

[0069] 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 8.9 Hz, 1H), 7.72 – 7.67 (m,3H), 7.52 – 7.46 (m, 2H), 7.42 (dd, J = 8.5, 1.6 Hz, 1H), 7.36 – 7.31 (m,2H), 7.30 – 7.25 (m, 1H), 7.19 (dd, J = 8.9, 2.5 Hz, 1H), 7.04 (s, 1H), 5.18(s, 2H), 3.74 (s, 2H), 3.01 (s, 2H), 2.61 (s, 1H); HRMS calcd for C 20 H 20 BrN2O2[M + H] + m / z 400.06301, found 400.05411.

[0070] Example 5

[0071] Preparation of 2-(((6-((3-methylbenzyl)oxy)naphth-2-yl)methyl)amino)acetamide (compound I-5)

[0072]

[0073] Following the preparation method of compound I-1, the starting material benzyl chloride (compound 2) was replaced with an equal amount of 3-methylbenzyl chloride, while all other steps remained the same, to obtain compound I-5.

[0074] 1 H NMR (400 MHz, DMSO-d6) δ 7.79 – 7.67 (m, 3H), 7.45 – 7.40 (m, 1H), 7.35 (d, J = 2.5 Hz, 1H), 7.32 – 7.22 (m, 4H), 7.17 (m, 1H), 7.11 (t, HRMS calcd for C 21 H 23 N₂O₂ [M + H] + m / z 335.1754, found 335.17581.

[0075] Example 6

[0076] Preparation of 2-(((6-((3-(trifluoromethyl)benzyl)oxy)naphth-2-yl)methyl)amino)acetamide (compound I-6)

[0077]

[0078] Following the preparation method of compound I-1, the starting material benzyl chloride (compound 2) was replaced with an equal amount of 3-trifluoromethylbenzyl chloride, while all other steps remained the same, to obtain compound I-6.

[0079] 1H NMR (400 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.78 (t, J = 7.8 Hz, 2H), 7.74 – 7.66 (m, 3H), 7.62 (t, J = 7.6 Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H), 7.38(d, J = 2.5 Hz, 1H), 7.29 (s, 1H), 7.21 (dd, J = 9.0, 2.6 Hz, 1H), 7.05 (s,1H), 5.28 (s, 2H), 3.75 (s, 2H), 3.01 (s, 2H), 2.61 (s, 1H); HRMS calcd forC 21 H 20 F3N2O2 [M + H] + m / z 389.14714, found 389.14690.

[0080] Example 7

[0081] Preparation of 2-(((6-((3-methoxybenzyl)oxy)naphth-2-yl)methyl)amino)acetamide (compound I-7)

[0082]

[0083] Following the preparation method of compound I-1, the starting material benzyl chloride (compound 2) was replaced with an equal amount of 3-methoxybenzyl chloride, while all other steps remained the same, to obtain compound I-7.

[0084] 1 H NMR (400 MHz, DMSO-d6) δ 7.78 – 7.68 (m, 3H), 7.42 (d, J = 8.5 Hz,1H), 7.35 (d, J = 2.6 Hz, 1H), 7.32 – 7.24 (m, 2H), 7.18 (dd, J = 9.0, 2.6Hz, 1H), 7.03 (dd, J = 4.7, 2.4 Hz, 3H), 6.87 (dd, J = 8.4, 2.5 Hz, 1H), 5.14(s, 2H), 3.74 (d, J = 8.7 Hz, 5H), 3.01 (s, 2H), 2.65 (s, 1H); HRMS calcd forC 21 H 23 N₂O₃ [M + H] +m / z 351.17032, found 351.17094.

[0085] Example 8

[0086] Preparation of 2-(((6-((4-fluorobenzyl)oxy)naphth-2-yl)methyl)amino)acetamide (compound I-8)

[0087]

[0088] Following the preparation method of compound I-1, the starting material benzyl chloride (compound 2) was replaced with an equal amount of 4-fluorobenzyl chloride, while all other steps remained the same, to obtain compound I-8.

[0089] 1 H NMR (400 MHz, DMSO-d6) δ 7.77 – 7.69 (m, 3H), 7.52 (t, J = 7.0 Hz,2H), 7.42 (d, J = 8.5 Hz, 1H), 7.36 (s, 1H), 7.28 (s, 1H), 7.19 (q, J = 9.0Hz, 3H), 7.04 (s, 1H), 5.15 (s, 2H), 3.75 (s, 2H), 3.01 (s, 2H), 2.67 (d, J =31.9 Hz, 1H); HRMS calcd for C 20 H 20 FN2O2 [M + H] + m / z 339.15033, found339.15069.

[0090] Example 9

[0091] Preparation of 2-(((6-(cyclopropylmethoxy)naphth-2-yl)methyl)amino)acetamide (compound I-9)

[0092]

[0093] In a 100 mL round-bottom flask, 6-hydroxy-2-naphthaldehyde (compound 1, 1 g, 5.81 mmol) was dissolved in DMF (15 mL). NaH (488 mg, 20.3 mmol) was slowly added at 0 °C and stirred for 30 min. Then, bromomethylcyclopropane (compound 5, 941 mg, 6.97 mmol) was added, and the mixture was refluxed at 120 °C and stirred overnight. TLC showed that the starting material had disappeared. The mixture was extracted with water and ethyl acetate, and the organic layers were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 25:1, V / V) to obtain intermediate 6 (compound 6, 520 mg, yield 39%).

[0094] Following the preparation method of compound I-1, compound 3 was replaced with an equal amount of compound 6, and all other steps remained the same, to prepare compound I-9.

[0095] 1 H NMR (400 MHz, DMSO-d6) δ 7.74 – 7.67 (m, 3H), 7.40 (dd, J = 8.2,1.7 Hz, 1H), 7.28 (s, 1H), 7.20 (d, J = 2.5 Hz, 1H), 7.11 (dd, J = 8.9, 2.5Hz, 1H), 7.06 – 6.96 (m, 1H), 3.87 (d, J = 7.0 Hz, 2H), 3.74 (s, 2H), 3.01(s, 2H), 2.57 (s, 1H), 1.24 (m, 1H), 0.55 (dt, J = 8.0, 3.0 Hz, 2H), 0.35 –0.29 (m, 2H); HRMS calcd for C 17 H 21 N₂O₂ [M + H] + m / z 285.15305, found284.16034.

[0096] Example 10

[0097] Preparation of 2-(((6-(cyclobutylmethoxy)naphth-2-yl)methyl)amino)acetamide (compound I-10)

[0098]

[0099] Following the preparation method of compound I-9, bromomethylcyclopropane (compound 5) was replaced with an equal amount of bromomethylcyclobutane, while all other steps remained the same, to prepare compound I-10.

[0100] 1 H NMR (400 MHz, DMSO-d6) δ 7.70 (dd, J = 13.8, 6.5 Hz, 3H), 7.41 (d,J = 8.5 Hz, 1H), 7.30 – 7.21 (m, 2H), 7.13 – 6.96 (m, 2H), 4.01 (d, J = HRMS calcd for C 18 H 23 N₂O₂ [M + H] + m / z 299.16847, found 299.17572.

[0101] Example 11

[0102] Preparation of 2-(((6-(cyclopentylmethoxy)naphth-2-yl)methyl)amino)acetamide (compound I-11)

[0103]

[0104] Following the preparation method of compound I-9, bromomethylcyclopropane (compound 5) was replaced with an equal amount of bromomethylcyclopentane, with all other steps remaining the same, to prepare compound I-11.

[0105] 1H NMR (400 MHz, DMSO-d6) δ 7.74 – 7.67 (m, 3H), 7.40 (dd, J = 8.6,1.7 Hz, 1H), 7.27 (s, 1H), 7.24 (d, J = 2.6 Hz, 1H), 7.09 (dd, J = 8.9, 2.5Hz, 1H), 7.02 (s, 1H), 3.90 (d, J = 6.9 Hz, 2H), 3.74 (s, 2H), 3.01 (s, 2H), 2.56 (s, 1H), 2.32 (p, J = 7.4 Hz, 1H), 1.81 – 1.73 (m, 2H), 1.61 – 1.55 (m, 2H), 1.54 – 1.45 (m, 2H), 1.37 – 1.33 (m, 1H), 1.31 (d, J = 6.2 Hz, 1H); HRMScalcd for C 19 H 25 N₂O₂ [M + H] + m / z 313.18482, found 313.19226.

[0106] Example 12

[0107] Preparation of 2-(((6-(cyclohexylmethoxy)naphth-2-yl)methyl)amino)acetamide (compound I-12)

[0108]

[0109] Following the preparation method of compound I-9, bromomethylcyclopropane (compound 5) was replaced with an equal amount of bromomethylcyclohexane, with all other steps remaining the same, to prepare compound I-12.

[0110] 1 H NMR (400 MHz, DMSO-d6) δ 7.74 – 7.65 (m, 3H), 7.40 (dd, J = 8.5,1.7 Hz, 1H), 7.33 – 7.19 (m, 2H), 7.14 – 6.98 (m, 2H), 3.83 (d, J = 6.2 HRMS calcd for C 20 H 27N₂O₂ [M + H] + m / z 327.19958, found327.20685.

[0111] Example 13

[0112] Preparation of 2-(((6-((tetrahydro-2H-pyran-4-yl)methoxy)naphth-2-yl)methyl)amino)acetamide (compound I-13)

[0113]

[0114] Following the preparation method of compound I-9, bromomethylcyclopropane (compound 5) was replaced with an equal amount of 4-bromomethyltetrahydropyran, with all other steps remaining the same, to prepare compound I-13.

[0115] 1 H NMR (400 MHz, DMSO-d6) δ 7.71 (dd, J = 15.5, 7.5 Hz, 3H), 7.41 (d,J = 8.4 Hz, 1H), 7.26 (d, J = 7.1 Hz, 2H), 7.09 (dd, J = 8.9, 2.4 Hz, 1H),7.01 (s, 1H), 3.90 (d, J = 6.4 Hz, 2H), 3.87 – 3.82 (m, 2H), 3.74 (s, 2H),3.33 (s, 1H), 3.01 (s, 2H), 2.55 (s, 1H), 2.03 (d, J = 8.8 Hz, 1H), 1.70 (s, 2H), 1.33 (m, 2H); 13 C NMR (101 MHz, DMSO-d6) δ 173.94, 156.87, 136.09,133.91, 129.55, 128.84, 127.70, 127.13, 126.52, 119.20, 107.16, 72.61, 67.19,53.24, 51.78, 34.99, 29.84; HRMS calcd for C 19 H 25 N₂O₃ [M + H] + m / z 329.18597, found 329.18696.

[0116] Example 14

[0117] Preparation of 2-(((6-((3-fluorobenzyl)oxy)naphth-2-yl)methyl)amino)propionamide (compound I-14)

[0118]

[0119] Following the preparation method of compound I-1, using 6-hydroxy-2-naphthaldehyde and 3-fluorochlorobenzyl as starting materials, glycine amino hydrochloride was replaced with an equal amount of 2-aminopropionamide hydrochloride to prepare compound I-14.

[0120] 1 H NMR (400 MHz, DMSO-d6) δ 7.78 – 7.69 (m, 3H), 7.43 (d, J = 9.1 Hz,2H), 7.37 – 7.26 (m, 4H), 7.21 – 7.13 (m, 2H), 7.00 (d, J = 19.3 Hz, 1H),5.20 (s, 2H), 3.75 (s, 2H), 3.02 (s, 2H), 2.82 (d, J = 25.5 Hz, 1H); HRMScalcd for C 21 H 22 FN2O2 [M + H] + m / z 353.16598, found 353.16697.

[0121] Example 15

[0122] Preparation of 2-((1-(6-((3-fluorobenzyl)oxy)naphth-2-yl)ethyl)amino)acetamide (compound I-15)

[0123]

[0124] Following the preparation method of compound I-1, the starting material benzyl chloride (compound 2) was replaced with an equimolar amount of 3-fluorobenzyl chloride (compound 7) to prepare intermediate 8. Under nitrogen protection at 0 °C, intermediate 8 (720 mg, 2.56 mmol) was dissolved in THF (10 mL), and a CH3MgCl THF solution (1 M, 3 mL) was slowly added dropwise. The mixture was stirred for 30 min, then cooled to room temperature and stirred overnight. TLC showed that the starting material had disappeared. At 0 °C, saturated NH4Cl solution was slowly added until no more bubbles were produced. The mixture was stirred for 10 min, and ethyl acetate was added for extraction. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 20:1, V / V) to obtain a white solid (compound 9, 690 mg, yield 91%).

[0125] In a 100 mL round-bottom flask, compound 9 (690 mg, 2.33 mmol) was dissolved in DCM (10 mL). Dess-Martin reagent (1.2 g, 2.83 mmol) was added at 0 °C and stirred for 20 min. The mixture was then moved to room temperature and stirred for 5 h. TLC showed that the starting material had disappeared. Sodium thiosulfate was added at 0 °C, and the pH was adjusted to 7–8 using saturated NaHCO3. Water and ethyl acetate were then added for extraction. The organic layers were combined, washed with saturated brine, dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 50:1, V / V) to give a white solid (compound 10, 580 mg, yield 85%).

[0126] Glycine amino hydrochloride (compound 4, 113 mg, 1.02 mmol) was dissolved in a mixed solvent of triethylamine (1 mL) and methanol (10 mL) and stirred at room temperature for 20 min. Then, compound 10 (250 mg, 0.85 mmol) was added, followed by slow addition of NaBH3CN (107 mg, 1.70 mmol). The mixture was refluxed at 80 °C and stirred overnight. The starting material disappeared at this point, as detected by TLC. The mixture was extracted with water and ethyl acetate, and the organic layers were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography (eluent: DCM / MeOH = 250 / 1 ~ 100 / 1, V / V) to obtain a white solid (compound I-15, 220 mg, yield 73%).

[0127] 1H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 9.0 Hz, 1H), 7.71 (d, J = 8.5Hz, 1H), 7.67 (d, J = 1.7 Hz, 1H), 7.43 (ddd, J = 10.5, 8.3, 1.9 Hz, 2H),7.34 (d, J = 2.6 Hz, 1H), 7.33 – 7.29 (m, 2H), 7.24 – 7.17 (m, 2H), 7.16 –7.11 (m, 1H), 6.98 (s, 1H), 5.20 (s, 2H), 3.75 (q, J = 6.5 Hz, 1H), 2.90 –2.79 (m, 2H), 2.51 (s, 1H), 1.27 (d, J = 6.5 Hz, 3H); HRMS calcd forC 21 H 22 FN2O2 [M + H] + m / z 353.16598, found 353.16616.

[0128] Example 16

[0129] Preparation of (R)-2-((1-(6-((3-fluorobenzyl)oxy)naphth-2-yl)ethyl)amino)acetamide (compound I-16)

[0130]

[0131] Compound 8 (1 g, 3.56 mmol) was dissolved in DCM (20 mL), and Cs2CO3 (2.5 g, 7.67 mmol) and (R)-tert-butylsulfinamide (compound 11, 865 mg, 7.14 mmol) were added sequentially. The mixture was stirred overnight at room temperature. After the reaction was completed by TLC monitoring, water and DCM were added for extraction. The organic layer was retained and dried with anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to give a white solid (intermediate 12, 1.3 g, 95% yield).

[0132] Under nitrogen protection at 0 °C, intermediate 12 (800 mg, 2.1 mmol) was dissolved in THF (10 mL), and then a 3 M, 5 mL solution of CH3MgCl in THF was slowly added dropwise. The mixture was stirred for 2 h, then moved to room temperature and stirred overnight. The reaction was monitored by TLC until it was complete. The reaction was quenched at 0 °C by adding saturated NH4Cl solution (20 mL), and then extracted with water and ethyl acetate. The organic layer was retained and dried with anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by recrystallization from petroleum ether / ethyl acetate (1:1, V / V) at room temperature to obtain intermediate 13 (750 mg, 90% yield).

[0133] At room temperature, intermediate 13 (600 mg, 1.5 mmol) was placed in a 100 mL flask, and a 2 M, 6 mL solution of HCl in 1,4-dioxane was added. The mixture was stirred slowly for 3 h, and the reaction was monitored by TLC until completion. After filtration, the filter cake was collected to obtain intermediate 14 (400 mg, 80% yield). A single crystal was prepared by slow evaporation of the DMSO solution of intermediate 14 at 20 °C. Single-crystal X-ray diffraction analysis confirmed the R configuration. Figure 1 ).

[0134] 2-Bromoacetamide (compound 15, 247 mg, 1.63 mmol) was dissolved in acetonitrile (10 mL), and anhydrous potassium carbonate (225 mg, 1.63 mmol) was added. The mixture was stirred at room temperature for 30 min, followed by the sequential addition of intermediate 14 (400 mg, 1.35 mmol) and KI (45 mg, 0.27 mmol). The mixture was refluxed at 80 °C and stirred overnight. The reaction was monitored by TLC until it was complete. The mixture was extracted with water and ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to obtain the crude product, which was purified by normal-phase silica gel column chromatography (eluent: DCM:MeOH = 250:1~100:1, V / V) to obtain compound I-16 (353 mg, 74% yield). The ee value of compound I-16 was 98.3% (chiral column CHIRALPAK-IC00CE-TG001; mobile phase: n-hexane:ethanol:diethylamine = 60:40:0.1, V / V / V; flow rate 0.7 mL / min; detection wavelength 220 nm).

[0135] 1H NMR (400 MHz, DMSO-d6) δ 7.78 – 7.68 (m, 3H), 7.47 – 7.38 (m, 2H), 7.35 (d, J = 2.5 Hz, 1H), 7.32 – 7.25 (m, 3H), 7.20 (dd, J = 8.9, 2.5 Hz,1H), 7.13 (m, J = 8.5, 2.7 Hz, 1H), 7.05 – 6.99 (m, 1H), 5.20 (s, 2H), 3.80(q, J = 6.6 Hz, 1H), 2.89 (d, J = 3.3 Hz, 2H), 1.30 (d, J = 6.4 Hz, 3H); HRMScalcd for C 21 H 22 FN2O2 [M + H] + m / z 353.16598, found 353.16528.

[0136] Example 17

[0137] Preparation of (S)-2-((1-(6-(((3-fluorobenzyl)oxy)naphth-2-yl)ethyl)amino)acetamide (compound I-17)

[0138]

[0139] Following the preparation method of compound I-16, (R)-tert-butylsulfinamide (compound 11) was replaced with an equimolar amount of (S)-tert-butylsulfinamide (compound 16) to prepare compound I-17. The ee value of compound I-17 was detected to be 98.2% (chiral column CHIRALPAK-IC00CE-TG001; mobile phase: n-hexane:ethanol:diethylamine = 60:40:0.1, V / V / V; flow rate 0.7 mL / min; detection wavelength 220 nm).

[0140] 1H NMR (400 MHz, DMSO-d6) δ 7.79 – 7.64 (m, 3H), 7.43 (dd, J = 11.8,7.8 Hz, 2H), 7.31 (dd, J = 15.0, 7.9 Hz, 3H), 7.19 (d, J = 9.8 Hz, 2H), HRMS calcd for C 21 H 22 FN2O2 [M +H] + m / z 353.16598, found 353.16513.

[0141] Single crystals were prepared by slow evaporation of the DMSO solution of intermediate 19 at 20°C, and the S-configuration was confirmed by single-crystal X-ray diffraction analysis. Figure 2 ).

[0142] Example 18

[0143] In vitro assay and analysis of recombinant human MAOs enzyme inhibitory activity

[0144] (1) Experimental Principle

[0145]

[0146] MAOs enzymes in the human body can catalyze the oxidative deamination of monoamines. Kyrenuramine is a non-specific substrate of MAOs enzymes and can be catalyzed by MAOs to convert into 4-hydroxyquinoline. The inventors established an in vitro method for detecting MAOs enzyme inhibitory activity, using fluorescence spectrophotometry to detect the content of 4-hydroxyquinoline to determine the degree of inhibition of MAOs enzyme by the test compound.

[0147] (2) Experimental materials and main instruments

[0148] Experimental materials: recombinant human MAO-A and MAO-B proteins, kynurenamine dihydrobromide (relative molecular weight 326.03), 4-hydroxyquinoline (relative molecular weight 145.16), safinamide, tripotassium phosphate, DMSO, 1N hydrochloric acid, ultrapure water, PCR tubes and cryovials.

[0149] Main instruments: Bio-Tek microplate reader, centrifuge, constant temperature shaking incubator, vortex mixer, pH meter.

[0150] (3) Experimental steps

[0151] The reaction volume per well was 200 μL: 180 μL enzyme working solution + 10 μL inhibitor + 10 μL kynurenamine stock solution (50 μM). Finally, 80 μL NaOH solution (2N) was added to terminate the reaction.

[0152] Preparation of 100 mM buffer solution: Take a 200 mL cryovial, add 160 mL of ultrapure water and 4.246 g of tripotassium phosphate sequentially, adjust the pH of the system to 7.4 with 1N hydrochloric acid, and bring the volume to 200 mL with ultrapure water. The concentration of tripotassium phosphate in this buffer solution is 100 mM. Unless otherwise specified, use this buffer solution to prepare all solutions.

[0153] 1) Preparation of the experimental stock solution:

[0154] Preparation of kynurenamine stock solution: Weigh 3.26 mg of kynurenamine dihydrobromide and dissolve it in 10 mL of buffer solution to obtain a 1 mM kynurenamine dihydrobromide stock solution.

[0155] Preparation of inhibitor stock solution: The positive control drug safinamide and the test compounds (compounds I-1 to I-17) were prepared into an inhibitor stock solution with a concentration of 1 mM using DMSO. Then, the inhibitor stock solution was diluted 3 times by volume with DMSO in sequence, and finally 10 concentrations were obtained for each inhibitor (safinamide, test compound).

[0156] Preparation of 4-hydroxyquinoline solution: Weigh 1.4516 mg and dissolve it in 10 mL of buffer to obtain a 1 mM 4-hydroxyquinoline solution; dilute it to 100 μM with buffer, and then use 100 μM as the starting concentration to dilute it by volume in 2-fold increments to obtain 12 concentrations.

[0157] 2) Preparation of enzyme working solution:

[0158] Preparation of MAO-A working solution: 12.6 mL buffer solution + 21 μL MAO-A stock solution.

[0159] Preparation of MAO-B working solution: 12.6 mL buffer solution + 21 μL MAO-B stock solution.

[0160] The final concentrations of MAO-A and MAO-B enzymes in the reaction system (200 μL) were 7.5 μg / mL and 7.5 μg / mL, respectively.

[0161] 3) Determination of the standard curve:

[0162] The fluorescence of the 4-hydroxyquinoline solution prepared above was detected under the conditions of excitation wavelength of 310 nm and emission wavelength of 400 nm. A standard linear curve was plotted with the concentration of 4-hydroxyquinoline as the x-axis and the fluorescence intensity as the y-axis.

[0163] 4) Enzymatic reactions:

[0164] Two blank control groups: containing neither enzyme nor inhibitor; the inhibitor solution was replaced with a 4% DMSO buffer solution; all other conditions were replicated. Two negative control groups: containing neither inhibitor nor inhibitor; the inhibitor solution was replaced with a 4% DMSO buffer solution; all other conditions were replicated. One positive control group and 17 test compound groups were included. Except for heating and incubation, all other procedures were performed at 0 °C. Each group was replicated twice.

[0165] Positive control group or test compound group: Add 180 μL of enzyme working solution to each PCR tube, add 10 μL of positive control drug (safinamide) or test compound (compound I-1 to compound I-17) stock solution, vortex to mix; add 10 μL of kynurenamine stock solution, vortex to mix, transfer to 37 ℃ and incubate for 25 min. After returning to room temperature (25 ℃), add 80 μL of sodium hydroxide solution (2N, i.e., 2 g NaOH dissolved in 25 mL buffer, freshly prepared) to each PCR tube, centrifuge at 9000 r / min for 3 min to remove precipitate, transfer 200 μL of supernatant from each tube to a 96-well plate, and detect fluorescence intensity using a microplate reader at an excitation wavelength of 310 nm and an emission wavelength of 400 nm. Calculate the MAOs enzyme inhibition rate (%) of the test compound (concentration 50 μM).

[0166] MAOs enzyme inhibition rate (%) = [(Negative group intensity - Test group intensity) / (Negative group intensity - Blank group intensity)] × 100

[0167] If the MAOs enzyme inhibition rate of the test compound is >70% at a concentration of 50 μM, the test compound is diluted to obtain 10 concentrations according to the "Preparation of Inhibitor Stock Solution". The inhibition rate of MAOs enzyme at different concentrations is detected, and the dose-response curve is fitted using GraphPad software to calculate the half-maximal inhibitory concentration (IC50). 50 Value. Repeated at least twice at different time points.

[0168] (4) Experimental Results

[0169] As shown in Table 1, most of the compounds in this invention exhibit high selective inhibition of MAO-B, while showing weak inhibitory activity against MAO-A. Among them, compounds I-1 to I-8 and I-15 to I-17 show superior in vitro inhibitory activity compared to the third-generation MAO-B inhibitor safinamide (IC50).50 = 0.0814 μM). In particular, the in vitro MAO-B inhibitory activity of compounds I-1 to I-8 was IC50 0.0814 μM. 50 The value reached 10 nM, which is about 10 times that of safinamide. In addition, compounds I-9 to I-11 of the present invention showed superior in vitro MAO-A inhibitory activity, reaching about 10 to 20 nM; while compounds I-12 to I-14 showed moderate levels of MAO-A / B inhibitory activity.

[0170] Table 1. Test data on in vitro recombinant human MAOs enzyme inhibitory activity

[0171]

[0172] Note: nd indicates that at a concentration of 50 μM, the test compound inhibits MAOs by ≤70%, and IC50 was not tested. 50 .

[0173] Example 19

[0174] Analysis of the reversibility of in vitro inhibition of recombinant human MAO-B enzyme activity by compounds I-2 and I-16

[0175] The reversibility of MAO-B activity inhibition of compounds I-2 and I-16 in vitro was analyzed by dilution method to evaluate the type of MAO-B inhibition by the compounds of the present invention.

[0176] The preparation of the enzyme working solution, the test compound, and the kynurenamine stock solution followed the instructions in Example 18. Four test groups, one blank group, and one negative group were set up. Test groups: selegiline, safinamide, compound I-2, and compound I-16, respectively, with other conditions paralleled. Blank group: without enzyme and inhibitor; the inhibitor solution was replaced with a 4% DMSO buffer solution; other conditions paralleled. Negative group: without inhibitor; the inhibitor solution was replaced with a 4% DMSO buffer solution; other conditions paralleled. Except for heating and incubation, all operations were performed at 0 °C.

[0177] The experiment was performed in PCR tubes (1 mL). 900 μL of enzyme working solution and 50 μL of stock solution of the test compound (rasagiline, safenamide, compound I-2, or compound I-16) were added to the PCR tubes. The mixture was vortexed and mixed. The blank and negative groups were also processed simultaneously. The mixture was transferred to 37 °C and incubated for 15 min. After returning to room temperature (25 °C), the incubated mixture was taken and diluted with kynurenamine stock solution to 1 μM, 0.1 μM, and 0.01 μM, respectively, to a final volume of 400 μL. The mixture was then transferred to 37 °C and incubated for 15 min. After restoring to room temperature (25 °C), add 160 μL of sodium hydroxide solution (2N, i.e., 2g NaOH dissolved in 25 mL buffer, freshly prepared); centrifuge at 9000 r / min for 3 min to remove the precipitate, transfer 200 μL of the supernatant to a 96-well plate, and detect the fluorescence intensity using a microplate reader at an excitation wavelength of 310 nm and an emission wavelength of 400 nm. Calculate the MAO-B enzyme inhibition rate (%) of the compound at concentrations of 1 μM, 0.1 μM, and 0.01 μM.

[0178] MAO-B enzyme activity (%) = [(Test group intensity - Blank group intensity) / (Negative group intensity - Blank group intensity)] × 100

[0179] Experimental results are as follows Figure 4 As shown, compounds I-2 and I-16 of this invention exhibit reversible inhibition of MAO-B, and their pharmacodynamic behavior is similar to that of the third-generation selective and reversible MAO-B inhibitor safinamide. This indicates that the compounds of this invention are reversible MAO-B inhibitors.

[0180] Example 20

[0181] Pharmacokinetics of Compound I-16

[0182] Three male C57BL / 6J mice (n=3 for each administration route) were administered compound I-16 via intravenous (IV) and oral (PO) routes (dose 20 mg / kg, solvent: 10% DMSO + 10% Solutol (polyethylene glycol-15-hydroxystearate) + 80% (10% HP-B-CD)). Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 h after IV administration or at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after oral administration. Blood samples were placed in centrifuge tubes containing K2-EDTA, stored on ice, and centrifuged at 6800 rpm for 6 min at 2–8 °C. The resulting supernatant plasma was temporarily stored at approximately -80 °C until LC-MS analysis. Relevant pharmacokinetic properties were calculated using Phoenix WinNonlin 7.0.

[0183] Bioavailability (F) (%) = (AUC po / AUC iv) × (dose i.v. / dose po) × 100

[0184] The experimental results are shown in Table 2. Compound I-16 has good pharmacokinetic parameters, among which the oral half-life T0 is relatively good. 1 / 2 = 2.378 h, AUC (0−∞) = 3273.235 h*ng / mL, oral bioavailability F (%) = 56.335%. This indicates that compound I-16 has a high in vivo exposure, and its oral half-life and bioavailability are relatively ideal.

[0185] Table 2. Pharmacokinetic parameters of compound I-16 (mean ± SD)

[0186]

[0187] Example 21

[0188] Blood-brain barrier permeability test of compound I-16

[0189] Nine male C57BL / 6J mice were administered compound I-16 (20 mg / kg, solvent: 10% DMSO + 10% Solutol (polyethylene glycol-15-hydroxystearate) + 80% (10% HP-B-CD)) orally once. Blood and brain tissue samples were collected from three mice at 1 hour post-administration. Blood was collected via the submandibular vein or other suitable method, approximately 30 μL per time point, anticoagulated with K2-EDTA, and placed on ice after collection. Animals were euthanized with CO2, and brain tissue was then collected. Plasma was separated by centrifugation within 2 hours of blood sample collection (centrifugation conditions: 2–8℃, 6800 rpm for 6 min). Collected plasma and brain tissue samples were stored at -80℃ before analysis. o The sample was kept in a refrigerator at room temperature until LC-MS analysis.

[0190] Experimental results are as follows Figure 5 As shown, compound I-16 can cross the blood-brain barrier in mice. One hour after oral administration, the concentration of compound I-16 in brain tissue exceeded 6000 ng / g, and the brain tissue / plasma ratio (Ratio-Brain tussue / Plasma) exceeded 5. These experimental results suggest that compound I-16 has good blood-brain barrier permeability.

[0191] Example 22

[0192] Pharmacodynamic evaluation of compound I-16 in improving motor function in a mouse model of Parkinson's disease

[0193] Experimental protocol

[0194] Forty-eight C57BL / 6J mice were randomly divided into six groups: control group, model group, safinamide group, low-dose compound I-16 group, medium-dose compound I-16 group, and high-dose compound I-16 group. Mice in the model group, safinamide group, and three dosage groups of compound I-16 were intraperitoneally injected with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, dissolved in physiological saline, 30 mg / kg / d, for 7 consecutive days). After the last MPTP administration, one day later (referred to as day 0), mice in the safinamide group and the three dosage groups of compound I-16 were administered the same amount of MPTP by gavage for 14 consecutive days (the dosage of safinamide in the safinamide group was 2.5 mg / kg / d, and the dosage of compound I-16 in the three dosage groups of compound I-16 was 0.625 mg / kg / d, 1.25 mg / kg / d, and 2.5 mg / kg / d, respectively, all administered by gavage using a blank solvent; the blank solvent was PBS containing 0.1% DMSO). Mice in the normal control group and the model group were administered the same volume of blank solvent by gavage daily. Behavioral changes in mice were assessed during the administration period.

[0195] Grasp test: A pull test was conducted on days 0, 7, and 14 to evaluate the muscle strength and endurance of the mice. A grid was secured to the pull gauge, ensuring it was stable. The mouse's tail was grasped, allowing its front paws to grip the grid. The mouse's tail was slowly pulled backward until it released the grid, and the maximum value before release was recorded. This was repeated three times for each mouse, and the average value was taken as the final result.

[0196] Spinner test: On day 12, a spinner test was conducted to evaluate the mice's motor coordination, balance, and endurance. The mice were placed on a spinner at a speed of 40 r / min. The time from the start of the spinner's rotation to the mouse leaving the spinner was measured as the spinner latency. The test duration was 5 minutes, repeated 3 times with a 1-hour interval. Prior to the test, mice were trained for 2 consecutive days at a speed of 10 r / min for 5 minutes each day.

[0197] Forced swimming test: A forced swimming test was conducted on day 9 to evaluate the degree of depression-like symptoms in mice. Two water depths of 15-20 cm and water temperatures of 23-25°C were used. o Mice were gently placed in a cylindrical acrylic container (C) and allowed to swim for 6 minutes. Behavioral data were recorded for the last 4 minutes using ANY-maze. Immediately after the experiment, the mice were removed, dried with a towel, and placed in a warm environment to recover and prevent hypothermia.

[0198] Experimental results

[0199] (1) General state observation

[0200] A series of acute behavioral changes were observed in mice a few minutes after each MPTP injection, including tremors, reduced movement, spinal rigidity, and drooling. These symptoms disappeared within 0.5 to 1 hour, with no significant differences between groups.

[0201] (2) Evaluation of the effect of compound I-16 on the motor ability of mice based on grip test

[0202] The changes in muscle strength and endurance in mice were evaluated by recording the changes in maximum pulling force before release. Results are as follows: Figure 6 As shown, MPTP-induced pulling force in model mice decreased significantly. Mice in the medium and high dose groups of compound I-16 showed significant recovery in this evaluation, reaching statistical significance compared with pre-administration levels (day 0).

[0203] (3) Evaluation of the effect of compound I-16 on the motor ability of mice based on rotarod test

[0204] Changes in the motor abilities of mice were assessed by varying the time it took for them to fall from a rotating rotundus at a certain speed. The results were as follows: Figure 7 As shown, MPTP-induced model mice exhibited significantly weaker balance maintenance on a rotundus at a higher rotation speed (40 r / min) compared to the normal control group, with a significantly reduced maintenance time on the rotundus. Compound I-16 effectively improved the aforementioned motor dysfunction behaviors in model mice, showing a statistically significant difference compared to the model group. (4) Evaluation of the effect of compound I-16 on depressive symptoms in mice based on forced swimming experiment.

[0205] The degree of depression-like symptoms in mice was assessed by analyzing the percentage of immobility time between 2 and 6 minutes. Results are as follows: Figure 8 As shown, MPTP-induced immobility time in the model mice was significantly increased. Administration of medium and high doses of compound I-16 significantly reduced the proportion of immobility time and improved the depressive-like symptoms in the mice, achieving statistical significance compared to the model group.

[0206] The above experimental results indicate that MPTP modeling leads to decreased limb motor coordination and depression-like symptoms in mice, and intervention with compound I-16 can improve the above-mentioned motor dysfunction and depressive state.

[0207] Example 23

[0208] Preparation of compound I-16 hydrochloride

[0209] Weigh 10 g of compound I-16 and place it in a 250 mL three-necked flask. Add 150 mL of 95% ethanol and stir to dissolve at room temperature. Turn on the condenser and control the temperature at 0–5 °C. Measure 18 mL of hydrogen chloride / ethanol solution (2.0 mol / L) and slowly add it dropwise to the reaction solution. After the addition is complete, keep the temperature at 0–5 °C for 2 h, and white crystals slowly precipitate. Filter under reduced pressure and dry under vacuum at 50 °C to obtain the hydrochloride salt of compound I-16.

[0210] Example 24

[0211] Preparation of Compound I-16 Tablets

[0212] Prescription (based on a prescription of 500 tablets): 25 g of pure compound I-16, 30 g of sucrose, 40 g of corn starch, and 1 g of magnesium stearate.

[0213] Preparation method: The active ingredient compound I-16 is mixed with sucrose and corn starch, moistened with water, stirred evenly, dried, pulverized and sieved, magnesium stearate is added, mixed evenly, and compressed into tablets. The average tablet weight is 242 mg / tablet, and the active ingredient content is 50 mg.

[0214] This invention is not limited to the specific technical solutions described in the above embodiments. All technical solutions formed by equivalent substitutions are within the scope of protection claimed by this invention.

Claims

1. 2-((naphthyl-2-ylmethyl)amino)acetamide compounds or pharmaceutically acceptable salts thereof, as shown in Formula I: ； in, R 1 For H or CH3; R 2 H or CH3; X is O, S or NH; ring A is a 3-6 membered cycloalkyl, 4-6 membered heterocyclic, aryl or heteroaryl; R 3 It can be H, halogen, methyl, trifluoromethyl, methoxy, cyano, nitro, vinyl, or ethynyl.

2. The 2-((naphthyl-2-ylmethyl)amino)acetamide compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R 1 For H or CH3; R 2 H or CH3; X is O, S or NH; ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolyl, tetrahydropyranyl, piperidinyl, phenyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; when ring A is phenyl, R 3 It is H, F, Cl, Br, methyl, trifluoromethyl or methoxy substituted at the meta or para position.

3. The 2-((naphthyl-2-ylmethyl)amino)acetamide compound or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that: R 1 For H or CH3, R 2 For H or CH3, X is O, and ring A is cyclobutyl, cyclopentyl, cyclohexyl, or phenyl; when ring A is phenyl, R 3 The derivative is H, meta- or para-substituted F, Cl, Br, methyl, trifluoromethyl, or methoxy; preferably, R 1 For H, R 2 For H or CH3, X is O, and ring A is cyclobutyl, cyclopentyl, cyclohexyl, or phenyl; when ring A is phenyl, R 3 It is H, F, Cl, Br, methyl, trifluoromethyl or methoxy substituted at the meta or para position.

4. The 2-((naphthyl-2-ylmethyl)amino)acetamide compound or a pharmaceutically acceptable salt thereof according to claim 3, characterized in that: R 1 For H, R 2 It is H or CH3, X is O, ring A is phenyl, R 3 F, Cl, or Br are H, meta- or para-substituted.

5. 2-((naphthyl-2-ylmethyl)amino)acetamide compounds or pharmaceutically acceptable salts thereof, as shown in the following structures: ； 。 6. The 2-((naphthyl-2-ylmethyl)amino)acetamide compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-5, characterized in that: The pharmaceutically acceptable salts of the 2-((naphthyl-2-ylmethyl)amino)acetamide compounds are hydrochloride, hydrobromide, sulfate, acetate, maleate, or methanesulfonate.

7. Use of the 2-((naphthyl-2-ylmethyl)amino)acetamide compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-5 in the preparation of monoamine oxidase A and / or monoamine oxidase B inhibitors.

8. Use of the 2-((naphthyl-2-ylmethyl)amino)acetamide compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-5 in the preparation of a medicament for treating and / or preventing monoamine oxidase A and / or monoamine oxidase B mediated diseases.

9. The use according to claim 8, characterized in that: The diseases mediated by monoamine oxidase A and / or monoamine oxidase B are Parkinson's disease, Alzheimer's disease, depression, anxiety disorder, and panic disorder.

10. A pharmaceutical composition, characterized in that: The pharmaceutical composition described herein is a tablet, capsule, granule, powder, microcapsule, drop pill, aerosol, suspension or oral liquid prepared by using the 2-((naphthyl-2-methyl)amino)acetamide compound or its pharmaceutically acceptable salt as the active ingredient and a pharmaceutically acceptable carrier.

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