Benzodihydrofuran compound as well as pharmaceutical composition and application thereof

Abstract

The invention discloses a benzodihydrofuran compound as well as a pharmaceutical composition and application thereof. The invention provides a compound shown as a formula I or pharmaceutically acceptable salt thereof. The compound disclosed by the invention has a sedative effect and is beneficial to relieving manic symptoms of patients with mental diseases. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of medicine, and specifically relates to benzodihydrofuran compounds, pharmaceutical compositions and applications thereof. Background Art

[0002] Serotonin is a monoamine neurotransmitter that achieves its various biological functions including emotion, cognition, reward, learning, memory, etc. through different receptor subtypes (Young SN. J Psychiatry Neurosci. 2007 Nov;32(6):394-9). The 5-HT2A receptor belongs to a serotonin receptor family, which currently consists of more than 15 different receptors encoded by different genes and is divided into 7 major categories: 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 (Roth BL, Lopez E, The Neuroscientist. 2000;6(4):252-262).

[0003] Stimulation of 5-HT2A receptors can lead to neuronal excitation in a variety of brain regions. Among all 14 serotonin receptor subtypes, 5-HT2A receptors are widely present in the central nervous system and have the highest concentration among monoamine receptors in the cerebral cortex. They are distributed in structural areas involved in emotion regulation, such as the median nucleus / dorsal raphe nucleus, locus coeruleus, and ventral tegmental area (Zięba A, Stępnicki P, Matosiuk D, et al. Int J Mol Sci. 2021 Dec 21;23(1):10). Consistent with their location in the brain, they are not only related to various central physiological functions, including memory, sleep, nociception, eating, and reward behavior, but also to many neuropsychiatric diseases, such as schizophrenia, depression, and anxiety (Guiard BP, DiGiovanni G. Front Pharmacol. 2015 Mar 17;6:46). Summary of the invention

[0004] The technical problem to be solved by the present invention is to overcome the defect of the single structure of sedative drugs in the prior art. To this end, the present invention provides a class of novel benzodihydrofuran compounds, pharmaceutical compositions and applications thereof. The compounds of the present invention have a sedative effect and are helpful in alleviating the manic symptoms of patients with mental illnesses.

[0005] The present invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof;

[0006] ;

[0007] wherein Ring A is "a 5-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S" or "a 5-10 membered heterocycloalkenyl group having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S";

[0008] R 1 is hydroxyl group;

[0009] Ring B is or ;

[0010] X 1 is -NH-, oxygen or -CH2-;

[0011] X 2 For-NR 3 - or oxygen;

[0012] X 3 for nitrogen;

[0013] R 3 is C1-C6 alkyl or -C(O)-C1-C6 alkyl;

[0014] R 2 is C1-C6 alkyl or oxo (=O);

[0015] n is 2, 3 or 4;

[0016] m and x are independently 0, 1, 2 or 3.

[0017] In certain preferred embodiments of the present invention, certain groups in the compound of Formula I or a pharmaceutically acceptable salt thereof are defined as follows, and the unmentioned groups are the same as those described in any embodiment of the present invention (referred to as "in a certain embodiment of the present invention").

[0018] In a certain embodiment of the present invention, the 5-10 membered heterocycloalkyl group is a monocyclic ring or a spirocyclic ring.

[0019] In one embodiment of the present invention, the heteroatoms in the 5-10 membered heterocycloalkyl are independently selected from N, and the number of heteroatoms is 1 or 2; for example, , , or .

[0020] In a certain embodiment of the present invention, the 5-10 membered heterocycloalkenyl group is a 6-8 membered heterocycloalkenyl group.

[0021] In one embodiment of the present invention, the heteroatoms in the 5-10 membered heterocycloalkenyl group are independently selected from N, and the number of heteroatoms is 1; for example, or .

[0022] In a certain embodiment of the present invention, the C1-C6 alkyl groups are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl; preferably methyl.

[0023] In one embodiment of the present invention, ring A is "a 5- to 10-membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S".

[0024] In one embodiment of the present invention, ring B is .

[0025] In one embodiment of the present invention, X 1 It is oxygen or -CH2-; preferably oxygen.

[0026] In one embodiment of the present invention, X 2 For-NR 3 -.

[0027] In one embodiment of the present invention, R 3 for or methyl; preferably .

[0028] In one embodiment of the present invention, R 2 It is an oxo group.

[0029] In one embodiment of the present invention, n is 2 or 3, preferably 2.

[0030] In one embodiment of the present invention, m is 0 or 1; preferably 0.

[0031] In one embodiment of the present invention, x is 0 or 1; preferably 0.

[0032] In one embodiment of the present invention, ring A is , , , , or ; preferably, , , or ; More preferably, , or ; Among them, the a end is connected to the ring B, and the b end is connected to connected.

[0033] In one embodiment of the present invention, for , , , , , or ; preferably , , , or ; further preferably , or ; Among them, the a end is connected to the ring B, and the b end is connected to connected.

[0034] In one embodiment of the present invention, ring B is , , , or ; preferably , , , , or ; further preferably , , , or More preferably or .

[0035] In one embodiment of the present invention, for , , , , , or ; preferably , , , or ; further preferably or .

[0036] In one embodiment of the present invention, the compound as shown in formula I is a compound as shown in formula I-1 or formula I-2:

[0037] or ;

[0038] Among them, ring A, R 1 , X 1 , X 2 , X 3 , R 2, n, m and x are defined as described in any embodiment of the present invention.

[0039] In one embodiment of the present invention, the compound as shown in formula I is a compound as shown in formula I-1-1 or I-1-2:

[0040] or ;

[0041] Wherein, Y is -CH- or N, X 2 and n are defined as described in any embodiment of the present invention.

[0042] In one embodiment of the present invention, the compound as shown in Formula I or a pharmaceutically acceptable salt thereof is any of the following compounds:

[0043] .

[0044] The present invention provides a pharmaceutical composition, comprising:

[0045] (1) A compound of formula I or a pharmaceutically acceptable salt thereof according to any one of the present invention and

[0046] (2) Pharmaceutically acceptable excipients.

[0047] The present invention also provides the use of the "compound of formula I or a pharmaceutically acceptable salt thereof" as described in any one of the present invention or the pharmaceutical composition as described above, wherein the use is selected from:

[0048] (1) Preparation of 5-HT 2A Receptor agonists;

[0049] (2) Preparation for treatment and / or prevention with 5-HT 2A Drugs for receptor-related diseases;

[0050] (3) Preparation of drugs for treating and / or preventing mania in patients with mental illnesses.

[0051] In a certain embodiment of the present invention, the 5-HT 2A Receptor-related diseases include mania in patients with psychiatric diseases.

[0052] Terminology

[0053] Unless otherwise specified, the terms used in the present invention have the following meanings:

[0054] The term "pharmaceutically acceptable" means relatively non-toxic, safe, and suitable for use by patients.

[0055] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. For details, please refer to Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P.Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0056] The "-" at the end of a group means that the group is connected to the rest of the molecule through this site; the " " means that the structural fragment is connected to the rest of the molecule through this site, for example, It refers to the methoxy group.

[0057] The term "oxo" is =0.

[0058] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0059] The term "heterocycloalkyl" refers to a cyclic group having a specified number of ring atoms (e.g., 5-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatoms (one, two, or three of N, O, and S), which is a monocyclic, bridged, or spirocyclic ring, and each ring is saturated. Heterocycloalkyl is connected to the rest of the molecule through a carbon atom or a heteroatom. Heterocycloalkyl includes, but is not limited to: , , , wait.

[0060] The term "heterocycloalkenyl" refers to a cyclic group with a specified number of ring atoms (e.g., 5-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (one, two, or three of N, O, and S), which is a monocyclic, bridged, or spirocyclic unsaturated alkyl group. The heterocycloalkenyl group is connected to the rest of the molecule through a carbon atom or a heteroatom. Heterocycloalkenyl groups include, but are not limited to: , wait.

[0061] The term "alkyl" refers to a linear or branched, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (eg, C1-C6). Alkyl groups include, but are not limited to, methyl groups.

[0062] The term "pharmaceutically acceptable excipients" refers to all substances contained in pharmaceutical preparations other than active pharmaceutical ingredients, which are generally divided into two categories: excipients and additives. For details, please refer to the Pharmacopoeia of the People's Republic of China (2020 Edition) and Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, GaryP Moss, David J Goldfarb, 2020, 9th Edition).

[0063] The term "treating" refers to removing the cause or alleviating the symptoms.

[0064] The term "prevention" refers to reducing the risk of developing a disease.

[0065] The term "patient" refers to any animal, usually a mammal, such as a human, that needs to be treated or prevented. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.

[0066] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0067] The reagents and raw materials used in the present invention are commercially available.

[0068] The positive and progressive effects of the present invention are: the present invention provides a class of novel benzodihydrofuran compounds, pharmaceutical compositions and applications thereof. The compounds of the present invention have a sedative effect and are helpful in alleviating the manic symptoms of patients with mental illnesses. BRIEF DESCRIPTION OF THE DRAWINGS

[0069] Figure 1 The change in immobility time of the compound in the forced swimming test in mice. DETAILED DESCRIPTION

[0070] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0071] The following abbreviations represent the following reagents:

[0072]

[0073] Preparation of intermediates

[0074] Intermediate A: 3-(2,3-dihydrobenzofuran-7-yl)propanal

[0075]

[0076] Step 1: Dissolve 2,3-dihydrobenzofuran-7-carbaldehyde (1.0 g, 6.7 mmol) and methyl (triphenylphosphino) acetate (3.36 g, 10.05 mmol) in anhydrous tetrahydrofuran (15 mL) at room temperature. Stir the reaction mixture at 80 °C for 2 h. Cool the reaction mixture to room temperature and concentrate in vacuo to obtain a crude product. The crude product was purified by column chromatography (EtOAc / PE = 0 - 10%) to obtain A-1 (1.18 g, yield: 76.1%) as a white solid. MS m / z (ESI): 205.1 [M+H] +

[0077] Step 2: At room temperature, A-1 (1.18 g, 5.8 mmol) was dissolved in methanol (10 mL), and 10% wet palladium carbon (310 mg, 0.29 mmol) was added. The reaction solution was stirred at room temperature for 1 h under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, washed with methanol, and the filtrate was combined and concentrated in vacuo to obtain A-2 (1.15 g, yield: 96.6%) as a colorless viscous oil. The crude product was not purified and used directly in the next reaction. MS m / z (ESI): 207.1 [M+H] +

[0078] Step 3: A-2 (500 mg, 2.4 mmol) was dissolved in tetrahydrofuran (8 mL) at room temperature, cooled to zero degrees under a nitrogen atmosphere, and then a 1M solution of lithium aluminum hydride in tetrahydrofuran (8 mL) was added and stirred at room temperature for 1 hour. The reaction solution was stirred at zero degrees, and ethyl acetate (20 mL) was slowly added to dilute it, sodium sulfate decahydrate was added, filtered through diatomaceous earth, washed with methanol, and concentrated in vacuo to obtain a crude product. The crude product was purified by chromatography column separation (EtOAc / PE = 0 - 15%) to obtain A-3 (340 mg, yield: 78.7%) as a colorless oily liquid. MS m / z (ESI): 179.1 [M+H] +

[0079] Step 4: At room temperature, A-3 (3 g, 16.9 mmol) was dissolved in dichloromethane (100 mL), placed in a nitrogen atmosphere, and Dess-Martin reagent (DMP) (21.4 g, 50.6 mmol) was added and stirred at room temperature for 5 hours. The reaction solution was filtered through diatomaceous earth, the filtrate was washed with a saturated sodium bicarbonate aqueous solution, and the organic phase was concentrated in vacuo to obtain a crude product. The crude product was purified by chromatography column separation (EtOAc / PE = 0 - 20%) to obtain A (2.5 g, yield: 84.2%) as a colorless oily liquid.

[0080] Intermediate B: 2-(2,3-dihydrobenzofuran-7-yl)acetaldehyde

[0081]

[0082] Step 1: Add compound 7-bromo-2,3-dihydrobenzofuran (5.0 g, 25.1 mmol), potassium vinyl fluoroborate (6.7 g, 50.2 mmol), Pd(dppf)Cl2 dichloromethane complex (0.8 g, 1.25 mmol) and potassium carbonate (7.0 g, 50.2 mmol) into a 100 mL single-necked bottle, followed by adding dioxane / water (45 mL, V1 / V2 = 8:1). After the addition is complete, slowly heat to 110 °C under a nitrogen atmosphere and stir overnight. After TLC detected that the reaction was complete, the reaction solution was cooled to room temperature and filtered under reduced pressure. Water (30 mL) was added to the filtrate, extracted with ethyl acetate (50 mL x 2), the organic phases were combined, washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product was separated by chromatography column (EtOAc / PE = 0 - 2%) and purified to obtain a light yellow oil B-1 (3.20 g, yield: 87%).

[0083] Step 2: Compound B-1 (1.0 g, 6.8 mmol) and anhydrous THF (10 mL) were added to a 100 mL three-necked flask, and 2M B2H6 / dimethyl sulfide solution (6 mL) was slowly added dropwise under N2 and ice-water bath. After the addition, the mixture was allowed to stir at room temperature for 3 h. Subsequently, 10% NaOH aqueous solution (7 mL) and 30% H2O2 solution (1 mL) were slowly added dropwise under ice-water bath, and after the addition, the mixture was allowed to stir at room temperature overnight. After TLC detection of the reaction was complete, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product was separated by chromatography column (EtOAc / PE = 0 - 30%) to obtain a light yellow oil B-2 (0.6 g, yield: 54%). 1H NMR (500 MHz, CDCl3) δ 7.09 (dd, J = 7.3, 0.9 Hz, 1H), 6.97 (d, J = 7.5 Hz, 1H), 6.80 (t, J= 7.4 Hz, 1H), 4.56 (t, J = 8.7 Hz, 2H), 3.86 (t, J = 6.3 Hz, 2H), 3.22 (t, J= 8.7 Hz, 2H), 2.86 (t, J = 6.3 Hz, 2H). MS m / z (ESI): 164.5 [M+H] + .

[0084] Step 3: At room temperature, C-2 (600 mg, 3.7 mmol) and anhydrous DCM (10 mL) were added to a 50 mL single-mouth bottle, followed by adding Dess-Martin reagent (2.3 g, 5.5 mmol) in batches, and stirred at room temperature for 1 hour. After TLC detection, the reaction solution was filtered, and the filtrate was slowly added with saturated NaHCO3 solution to adjust the pH of the system to alkaline, extracted with DCM (20 mL x 2), combined with organic phases, washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product was separated by chromatography (EtOAc / PE = 0 - 10%) to obtain colorless oil B (0.4 g, yield: 67%).

[0085] Example 1: 1-(8-(1-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one

[0086]

[0087] Step 1: Dissolve 8-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine (330 mg, 1.54 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (480 mg, 1.56 mmol) in 8 mL of dioxane, add potassium phosphate aqueous solution (816 mg, 3.85 mmol, 2 mL H2O), replace the atmosphere with N2, add Pd(dppf)Cl2DCM (63 mg, 0.077 mmol), heat to 90 °C, and evaporation. oC for 16 h. After TLC detection, the reaction was complete, water and EtOAc were added to separate the layers, the aqueous phase was extracted with EtOAc, the organic phases were combined, washed three times with saturated sodium chloride solution, dried and concentrated, and passed through a normal phase silica gel column (PE / EtOAc = 3 / 1) to obtain compound 1-1 (430 mg, off-white solid, yield 88%). MS m / z (ESI): 317.2 [M+H] + .

[0088] Step 2: Dissolve 1-1 (430 mg, 1.36 mmol) in 10 mL DCM, add DIEA (0.67 mL, 4.1 mmol), and cool to 0 o C, add acetyl chloride (128 mg, 1.63 mmol), stir at room temperature for 16 h, concentrate and pass through a normal phase silica gel column (PE / EtOAc = 3 / 1) to obtain compound 1-2 (410 mg, off-white solid, yield 84%). MS m / z (ESI): 359.2 [M+H] + .

[0089] Step 3: Dissolve 1-2 (95 mg, 0.265 mmol) in 2 mL DCM, add TFA (0.5 mL, 6.73 mmol), stir at room temperature for 1 h, and concentrate to obtain compound 1-3. The crude product is directly used in the next step. MS m / z (ESI): 259.3 [M+H] + .

[0090] Step 4: Compound 1-3 (99 mg, 0.265 mmol) was dissolved in 2 mL DCM, 3-(2,3-dihydrobenzofuran-7-yl)propanal (47 mg, 0.265 mmol) was added at room temperature, and the mixture was stirred at room temperature for 5 min. NaBH(OAc)3 (170 mg, 0.8 mmol) was then added, and the mixture was stirred at room temperature for 16 h. Water and DCM were added to separate the layers. The organic phase was washed with water and then chromatographed on a normal phase silica gel column (DCM / MeOH = 10 / 1) to obtain compound E1 (55 mg, off-white solid, yield 50%). 1H NMR (500MHz, CD3OD) δ 7.09-7.07 (m, 2H), 7.00-6.98 (m, 3H), 6.78 (t, J = 5.0 Hz, 1H), 5.78 (s, 1H), 4.54 (t, J = 10.0 Hz, 2H), 4.31 (t, J = 5.0 Hz, 2H), 3.92 (t, J = 10.0 Hz, 2H), 3.75 (t, J = 5.0 Hz, 2H), 3.34 (t, J = 5.0 Hz, 2H), 3.20 (t,J = 10.0 Hz, 2H), 3.12-3.08 (m, 2H), 2.77 (t, J = 5.0 Hz, 2H), 2.68 (t, J =10.0 Hz, 2H), 2.29 (s, 3H), 2.10-2.03 (m, 2H). MS m / z (ESI): 419.8 [M+H] + .

[0091] Example 2: 1-(8-(1-(3-(2,3-dihydrobenzofuran-7-yl)propyl)piperidin-4-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one

[0092]

[0093] Compound E1 (20 mg, 0.048 mmol) was dissolved in MeOH (3 mL), 10% Pd / C (15 mg) was added, and the mixture was stirred and hydrogenated at room temperature for 2 hours. After filtration, prep-HPLC purification and separation (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30% –70%) were performed to obtain compound E2 (10.0 mg, white solid, yield 50%). 1H NMR (500 MHz, CD3OD) δ 7.06-7.04 (m, 3H), 7.00-6.98 (m, 2H), 6.75 (t, J = 5.0 Hz, 1H), 4.53 (t, J = 10.0 Hz, 2H), 4.33 (t, J = 5.0 Hz, 2H), 3.91 (t, J = 10.0 Hz, 2H), 3.28-3.26 (m, 2H), 3.19 (t, J = 10.0 Hz, 2H), 3.08-3.01 (m, 1H), 2.69 (t, J =5.0 Hz, 2H), 2.61 (t, J = 10.0 Hz, 2H), 2.49-2.45 (m, 2H), 2.29 (s, 3H), 1.96-1.79 (m, 6H). MS m / z (ESI): 421.9 [M+H] + .

[0094] Example 3: 1-(8-(1-(2-(2,3-dihydrobenzofuran-7-yl)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one

[0095]

[0096] The preparation of E3 refers to the synthetic method of step 4 of E1. 1 H NMR (500 MHz, CD3OD) δ 7.12 (t, J =10.0 Hz, 1H), 7.01 (t, J = 10.0 Hz, 1H), 6.99 (t, J = 5.0 Hz, 1H), 6.93-6.89(m, 2H), 6.80 (t, J = 5.0 Hz, 1H), 5.80 (s, 1H), 4.52 (t, J = 10.0 Hz, 2H), 4.26 (t, J = 5.0 Hz, 2H), 3.95 (t, J = 10.0 Hz, 2H), 3.76 (t, J = 5.0 Hz, 2H), 3.32-3.15 (m, 6H), 2.98 (t, J = 5.0 Hz, 2H), 2.77 (t, J = 10.0 Hz, 2H), 2.30 (s, 3H). MS m / z (ESI): 405.8 [M+H] + .

[0097] Example 4: 1-(8-(1-(2-(2,3-dihydrobenzofuran-7-yl)ethyl)piperidin-4-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one

[0098]

[0099] The preparation of E4 refers to the synthesis method of E2. 1 H NMR (500 MHz, CD3OD) δ 7.08-7.04 (m, 3H), 6.95-6.88 (m, 2H), 6.76 (t, J = 5.0 Hz, 1H), 4.53 (t, J = 10.0 Hz, 2H), 4.34(t, J = 5.0 Hz, 2H), 3.91 (t, J = 10.0 Hz, 2H), 3.25-3.17 (m, 4H), 3.04-3.00(m, 1H), 2.85-2.82 (m, 2H), 2.75-2.72 (m, 2H), 2.38 (t, J = 10.0 Hz, 2H),2.33 (s, 3H), 1.87-1.77 (m, 4H). MS m / z (ESI): 407.8 [M+H] + .

[0100] Example 5: 1-(8-(1-(2-(2-3-dihydrobenzofuran-7-yl)ethyl)-1,2,5,6-tetrahydropyridin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate-1-one

[0101]

[0102] Step 1: Add compound 8-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.0 g, 4.67 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.7 g, 5.61 mmol), Pd(dppf)Cl2 dichloromethane complex (0.19 g, 0.23 mmol) and potassium carbonate (1.9 g, 14.01 mmol) into a 100 mL single-necked bottle, and then add 1, 4-dioxane / water (12 mL, V1 / V2=5:1). After the addition is completed, slowly heat to 80°C under nitrogen atmosphere and stir overnight. After the reaction was complete as detected by LCMS, the reaction solution was cooled to room temperature, filtered under reduced pressure, water (30 mL) was added to the filtrate, extracted with ethyl acetate (50 mL x 2), the organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product was separated by chromatography (EtOAc / PE = 0-50%) to obtain compound 5-1 (light yellow oil, 1.4 g, yield: 95%). MS m / z (ESI): 261.3 [M+H-tBu] + .

[0103] Step 2: Compound 5-1 (0.7 g, 2.21 mmol) was added to a 100 mL single-mouth bottle, followed by dichloromethane (15 mL) and triethylamine (0.68 g, 6.72 mmol), followed by acetyl chloride (0.2 g, 2.43 mmol). After addition, the mixture was stirred at room temperature for 1 h, the reaction solution was dried under reduced pressure, and the crude product was purified by chromatography column separation (EtOAc / PE = 0 - 50%) to obtain compound 5-2 (yellow oil, 0.7 g, yield: 88%). MS m / z (ESI): 303.4 [M+H-tBu] + .

[0104] Step 3: Compound 5-2 (200 mg, 0.56 mmol) and anhydrous DCM (2 mL) were added to a 10 mL single-mouth bottle, followed by HCl / Dioxane (1 mL). After addition, the mixture was stirred at room temperature for 12 h. The reaction was completed by LCMS detection, and the reaction solution was decompressed and dried to obtain crude compound 5-3 (gray solid, 0.13 g, yield 90%). The crude product was not further purified and was directly used in the next reaction. MS m / z (ESI): 259.4 [M+H] + .

[0105] Step 4: The preparation method of E5 refers to the synthesis method of the fourth step in Example 1. 1 H NMR (500 MHz, CDCl3) δ 7.11-6.94 (m, 4H), 6.85 (t, J = 7.8 Hz, 1H), 6.78 (t, J = 7.4 Hz, 1H), 5.85 (s, 1H), 4.54 (t, J = 8.7 Hz, 2H), 4.34-4.29 (m, 2H), 3.95 (s, 2H), 3.40 (d, J = 28.3 Hz, 2H), 3.22-3.18 (m, 2H), 2.85 (d, J = 41.4 Hz, 6H), 2.42(s, 2H), 2.32 (s, 3H). MS m / z (ESI): 405.8 [M+H] + .

[0106] Example 6: 1-(8-(1-(2-(2-)2-dihydrobenzofuran-7-yl)ethyl)piperidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one

[0107]

[0108] Compound E5 (30 mg, 0.074 mmol) and methanol (3 mL) were added to a 100 mL single-mouth bottle, followed by the addition of Pd / C (2 mg, 0.015). After the addition was complete, the mixture was stirred at room temperature for 5 h under a hydrogen atmosphere. After the reaction was complete as detected by LCMS, the mixture was filtered under reduced pressure, and the filtrate was directly purified and separated by Prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) to obtain compound E6 (white solid, 11 mg, yield 37%). 1 H NMR (500 MHz, CDCl3) δ 7.12-6.89 (m, 4H), 6.86 (t, J = 7.8 Hz, 1H), 6.77 (t, J = 7.4 Hz, 1H), 4.53 (t, J = 8.7 Hz, 2H), 4.33 (t, J = 4.9 Hz, 2H), 3.95 (s, 2H), 3.20 (t, J = 8.7 Hz, 5H), 2.74 (d, J= 81.5 Hz, 4H), 2.32 (s, 3H), 2.15-1.61 (m, 6H).MS m / z (ESI): 407.8 [M+H] + .

[0109] Example 7: 4-(1-(3-(2,3-dihydrobenzofuran-7-yl)propyl)piperidin-4-yl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one

[0110]

[0111] Step 1: Add compound 8-3 (200 mg, 0.6 mmol) and potassium carbonate (414 mg, 3 mmol) into a 50 mL single-necked bottle, then add DMF (10 mL) and finally iodomethane (0.4 ml, 6 mmol). After the addition, slowly heat to 80°C under nitrogen protection. 0 C and stirred overnight. LCMS detected that the reaction was complete, and the reaction solution was cooled to room temperature, filtered, concentrated, and passed through a column to obtain product 7-1 (yellow solid, 150 mg, yield 72.4%). MS m / z (ESI): 290.5[M+H-tBu] +

[0112] Step 2: The preparation method of 7-2 refers to the preparation method of E2. MS m / z (ESI): 246.3 [M+H] + .

[0113] Step 3: The preparation method of E7 refers to the synthesis method of the fourth step in Example 1. 1 H NMR (500 MHz, CD3OD) δ 7.15–7.03 (m, 3H), 6.99 (d, J = 7.2 Hz, 1H), 6.97–6.92 (m, 2H), 6.78 (t, J = 7.4 Hz, 1H), 4.59–4.51 (m, 2H), 3.99–3.92 (m, 1H), 3.68 (d, J = 13.1Hz, 4H), 3.49–3.41 (m, 1H), 3.36–3.33 (m, 3H), 3.23–3.10 (m, 7H), 2.68 (q, J= 7.2 Hz, 2H), 2.08 (ddd, J = 12.3, 9.7, 6.4 Hz, 4H). MS m / z (ESI): 406.7 [M+H] + 。

[0114] Example 8: 1-(4-(1-(3-(2,3-dihydrobenzofuran-7-yl)propyl)piperidin-4-yl)-3,4-dihydroquinoxalin-1(2H)-yl)ethan-1-one

[0115]

[0116] Step 1: Add compound 1-fluoro-2-nitrobenzene (2 g, 14.2 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (5.6 g, 28.4 mmol) and potassium carbonate (7.8 g, 56.8 mmol) into a 100 mL single-mouth bottle, and then add acetonitrile (100 mL) respectively. After the addition is completed, slowly heat to reflux under nitrogen protection and stir overnight. LCMS detection reaction is complete, the reaction solution is cooled to room temperature, filtered, concentrated, and column column to obtain product 8-1 (yellow solid, 3 g, yield 65.5%). MS m / z (ESI): 266.0 [M+H- tBu] +

[0117] Step 2: The preparation method of 8-2 refers to the preparation method of E2. MS m / z (ESI): 292.3 [M+H] + .

[0118] Step 3: Compound 8-2 (1.6 g, 5.5 mmol) was dissolved in DCM (20 mL) and then 0 C. Chloroacetyl chloride (807 mg, 7.1 mmol) was slowly added and the reaction was continued at 0 0 C for 1 h, then the reaction solution was drained, and then acetonitrile (20 mL) and sodium bicarbonate ((2.3 g, 27.5 mmol,) were added respectively. After the addition, the temperature was slowly raised to reflux under nitrogen protection and stirred overnight. LCMS detected that the reaction was complete, and the reaction solution was cooled to room temperature, filtered, concentrated, and passed through a column to obtain the product 8-3 (yellow solid, 800 mg, yield 43.6%). MS m / z (ESI): 276.4 [M+H- tBu] + 。

[0119] Step 4: The preparation method of 8-4 refers to the synthesis method of the third step of intermediate A. MS m / z (ESI): 318.2[M+H] + .

[0120] Step 5: The preparation method of 8-5 refers to the synthesis method of the second step of Example 1. MS m / z (ESI): 260.4[M+H-100] +

[0121] Step 6: The preparation method of 8-6 refers to the synthesis method of the third step of Example 1. MS m / z (ESI): 260.4[M+H]+

[0122] Step 7: The preparation method of E8 refers to the synthesis method of the fourth step of Example 1. 1 H NMR (500 MHz, CDCl3) δ 7.06 (d, J = 7.2 Hz, 2H), 7.00 (s, 1H), 6.93 (d, J = 7.5 Hz, 1H), 6.76 (dd, J = 21.0, 13.6 Hz, 1H), 6.69 (d, J = 7.8 Hz, 1H), 6.64 (s, 1H), 4.55 (t, J = 8.7 Hz, 2H), 3.82 (s, 2H), 3.71 (s, 1H), 3.36 (s, 3H), 3.21 (t,J = 8.7 Hz, 3H), 2.49 (d, J = 135.1 Hz, 6H), 2.22 (s, 3H), 1.97 (d, J = 127.4Hz, 6H). MS m / z (ESI): 420.8 [M+H] + .

[0123] Example 9: 1-(4-(1-(2-(2,3-dihydrobenzofuran-7-yl)ethyl)piperidin-4-yl)-3,4-dihydroquinoxalin-1(2H)-yl)ethan-1-one

[0124]

[0125] The preparation method of E9 refers to the synthesis method of the fourth step of Example 1. 1 H NMR (500 MHz, CDCl3) δ 7.06(t, J = 7.4 Hz, 2H), 6.95 (dd, J = 17.1, 7.5 Hz, 2H), 6.78 (dd, J = 14.1, 6.6Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.63 (t, J = 7.5 Hz, 1H), 4.55 (td, J =8.7, 3.5 Hz, 2H), 3.83 (s, 2H), 3.68 (s, 1H), 3.36 (s, 2H), 3.21 (t, J = 8.7Hz, 4H), 2.91-2.57 (m, 4H), 2.36-2.15 (m, 5H), 1.79 (t, J = 33.5 Hz, 4H). MSm / z (ESI): 406.7 [M+H] +.

[0126] Example 10: 1-(8-(1-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-1,2,5,6-tetrahydropyridin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one

[0127]

[0128] The preparation method of E10 refers to the synthesis method of E5. 1 H NMR (500 MHz, DMSO-d6) δ 7.09 (d, J =7.3 Hz, 1H), 6.93 (dt, J = 38.6, 7.6 Hz, 3H), 6.77 (t, J = 7.4 Hz, 1H), 5.99(s, 1H), 4.50 (t, J = 8.7 Hz, 2H), 4.29 (t, J = 4.8 Hz, 2H), 4.02 (s, 2H), 3.86–3.84 (m, 3H), 3.52 (dd, J = 11.9, 5.8 Hz, 1H), 3.17 (dd, J = 11.0, 6.3Hz, 5H), 2.57 (q, J = 7.7, 7.1 Hz, 3H), 2.48-2.39 (m, 1H), 2.24 (s, 3H), 2.06-1.95 (m, 2H). MS m / z (ESI): 419.7 [M+H] + .

[0129] Example 11: 1-(8-(1-(3-(2,3-dihydrobenzofuran-7-yl)propyl)piperidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one

[0130]

[0131] Step 1: The preparation method of 11-1 refers to the second step synthesis method of intermediate A.

[0132] Step 2: The preparation method of 11-2 refers to the third step of the synthesis method of Example E10.

[0133] Step 3: The preparation method of E11 refers to the fourth step of the synthesis method of Example E10. 1H NMR (500 MHz, CDCl3) δ 7.14-6.79 (m, 5H), 6.76 (t, J = 7.4 Hz, 1H), 4.53 (t, J = 8.7 Hz, 2H), 4.33 (s, 2H), 3.93 (s, 2H), 3.49-3.14 (m, 4H), 2.99 (s, 2H), 2.60 (s,5H), 2.31 (s, 3H), 1.86 (s, 6H). MS m / z (ESI): 421.6 [M+H] + .

[0134] Example 12: 4-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-1-(2-(2,3-dihydrobenzofuran-7-yl)ethyl)piperidine

[0135]

[0136] Step 1: The preparation method of 12-1 refers to the first step of the synthesis method of Example 5. MS m / z (ESI): 262.2[M+H-tBu] +

[0137] Step 2: The preparation method of 12-2 refers to the synthesis method of Example 6. MS m / z (ESI): 264.2 [M+H-tBu] +

[0138] Step 3: The preparation method of 12-3 refers to the third step of the synthesis method of Example 5. MS m / z (ESI): 220.2[M+H] + .

[0139] Step 4: The preparation method of E12 refers to the synthesis method of the fourth step in Example 1. 1 H NMR (500 MHz, CDCl3) δ 7.07 (t, J = 9.4 Hz, 1H), 7.01 (d, J = 7.4 Hz, 1H), 6.84-6.73 (m,4H), 4.55 (t, J = 8.7 Hz, 2H), 4.33-4.17 (m, 4H), 3.29 (d, J = 54.1 Hz, 2H), 3.21 (t, J = 8.2 Hz, 2H), 2.98 (s, 5H), 2.58-2.14 (m, 2H), 1.91 (s, 2H), 1.62(s, 2H).MS m / z (ESI): 366.7 [M+H] + .

[0140] Example 13: 8-(1-(2-(2,3-dihydrobenzofuran-7-yl)ethyl)piperidin-4-yl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine

[0141]

[0142] Step 1: Dissolve compound 1-1 (150 mg, 0.48 mmol) in 8 mL acetonitrile, add cesium carbonate (315 mg, 0.96 mmol), then add iodomethane (204 mg, 1.44 mmol), and heat to reflux for 16 h. TLC detection shows that the reaction is complete, add water and EtOAc to separate the layers, extract the aqueous phase with EtOAc, combine the organic phases, wash three times with saturated sodium chloride solution, dry and concentrate, and pass through a normal phase silica gel column (PE / EtOAc = 3 / 1) to obtain compound 13-1 (115 mg, colorless oil, yield 72%). MS m / z (ESI): 331.2 [M+H] + .

[0143] Step 2: The preparation method of 13-2 refers to the synthesis method of E1 step 3. MS m / z (ESI): 231.4 [M+H] +

[0144] Step 3: The preparation method of 13-3 refers to the synthesis method of E1 step 4. MS m / z (ESI): 377.8 [M+H] +

[0145] Step 4: The preparation method of E13 refers to the synthesis method of E2. 1 H NMR (500 MHz, CD3OD) δ 7.14 (d,J = 10.0 Hz, 1H), 7.01 (d, J = 5.0 Hz, 1H), 6.83-6.76 (m, 2H), 6.62 (d, J =5.0 Hz, 1H), 6.53 (d, J = 10.0 Hz, 1H), 4.58 (t, J = 10.0 Hz, 2H), 4.29 (t, J= 5.0 Hz, 2H), 3.67 (d, J = 10.0 Hz, 2H), 3.26-3.00 (m, 10H), 2.86 (s, 3H), 2.06-1.93 (m, 5H). MS m / z (ESI): 379.6 [M+H] + .

[0146] Example 14: 1-(2-(2,3-dihydrobenzofuran-7-yl)ethyl)-4-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)piperidin-3-ol

[0147]

[0148] Compound 13-3 (20 mg, 0.053 mmol) was dissolved in 2 mL THF, borane dimethyl sulfide (0.11 mL, 0.11 mmol) was added, the mixture was stirred at room temperature for 16 h, NaOH aqueous solution (0.13 mL, 0.13 mmol) was added, and then hydrogen peroxide aqueous solution (0.015 mL, 0.13 mmol) was added and stirred at room temperature for 3 h. The reaction was complete by TLC detection, water and EtOAc were added to separate the layers, the aqueous phase was extracted with EtOAc, the organic phases were combined, washed with saturated sodium chloride solution, concentrated and filtered, and then purified and separated by prep-HPLC (eluent (v / v): acetonitrile / (water+0.05% NH4HCO3) = 30% –70%) to obtain compound E14 (4.0 mg, white solid, yield 18%). 1 H NMR (500 MHz, CD3OD) δ 7.09 (d, J = 10.0 Hz, 1H), 6.96 (d, J= 5.0 Hz, 1H), 6.80-6.76 (m, 2H), 6.62-6.58 (m, 2H), 4.58 (t, J = 10.0 Hz,2H), 4.41-4.24 (m, 2H), 3.28-3.15 (m, 6H), 3.13-3.03 (m, 4H), 2.88 (s, 3H), 2.65-2.60 (m, 2H), 2.21-2.15 (m, 1H), 1.84-1.68 (m, 3H). MS m / z (ESI): 395.6[M+H] + .

[0149] Example 15: 1-(5-(1-(2-(2-3-dihydrobenzofuran-7-yl)ethyl)piperidin-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one

[0150]

[0151] Step 1: The preparation method of 15-1 refers to the synthesis method of the second step of Example E5.

[0152] Step 2: The preparation method of 15-2 refers to the synthesis method of the first step in Example E5.

[0153] Step 3: The preparation method of 15-3 refers to the synthesis method of Example 6.

[0154] Step 4: The preparation method of 15-4 refers to the synthesis method of the third step of Example E5.

[0155] Step 5: The preparation method of E15 refers to the synthesis method of Example 3. 1 H NMR (500 MHz, CDCl3) δ7.24-6.90 (m, 5H), 6.80 (t, J = 7.4 Hz, 1H), 4.56 (t, J = 8.7 Hz, 2H), 3.79(t, J = 6.5 Hz, 2H), 3.22 (t, J = 8.7 Hz, 4H), 3.11-2.46 (m, 8H), 2.19 (s,5H), 1.96 (p, J = 6.7 Hz, 3H), 1.83 (s, 2H). MS m / z (ESI): 405.8 [M+H] + .

[0156] Example 16: 1-(8-(5-(2-(2,3-dihydrobenzofuran-7-yl)ethyl)-5-azaspiro[2.5]octan-8-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one

[0157]

[0158] Step 1: Add tert-butyl 8-oxo-5-aza[2.5]octane-5-carboxylate (100 mg, 0.44 mmol) and 4-methylbenzenesulfonyl hydrazide (83 mg, 0.44 mmol) into a 25 mL single-mouth bottle, then add anhydrous methanol (10 mL). After the addition is complete, stir at room temperature overnight under nitrogen protection. LCMS detected that the reaction was complete, and the reaction solution was dried under reduced pressure to obtain the crude compound 16-1 (white solid, 170 mg, yield 98%). The crude product was not further purified and was directly used in the next step. MS m / z (ESI): 394.7 [M+H] + .

[0159] Step 2: Compound 16-1 (130 mg, 0.33 mmol), 8-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.36 g, 0.36 mmol), Pd2(dba)3 (30 mg, 0.03 mmol), X-Phos (15 mg, 0.1 mmol), and t-BuOLi (80 mg, 1.00 mmol) were added into a 100 mL single-necked bottle, followed by anhydrous dioxane (5 mL). After the addition was completed, the temperature was slowly raised to 110 °C under nitrogen protection and stirred overnight. The reaction was completed after LCMS detection. The reaction solution was cooled to room temperature, water (20 mL) was added to the reaction solution, and EtOAc was used for extraction (2 x 20 mL). The organic phases were combined, washed with saturated brine (1 x 20 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product was separated by chromatography (EtOAc / PE = 0 - 30%) to obtain compound 16-2 (light yellow solid, 100 mg, yield: 88%). MS m / z (ESI): 243.6 [M-Boc] +

[0160] Step 3: Compound 16-2 (60 mg, 0.18 mmol), TEA (40 mg, 0.54 mmol) and anhydrous DCM (5 mL) were added to a 25 mL single-necked bottle, and acetyl chloride (12 mg) was slowly added dropwise under an ice-water bath. After the addition, the mixture was allowed to stir at room temperature for 1 h. LCMS detected that the reaction was complete, saturated NH4Cl solution (10 mL) was added to the reaction solution, and DCM was extracted (2 x 10 mL). The organic phases were combined, washed with saturated brine (1 x 20 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product was separated by chromatography (EtOAc / PE = 0 - 30%) to obtain compound 16-3 (light yellow solid, 30 mg, yield: 45%). MS m / z(ESI): 285.7 [M-Boc] + .

[0161] Step 4: Compound 16-3 (30 mg, 0.08 mmol) and methanol (10 mL) were added to a 25 mL single-mouth bottle, followed by 10% Pd / C (wet, 30 mg). After the addition was completed, the temperature was slowly raised to 40°C and stirred for 5 h under a hydrogen atmosphere. The reaction was completed by LCMS detection, the reaction solution was filtered, and the filtrate was dried under reduced pressure to obtain a crude compound 16-4 (light yellow oil, 25 mg, yield 83%). The crude product was not further purified and was directly used in the next step. MS m / z (ESI): 387.6 [M+H] + .

[0162] Step 5: Compound 16-4 (25 mg, 0.09 mmol) and anhydrous DCM (5 mL) were added to a 25 mL single-necked bottle, followed by TFA (1 mL). After the addition was complete, the mixture was stirred at room temperature for 1 h. After the reaction was completed by LCMS, the reaction solution was decompressed and dried to obtain a crude compound 16-5 (light yellow oil, 20 mg). The crude product was not further purified and was directly used in the next step. MS m / z (ESI): 287.5 [M+H] + .

[0163] Step 6: Preparation of E16 The synthetic method of step 4 of reference example E1 was used. 1 H NMR (500 MHz, CDCl3) δ7.06 (d, J = 7.1 Hz, 1H), 6.98 (d, J = 7.3 Hz, 3H), 6.84 (t, J = 7.9 Hz, 1H), 6.78 (t, J = 7.4 Hz, 1H), 4.55 (t, J = 8.7 Hz, 2H), 4.36-4.28 (m, 2H), 4.02 -3.84 (m, 2H), 3.44 - 3.34 (m, 1H), 3.21 (t, J = 8.7 Hz, 3H), 3.03-2.09 (m,9H), 2.30 (s, 3H), 1.83 - 1.75 (m, 1H), 0.50-0.15 (m, 3H). MS m / z (ESI):433.7 [M+H] + .

[0164] Example 17: 1-(8-(4-(2-(2-)2-dihydrobenzofuran-7-yl)ethyl)piperazin-1-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetate-1-one

[0165]

[0166] Step 1: 8-Bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine (500 mg, 2.34 mmol) and TEA (473 mg, 4.68 mmol) were dissolved in DCM (10 mL) at room temperature, replaced with N2 three times, and acetyl chloride (220 mg, 2.80 mmol) was added. The reaction solution was stirred at room temperature for 10 min. LC-MS monitored the reaction completion, added sat.NaCl solution, separated, dried, and concentrated in vacuo to obtain a crude product. The crude product was purified by column chromatography (EtOAc / PE = 0 - 30%) to obtain 17-1 (550 mg, yield: 91.6%) as a yellow solid. MS m / z (ESI): 255.9, 257.9 [M+H] + .

[0167] Step 2: 17-1 (500 mg, 1.95 mmol), tert-butylpiperazine-1-carboxylate (550 mg, 2.93 mmol), Pd(OAc)2 (50 mg, 0.195 mmol), BINAP (120 mg, 0.195 mmol) and NaOt-Bu (570 mg, 5.95 mmol) were added to a three-necked flask containing 1,4-dioxane (15 mL) at room temperature. The atmosphere was replaced with N2 three times. The reaction solution was stirred at 100 °C for 2 h. o C and stirred for 16 h. LC-MS monitored ~40% product formation, water and EA were added, the liquids were separated, the aqueous phase was extracted twice with EA, dried, and concentrated in vacuo to obtain a crude product. The crude product was purified by column chromatography (EtOAc / PE = 0 - 30%) to obtain 17-2 (400 mg, yield: 64.3%) as a brown solid. MS m / z (ESI): 320.3 [M+H] + .

[0168] Step 3: The preparation of 17-3 refers to the synthesis method of step 1. MS m / z (ESI): 362.2 [M+H] + .

[0169] Step 4: At room temperature, 17-3 (300 mg, 0.83 mmol) was dissolved in DCM (6 mL) and TFA (2 mL) was added. The reaction solution was stirred at room temperature for 1 h. LC-MS monitored the reaction to be complete, concentrated most of the TFA, added sat.NaHCO3 solution to adjust the pH to 7~8, and then extracted the aqueous phase with a mixed solvent of DCM / MeOH=10 / 1, dried, and concentrated in vacuo to obtain a crude product. The crude product was purified by chromatography column separation (EtOAc / PE = 0 - 30%) to obtain 17-4 (140 mg, yield: 64.6%) as a brown oil. MS m / z(ESI): 262.2[M+H] + .

[0170] Step 5: The preparation method of E17 refers to the fourth step of the synthesis method of Example 1. 1 H NMR (500 MHz, CDCl3) δ 7.06 (d, J = 7.5 Hz, 1H), 6.98 (d, J = 7.5 Hz, 1H), 6.87-6.77 (m,4H), 4.55 (t, J = 8.5 Hz, 2H), 4.39 (m, J = 4.5 Hz, 2H), 3.96 (s, 2H), 3.21(t, J = 8.5 Hz, 2H), 3.14 (s, 4H), 2.90-2.55 (m, 8H), 2.31 (s, 3H). MS m / z(ESI):408.2 [M+H] + .

[0171] Effect Example 1: Testing of downstream beta-arrestin functional activity of 5-HT2A receptor

[0172] The NanoBret kit of Promega was mainly used. Specifically, the 5HT2A receptor plasmid with Nanoluc at the C-terminus, the beta-arrestin plasmid with Halo-tag at the C-terminus, and the pcDNA3.1 plasmid expressing GRK2 were constructed respectively. Before transfection, HEK293 cells (ATCC, CRL-1573) were seeded in 6-well plates. After overnight culture, the plasmids of Nanoluc-5HT2AR, GRK2, and beta-arrestin-halotag were mixed in a ratio of 1:1:10 and added to the 6-well plates together with the transfection reagent. The transfection amount per well was 2ug. After 4 hours, the cells were digested and transferred to 384-well plates, with 20,000 cells per well, and the compounds to be tested or 5-HT were added as positive controls, and incubated overnight at 37°C and 5% CO2. The next day, the cells were taken out and diluted NanoBRET™ Nano-Glo substrate (10ul per well after dilution according to the instructions) was added, and the readings at 618nm / 460nm were read on a microplate reader. The readings at the highest 5-HT concentration were taken as 100% of the activation degree of the downstream pathway, and the data were analyzed using Prism software. The "log(agonist) vs. response -- Variable slope (fourparameters)" model was used to fit the data and obtain the EC 50 and E max .

[0173] Table 1

[0174]

[0175] Effect Example 2: Animal Behavior Test

[0176] This experiment is a forced swimming test for mice. The animals are 7-8 week old C57BL / 6J male mice, 12 per group. 24 hours before the test, the mice were placed in a 5L glass beaker with a water surface height of 15cm to swim for 15 minutes. On the day of the test, blank solvent (5% DMSO, 10% polyethylene glycol-15-hydroxystearate, 85% saline) ketamine (20mpk) or the test substance (15mpk) was intraperitoneally injected for 30 minutes and the mice were placed in the same beaker for 6 minutes. The software (Shanghai Jiliang, JLBehv-FSG-4) analyzed the immobility time of mice in the last four minutes. The immobility time of each drug group and the immobility time of the control group of the same batch of solvent were calculated for statistical analysis. If the data meet the normal distribution, the statistical method uses parametric test, that is, independent sample t test. If the data do not meet the normal distribution, the statistical method uses non-parametric test, see Table 2 and Appendix. Figure 1. The bar graphs are expressed as mean ± standard error, (* p<0.05, ** p<0.01). The bar graphs are expressed as mean ± standard error, (* p<0.05, ** p<0.01). The experimental results show that under the same experimental conditions, compared with the solvent control group, the control compound ketamine significantly reduced the immobility time of mice, while the example compounds 16 and 17 of the present invention can significantly increase the immobility time of mice and have a sedative effect on mice.

[0177] Table 2

[0178] .

Claims

1. A compound as shown in formula I or a pharmaceutically acceptable salt thereof, characterized in that ； ； wherein Ring A is "a 5-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S" or "a 5-10 membered heterocycloalkenyl group having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S"; R 1 is hydroxyl group; Ring B is or ; X 1 is -NH-, oxygen or -CH2-; X 2 For-NR 3 - or oxygen; X 3 for nitrogen; R 3 is C1-C6 alkyl or -C(O)-C1-C6 alkyl; R 2 is a C1-C6 alkyl or oxo group; n is 2, 3 or 4; m and x are independently 0, 1, 2 or 3.

2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1; characterized in that: It meets one or more of the following conditions: (1) The 5-10 membered heterocycloalkyl group is a monocyclic ring or a spirocyclic ring; (2) The heteroatoms in the 5-10 membered heterocycloalkyl are independently selected from N, and the number of heteroatoms is 1 or 2; for example, , , or ; (3) The 5-10 membered heterocycloalkenyl group is a 6-8 membered heterocycloalkenyl group; (4) The heteroatoms in the 5-10 membered heterocycloalkenyl group are independently selected from N, and the number of heteroatoms is 1; for example, or ;and (5) The C1-C6 alkyl groups are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl; preferably methyl.

3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1; characterized in that: It meets one or more of the following conditions: (1) Ring A is "a 5- to 10-membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S"; (2) Ring B is ; (3) X 1 is oxygen or -CH2-; preferably oxygen; (4) X 2 For-NR 3 -; (5) R 3 for or methyl; preferably ; (6) R 2 is an oxo group; (7) n is 2 or 3, preferably 2; (8) m is 0 or 1; preferably 0; and (9) x is 0 or 1; preferably 0.

4. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1; characterized in that: It meets one or both of the following conditions: (1) Ring A is , , , , or ; preferably, , , or ; More preferably, , or ; Among them, the a end is connected to the ring B, and the b end is connected to connected; and (2) Ring B is , , , or ; preferably , , , , or ; further preferably , , , or More preferably or .

5. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1; characterized in that: It meets one or both of the following conditions: (1) for , , , , , or ; preferably , , , or ; further preferably , or ; Among them, the a end is connected to the ring B, and the b end is connected to connected; and (2) for , , , , , or ; preferably , , , or ; further preferably or .

6. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1; characterized in that: The compound shown in formula I is a compound shown in formula I-1 or formula I-2: or ; Among them, ring A, R 1 , X 1 , X 2 , X 3 , R 2 , n, m and x are as defined in any one of claims 1-5.

7. The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6; characterized in that: The compound shown in formula I is a compound shown in formula I-1-1 or I-1-2: or ; Wherein, Y is -CH- or N, X 2 and n are as defined in any one of claims 1-6.

8. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1; characterized in that: The compound as shown in Formula I or a pharmaceutically acceptable salt thereof is any of the following compounds: .

9. A pharmaceutical composition, comprising: (1) A compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 and (2) Pharmaceutically acceptable excipients.

10. A use of the "compound of formula I or a pharmaceutically acceptable salt thereof" as described in any one of claims 1 to 8 or the pharmaceutical composition as described in claim 9, wherein the use is selected from: (1) Preparation of 5-HT 2A Receptor agonists; (2) Preparation for treatment and / or prevention with 5-HT 2A Preferably, the disease associated with the 5-HT2A receptor is mania in patients with mental illness; and (3) Preparation of drugs for treating and / or preventing mania in patients with mental illnesses.

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