Benzodihydrofuran three-ring compound, and pharmaceutical composition and application thereof

Abstract

The invention discloses a benzodihydrofuran tri-fused ring compound as well as a pharmaceutical composition and application of the benzodihydrofuran tri-fused ring compound. Specifically, the invention provides a compound shown as a formula I or pharmaceutically acceptable salt thereof. The compound disclosed by the invention has a good effect on a 5-HT2A receptor, has an effect of treating mental diseases, and particularly has a relatively good effect on resisting depression. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and particularly relates to benzodihydrofuran tricyclic compounds, their pharmaceutical compositions and uses. Background Art

[0002] 5-Hydroxytryptamine is a monoamine neurotransmitter that exerts its various biological functions including mood, 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 family of 5-hydroxytryptamine receptors, 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 the 5-HT2A receptor leads to neuronal excitation in multiple brain regions. Among all 14 5-hydroxytryptamine receptor subtypes, the 5-HT2A receptor is widely present in the central nervous system and has the highest concentration level among the monoamine receptors in the cerebral cortex. It is distributed in structural regions involved in mood regulation such as the median raphe 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, diet and reward behavior, but also related to many neuropsychiatric diseases such as schizophrenia, depression and anxiety disorders, etc. (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 drugs for treating depression in the prior art. To this end, the present invention provides a class of benzodihydrofuran tricyclic compounds with novel structures, their pharmaceutical compositions and uses. The compounds of the present invention have good effects on the 5-HT2A receptor and have the effect of treating mental diseases, especially having a good effect against depression.

[0005] The present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0006] ;

[0007] Among them, X1 is NR X1 , CR X2 R X3 , -O- or -S-;

[0008] R X1 is H, C1-C6 alkyl or -C(O)-C1-C6 alkyl;

[0009] R X2 and R X3 are independently H or C1-C6 alkyl;

[0010] R 1 is independently an oxo group (=O), halogen, C1-C6 alkyl, -C(O)-C1-C6 alkyl or a thio group (=S);

[0011] R 2 is H or C1-C6 alkyl;

[0012] L 1 is -(CR L1 R L2 ) m1 -;

[0013] R L1 and R L2 are independently H or C1-C6 alkyl;

[0014] n1 is 0, 1 or 2;

[0015] m1 is 1, 2, 3 or 4;

[0016] n is 1 or 2.

[0017] In certain preferred embodiments of the present invention, some groups in the compound of formula I or its pharmaceutically acceptable salt are defined as follows, and the groups not mentioned are the same as those described in any embodiment of the present invention (abbreviated as "in an embodiment of the present invention").

[0018] In an embodiment of the present invention, each "C1-C6 alkyl" and "C1-C6 alkyl" in "-C(O)-C1-C6 alkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl or ethyl.

[0019] In an embodiment of the present invention, in R 1 , the halogen is fluorine, chlorine, bromine or iodine.

[0020] In an embodiment of the present invention, X1 is NR X1 .

[0021] In an embodiment of the present invention, RX1 is H or -C(O)-C1-C6 alkyl, such as -C(O)-C1-C6 alkyl, and further such as -C(O)-C1-C3 alkyl.

[0022] In one embodiment of the present invention, R X1 is H, methyl or .

[0023] In one embodiment of the present invention, R 1 is an oxo group (=O). In one embodiment of the present invention, n1 is 0 or 1, for example, n1 is 0.

[0024] In one embodiment of the present invention, R 2 is C1-C6 alkyl, such as C1-C3 alkyl, and further such as methyl.

[0025] In one embodiment of the present invention, R 2 is H or methyl.

[0026] In one embodiment of the present invention, R L1 and R L2 are H.

[0027] In one embodiment of the present invention, m1 is 1, 2 or 3, for example, m1 is 2 or 3. In one embodiment of the present invention, L 1 is or .

[0028] In one embodiment of the present invention, n is 1.

[0029] In one embodiment of the present invention, the compound represented by Formula I is the compound represented by Formula I-1:

[0030] ;

[0031] wherein, the definitions of n, n1, R X1 , R 1 , R 2 and L 1 are as described in any one of the present invention.

[0032] In one embodiment of the present invention, the compound represented by Formula I is the compound represented by Formula I-1:

[0033] R X1 is H, C1-C6 alkyl or -C(O)-C1-C6 alkyl;

[0034] n is 1 or 2;

[0035] n1 is 0, 1 or 2;

[0036] R 1is an oxo group;

[0037] R 2 is H or a C1-C6 alkyl group;

[0038] L 1 is -(CR L1 R L2 ) m1 -;

[0039] R L1 and R L2 are H;

[0040] m1 is 1, 2, 3 or 4.

[0041] In one embodiment of the present invention, the compound represented by Formula I is the compound represented by Formula I-2:

[0042]

[0043] wherein, X1, R 2 and L 1 are defined as described in any one of the present invention.

[0044] In one embodiment of the present invention, in the compound represented by Formula I-2,

[0045] X1 is NR X1 ;

[0046] R X1 is H;

[0047] R 2 is a C1-C6 alkyl group,

[0048] L 1 is -(CR L1 R L2 ) m1 -;

[0049] R L1 and R L2 are H;

[0050] m1 is 2.

[0051] In one embodiment of the present invention, the compound represented by Formula I-1 is the compound represented by Formula I-1-1:

[0052] ;

[0053] R X1 is -C(O)-C1-C6 alkyl group,

[0054] R 2 is a C1-C6 alkyl group,

[0055] L 1 is -(CR L1 R L2 ) m1 -;

[0056] R L1 and R L2 is H;

[0057] m1 is 2 or 3.

[0058] In one embodiment of the present invention, the compound represented by formula I is any one of the following compounds:

[0059] , , , , , ,

[0060] , , , , , , , .

[0061] The present invention also provides a pharmaceutical composition, which comprises:

[0062] (1) a compound represented by formula I as described in any one of the present invention or a pharmaceutically acceptable salt thereof, and

[0063] (2) a pharmaceutically acceptable excipient.

[0064] The present invention also provides the use of a compound represented by formula I as described in any one of the present invention or a pharmaceutically acceptable salt thereof or the pharmaceutical composition as described above, and the use is selected from one or more of the following uses:

[0065] (1) use in the preparation of a drug for treating and / or preventing a disease related to the 5-HT2A receptor;

[0066] (2) use in the preparation of a 5-HT2A receptor agonist and / or inhibitor;

[0067] (3) use in the preparation of a drug for treating and / or preventing mental diseases.

[0068] In one embodiment of the present invention, the disease related to the 5-HT 2A receptor is a mental disease, such as depression.

[0069] In one embodiment of the present invention, the use is for the preparation of a 5-HT2A receptor agonist.

[0070] In one embodiment of the present invention, the mental disorder is depression.

[0071] Term Explanation

[0072] Unless otherwise specified, the terms used in the present invention have the following meanings:

[0073] The term "pharmaceutically acceptable" means relatively non-toxic, safe, and suitable for use by patients.

[0074] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, the 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 a compound contains a relatively basic functional group, the 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, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0075] Those skilled in the art can understand that, according to the convention used in the art, the " " used in the structural formula of the group described in the present invention means that the corresponding group is connected to other fragments or groups in the compound through this site.

[0076] The "-" at the end of the group means that the group is connected to the rest of the molecule through this site.

[0077] When any variable (such as R 1 ) appears multiple times in the definition of a compound, the definition of each occurrence of the variable is independent of the definition of the other occurrences, and their meanings are independent of each other and do not affect each other. Therefore, if a group is substituted by 1, 2, or 3 R 1 groups, that is to say, the group may be substituted by up to 3 R 1 substituents, the definition of R 1 at this position is independent of the definition of R 1 at the other positions. In addition, the combination of substituents and / or variables is only allowed when the combination produces a stable compound.

[0078] The term "oxo group" is =O.

[0079] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0080] The term "alkyl" refers to a straight-chain or branched-chain, saturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C1-C6). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl and similar alkyl groups, with methyl being preferred.

[0081] The term "pharmaceutically acceptable excipients" refers to all substances contained in a pharmaceutical preparation other than the active pharmaceutical ingredient, and is generally divided into two categories: excipients and additives. For details, reference can be made to the Pharmacopoeia of the People's Republic of China (2020 Edition), Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0082] The term "treatment" refers to eliminating the cause or alleviating the symptoms.

[0083] The term "prevention" refers to reducing the risk of developing a disease.

[0084] The term "patient" refers to any animal that needs to receive treatment or prevention of a disease, usually a mammal, such as a human. Mammals include, but are not limited to: cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.

[0085] On the basis of not violating the common knowledge in the art, the above preferred conditions can be arbitrarily combined to obtain various preferred examples of the present invention.

[0086] The reagents and raw materials used in the present invention are all commercially available.

[0087] The positive and progressive effects of the present invention are as follows: The present invention provides a class of benzodihydrofuran tricyclic compounds with novel structures, their pharmaceutical compositions and uses. The compounds of the present invention have good effects on the 5-HT2A receptor and have the function of treating mental diseases, especially having a good effect against depression. Detailed Embodiments

[0088] The present invention will be further illustrated below by way of examples, but the present invention is not limited to the scope of the examples described herein. The experimental methods without specific conditions noted in the following examples are carried out according to conventional methods and conditions, or are selected according to the product specifications.

[0089] Preparation of Intermediates

[0090] Intermediate A: 3-(2,3-dihydrobenzofuran-7-yl)propanal

[0091]

[0092] Step 1: At room temperature, dissolve 2,3-dihydrobenzofuran-7-carbaldehyde (1.0 g, 6.7 mmol) and methyl (triphenylphosphoranylidene)acetate (3.36 g, 10.05 mmol) in anhydrous tetrahydrofuran (15 mL). Stir the reaction mixture at 80 °C for 2 h. Cool the reaction mixture to room temperature and concentrate it under vacuum to obtain the crude product. Purify the crude product 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] +

[0093] Step 2: At room temperature, dissolve methyl A-1 (1.18 g, 5.8 mmol) in methanol (10 mL), and then add 10% wet palladium on carbon (310 mg, 0.29 mmol). Stir the reaction mixture at room temperature under a hydrogen atmosphere for 1 h. Filter the reaction mixture through diatomaceous earth, wash it with methanol, and combine and concentrate the filtrate under vacuum to obtain A-2 (1.15 g, yield: 96.6%) as a colorless viscous oil. The crude product is used directly in the next step without purification. MS m / z (ESI): 207.1 [M+H] +

[0094] Step 3: At room temperature, dissolve A-2 (500 mg, 2.4 mmol) in tetrahydrofuran (8 mL), cool it to 0 °C under a nitrogen atmosphere, and then add a 1 M solution of lithium aluminum hydride in tetrahydrofuran (8 mL). Stir the reaction mixture at room temperature for 1 h. Stir the reaction mixture at 0 °C, slowly dilute it with ethyl acetate (20 mL), add sodium sulfate decahydrate, filter it through diatomaceous earth, wash it with methanol, and concentrate it under vacuum to obtain the crude product. Purify the crude product by column chromatography (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] +

[0095] Step 4: At room temperature, dissolve A-3 (3 g, 16.9 mmol) in dichloromethane (100 mL), place it in a nitrogen atmosphere, then add DMP (21.4 g, 50.6 mmol), and stir at room temperature for 5 hours. Filter the reaction solution through diatomaceous earth, wash the filtrate with saturated aqueous sodium bicarbonate solution, and concentrate the organic phase under vacuum to obtain the crude product. The crude product is purified by column chromatography (EtOAc / PE = 0 - 20%) to obtain A (2.5 g, yield: 84.2%) as a colorless oily liquid.

[0096] Intermediate B: 2-(2,3-dihydrobenzofuran-7-yl)acetaldehyde

[0097]

[0098] Step 1: Add 7-bromo-2,3-dihydrobenzofuran (5.0 g, 25.1 mmol), potassium vinyltrifluoroborate (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) together into a 100 mL single-necked flask, then add dioxane / water (45 mL, V1 / V2 = 8:1). After adding, slowly heat up to 110 °C under a nitrogen atmosphere and stir overnight. After TLC detects that the reaction is complete, cool the reaction solution to room temperature, filter it under reduced pressure, add water (30 mL) to the filtrate, extract with ethyl acetate (50 mL x 2), combine the organic phases, wash with saturated brine (50 mL x 1), dry over anhydrous sodium sulfate, evaporate under reduced pressure, and purify the crude product by column chromatography (EtOAc / PE = 0 - 2%) to obtain a pale yellow oily substance B-1 (3.20 g, yield: 87%).

[0099] Step 2: Add compound B-1 (1.0 g, 6.8 mmol) and anhydrous THF (10 mL) together into a 100 mL three-necked flask, slowly dropwise add 2M B2H6 / dimethyl sulfide solution (6 mL) under N2 and an ice-water bath. After adding, stir at room temperature for 3 h. Then slowly dropwise add 10% aqueous NaOH solution (7 mL) and 30% H2O2 solution (1 mL) respectively under an ice-water bath. After adding, stir at room temperature overnight. After TLC detects that the reaction is complete, add water (20 mL) to the reaction solution, extract with ethyl acetate (20 mL x 2), combine the organic phases, wash with saturated brine (30 mL x 1), dry over anhydrous sodium sulfate, evaporate under reduced pressure, and purify the crude product by column chromatography (EtOAc / PE = 0 - 30%) to obtain a pale yellow oily substance B-2 (0.6 g, yield: 54%). 11H 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] + .

[0100] Step 3: At room temperature, B-2 (600 mg, 3.7 mmol) and anhydrous DCM (10 mL) were added together into a 50 mL single-necked flask, and then Dess-Martin reagent (2.3 g, 5.5 mmol) was added in batches. After addition, the mixture was stirred at room temperature for 1 h. After TLC detection showed that the reaction was complete, the reaction solution was filtered, and the filtrate was slowly added dropwise with saturated NaHCO3 solution to adjust the pH of the system to alkaline. It was extracted with DCM (20 mL × 2), the organic phases were combined, washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (EtOAc / PE = 0 - 10%) to obtain a colorless oil B (0.4 g, yield: 67%).

[0101] Example 1: 1-(6-(((3-(2,3-dihydrobenzofuran-7-yl)propyl)amino)methyl)-2,3,5,6-tetrahydro-1H-pyrrolo[1,2,3-de]quinoxalin-1-yl)ethanone

[0102]

[0103] Step 1: 7-Nitro-1H-indole (5.00 g, 30.8 mmol) was dissolved in DCM (50.0 mL), and NBS (6.59 g, 37.0 mmol) was added. The reaction was carried out at 25 o °C for 12 h. After LCMS detection showed that the reaction was complete, water was added, and it was extracted with EA, dried over sodium sulfate, filtered and concentrated, and purified by silica gel column (PE: EA = 5: 1) to obtain compound 1-1 (yellow solid, 4.00 g, yield 54%). MS m / z (ESI): 241.2, 243.2 [M+H] + .

[0104] Step 2: 1-1 (2.20 g, 9.12 mmol) was dissolved in DMF (20.0 mL), and K2CO3 (3.78 g, 27.4 mmol) and ethyl 2-bromoacetate (2.29 g, 13.7 mmol) were added. The reaction was carried out at 25 o °C for 2 h. After completion of the reaction detected by LCMS, water was added, and the mixture was extracted with EA, dried over sodium sulfate, filtered and concentrated, and purified by silica gel column (PE: EA = 5: 1) to obtain compound 1-2 (yellow solid, 1.93 g, yield 61%). MS m / z (ESI): 349.0, 351.0 [M+Na] + .

[0105] Step 3: 1-2 (1.93 g, 5.90 mmol) was dissolved in THF (20.0 mL) and H2O (10.0 mL), and Fe (1.65 g, 29.5 mmol) and NH4Cl (1.58 g, 29.5 mmol) were added. The reaction was carried out at 70 o °C for 3 h. After completion of the reaction detected by LCMS, methanol was added, filtered and concentrated, and purified by silica gel column (DCM: MeOH = 10: 1) to obtain compound 1-3 (yellow solid, 900 mg, yield 61%). MS m / z (ESI): 251.0, 253.0 [M+H] +

[0106] Step 4: 1-3 (120 mg, 0.478 mmol) was dissolved in THF (5.0 mL), and BH3 / Me2S (3.58 mL, 7.17 mmol, 2 M) was added. The reaction was carried out at 20 o °C for 12 h. After completion of the reaction detected by LCMS, methanol was added, filtered and concentrated to obtain compound 1-4 (yellow solid, 100 mg, yield 88%). MS m / z (ESI): 237.4, 239.4 [M+H] +

[0107] Step 5: 1-4 (15.0 g, 63.2 mmol) was dissolved in DCM (200.0 mL), and TEA (17.5 mL, 126 mmol) and AcCl (7.40 g, 94.9 mmol) were added. The reaction was carried out at 25 oReact at C for 3 h. After detecting the completion of the reaction by LCMS, add water, extract with EA, add sodium sulfate for drying, filter and concentrate, and purify by silica gel column (DCM: MeOH = 10: 1) to obtain compounds 1-5 (yellow solid, 15.0 g, yield 85%). MS m / z (ESI): 279.2, 281.2 [M+H] + .

[0108] Step 6: Under nitrogen, dissolve 1-5 (5.00 g, 17.9 mmol) in 1,4-dioxane (60.0 mL) and water (20.0 mL), add potassium N-aminomethyltrifluoroborate (6.37 g, 26.8 mmol), Pd(OAc)2 (400 g, 1.79 mmol), n-butyldi(1-adamantyl)phosphine (640 mg, 1.79 mmol) and Cs2CO3 (11.6 g, 35.8 mmol). React at 100 o C for 18 h. After detecting the completion of the reaction by LCMS, add water, extract with EA, add sodium sulfate for drying, filter and concentrate, and purify by silica gel column (DCM: MeOH = 10: 1) to obtain compound 1-6 (yellow gel, 3.00 g, yield 50%). MS m / z (ESI): 330.2 [M+H] + .

[0109] Step 7: Under ice bath, dissolve 1-6 (1.00 g, 3.03 mmol) in THF (10 mL) and TFA (6 mL), add NaBH3CN (1.91 mg, 30.3 mmol). React at 25 o C for 16 h. After detecting the completion of the reaction by LCMS, add water, extract with EA, add sodium sulfate for drying, filter and concentrate, and purify by silica gel column (DCM: MeOH = 10: 1) to obtain compound 1-7 (yellow solid, 800 mg, yield 79%). MS m / z (ESI): 332.2 [M+H] + .

[0110] Step 8: Dissolve 1-7 (800 mg, 2.41 mmol) in DCM (5 mL), add TFA (3 mL). React at 25 o C for 1 h. After detecting the completion of the reaction by LCMS, add water, extract with EA, add sodium sulfate for drying, filter and concentrate to obtain compound 1-8 (yellow solid, 400 mg, yield 71%). MS m / z (ESI): 232.2 [M+H] +

[0111] Step 9: Under nitrogen, 1-8 (180 mg, 0.623 mmol) was dissolved in MeOH (35 mL) and DCM (21 mL), and intermediate A (87.7 mg, 0.498 mmol) and NaBH(AcO)3 (919 mg, 4.35 mmol) were added. The reaction was carried out at 25 o °C for 1 h. After completion of the reaction detected by LCMS, water was added, and the mixture was extracted with EA, dried over sodium sulfate, filtered and concentrated, and then purified by preparative chromatography (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30% - 70%) to obtain compound E1 (white solid, 26.5 mg, yield 12%). 1 1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.04 (dd, J = 7.2, 1.2 Hz, 1H), 6.91 (d, J = 7.2 Hz, 1H), 6.85 (d, J = 7.2 Hz, 1H), 6.73 (t, J = 7.2 Hz, 1H), 6.54 (dd, J = 8.0, 7.2 Hz, 1H), 4.49 (t, J = 8.8 Hz, 2H), 3.98 - 3.69 (m, 2H), 3.58 - 3.38 (m, 2H), 3.21 - 2.95 (m, 6H), 2.88 - 2.75 (m, 1H), 2.63 - 2.51 (m, 5H), 2.21 (s, 3H), 1.76 - 1.58 (m, 2H). MS m / z (ESI): 392.2 [M+H] + .

[0112] Example 2: 1-(6-(((3-(2,3-dihydrobenzofuran-7-yl)propyl)(methyl)amino)methyl)-2,3,5,6-tetrahydro-1H-pyrrolo[1,2,3-de]quinoxalin-1-yl)ethan-1-one

[0113]

[0114] Step 1: Under nitrogen, E1 (110 mg, 0.281 mmol l) was dissolved in MeOH (20 mL) and DCM (12 mL), and paraformaldehyde (42.1 mg, 1.40 mmol) and NaBH(AcO)3 (592.6 mg, 2.81 mmol) were added. The reaction was carried out at 25 oReact at 12 h under C. After detecting the completion of the reaction by LCMS, add water, extract with EA, add sodium sulfate for drying, filter and concentrate, and then prepare and purify (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30% - 70%) to obtain compound E2 (white solid, 36.5 mg, yield 32%). 1 1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.03 (d, J = 7.2 Hz,1H), 6.90 (d, J = 7.6 Hz, 1H), 6.85 (d, J = 7.2 Hz, 1H), 6.72 (t, J = 7.6 Hz,1H), 6.54 (t, J = 7.6 Hz, 1H), 4.48 (t, J = 8.8 Hz, 2H), 3.99 - 3.71 (m, 2H),3.51 - 3.36 (m, 2H), 3.32 - 3.27 (m, 1H), 3.15 (t, J = 8.8 Hz, 3H), 3.09 - 2.98 (m,2H), 2.58 - 2.52 (m, 1H), 2.48 - 2.27 (m, 4H), 2.22 (s, 3H), 2.21 (s, 3H), 1.72 - 1.61 (m, 2H). MS m / z (ESI): 406.4 [M+H] + .

[0115] Example 3: 1-(6-(((2-(2,3-dihydrobenzofuran-7-yl)ethyl)amino)methyl)-2,3,5,6-tetrahydro-1H-pyrrolo[1,2,3-de]quinoxalin-1-yl)ethan-1-one

[0116]

[0117] Step 1: Under nitrogen, 1-8 (100 mg, 0.432 mmol) was dissolved in MeOH (10 mL) and DCM (6 mL), and intermediate B (56.1 mg, 0.346 mmol) and NaBH(AcO)3 (638.3 mg, 3.02 mmol) were added. React at 25 o C for 1 h. After detecting the completion of the reaction by LCMS, add water, extract with EA, add sodium sulfate for drying, filter and concentrate, and then prepare and purify (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30% - 70%) to obtain compound E3 (white solid, 27.0 mg, yield 16%). 11H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.08 - 7.03 (m, 1H), 6.94 (d, J = 7.4 Hz, 1H), 6.81 (d, J = 6.8 Hz, 1H), 6.73 (t, J = 7.4 Hz, 1H), 6.53 (dd, J = 8.1, 7.4 Hz, 1H), 4.48 (t, J = 8.8 Hz, 2H), 3.85 (s, 2H), 3.40 (s, 3H), 3.19 - 2.99 (m, 5H), 2.85 (dd, J = 11.4, 5.7 Hz, 1H), 2.75 (dd, J = 11.1, 4.3 Hz, 2H), 2.63 (dd, J = 12.3, 5.4 Hz, 3H), 2.21 (s, 3H). MS m / z (ESI): 378.2 [M+H] + .

[0118] Example 4: 1-(6-(((2-(2,3-dihydrobenzofuran-7-yl)ethyl)(methyl)amino)methyl)-2,3,5,6-tetrahydro-1H-pyrrolo[1,2,3-de]quinoxalin-1-yl)ethan-1-one

[0119]

[0120] The preparation of E4 refers to the synthetic method of E2. 1H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.07 - 7.02 (m, 1H), 6.95 (d, J = 7.2 Hz, 1H), 6.79 (d, J = 6.8 Hz, 1H), 6.73 (t, J = 7.2 Hz, 1H), 6.54 - 6.46 (m, 1H), 4.48 (t, J = 8.8 Hz, 2H), 4.04 - 3.63 (m, 2H), 3.49 - 3.36 (m, 2H), 3.20 - 2.92 (m, 6H), 2.71 - 2.53 (m, 5H), 2.37 - 2.26 (m, 3H), 2.21 (s, 3H). MS m / z (ESI): 392.2 [M+H] + .

[0121] Example 5: 6 - ((((3 - (2,3 - Dihydrobenzofuran - 7 - yl)propyl)(methyl)amino)methyl)-1 - methyl - 5,6 - dihydro - 1H - pyrrolo[1,2,3 - de]quinoxaline - 2,3 - dione

[0122]

[0123] Step 1: Add compound 7 - bromo - 1H - indole - 3 - carbaldehyde (6 g, 26.78 mmol), methylamine hydrochloride (26.2 g, 340.1 mmol), and MeOH (200 mL) into a 500 - mL single - necked flask. Add NaBH(OAc)3 (51.7 g, 245.5 mmol) in batches (once every half an hour), and then stir the reaction at room temperature for 16 hours. After detecting the completion of the reaction by LCMS, concentrate the methanol, adjust the pH to 9 - 10 with 2N NaOH, extract three times with DCM, dry and concentrate, and then purify by column chromatography (DCM / MeOH = 10 / 1) to obtain 5 - 1 (yellow oil, 7 g, yield >100%). MS m / z (ESI): 239.2, 241.2 [M + H] + .

[0124] Step 2: Add compound 5 - 1 (7 g, 29.29 mmol) and 100 ml of TFA into a 250 - mL single - necked flask. Then add NaBH3CN (14.6 g, 234.3 mmol) in batches under an ice - bath. After addition, stir under an ice - bath for 2 hours under nitrogen protection. After detecting the completion of the reaction by LCMS, quench the reaction with water, concentrate most of the TFA, then adjust the pH to 7 - 8 with saturated sodium bicarbonate, extract three times with DCM, dry and concentrate to obtain the crude compound 5 - 2 (yellow oil, 6 g, yield 86%). The crude product was not further purified and was directly used in the next step. MS m / z (ESI): 241.2, 243.2 [M + H] + .

[0125] Step 3: Add compound 5 - 2 (6 g, 24.89 mmol), TEA (6.5 g, 49.78 mmol), and 100 mL of DCM into a 250 - mL single - necked flask. Then add Boc2O (6.5 g, 29.87 mmol) under an ice - bath. After addition, stir at room temperature for 10 min under nitrogen protection. After detecting the completion of the reaction by LCMS, concentrate and purify by column chromatography (PE / EA = 5 / 1) to obtain compound 5 - 3 (yellow oil, 5.2 g, yield 62%). MS m / z (ESI): 241.2, 243.2 [M + H] + .

[0126] Step 4: Add compound 5-3 (2.7 g, 11.25 mmol), 2-bromo-N-methylamide (3.6 g, 23.4 mmol) and DMAc (20 mL) into a 100 mL single-neck flask. Subsequently, add DIEA (1.5 g, 11.8 mmol) and TBAB (1 g, 0.59 mmol) respectively. After adding, stir at 110 o °C for 16 h. When the reaction is completed as detected by LCMS, add water and EA, separate the layers. The aqueous phase is extracted with EA three times. The combined organic phases are washed with saturated sodium chloride three times, dried, concentrated, and purified by column chromatography (DCM / MeOH = 100 / 1) to obtain compound 5-4 (white solid, 2.8 g, yield 61%). MS m / z (ESI): 411.2, 413.2 [M+H] + .

[0127] Step 5: Add compound 5-4 (500 mg, 1.22 mmol), Pd2(dba)3 (125 mg, 0.14 mmol), BINAP (150 mg, 0.42 mmol), sodium tert-butoxide (150 mg, 1.56 mmol), and dioxane (8 mL) into a 25 mL microwave tube. Bubble with N2 for 1 min, and carry out microwave reaction at 100 o °C for 2 h. When the reaction is completed as detected by LCMS, add water and EA, separate the layers. The aqueous phase is extracted with EA three times. The combined organic phases are washed with saturated sodium chloride three times, dried, and concentrated to obtain compounds 5-5 and 5-5-1 (brown oil, 500 mg, yield >100%), which are directly used for the next step. MS m / z (ESI): 346.2, 332.2 [M+H] + .

[0128] Step 6: Add compound 5-5 (30 mg, 0.087 mmol) and hydrochloric acid dioxane solution (2 mL) into a 25 mL single-neck flask, and react at room temperature for 1 h. When the reaction is completed as detected by LCMS, concentrate to obtain compound 5-6 (crude product, 20 mg, yield >100%), which is directly used for the next step. MS m / z (ESI): 246.2 [M+H] + .

[0129] Step 7: Dissolve compound 5-6 (20 mg, 0.086 mmol) in DCM / MeOH (1:1, 2 mL), add intermediate A (18 mg, 0.104 mmol) and Na(OAc)3BH (46 mg, 0.216 mmol), and at 20o React for 30 min. LCMS was used to detect the completion of the reaction. The reaction was quenched with sodium bicarbonate solution, extracted with DCM, dried over sodium sulfate, filtered and concentrated, and purified by Prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30% - 70%) to obtain compound E5 (gray solid, 1.22 mg, yield 3.5%). 1 1H NMR (500 MHz, CDCl3) δ 7.19 (d, J = 6.5 Hz, 2H), 7.04 (d, J = 7.5 Hz, 1H), 7.02 - 7.00 (m, 1H), 6.91 (d, J = 7.5 Hz, 1H), 6.75 (t, J = 7.5 Hz, 1H), 4.55 (t, J = 8.5 Hz, 2H), 4.48 - 4.39 (m, 1H), 4.26 (dd, J = 8.5 5.0 Hz, 1H), 3.91 (s, 1H), 3.62 (s, 3H), 3.21 (t, J = 9.0 Hz, 2H), 2.86 - 2.51 (m, 5H), 2.40 (s, 3H), 2.22 - 1.79 (m, 3H). MS m / z (ESI): 406.2 [M + H]+ + .

[0130] Example 6: 3-(2,3-Dihydrobenzofuran-7-yl)-N-methyl-N-((1-methyl-2,3,5,6-tetrahydro-1H-pyrrolo[1,2,3-de]quinoxalin-6-yl)methyl)propan-1-amine

[0131]

[0132] Step 1: Add 5-5-1 (310 mg, 0.94 mmol) and THF (10 mL) to a 50 mL three-necked flask, displace with N2 three times, and add 1M BH3Me2S (0.9 mmol, 0.9 mL) at 0 o °C. After the addition was complete, the temperature was raised to 70 o °C and react for 16 h. LCMS was used to monitor the completion of the reaction. Cool the reaction solution to 0 o °C, add methanol to quench the reaction, concentrate and column chromatograph (PE / EA = 3 / 1) to obtain compound 6-1 (150 mg, yellow oil, yield: 50%). MS m / z (ESI): 318.2 [M + H]+.

[0133] Step 2: The preparation method of 6-2 refers to the synthesis method of the sixth step of E5. MS m / z (ESI): 409.7 [M+H] + .

[0134] Step 3: The preparation method of E6 refers to the synthesis method of the ninth step of Example 1. 1 H NMR (500 MHz, CDCl3)δ 7.05 (d, J = 7.5 Hz, 1H), 6.92 (d, J = 7.5 Hz, 1H), 6.77 (d, J = 7.5 Hz,1H), 6.65 (s, 1H), 6.49 (d, J = 3.0 Hz, 1H), 6.39 (d, J = 5.0 Hz, 1H), 4.55(t, J = 8.5 Hz, 2H), 3.58-3.35 (m, 4H), 3.22-3.10 (m, 5H), 2.98-2.76 (m, 5H),2.67-2.43 (m, 6H), 2.03-1.90 (m, 3H). MS m / z (ESI): 378.3 [M+H] + .

[0135] Example 7: 6-(((3-(2,3-dihydrobenzofuran-7-yl)propyl)(methyl)amino)methyl)-5,6-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0136]

[0137] Step 1: Add compound 5-3 (1.0 g, 2.93 mmol), 2-chloro-acetamide (1.4 g, 14.67 mmol) and anhydrous dioxane (20 mL) into a 100 mL single-necked flask. Subsequently, add DIEA (2.0 g, 14.67mmol) and KI (2.0 g, 11.72 mmol) respectively. After adding, heat to 110 o °C under nitrogen protection and stir for 48 h. After the reaction is completed by LCMS detection, add water (50 mL) to the reaction solution, extract with EA (50 mL x 3), combine the organic phases, wash with saturated NaCl (50mL x 2), dry over anhydrous sodium sulfate, concentrate, and purify the crude product by normal-phase column chromatography (eluent gradient (0-80% EA / PE)) to obtain compound 7-1 (pale yellow oil, 1.0 g, yield 85%). MS m / z (ESI): 398.1 and 400.0 [M+H] + .

[0138] Step 2: The preparation method of 7-2 refers to the synthesis method in Step 6 of E5. MS m / z (ESI): 298.2 and 300.1 [M+H] + .

[0139] Step 3: The preparation method of 7-3 refers to the synthesis method in Step 9 of Example 1. MS m / z (ESI): 459.4 [M+H] + .

[0140] Step 4: Add compound 7-3 (35 mg, 1.22 mmol), CuI (3.0 mg, 0.14 mmol), K2CO3 (20 mg, 0.42 mmol), N1,N2-dimethylethane-1,2-diamine (30 mg, 1.56 mmol) and anhydrous dioxane (2 mL) into a 10 mL microwave tube together. Bubble with N2 for 1 min and heat to 100 o C and carry out microwave reaction for 1.5 h. After detecting the end of the reaction by LCMS, directly filter and concentrate the reaction solution. Dissolve the crude product with DMF (2 mL), and then carry out preparative separation and purification by Prep-HPLC reverse phase (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30% - 70%) to obtain compound E7 (white solid, 10 mg, yield 35%). 1 1H NMR (500 MHz, CDCl3) δ 7.82 (s, 1H), 7.13 - 7.01 (m, 2H), 6.99 - 6.83 (m, 2H), 6.81 - 6.64 (m, 2H), 4.54 (t, J = 8.7 Hz, 2H), 3.80 - 3.64 (m,1H), 3.20 (t, J = 8.6 Hz, 3H), 2.70 - 2.30 (m, 8H), 1.91 - 1.64 (m, 6H). MS m / z(ESI): 378.8 [M+H] + .

[0141] Example 8: 3-(2,3-dihydrobenzofuran-7-yl)-N-methyl-N-((2,3,5,6-tetrahydro-1H-pyrrolo[1,2,3-de]quinoxalin-6-yl)methyl)propan-1-amine

[0142]

[0143] The preparation method of E8 refers to the synthesis method in Step 1 of E6. 11H NMR (500 MHz, CDCl3) δ 7.07 (d, J = 6.9 Hz, 1H), 6.92 (d, J = 7.4 Hz, 1H), 6.78 (t, J = 7.2 Hz, 1H), 6.64 - 6.56(m, 1H), 6.55 - 6.47 (m, 1H), 6.37 (d, J = 7.6 Hz, 1H), 4.53 (t, J = 8.5 Hz,2H), 3.80 - 3.43 (m, 5H), 3.25 - 3.10 (m, 4H), 3.09 - 2.83 (m, 5H), 2.60 (d, J =12.1 Hz, 5H), 2.10 - 1.99 (m, 2H). MS m / z (ESI): 364.7 [M+H] + .

[0144] Example 9: 2-(2,3-Dihydrobenzofuran-7-yl)-N-methyl-N-((2,3,5,6-tetrahydro-1H-pyrrolo[1,2,3-de]quinoxalin-6-yl)methyl)ethan-1-amine

[0145]

[0146] The preparation of E7 refers to the synthesis method of E3. 1 1H NMR (400 MHz, CDCl3) δ 7.04–7.01 (m, 1H),6.94 (d, J = 7.6 Hz, 1H), 6.76 (t, J = 7.2 Hz, 1H), 6.64 (t, J = 7.6 Hz, 1H),6.53 (d, J = 7.2 Hz, 1H), 6.38 (d, J = 7.6 Hz, 1H), 4.53 (t, J = 8.8 Hz, 2H),3.50 - 3.33 (m, 4H), 3.19 (td, J = 8.4, 3.5 Hz, 3H), 3.08 - 2.96 (m, 2H), 2.85(s, 3H), 2.80 - 2.59 (m, 4H), 2.38 (s, 3H). MS m / z (ESI): 350.3 [M+H] +

[0147] Example 10: 7-(((3-(2,3-Dihydrobenzofuran-7-yl)propyl)(methyl)amino)methyl)-3,4,6,7-tetrahydro-[1,4]diazepino[3,2,1-hi]indol-2(1H)-one

[0148]

[0149] Step 1: 5 - 3 (1 g, 2.93 mmol) was dissolved in DMF (10 mL). Sodium hydride (600 mg, 14.6 mmol) was added at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. Subsequently, 3 - bromopropionamide (2.23 g, 14.6 mmol) was added. The reaction was monitored by LCMS until completion, then poured into ice water for quenching, and extracted with ethyl acetate and water. It was eluted through a column with (75% ethyl acetate / petroleum ether) to obtain the crude compound 10 - 1 (white oil, 300 mg, yield 27.3%). MS m / z (ESI): 412.3, 414.3 [M + H] + .

[0150] Step 2: 10 - 1 (300 mg, 0.776 mmol) was dissolved in 1,4 - dioxane solution (5 mL), and N,N - dimethylethylenediamine (200 mg, 2.17 mmol), potassium carbonate (210 mg, 1.55 mmol), and copper(I) iodide (30 mg, 0.155 mmol) were added. The reaction was carried out at 100 o °C for 3 h. The reaction was monitored by LCMS until completion. Water was added, and the mixture was extracted with ethyl acetate, dried with sodium sulfate, filtered, and concentrated. First, it was purified by a silica gel column, and then separated and purified by Prep - HPLC reverse - phase preparation (eluent (v / v): acetonitrile / (water + 0.05% HCOOH) = 30% - 70%) to obtain compound 10 - 2 (white solid, 110 mg, yield 42.7%). MS m / z (ESI): 332.2, [M + H] + .

[0151] Step 3: 10 - 2 (70 mg, 0.211 mmol) was dissolved in a dioxane solution of hydrogen chloride (2 mL). After stirring at room temperature for 1 h, the reaction was monitored. When the reaction was complete, the reaction solution was rotary - evaporated and directly used for the next step without purification to obtain compound 10 - 3 (white solid, 56 mg, yield 100%). MS m / z (ESI): 232.2, [M + H] + .

[0152] Step 4: 10 - 3 (30 mg, 0.130 mmol) was dissolved in 1 ml each of dichloromethane and methanol, and sodium triacetoxyborohydride (140 mg, 0.650 mmol) was added. After stirring for 0.5 h, 3 - (2,3 - dihydrobenzofuran - 7 - yl) propanal (35 mg, 0.195 mmol) was further added. 25o React at C for 3 h. When the reaction is completed as detected by LCMS, rotary evaporate the reaction solution, dissolve it in acetonitrile, filter it, and then separate and purify it by preparative reverse-phase HPLC (eluent (v / v): acetonitrile / (water + 0.05% HCOOH) = 30% - 70%) to obtain compound E10 (yellow solid, 15.28 mg, yield 30%).

[0153] 1 H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.05 (d, J = 7.2 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.85 - 6.81 (m, 1H), 6.77 (t, J = 7.6 Hz, 1H), 6.68 - 6.62 (m, 2H), 4.53 (t, J = 8.8 Hz, 2H), 3.60 (t, J = 8.6 Hz, 1H), 3.50 – 3.48 (m, 1H), 3.36 - 3.30 (m, 2H), 3.19 (t, J = 8.8 Hz, 2H), 2.87 – 2.84 (m, 2H), 2.83 - 2.57 (m, 6H), 2.50 (s, 3H), 1.95 - 1.86 (m, 2H). MS m / z (ESI): 392.3 [M+H] +

[0154] Example 11: 7 - ((((2 - (2,3 - Dihydrobenzofuran - 7 - yl)ethyl)(methyl)amino)methyl) - 3,4,6,7 - tetrahydro - [1,4]diazepino[3,2,1 - hi]indol - 2(1H) - one

[0155]

[0156] The preparation of E11 refers to the synthesis method of E3. 11H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 7.07–6.86 (m, 1H), 6.95 (d, J = 7.6 Hz, 1H), 6.84 - 6.75 (m, 2H), 6.66 - 6.62 (m, 2H), 4.54 (t, J = 8.8 Hz, 2H), 3.57–3.42 (m, 2H), 3.39 - 3.36 (m, 1H), 3.35 - 3.30 (m, 2H), 3.20 (t, J = 8.6 Hz, 2H), 2.99 - 2.89 (m, 2H), 2.88 - 2.80 (m, 6H), 2.56 (s, 3H). MS m / z (ESI): 378.5 [M+H] +

[0157] Example 12: 1-(7-(((3-(2,3-dihydrobenzofuran-7-yl)propyl)(methyl)amino)methyl)-3,4,6,7-tetrahydro-[1,4]diazepino[3,2,1-hi]indol-1(2H)-yl)ethan-1-one

[0158]

[0159] Step 1: 10-2 (130 mg, 0.392 mmol) was dissolved in borane tetrahydrofuran (2.0 mL), and the reaction was carried out at 50 °C for 2 h under nitrogen protection. The reaction was monitored by LCMS. After completion, the reaction solution was concentrated in vacuo to obtain the crude product 12-1 (colorless oil, 120 mg, yield 100%), which was directly used in the next step. MS m / z (ESI): 318.3 [M+H] + .

[0160] Step 2: 12-1 (120 mg, 0.378 mmol) was dissolved in dichloromethane (3.0 mL). Acetyl chloride (30 mg, 0.378 mmol) and triethylamine (76 mg, 0.756 mmol) were added at 0 °C, and then the reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was monitored by LCMS. After completion, the reaction solution was filtered and concentrated in vacuo to obtain the crude product compound 12-2 (yellow solid, 140 mg, yield 100%), which was directly used in the next step without purification. MS m / z (ESI): 359.3 [M+H] + .

[0161] Step 3: 12-2 (140 mg, 0.389 mmol) was dissolved in hydrochloric acid dioxane solution (2.0 mL), 25o React at C for 2 h. LCMS detected the completion of the reaction, and the reaction mixture was directly dried to obtain crude product 12-3 (yellow solid, 110 mg, yield 95.5%), which was directly used for the next step. MS m / z (ESI): 260.2 [M+H] + .

[0162] Step 4: 12-3 (45 mg, 0.174 mmol) was dissolved in dichloromethane (1.0 mL) and methanol (1.0 mL). Sodium cyanoborohydride (190 mg, 0.868 mmol) was added at room temperature, and after stirring for 0.5 h, intermediate A (32 mg, 0.174 mmol) was added continuously. LCMS detected the completion of the reaction, the reaction mixture was filtered and dried, dissolved in a small amount of acetonitrile, and product E13 (yellow solid, 30.18 mg, yield 41.4%) was obtained by preparative Pre-HPLC (H2O / ACN, FA). 1 1H NMR (400 MHz, CDCl3) δ 7.04 (t, J = 9.0 Hz, 2H), 6.89 –6.85 (m, 2H),6.74–6.70 (m, 2H), 5.23 (s, 1H), 4.78 (s, 1H), 4.53 (t, J = 8.8 Hz, 2H), 3.45(s, 2H), 3.20 (t, J = 8.8 Hz, 3H), 2.92-2.65 (m, 6H), 2.63-2.56 (m, 3H), 2.45(s, 3H), 1.92–1.86 (m, 6H). MS m / z (ESI): 420.2[M+H]+.

[0163] Example 13: 1-(7-(((2-(2,3-dihydrobenzofuran-7-yl)ethyl)(methyl)amino)methyl)-3,4,6,7-tetrahydro-[1,4]diazepino[3,2,1-hi]indol-1(2H)-yl)ethan-1-one

[0164]

[0165] The preparation of E13 refers to the synthesis method of E3. 11H NMR (400 MHz, CDCl3) δ 7.03 (t, J = 11.2 Hz, 2H), 6.94 (d, J = 7.6 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.77 (t, J = 7.2 Hz, 1H), 6.69 (t, J = 7.6 Hz, 1H), 4.79 (s, 1H), 4.53 (t, J = 8.8 Hz, 2H), 3.45–3.42 (m, 2H), 3.27 - 3.12 (m, 3H), 2.97 (d, J = 49.6 Hz, 1H), 2.80 - 2.57 (m, 7H), 2.38 (s, 3H), 1.98 (d, J = 16.4 Hz, 4H), 1.61 (s, 2H). MS m / z (ESI): 406.2 [M+H]+.

[0166] Example 14: 1-(6-((((2,3-dihydrobenzofuran-7-yl)methyl)(methyl)amino)methyl)-2,3,5,6-tetrahydro-1H-pyrrolo[1,2,3-de]quinoxalin-1-yl)ethan-1-one

[0167]

[0168] Step 1: Under nitrogen, 1-8 (70 mg, 0.303 mmol) was dissolved in MeOH (1 mL) and DCM (1 mL), and 2,3-dihydrobenzofuran-7-carbaldehyde (45 mg, 0.303 mmol) and NaBH(OAc)3 (190 mg, 0.908 mmol) were added. The reaction was carried out at 25 o °C for 1 h. After the reaction was completed as detected by LCMS, water was added, and the mixture was extracted with EA, dried over sodium sulfate, filtered, and concentrated to obtain compound 14-1 (white solid, 50 mg, yield 45%).

[0169] Step 2: The preparation method of E14 refers to the synthesis method of E2. 1H NMR (400 MHz, CDCl3) δ 7.10 (dd, J = 7.5, 1.9 Hz, 2H), 6.85 (dt, J = 14.9, 7.3 Hz, 3H), 6.65 (d, J = 36.9Hz, 1H), 4.56 (td, J = 8.8, 1.4 Hz, 2H), 4.02 - 3.83 (m, 2H), 3.64 (d, J = 13.3Hz, 3H), 3.48 (d, J = 13.3 Hz, 1H), 3.34 - 3.02 (m, 5H), 2.74 - 2.66 (m, 1H), 2.64 - 2.57 (m, 1H), 2.31 (d, J = 4.1 Hz, 6H). MS m / z (ESI): 378.3 [M+H] + .

[0170] Effect Example 1: Test of the downstream beta - arrestin functional activity of the 5 - HT2A receptor

[0171] It was mainly carried out using the NanoBret kit from Promega Corporation. The specific steps are as follows: Construct plasmids of 5HT2A receptor with Nanoluc at the C-terminus, beta-arrestin plasmid with Halo-tag at the C-terminus, and pcDNA3.1 plasmid expressing GRK2 respectively. Before transfection, seed HEK293 cells (ATCC, CRL-1573) into 6-well plates. After overnight culture, mix the plasmids of Nanoluc-5HT2AR, GRK2, and beta-arrestin-halotag in a ratio of 1:1:10 and add them to the 6-well plates together with the transfection reagent. The transfection amount per well is 2 μg. After 4 hours, digest the cells and transfer them to 384-well plates, with 20,000 cells per well, and add the compound to be tested or 5-HT as a positive control. The test substance is added in solution form, and the solvent is DMSO. The final concentration of the test compound is up to 100 μM, diluted 5-fold, with 9 points; the highest concentration of 5HT is 100 μM, diluted 5-fold, with 11 points. Continue to incubate overnight at 37 °C in a 5% CO2 environment. The next day, after taking out, add the diluted NanoBRET™ Nano-Glo substrate (10 μl per well after dilution according to the instruction manual), and read the values at 618 nm / 460 nm on a microplate reader. Take the value of the highest concentration of 5-HT (5-hydroxytryptamine) as 100% of the activation degree of the downstream pathway, analyze the data using Prism software, and use the "log(agonist) vs. response -- Variable slope (four parameters)" model to fit the data to obtain EC 50 and E max , as shown in Table 1 specifically.

[0172] Table 1

[0173]

Claims

1. A compound as shown in formula I or a pharmaceutically acceptable salt thereof: ； in, X1 is NR X1 , CR X2 R X3 , -O- or -S-; R X1 is H, C1-C6 alkyl or -C(O)-C1-C6 alkyl; R X2 and R X3 are independently H or C1-C6 alkyl; R 1 are independently oxo, halogen, C1-C6 alkyl, -C(O)-C1-C6 alkyl or thio; R 2 is H or C1-C6 alkyl; L 1 For-(CR L1 R L2 ) m1 -; R L1 and R L2 are independently H or C1-C6 alkyl; n1 is 0, 1 or 2; m1 is 1, 2, 3 or 4; n is 1 or 2.

2. 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) Each "C1-C6 alkyl" and "-C(O)-C1-C6 alkyl" in "C1-C6 alkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl or ethyl, and also such as methyl; (2) R 1 wherein the halogen is fluorine, chlorine, bromine or iodine.

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) X1 is NR X1 ; (2) R X1 is H or -C(O)-C1-C6 alkyl, for example -C(O)-C1-C6 alkyl, for example -C(O)-C1-C3 alkyl; (3) R 1 is an oxo group; (4) n1 is 0 or 1, for example, n1 is 0; (5) R 2 is C1-C6 alkyl, such as C1-C3 alkyl, and also such as methyl; (6) R L1 and R L2 is H; (7) m1 is 1, 2 or 3, for example, m1 is 2 or 3; (8)n is 1.

4. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: It is any of the following: Scenario 1: The compound shown in formula I is a compound shown in formula I-1: ； Among them, n, n1, R X1 , R 1 , R 2 and L 1 Definition as defined in any one of claims 1-3; Scenario 2: The compound shown in formula I is a compound shown in formula I-2: ； Among them, X1, R 2 and L 1 The definition as described in any one of claims 1 to 3.

5. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 4, characterized in that: It is any of the following: Scenario 1: In the compound shown in formula I-1: R X1 is H, C1-C6 alkyl or -C(O)-C1-C6 alkyl; n is 1 or 2; n1 is 0, 1 or 2; R 1 is an oxo group; R 2 is H or C1-C6 alkyl; L 1 For-(CR L1 R L2 ) m1 -; R L1 and R L2 is H; m1 is 1, 2, 3 or 4; Scenario 2: In the compound shown in formula I-2, X1 is NR X1 ; R X1 is H; R 2 is a C1-C6 alkyl group, L 1 For-(CR L1 R L2 ) m1 -; R L1 and R L2 is H; m1 is 2; Scenario 3: The compound as shown in formula I-1 is a compound as shown in formula I-1-1: ； R X1 is -C(O)-C1-C6 alkyl, R 2 is a C1-C6 alkyl group, L 1 For-(CR L1 R L2 ) m1 -; R L1 and R L2 is H; m1 is 2 or 3.

6. 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) R X1 is H, methyl or ; (2) R 2 is H or methyl; (3) L 1 for or .

7. 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 is any of the following compounds: 、 、 、 、 、 、 、 、 、 、 、 、 、 。 8. A pharmaceutical composition, comprising: (1) a compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, and (2) Pharmaceutically acceptable excipients.

9. A use of a compound of formula I or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 7 or a pharmaceutical composition as described in claim 8, wherein the use is selected from one or more of the following uses: (1) Use in the preparation of drugs for treating and / or preventing diseases associated with 5-HT2A receptors; (2) Use in the preparation of 5-HT2A receptor agonists and / or inhibitors; (3) Use in the preparation of drugs for treating and / or preventing mental illnesses.

10. The use according to claim 9, characterized in that It meets one or both of the following conditions: (1) The above and 5-HT 2A Diseases associated with the receptor are psychiatric disorders, such as depression; (2) Use in the preparation of 5-HT2A receptor agonists; (3) The mental illness is depression.

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