Benzodihydrofuran compounds, pharmaceutical compositions thereof and uses thereof

Abstract

The application discloses a benzodihydrofuran compound, a pharmaceutical composition thereof and application. The application provides a compound as shown in formula I or a pharmaceutically acceptable salt thereof. The compound has a sedative effect and helps to relieve the mania symptoms of patients with mental diseases.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and particularly relates to a benzodihydrofuran compound, a pharmaceutical composition thereof and application. BACKGROUND

[0002] Serotonin is a monoamine neurotransmitter, and through different receptor subtypes, it realizes its various biological functions including mood, cognition, reward, learning, memory, etc. (Young SN. J Psychiatry Neurosci. 2007 Nov;32(6):394-9). 5-HT2A receptors belong to a serotonin receptor family, which currently consists of more than 15 different receptors encoded by different genes, and are 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 cause neuronal excitation in multiple brain regions, and among all 14 serotonin receptor subtypes, 5-HT2A receptors are widely present in the central system, are the highest concentration level among the monoamine receptors in the cerebral cortex, and are distributed in the median nucleus / dorsal raphe nucleus, locus coeruleus and ventral tegmental area, and other structure regions involved in emotion regulation (Zieba A, Stepnicki 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 related to many neuropsychiatric diseases such as schizophrenia, depression and anxiety, etc. (Guiard BP, DiGiovanni G. Front Pharmacol. 2015 Mar 17;6:46). SUMMARY

[0004] The technical problem to be solved by the present application is to overcome the defect of single structure of sedative drugs in the prior art. To this end, the present application provides a class of novel benzodihydrofuran compounds, a pharmaceutical composition thereof and application. The compound of the present application has a sedative effect, which helps to relieve the symptoms of mania in patients with mental diseases.

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

[0006] ;

[0007] wherein ring A is "5-10 membered heterocycloalkyl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, or 3 rings" or "5-10 membered heterocycloalkenyl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, or 3 rings";

[0008] R 1 is hydroxy;

[0009] ring B is or ;

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

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

[0012] X 3 is 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 application, certain groups in the compounds of Formula I, or pharmaceutically acceptable salts thereof, are defined as follows, and any group not mentioned is as described in any embodiment of the application (simply "in an embodiment of the application").

[0018] In an embodiment of the application, the 5-10 membered heterocycloalkyl is monocyclic or spirocyclic.

[0019] In an embodiment of the application, the 5-10 membered heterocycloalkyl has 1 or 2 heteroatoms independently selected from N; for example, , , or .

[0020] In an embodiment of the application, the 5-10 membered heterocycloalkenyl is 6-8 membered heterocycloalkenyl.

[0021] In an embodiment of the application, the 5-10 membered heterocycloalkenyl has 1 heteroatom independently selected from N; for example, or .

[0022] In a certain embodiment of the present application, each of said C1-C6 alkyl groups is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl or s-butyl; preferably methyl.

[0023] In a certain embodiment of the present application, ring A is "5-10 membered heterocycloalkyl, wherein the heteroatoms are selected from 1, 2 or 3 N, O and S, and the number of heteroatoms is 1, 2 or 3".

[0024] In a certain embodiment of the present application, ring B is .

[0025] In a certain embodiment of the present application, X 1 is oxygen or -CH2-; preferably oxygen.

[0026] In a certain embodiment of the present application, X 2 is -NR 3 .

[0027] In a certain embodiment of the present application, R 3 is or methyl; preferably .

[0028] In a certain embodiment of the present application, R 2 is oxo.

[0029] In a certain embodiment of the present application, n is 2 or 3, preferably 2.

[0030] In a certain embodiment of the present application, m is 0 or 1; preferably 0.

[0031] In a certain embodiment of the present application, x is 0 or 1; preferably 0.

[0032] In a certain embodiment of the present application, ring A is , , , , or ; preferably, , , or ; further preferably, , or ; wherein a is attached to ring B and b is attached to .

[0033] In a certain embodiment of the present application, is , , , 、 、 or ; preferably 、 、 、 or ; further preferably 、 or ; wherein a is connected to ring B and b is connected to .

[0034] In one embodiment of the present application, ring B is 、 、 、 or ; preferably 、 、 、 、 or ; further preferably 、 、 、 or ; more preferably or .

[0035] In one embodiment of the present application, is 、 、 、 、 、 or ; preferably 、 、 、 or ; further preferably or .

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

[0037] or ;

[0038] wherein ring A, R 1 , X 1 , X 2 , X 3 , R 2, n, m and x are as defined in any aspect of the present application.

[0039] In an aspect of the present application, the compound of Formula I is a compound of Formula I-1-1 or I-1-2:

[0040] or ;

[0041] wherein Y is -CH- or N, X 2 and n are as defined in any aspect of the present application.

[0042] In an aspect of the present application, the compound of Formula I or a pharmaceutically acceptable salt thereof is any one of the following compounds:

[0043] .

[0044] The present application provides a pharmaceutical composition comprising:

[0045] (1) a compound of Formula I or a pharmaceutically acceptable salt thereof as described in any aspect of the present application and

[0046] (2) a pharmaceutically acceptable excipient.

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

[0048] (1) the preparation of a 5-HT 2A receptor agonist;

[0049] (2) the preparation of a medicament for treating and / or preventing a disease associated with 5-HT 2A receptors;

[0050] (3) the preparation of a medicament for treating and / or preventing mania in a patient with a psychiatric disease.

[0051] In an aspect of the present application, the disease associated with 5-HT 2A receptors is mania in a patient with a psychiatric disease.

[0052] Explanation of terms

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

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

[0055] The term "pharmaceutically acceptable salt" refers to a salt of a compound prepared by reaction of the compound with a pharmaceutically acceptable acid or base. When a compound contains relatively acidic functionalities, base addition salts can be obtained by contacting the compound in a suitable inert solvent with a sufficient amount of the pharmaceutically acceptable base to produce the salt. When a compound contains relatively basic functionalities, acid addition salts can be obtained by contacting the compound in a suitable inert solvent with a sufficient amount of the pharmaceutically acceptable acid to produce the salt. See, e.g., Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0056] "-" at the end of a group denotes that the group is connected to the rest of the molecule at this point; "— " in the middle of a structural fragment denotes that the fragment is connected to the rest of the molecule at this point, e.g., "=0" denotes an oxo 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 membered), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified kind of heteroatoms (one, two, or three of N, O, and S), which is monocyclic, bridged cyclic, or spirocyclic, and each ring is saturated. Heterocycloalkyl is connected to the rest of the molecule by a carbon atom or a heteroatom. Heterocycloalkyl includes, but is not limited to:

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

[0061] The term "alkyl" refers to a straight or branched, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., Ci-C6). Alkyl includes, but is not limited to, methyl, and the like.

[0062] ​​​​​​​The term "pharmaceutically acceptable excipient" refers to all substances other than the active pharmaceutical ingredient contained in a pharmaceutical preparation, which are generally divided into two categories of excipients and additional agents. For details, see the People's Republic of China Pharmacopoeia (2020 Edition), Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0063] The term "treatment" refers to eliminating the cause or relieving 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, in need of treatment or prevention of a disease. Mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.

[0066] On the basis of not violating the common sense of the art, the above-mentioned preferred conditions can be combined arbitrarily, i.e., to obtain each preferred example of the present application.

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

[0068] The positive progress effect of the present application is that the present application provides a class of novel benzodihydrofuran compounds, pharmaceutical compositions and applications thereof. The compounds of the present application have a sedative effect, which helps to alleviate the symptoms of mania in patients with mental diseases. BRIEF DESCRIPTION OF DRAWINGS

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

[0070] The present application will be further illustrated by the following examples, but the present application is not limited in the scope of the examples. The experimental methods in the following examples are not specified, which are selected according to the conventional methods and conditions, or according to the instructions of the goods.

[0071] The following abbreviations represent the following reagents, respectively:

[0072]

[0073] Preparation of intermediates

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

[0075] The term "pharmaceutically acceptable excipient" refers to all substances other than the active pharmaceutical ingredient contained in a pharmaceutical preparation, which are generally divided into two categories of excipients and additional agents. For details, see the People's Republic of China Pharmacopoeia (2020 Edition), Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0063] The term "treatment" refers to eliminating the cause or relieving 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, in need of treatment or prevention of a disease. Mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.

[0066] On the basis of not violating the common sense of the art, the above-mentioned preferred conditions can be combined arbitrarily, i.e., to obtain each preferred example of the present application.

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

[0068] The positive progress effect of the present application is that the present application provides a class of novel benzodihydrofuran compounds, pharmaceutical compositions and applications thereof. The compounds of the present application have a sedative effect, which helps to alleviate the symptoms of mania in patients with mental diseases. BRIEF DESCRIPTION OF DRAWINGS

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

[0070] The present application will be further illustrated by the following examples, but the present application is not limited in the scope of the examples. The experimental methods in the following examples are not specified, which are selected according to the conventional methods and conditions, or according to the instructions of the goods.

[0071] The following abbreviations represent the following reagents, respectively:

[0072]

[0073] Preparation of intermediates

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

[0075]

[0076] Step 1: 2,3-Dihydrobenzofuran-7-carbaldehyde (1.0 g, 6.7 mmol) and (triphenylphosphoranyl) acetate (3.36 g, 10.05 mmol) were dissolved in anhydrous tetrahydrofuran (15 mL) at room temperature. The reaction was stirred at 80 °C for 2 h. The reaction was cooled to room temperature and concentrated in vacuo to give a crude product. The crude product was purified by column chromatography (EtOAc / PE = 0 - 10%) to give A-1 (1.18 g, yield: 76.1%) as a white solid. MS m / z (ESI): 205.1 [M+H] +

[0077] Step 2: A-1 (1.18 g, 5.8 mmol) was dissolved in methanol (10 mL) at room temperature, and then 10% wet palladium on carbon (310 mg, 0.29 mmol) was added. The reaction was stirred at room temperature under hydrogen atmosphere for 1 h. The reaction was filtered through celite, washed with methanol, and the filtrate was concentrated in vacuo to give A-2 (1.15 g, yield: 96.6%) as a colorless viscous oil. The crude product was used directly in the next reaction without purification. 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, and then cooled to zero degree under nitrogen atmosphere, and then 1M lithium aluminum hydride in tetrahydrofuran (8 mL) was added, and stirred at room temperature for 1 h. The reaction was stirred at zero degree, diluted with ethyl acetate (20 mL) and sodium sulfate decahydrate was added, filtered through celite, washed with methanol, and concentrated in vacuo to give a crude product. The crude product was purified by column chromatography (EtOAc / PE = 0 - 15%) to give A-3 (340 mg, yield: 78.7%) as a colorless oil. MS m / z (ESI): 179.1 [M+H] +

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

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

[0081]

[0082] Step 1 : Compound 7-bromo-2,3-dihydrobenzofuran (5.0 g, 25.1 mmol), potassium vinyltrifluoroborate (6.7 g, 50.2 mmol), Pd(dppf)Cl2dichloromethane complex (0.8 g, 1.25 mmol) and potassium carbonate (7.0 g, 50.2 mmol) were added together into a 100 mL single necked flask, followed by dioxane / water (45 mL, V1 / V2= 8:1), after addition, the reaction mixture was stirred at 110 °C under nitrogen atmosphere overnight. After TLC detection of the reaction was completed, the reaction mixture was cooled to room temperature, filtered under reduced pressure, the filtrate was added water (30 mL), extracted with ethyl acetate (50 mL x 2), combined organic phase was washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, rotary evaporated under reduced pressure, the crude product was purified by column chromatography (EtOAc / PE = 0 - 2%) to give B-1 (3.20 g, yield: 87%) as a light yellow oil.

[0083] Step 2: Compound B-1 (1.0 g, 6.8 mmol) and anhydrous THF (10 mL) were added together into a 100 mL three necked flask, 2M B2H6 / dimethyl sulfide solution (6 mL) was added slowly dropwise under N2and ice water bath, after dropwise addition, the reaction mixture was allowed to stir at room temperature for 3 h. Then 10% NaOH aqueous solution (7 mL) and 30% H2O2solution (1 mL) were added slowly dropwise under ice water bath respectively, after dropwise addition, the reaction mixture was allowed to stir at room temperature overnight. After TLC detection of the reaction was completed, water (20 mL) was added to the reaction mixture, extracted with ethyl acetate (20 mL x 2), combined organic phase was washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, rotary evaporated under reduced pressure, the crude product was purified by column chromatography (EtOAc / PE = 0 - 30%) to give B-2 (0.6 g, yield: 54%) as a light yellow oil. 1H NMR (500 MHz, CDC13) 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: C-2 (600 mg, 3.7 mmol) and anhydrous DCM (10 mL) were added into a 50 mL single neck flask at room temperature, followed by the addition of Dess-Martin reagent (2.3 g, 5.5 mmol) in portions. The reaction mixture was stirred at room temperature for 1 h. After TLC detection showed that the reaction was complete, the reaction mixture was filtered, and the filtrate was slowly added to a saturated NaHC03solution to adjust the pH of the system to basic, extracted with DCM (20 mL x 2), combined organic phase, washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, rotary evaporated under reduced pressure, and the crude product was purified by column chromatography (EtOAc / PE = 0-10%) to give B (0.4 g, yield: 67%) as a colorless oil.

[0085] Example 1: 1-(8-(1-(3-(2,3-dihydrobenofuran-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: 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) were dissolved in 8 mL of dioxane, and an aqueous solution of potassium phosphate (816 mg, 3.85 mmol, 2 mL of H20) was added. After replacement with N2, Pd(dppf)Cl2DCM (63 mg, 0.077 mmol) was added, and the mixture was heated to 90 oC, and stirred at room temperature for 16 h. TLC showed the reaction was complete, water and EtOAc were added to separate the layers, the aqueous phase was extracted with EtOAc, the combined organic phases were washed with saturated sodium chloride solution three times, dried and concentrated, and purified by column chromatography on normal silica gel (PE / EtOAc = 3 / 1) to give compound 1-1 (430 mg, off-white solid, yield 88%). MS m / z (ESI): 317.2 [M+H] + .

[0088] Step 2: 1-1 (430 mg, 1.36 mmol) was dissolved in 10 mL DCM, DIEA (0.67 mL, 4.1 mmol) was added, and the mixture was cooled to 0 o C, and acetyl chloride (128 mg, 1.63 mmol) was added. The mixture was stirred at room temperature for 16 h, concentrated, and purified by column chromatography on normal silica gel (PE / EtOAc = 3 / 1) to give compound 1-2 (410 mg, off-white solid, yield 84%). MS m / z (ESI): 359.2 [M+H] + .

[0089] Step 3: 1-2 (95 mg, 0.265 mmol) was dissolved in 2 mL DCM, TFA (0.5 mL, 6.73 mmol) was added, and the mixture was stirred at room temperature for 1 h, concentrated to give compound 1-3, which was used directly 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. before NaBH(OAc)3 (170 mg, 0.8 mmol) was added. The mixture was stirred at room temperature for 16 h, water and DCM were added to separate the layers, and the organic phase was washed with water, dried, and concentrated, and purified by column chromatography on normal silica gel (DCM / MeOH = 10 / 1) to give 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-dihydrobenofuran-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 at room temperature for 2 hours for hydrogenation. After filtration, prep-HPLC purification separation (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30% - 70%) gave 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: l-(8-(l-(2-(2,3-dihydrobenzo furan-7-yl)ethyl)-l,2,3,6-tetrahydropyridin-4-yl)- 2,3-dihydro-4H-benzo[b][l,4]oxazin-4-yl)ethan-l-one

[0095]

[0096] E3 was prepared according to the procedure for Step 4 of El. 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] E4 was prepared according to the synthetic procedure 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)ethan-1 -one

[0101]

[0102] Step 1: Compound 8-bromo-3,4-dihydro-2H-benzo[b][l,4]oxazine (1.0 g, 4.67 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)- carboxylate (1.7 g, 5.61 mmol), Pd(dppf)Cl2dichloromethane complex (0.19 g, 0.23 mmol) and potassium carbonate (1.9 g, 14.01 mmol) were added into a 100 mL single necked flask, then 1, 4-dioxane / water (12 mL, V1 / V2=5: 1) was added, after addition, the mixture was stirred at 80 °C under nitrogen atmosphere overnight. After the reaction was completed by LCMS detection, the reaction solution was cooled to room temperature, filtered under reduced pressure, water (30 mL) was added to the filtrate, and ethyl acetate (50 mL x 2) was extracted, the combined organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure. The crude product was purified by column chromatography (EtOAc / PE = 0 - 50%) to give compound 5-1 (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 into a 100 mL single necked flask, then dichloromethane (15 mL) and triethylamine (0.68 g, 6.72 mmol) were added, followed by dropwise addition of acetyl chloride (0.2 g, 2.43 mmol), after addition, the mixture was stirred at room temperature for 1 h. The reaction solution was rotary evaporated under reduced pressure, and the crude product was purified by column chromatography (EtOAc / PE = 0 - 50%) to give 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 into a 10 mL single necked flask, then HCl / dioxane (1 mL) was added, after addition, the mixture was stirred at room temperature for 12 h. After the reaction was completed by LCMS detection, the reaction solution was rotary evaporated under reduced pressure to give crude compound 5-3 (gray solid, 0.13 g, yield 90%). The crude product was used directly in the next step without further purification. MS m / z (ESI): 259.4 [M+H] + .

[0105] Step 4: Preparation of E5 was performed according to the synthetic procedure of Example 1, Step 4. 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] + .

[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 into a 100 mL single-neck flask, followed by the addition of Pd / C (2 mg, 0.015), which was stirred at room temperature under a hydrogen atmosphere for 5 h. After the reaction was completed as determined by LCMS, the reaction mixture was filtered under reduced pressure, and the filtrate was directly purified 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: Compound 8-3 (200 mg, 0.6 mmol) and potassium carbonate (414 mg, 3 mmol) were added into a 50 mL single-neck flask, followed by DMF (10 mL), and finally iodomethane (0.4 ml, 6 mmol). After addition, the reaction was slowly warmed to 80 °C under nitrogen protection and stirred overnight. After the reaction was completed, the reaction was cooled to room temperature, filtered, concentrated, and columned to obtain the product 7-1 (yellow solid, 150 mg, yield 72.4%). MS m / z (ESI): 290.5 [M+H-tBu] 0 C and stirred overnight. After the reaction was completed, the reaction was cooled to room temperature, filtered, concentrated, and columned to obtain the 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 is referred to the preparation method of E2. MS m / z (ESI): 246.3 [M+H] + .

[0113] Step 3: The preparation method of E7 is referred to the preparation method of the fourth step of 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 = 13.1 Hz, 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: Compound 1-fluoro-2-nitrobenzene (2 g, 14.2 mmol) and tert-butyl 4- aminopiperidine-1-carboxylate (5.6 g, 28.4 mmol), potassium carbonate (7.8 g, 56.8 mmol) were added into a 100 mL single-neck flask, then acetonitrile (100 mL) was added, after addition, the reaction was heated to reflux slowly under nitrogen protection and stirred overnight. LCMS detection showed that the reaction was completed, the reaction was cooled to room temperature, filtered, concentrated, and columned 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 was the same as that 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), then chloroacetyl chloride (807 mg, 7.1 mmol) was slowly added, and the reaction was carried out at 0 0 C for 1 h, then the reaction was pulled dry, then acetonitrile (20 mL) and sodium bicarbonate (2.3 g, 27.5 mmol) were added, after addition, the reaction was heated to reflux slowly under nitrogen protection and stirred overnight. LCMS detection showed that the reaction was completed, the reaction was cooled to room temperature, filtered, concentrated, and columned to obtain product 8-3 (yellow solid, 800 mg, yield 43.6%). MS m / z (ESI): 276.4 [M+H-tBu] 0 + 。

[0119] Step 4: The preparation method of 8-4 was the same as that of the third step of Intermediate A. MS m / z (ESI): 318.2 [M+H] + .

[0120] Step 5: The preparation method of 8-5 was the same as that 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 was the same as that of the third step of Example 1. MS m / z (ESI): 260.4 [M+H]​+

[0122] Step 7: Preparation of E8 was performed according to the synthetic procedure of Example 1, Step 4. 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] Preparation of E9 was performed according to the synthetic procedure of Example 1, Step 4. 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 synthesis method of the second step of Intermediate A.

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

[0133] Step 3: The preparation method of E11 refers to the synthesis method of the fourth step of Example E10. 1H NMR (500 MHz, CDC13) 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][l,4]dioxin-5-yl)-l-(2-(2,3-dihydrobenzofuran-7- yl)ethyl)piperidine

[0135]

[0136] Step 1: The preparation of 12-1 was performed according 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 of 12-2 was performed according to the synthesis method of Example 6. MS m / z (ESI): 264.2 [M+H-tBu] +

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

[0139] Step 4: The preparation of E12 was performed according to the fourth step of the synthesis method of Example 1. 1 H NMR (500 MHz, CDC13) 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-(l-(2-(2,3-dihydrobenzo[b]furan-7-yl)ethyl)piperidin-4-yl)-4- methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine

[0141]

[0142] Step 1: Compound 1-1 (150 mg, 0.48 mmol) was dissolved in 8 mL of acetonitrile, cesium carbonate (315 mg, 0.96 mmol) was added, followed by iodomethane (204 mg, 1.44 mmol), and heated to reflux for 16 h. TLC indicated the reaction was complete, water and EtOAc were added to separate the layers, the aqueous phase was extracted with EtOAc, the combined organic phases were washed with saturated sodium chloride solution three times, dried and concentrated and purified by normal phase silica gel chromatography (PE / EtOAc = 3 / 1) to give compound 13-1 (115 mg, colorless oil, 72% yield). MS m / z (ESI): 331.2 [M+H] + .

[0143] Step 2: Compound 13-2 was prepared according to the synthetic method described in E1 Step 3. MS m / z (ESI): 231.4 [M+H] +

[0144] Step 3: Compound 13-3 was prepared according to the synthetic method described in E1 Step 4. MS m / z (ESI): 377.8 [M+H] +

[0145] Step 4: Compound E13 was prepared according to the synthetic method described in 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][l,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 reaction was stirred at room temperature for 16 h, aqueous NaOH (0.13 mL, 0.13 mmol) was added, and then hydrogen peroxide solution (0.015 mL, 0.13 mmol) was added. The reaction was stirred at room temperature for 3 h. TLC detection showed that the reaction was complete. Water and EtOAc were added to separate the layers, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with saturated sodium chloride solution, concentrated, filtered, and purified 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-(l-(2-(2-3-dihydrobenzofuran-7-yl)ethyl)piperidin-4-yl)-3,4- dihydroquinolin-l(2H)-yl)ethan-l-one

[0150]

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

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

[0153] Step 3: Preparation of 15-3 was performed by the synthetic method similar to that of Example 6.

[0154] Step 4: Preparation of 15-4 was performed by the synthetic method similar to that of Example E5, Step 3.

[0155] Step 5: Preparation of E15 was performed by the synthetic method similar to that 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-dihydrobenofuran-7-yl)ethyl)-5-azaspiro[2.5]octan-8-yl)-2,3-dihydro-4H-benzo[b][l,4]oxazin-4-yl)ethan-l-one

[0157]

[0158] Step 1: Compound tert-butyl 8-oxo-5-azaspiro[2.5]octane-5-carboxylate (100 mg, 0.44 mmol) and 4-methylbenzenesulfonylhydrazide (83 mg, 0.44 mmol) were added into a single neck flask, followed by the addition of anhydrous methanol (10 mL), after the addition, the reaction was stirred at room temperature under nitrogen protection overnight. LCMS detection showed that the reaction was completed, the reaction solution was rotary evaporated under reduced pressure to obtain the crude compound 16-1 (white solid, 170 mg, yield 98%). The crude product was used directly in the next step without further purification. 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][l,4]oxazine (0.36 g, 0.36 mmol), Pd2(dba)3(30 mg, 0.03 mmol), X-Phos (15 mg, 0.1 mmol), t-BuOLi (80 mg, 1.00 mmol) were added into a 100 mL single neck flask, followed by the addition of anhydrous dioxane (5 mL), after addition, the reaction mixture was slowly warmed to 110 °C under nitrogen atmosphere and stirred overnight. LCMS detection showed the reaction was completed, the reaction mixture was allowed to cool to room temperature, water (20 mL) was added to the reaction mixture, EtOAc (2 x 20 mL) was used to extract the mixture, the combined organic phase was washed with saturated brine (1 x 20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, the crude product was purified by column chromatography (EtOAc / PE = 0 - 30%) to give compound 16-2 (yellowish 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 into a 25 mL single neck flask, acetyl chloride (12 mg) was added dropwise under ice water bath, after addition, the reaction mixture was allowed to stir at room temperature for 1 h. LCMS detection showed the reaction was completed, saturated NH4Cl solution (10 mL) was added to the reaction mixture, DCM (2 x 10 mL) was used to extract the mixture, the combined organic phase was washed with saturated brine (1 x 20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, the crude product was purified by column chromatography (EtOAc / PE = 0 - 30%) to give compound 16-3 (yellowish 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 into a 25 mL single neck flask, followed by the addition of 10% Pd / C (wet, 30 mg), after addition, the reaction mixture was stirred at 40 °C under hydrogen atmosphere for 5 h. LCMS detection showed the reaction was completed, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give crude compound 16-4 (yellowish oil, 25 mg, yield 83%). The crude product was used in the next step without further purification. 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 into a 25 mL single neck flask, followed by the addition of TFA (1 mL), after addition, it was stirred at room temperature for 1 h. After the reaction was detected by LCMS, the reaction solution was rotary evaporated under reduced pressure to give the crude compound 16-5 (pale yellow oil, 20 mg). The crude product was used directly in the next step without further purification. MS m / z (ESI): 287.5 [M+H] + .

[0163] Step 6: Preparation of E16 according to the synthetic method of Example E1, Step 4. 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)ethan-1-one

[0165]

[0166] Step 1: 8-bromo-3,4-dihydro-2H-benzo[b][l,4]oxazine (500 mg, 2.34 mmol) and TEA (473 mg, 4.68 mmol) were dissolved in DCM (10 mL) at room temperature, N2 was replaced for three times, acetyl chloride (220 mg, 2.80 mmol) was added. The reaction was stirred at room temperature for 10 min. LC-MS was used to monitor the reaction completion, sat. NaCl solution was added, the solution was separated, dried, and concentrated in vacuum to get the crude product. The crude product was purified by column chromatography (EtOAc / PE = 0 - 30%) to get 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-butyl piperazine-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 into a three-neck flask with 1,4-dioxane (15 mL) at room temperature, N2 was replaced for three times, the reaction was stirred at 100 o C for 16 h. LC-MS was used to monitor ~40% product formation, water and EA were added, the solution was separated, the water phase was extracted with EA twice, dried, and concentrated in vacuum to get the crude product. The crude product was purified by column chromatography (EtOAc / PE = 0 - 30%) to get 17-2 (400 mg, yield: 64.3%) as a brown solid. MS m / z (ESI): 320.3 [M+H] + .

[0168] Step 3: 17-3 was prepared according to the synthetic method of Step 1. MS m / z (ESI): 362.2 [M+H] + .

[0169] Step 4: 17-3 (300 mg, 0.83 mmol) was dissolved in DCM (6 mL) at room temperature, and TFA (2 mL) was added. The reaction was stirred at room temperature for 1 h. LC-MS was used to monitor the reaction. When the reaction was completed, most of the TFA was removed by concentration, sat. NaHC03solution was added to adjust the pH to 7-8, and the water phase was extracted with a mixture of DCM / MeOH=10 / 1. The organic phase was dried and concentrated under vacuum to obtain a crude product. The crude product was purified by column chromatography (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: E17 was prepared according 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: Test of downstream beta-arrestin functional activity of 5-HT2A receptor

[0172] The NanoBret kit of Promega Company was mainly used. Specifically as follows: 5HT2A receptor plasmid with Nanoluc at C terminal, beta-arrestin plasmid with Halo-tag at C terminal, and pcDNA3.1 plasmid expressing GRK2 were constructed. Before transfection, HEK293 cells (ATCC, CRL-1573) were seeded in 6-well plates and incubated overnight. Then the plasmids of Nanoluc-5HT2AR, GRK2, and beta-arrestin-halotag were mixed at a ratio of 1:1:10 and added to the 6-well plates together with the transfection reagent. The transfection amount of each well was 2 ug. After 4 hours, the cells were digested and transferred to 384-well plates, with 20,000 cells per well. The tested compounds or 5-HT were added as positive control, and the incubation was continued at 37°C, 5% CO2 overnight. The next day, diluted NanoBRET™ Nano-Glo substrate (10 ul per well after dilution according to the instructions) was added, and the reading value of 618 nm / 460 nm was read on the enzyme marker. The reading value of the highest concentration of 5-HT was taken as 100% of the activation degree of the downstream pathway. Prism software was used to analyze the data, and the "log(agonist) vs. response -- Variable slope (four parameters)" model was used to fit the data to obtain the EC50 value of the tested compound. 50 and E max .

[0173] Table 1

[0174]

[0175] Effect Example 2: Animal behavior test

[0176] This experiment was a forced swimming test for mice. The animals were 7-8 week old C57BL / 6J male mice, 12 in each group. Twenty-four hours before the test, the mice were placed in a 5L glass beaker with a water surface height of 15 cm for 15 minutes. On the test day, the mice were placed in the same beaker for 6 minutes after intraperitoneal injection of blank solvent (5% DMSO, 10% polyethylene glycol-15-hydroxystearate, 85% physiological saline), ketamine (20mpk), or the test substance (15mpk) 30 minutes before. The immobile time of the mice in the last four minutes was analyzed by software (Shanghai Jiliang, JLBehv-FSG-4). The immobile time of each administration group was compared with the immobile time of the solvent control group of the same batch. If the data met the normal distribution, the statistical method was the parametric test, i.e. independent sample t test. If the data did not meet the normal distribution, the statistical method was the non-parametric test, as shown in Table 2 and the attached figures. Figure 1The column chart is expressed by mean ± standard error, (* p<0.05, ** p<0.01). The column chart is expressed by 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 reduces the immobile time of the mice, and the compounds 16 and 17 of the present application can significantly increase the immobile time of the mice, and play a sedative effect on the mice.

[0177] Table 2

[0178] .

Claims

1. A compound as shown in Formula I or a pharmaceutically acceptable salt thereof, characterized in that... ； Among them, ring A is R 1 is hydroxyl; Ring B is X 1 It can be -NH-, oxygen, or -CH2-; X 2 For -NR 3 -or oxygen; X 3 It is nitrogen; R 3 It is a C1-C6 alkyl or -C(O)-C1-C6 alkyl; R 2 It 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 as claimed in claim 1, or a pharmaceutically acceptable salt thereof; characterized in that, Each of the C1-C6 alkyl groups is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, or sec-butyl.

3. The compound of formula I as described in claim 2, or a pharmaceutically acceptable salt thereof; characterized in that, Each of the C1-C6 alkyl groups is independently methyl.

4. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof; characterized in that, It meets one or more of the following conditions: (1) Ring B is (2)X 1 It is oxygen or -CH2-; (3)X 2 For -NR 3 -; (4)R 3 for or methyl; (5)R 2 It is an oxygen group; (6) n is 2 or 3; (7) m is 0 or 1; and (8) x is 0 or 1.

5. The compound of formula I as claimed in claim 4, or a pharmaceutically acceptable salt thereof; characterized in that, It meets one or more of the following conditions: (1)X 1 For oxygen; (2)R 3 for (3) n is 2; (4) m is 0; and (5) x is 0.

6. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof; characterized in that, Ring B is 7. The compound of formula I as claimed in claim 6, or a pharmaceutically acceptable salt thereof; characterized in that, It meets one or two of the following conditions: (1) Ring A is Among them, end a is connected to ring B, and end b is connected to... Connected; and (2) Ring B is 8. The compound of formula I as claimed in claim 7, or a pharmaceutically acceptable salt thereof; characterized in that, It meets one or two of the following conditions: (1) Ring A is Among them, end a is connected to ring B, and end b is connected to... Connected; and (2) Ring B is 9. The compound of formula I as claimed in claim 8, or a pharmaceutically acceptable salt thereof; characterized in that, Ring B is 10. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof; characterized in that, for 11. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof; characterized in that, It meets one or two of the following conditions: (1) for Among them, end a is connected to ring B, and end b is connected to... Connected; and (2) for 12. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof; characterized in that, It meets one or two of the following conditions: (1) for Among them, end a is connected to ring B, and end b is connected to... Connected; and (2) for 13. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof; characterized in that, The compound shown in Formula I is a compound shown in Formula I-1 or Formula I-2: Among them, rings A and R 1 X 1 X 2 X 3 R 2 The definitions of , n, m and x are as described in any one of claims 1-12.

14. A compound of formula I-1-1 or I-1-2, or a pharmaceutically acceptable salt thereof: in, Y is -CH- or N, X 2 The definition is as described in any one of claims 1-12; The definition of n is as described in any one of claims 1, 4, and 5.

15. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof; characterized in that, The compound represented by Formula I or a pharmaceutically acceptable salt thereof is any of the following compounds:

16. A pharmaceutical composition comprising: (1) The compound of formula I as claimed in any one of claims 1-13 and 15, or a pharmaceutically acceptable salt thereof, the compound of formula I-1-1 or I-1-2 as claimed in claim 14, or a pharmaceutically acceptable salt thereof, and (2) Pharmaceutically acceptable excipients.

17. Use of a compound of formula I or a pharmaceutically acceptable salt thereof as described in any one of claims 1-13 and 15, a compound of formula I-1-1 or I-1-2 as described in claim 14, or a pharmaceutical composition as described in claim 16, wherein the use is selected from: (1) Preparation of 5-HT 2A Receptor agonists; (2) Preparation of treatment and / or prevention with 5-HT 2A Drugs for receptor-related diseases; and (3) Prepare drugs for the treatment and / or prevention of mania in patients with mental illnesses.

18. The use as described in claim 17, characterized in that, The diseases associated with the 5-HT2A receptor are mania in patients with mental illnesses.

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