Salt form and crystal form of 5-HT2a receptor inverse agonist, preparation method therefor and use thereof

Abstract

The present invention relates to a salt form and a crystal form of a 5-HT2A receptor inverse agonist, a preparation method therefor and the use thereof. Specifically, provided are a pharmaceutically acceptable salt of a compound of formula (I), a crystal form of a fumarate thereof, a preparation method therefor, and the use thereof for treating 5-HT2A receptor-related diseases.

Description

A 5-HT 2A Salt form, crystal form of receptor inverse agonist, preparation method and application thereof Technical Field

[0001] The present invention belongs to the field of medicinal chemistry and specifically relates to a 5-HT 2A Receptor inverse agonist salt form, crystal form, preparation method and application thereof. Background Art

[0002] Parkinson's disease is a common degenerative disorder of the central nervous system. Previously, people often focused on the motor symptoms of PD, such as resting tremor, muscle rigidity, bradykinesia, and postural and gait disturbances. Currently, Parkinson's disease affects approximately 7 to 10 million people worldwide, and over 50% of these patients experience psychiatric symptoms. These symptoms, primarily hallucinations and delusions, pose significant challenges to the treatment and care of Parkinson's patients.

[0003] For a long time, antipsychotic drugs have been used clinically to treat hallucinations and delusions in Parkinson's patients. The first generation of antipsychotic drugs mainly inhibit dopamine D2 receptors and have serious extrapyramidal side effects. In addition to inhibiting D2 receptors, the second generation of antipsychotic drugs also inhibits specific 5-HT receptors, especially 5-HT 2A Second-generation antipsychotics inhibit D2 receptors and have a better safety profile, meaning fewer extrapyramidal side effects than first-generation antipsychotics. However, because second-generation antipsychotics still have D2 receptor inhibitory activity, they still have extrapyramidal side effects and can also cause varying degrees of weight gain. In 2016, the US FDA approved pimavanserin for the treatment of hallucinations and delusions associated with Parkinson's disease, making it the first drug approved for this indication.

[0004] Pimavanserin is a 5-HT 2A 5-HT receptor inverse agonist, which can eliminate the extrapyramidal and weight gain side effects associated with dopamine receptor inhibition of first-generation and second-generation antipsychotic drugs and has better safety. 2A It is a major excitatory receptor subtype in the 5-HT receptor family and belongs to ligand-gated channels and G protein-coupled receptors. 2A The receptor function is closely related to neuronal excitation, behavioral effects, learning and memory, and anxiety, and is an important target for antipsychotic drugs and the treatment of schizophrenia (Price, DL, et al. Behavioural Pharmacology (2012), 23(4), 426-433.).

[0005] 5-HT 2AThe receptors are intrinsically active and can produce effects even in the absence of agonists. 2A Receptor inverse agonists, 5-HT 2A After binding to the receptor, it can inhibit the inherent activity of the receptor, making the receptor inactive and producing an effect opposite to that of the agonist. Even in the absence of the agonist, it can still show activity. 2A After binding to the receptor, the receptor antagonist cannot cause biological effects and can only express its activity by inhibiting the agonist (WO2004064738A2). 2A Compounds with 5-HT receptor antagonist activity, but not necessarily 5-HT 2A Receptor inverse agonist activity.

[0006] PCT / CN2023 / 111052 provides a compound with the structure shown below. The test results show that the compound has good 5-HT 2A Receptor inverse agonist activity.

[0007] The pharmaceutical form (such as crystal form, salt) of a compound often affects the chemical stability of the drug. The difference between crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, and sometimes also be accompanied by the crystal formation of other forms. In general, amorphous drug products do not have regular crystal structures and often have defects such as poor product stability, finer crystallization, more difficult filtration, easy agglomeration, and poor fluidity. In view of the importance of solid drug salts, crystal forms and their stability in clinical treatment, in-depth research on the crystal forms of Formula I compounds is of great significance to the development of drugs suitable for industrial production and good biological activity. Summary of the Invention

[0008] In one aspect, the present disclosure provides a pharmaceutically acceptable salt of a compound of formula I, wherein the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, p-toluenesulfonate, maleate, phosphate, dihydroxybenzoate, mandelate, malate, succinate, acetate, hexanoate, palmitate, pamoate, citrate, L-tartrate or fumarate, preferably fumarate,

[0009] In an optional embodiment, the chemical ratio of the compound of formula I to the acid molecule is about 1:2 to 2:1, and can be about 1:2, 1:1, or 2:1.

[0010] In an optional embodiment, the chemical ratio of the compound of formula I to fumaric acid is about 1:1.

[0011] The present disclosure also provides a method for preparing the aforementioned pharmaceutically acceptable salt, comprising the step of forming a salt with an acid selected from hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, maleic acid, phosphoric acid, dihydroxybenzoic acid, mandelic acid, malic acid, succinic acid, acetic acid, hexanoic acid, palmitic acid, pamoic acid, citric acid, L-tartaric acid, or fumaric acid. The solvent used for forming the salt is selected from one or more of water, methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, ethyl acetate, and n-heptane.

[0012] In one aspect, the present disclosure provides a fumarate salt form A of the compound of formula I, which has characteristic diffraction peaks at the following 2θ angles in an X-ray powder diffraction pattern using Cu-Kα radiation: 7.564±0.2°, 18.942±0.2°, 22.787±0.2°, and 26.629±0.2°.

[0013] In some embodiments, the crystalline form A of the fumarate salt of the compound of formula I has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 7.564±0.2°, 11.335±0.2°, 15.212±0.2°, 18.942±0.2°, 22.787±0.2°, 24.571±0.2°, and 26.629±0.2°.

[0014] In some embodiments, the crystalline form A of the fumarate salt of the compound of Formula I has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Figure 1-1.

[0015] In some embodiments, the fumarate salt Form A of the compound of Formula I is an anhydrous crystalline form.

[0016] In one aspect, the present disclosure provides a method for preparing Form A of a fumarate salt of a compound of Formula I, comprising the following steps: obtaining Form A of a fumarate salt of a compound of Formula I by a suspension method, a cooling method, or the like.

[0017] In some embodiments, the present disclosure provides a method for preparing Form A of a fumarate salt of a compound of Formula I, comprising the following steps: suspending a fumarate salt of a compound of Formula I in acetonitrile at room temperature to obtain Form A.

[0018] In some embodiments, the present disclosure provides a method for preparing Form A of a fumarate salt of a compound of Formula I, comprising the following steps: cooling a fumarate salt of a compound of Formula I in acetonitrile or a toluene / acetonitrile mixed solvent to obtain Form A.

[0019] In one aspect, the present disclosure provides a fumarate salt form B of the compound of formula I, which has characteristic diffraction peaks at the following 2θ angles in an X-ray powder diffraction pattern using Cu-Kα radiation: 3.665±0.2°, 7.299±0.2°, 18.225±0.2°, 21.887±0.2°, and 25.564±0.2°.

[0020] In some embodiments, the present disclosure provides a fumarate salt form B of the compound of Formula I, which has characteristic diffraction peaks at the following 2θ angles in an X-ray powder diffraction pattern using Cu-Kα radiation: 3.665±0.2°, 7.299±0.2°, 18.225±0.2°, 21.887±0.2°, 25.564±0.2°, and 29.164±0.2°.

[0021] In some embodiments, the present disclosure provides a fumarate salt form B of the compound of formula I, which has characteristic diffraction peaks at the following 2θ angles in an X-ray powder diffraction pattern using Cu-Kα radiation: 3.665±0.2°, 7.299±0.2°, 18.225±0.2°, 19.628±0.2°, 21.061±0.2°, 21.887±0.2°, 25.564±0.2°, 25.949±0.2°, and 29.164±0.2°.

[0022] In some embodiments, the present disclosure provides a fumarate salt form B of the compound of formula I, which has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 3.665±0.2°, 7.299±0.2°, 10.921±0.2°, 11.923±0.2°, 18.225±0.2°, 19.628±0.2°, 21.061±0.2°, 21.887±0.2°, 25.564±0.2°, 25.949±0.2°, 29.164±0.2°.

[0023] In some embodiments, the fumarate crystalline form B of the compound of Formula I has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Figure 2-1.

[0024] In some embodiments, the fumarate salt Form B of the compound of Formula I is an anhydrous crystalline form.

[0025] In one aspect, the present disclosure provides a method for preparing Form B of a fumarate salt of a compound of Formula I, comprising the following steps: obtaining Form B of a fumarate salt of a compound of Formula I by a suspension method, a dissolution method, or the like.

[0026] In some embodiments, the present disclosure provides a method for preparing Form B of a fumarate salt of a compound of Formula I, comprising the following steps: completely dissolving a fumarate salt of a compound of Formula I in a tetrahydrofuran solvent, and then adding n-heptane dropwise until a solid precipitates.

[0027] In some embodiments, the present disclosure provides a method for preparing Form B of a fumarate salt of a compound of Formula I, comprising the following steps: suspending the fumarate salt of the compound of Formula I in an acetone / n-heptane mixed solvent at room temperature to obtain Form B.

[0028] In some embodiments, the present disclosure provides a method for preparing Form B of a fumarate salt of a compound of Formula I, comprising the following steps: suspending a fumarate salt of a compound of Formula I in n-heptane at 50° C. to obtain Form B.

[0029] In one aspect, the present disclosure provides a fumarate salt form C of the compound of Formula I, which has characteristic diffraction peaks at the following 2θ angles in an X-ray powder diffraction pattern using Cu-Kα radiation: 24.435±0.2°, 28.829±0.2°, and 38.312±0.2°.

[0030] In some embodiments, the fumarate salt form C of the compound of formula I has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 21.245±0.2°, 24.435±0.2°, 28.829±0.2°, 38.312±0.2°, and 39.979±0.2°.

[0031] In some embodiments, the fumarate crystalline form C of the compound of Formula I has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Figure 3-1.

[0032] In one aspect, the present disclosure provides a method for preparing Form C of a fumarate salt of a compound of Formula I, comprising the following steps: subjecting a fumarate salt of a compound of Formula I to Form C by a suspension method, a dissolution method, a vapor diffusion method, or the like.

[0033] In some embodiments, the present disclosure provides a method for preparing Form C of a fumarate salt of a compound of Formula I, comprising the following steps: completely dissolving the fumarate salt of the compound of Formula I in a tetrahydrofuran solvent, and then adding the solution dropwise to 10 times the volume of dichloromethane.

[0034] In some embodiments, the present disclosure provides a method for preparing Form C of a fumarate salt of a compound of Formula I, comprising the following steps: suspending Form A or Form B in toluene or dichloromethane at room temperature to obtain Form C.

[0035] In some embodiments, the present disclosure provides a method for preparing Form C of a fumarate salt of a compound of Formula I, comprising the following steps: suspending a fumarate salt of a compound of Formula I in toluene at 50° C. to obtain Form C.

[0036] In one aspect, the present disclosure provides a fumarate salt form D of the compound of formula I, which has characteristic diffraction peaks at the following 2θ angles in an X-ray powder diffraction pattern using Cu-Kα radiation: 7.160±0.2°, 18.004±0.2°, 21.436±0.2°, and 25.082±0.2°.

[0037] In some embodiments, the fumarate salt form D of the compound of formula I has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 3.537±0.2°, 7.160±0.2°, 15.745±0.2°, 18.004±0.2°, 18.893±0.2°, 19.269±0.2°, 21.436±0.2°, and 25.082±0.2°.

[0038] In some embodiments, the fumarate salt form D of the compound of formula I has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 3.537±0.2°, 7.160±0.2°, 10.700±0.2°, 15.745±0.2°, 18.004±0.2°, 18.893±0.2°, 19.269±0.2°, 20.965±0.2°, 21.436±0.2°, 25.082±0.2°, and 28.762±0.2°.

[0039] In some embodiments, the fumarate crystalline form D of the compound of Formula I has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in FIG4 .

[0040] In one aspect, the present disclosure provides a method for preparing a crystalline form D of a fumarate salt of a compound of formula I, comprising the following steps: obtaining a crystalline form D of a fumarate salt of a compound of formula I by a suspension method, a dissolution method, or the like.

[0041] In some embodiments, the present disclosure provides a method for preparing a fumarate salt of a compound of formula I, Form D, comprising the following steps: completely dissolving the fumarate salt of the compound of formula I in an ethyl acetate solvent, and then adding the solution dropwise to n-heptane until a solid precipitates.

[0042] In some embodiments, the present disclosure provides a method for preparing Form D of a fumarate salt of a compound of Formula I, comprising the following steps: suspending a fumarate salt of a compound of Formula I in a solvent system of ethyl acetate / n-heptane or tetrahydrofuran / n-heptane at room temperature to obtain Form D.

[0043] In some embodiments, the present disclosure provides a method for preparing Form D of a fumarate salt of a compound of Formula I, comprising the following steps: suspending Form B in a solvent system of tetrahydrofuran / n-heptane or ethyl acetate / n-heptane at room temperature to obtain Form D.

[0044] In some embodiments, the present disclosure provides a method for preparing Form D of a fumarate salt of a compound of Formula I, comprising the following steps: suspending Form A in methyl tert-butyl ether at room temperature to obtain Form D.

[0045] In one aspect, the present disclosure provides a fumarate salt form E of the compound of formula I, which has characteristic diffraction peaks at the following 2θ angles in an X-ray powder diffraction pattern using Cu-Kα radiation: 7.570±0.2°, 15.357±0.2°, 18.889±0.2°, 21.436±0.2°, 23.168±0.2°, and 27.084±0.2°.

[0046] In some embodiments, the fumarate salt form E of the compound of formula I has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 3.769±0.2°, 7.570±0.2°, 15.357±0.2°, 16.847±0.2°, 18.410±0.2°, 18.889±0.2°, 19.210±0.2°, 20.780±0.2°, 21.436±0.2°, 23.168±0.2°, 25.411±0.2°, 26.639±0.2°, 27.084±0.2°, 28.770±0.2°, 31.065±0.2°, and 32.507±0.2°.

[0047] In some embodiments, the fumarate salt form E of the compound of formula I has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 3.769±0.2°, 7.570±0.2°, 11.407±0.2°, 13.369±0.2°, 15.357±0.2°, 16.847±0.2°, 18.026±0.2°, 18.410±0.2°, 18.889±0.2°, 19.210±0.2°, 20.188±0.2°, 20.780± 0.2°, 21.436±0.2°, 23.168±0.2°, 25.411±0.2°, 26.639±0.2°, 27.084±0.2°, 28.770±0.2°, 31.065±0.2°, 32.058±0.2°, 32.507±0.2°, 33.754±0.2°, 35.513±0.2°, 39.105±0.2°, 40.919±0.2°, 41.883±0.2°, 42.848±0.2°, 44.342±0.2°.

[0048] In some embodiments, the fumarate crystalline form E of the compound of Formula I has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Figure 5-1.

[0049] In some embodiments, the fumarate salt of the compound of Formula I, Form E, is an anhydrous crystalline form.

[0050] In some embodiments, the present disclosure provides a method for preparing Form E of a fumarate salt of a compound of Formula I, comprising the following steps: vacuum drying Form A at 60-70°C.

[0051] In one aspect, the present disclosure also provides a pharmaceutical composition comprising a fumarate of a compound of formula I, any of the aforementioned pharmaceutically acceptable salts of the compound of formula I, or any of the fumarate crystalline forms of the compound of formula I, and a pharmaceutically acceptable carrier. The pharmaceutical composition can be prepared into various pharmaceutically acceptable dosage forms, such as tablets, capsules, oral liquids, granules, injections, or various sustained-release preparations. The pharmaceutical composition can be administered orally or parenterally (such as intravenously, subcutaneously, or topically). The dosage can be appropriately adjusted according to the patient's age, sex, and disease type, and the general daily dose is about 1 to 200 mg.

[0052] In one aspect, the present disclosure also provides any one of the aforementioned pharmaceutically acceptable salts of the compound of formula I or any one of the fumarate salt crystals or pharmaceutical compositions for the preparation of a pharmaceutical composition for treating 5-HT. 2AThe invention relates to a drug for treating a receptor-related disease. The disease or symptom includes: schizophrenia, psychosis, schizoaffective disorder, mania, psychotic depression, affective disorder, dementia, anxiety, sleep disorder, appetite disorder, bipolar disorder, psychosis secondary to hypertension, migraine, hypertension, thrombosis, vasospasm, ischemia, motor convulsion, depression, major depression, anxiety, sleep disorder and appetite disorder, non-motor symptoms caused by Parkinson's disease (including delusions, hallucinations, depression, anxiety, cognitive impairment or sleep disorder), mental illness related to dementia, negative symptoms of schizophrenia, Parkinson's disease, Huntington's disease, Alzheimer's disease, spinocerebellar ataxia, Tourette syndrome, Friedreich's ataxia, Machado-Joseph disease, dementia with Lewy bodies, movement disorders, dystonia, myoclonus, tremor, progressive supranuclear palsy and frontotemporal dementia; preferably hallucinations and delusions associated with Alzheimer's disease psychotic disorder (ADP), hallucinations and delusions associated with Parkinson's disease psychotic disorder (PDP), negative symptoms of schizophrenia (NSS); or other disease states and conditions obvious to those skilled in the art.

[0053] Definition and Description

[0054] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0055] The term "pharmaceutically acceptable" as used herein refers to compounds, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0056] The compounds of the present disclosure may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the present disclosure.

[0057] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure.

[0058] The term "pharmaceutically acceptable carrier" refers to any preparation or carrier medium representative of a carrier that can deliver an effective amount of the active substance of the present disclosure, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient, including but not limited to: binders, fillers, lubricants, disintegrants, wetting agents, dispersants, solubilizers, suspending agents, etc.

[0059] The present disclosure is intended to include all isotopes of atoms present in the compounds of the present disclosure. Isotopes include those atoms having the same atomic number but different mass numbers. As a general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13 C and 14 C. Isotopically labeled compounds of the present disclosure can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described herein, using an appropriate isotopically labeled reagent in place of the non-labeled reagent otherwise employed. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] Figures 1-1, 1-2, and 1-3 are XRPD patterns, TGA / DSC patterns, and 1 H NMR spectrum.

[0061] Figures 2-1, 2-2, and 2-3 are XRPD patterns, TGA / DSC patterns, and 1 H NMR spectrum.

[0062] Figures 3-1 and 3-2 are XRPD patterns of the fumarate salt of the compound of formula I, Form C, and 1 H NMR spectrum.

[0063] Figure 4: XRPD pattern of the fumarate salt form D of the compound of formula I.

[0064] Figures 5-1, 5-2, and 5-3 are XRPD patterns, TGA / DSC patterns, and 1 H NMR spectrum.

[0065] Figure 6: The number of head shakes in SD rats 1.0-1.5 h after a single oral administration (#P<0.05, compared with the Control group; *P<0.05, **P<0.01, compared with the Model group). DETAILED DESCRIPTION

[0066] The present disclosure is further described below with reference to specific embodiments and test examples, but they do not limit the scope of the present disclosure in any form.

[0067] Test conditions of the instruments used in the experiment:

[0068] NMR analysis ( 1 H NMR)

[0069] The solid sample was dissolved in MeOH-d4 solvent and subjected to nuclear magnetic resonance analysis on a Bruker AVANCE NEO 400 (Bruker, GER).

[0070] X-ray powder diffraction (XRPD)

[0071] Solid samples were analyzed using a Bruker D8 Advance X-ray powder diffractometer (Bruker, Germany). The 2θ scan angle ranged from 3° to 45°, with a scan step of 0.02° and an exposure time of 0.08 s. The test method used Cu target Kα1 radiation, a voltage of 40 kV, a current of 40 mA, and a zero-background sample pan.

[0072] Thermogravimetric analysis (TGA)

[0073] Thermogravimetric analyzers were TA Discovery 55 (TA, US) and TA Discovery 550 (TA, US). 2-5 mg of sample was placed in a equilibrated open aluminum sample pan and automatically weighed in the TGA furnace. The sample was heated to the final temperature at a rate of 10°C / min. A nitrogen purge rate of 60 mL / min was applied to the sample and 40 mL / min was applied to the balance.

[0074] Differential Scanning Calorimetry (DSC)

[0075] The differential scanning calorimeter was a TA Discovery 250 (TA, US). 1-2 mg of sample was accurately weighed and placed in a perforated DSC Tzero sample pan. The sample was heated to the final temperature at a rate of 10°C / min, with nitrogen purge rate of 50 mL / min.

[0076] Example 1 Synthesis of Compounds of Formula I

[0077] 1.1 Synthesis of Compound 1-2

[0078] Tetrahydrofuran (15 mL) and compound 1-4 (1.04 g, 1.00 eq, HCl) were added sequentially to a 100 mL three-necked flask. Diisopropylethylamine (1.11 g, 2.00 eq) was added dropwise under nitrogen and stirred at 20°C for 15 minutes. The temperature was then lowered to 0°C and N,N'-carbonyldiimidazole (765 mg, 1.10 eq) was added portionwise to the reaction solution to check for complete reaction of compound 1-4. Compound 1-1 (1.40 g, 1.00 eq) was dissolved in tetrahydrofuran (5 mL) and slowly added dropwise to the reaction solution. The mixture was stirred at 25°C for 12 hours. 100 mL of water was added to the reaction solution and extracted with ethyl acetate three times, each time using 50 mL. The organic phases were combined and washed with 80 mL of saturated brine, dried, and concentrated to yield the crude product. The crude product was purified by column chromatography to obtain compound 1-2 (colorless oil, 966 mg, yield: 38.8%).

[0079] 1.2 Synthesis of Compounds 1-3

[0080] Anhydrous dichloromethane (27 mL), compound 1-2 (966 mg, 1.00 eq), and trifluoroacetic acid (15.4 g, 78.0 eq) were added sequentially to a 50 mL single-necked bottle and stirred at 25°C for 20 minutes. The reaction mixture was dried to give crude compound 1-3 (pale yellow oil, 850 mg, yield: 91.4%).

[0081] 1.3 Synthesis of Compounds of Formula I

[0082] Tetrahydrofuran (8 mL), compound 1-3 (800 mg, 1.00 eq), sodium cyanoborohydride (219 mg, 2.00 eq), and formaldehyde (212 mg, 37%, 1.50 eq) were added sequentially to a 50 mL single-necked flask. The mixture was stirred at 25°C for 12 hours. 50 mL of water was added to the reaction solution, and the mixture was extracted three times with 30 mL of ethyl acetate each time. The organic phases were combined, washed with 40 mL of saturated brine, dried, concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to obtain the compound of formula I (white solid, 643 mg, yield: 78.1%). 1H NMR (400MHz, CDCl3) δ7.87 (d, J=1.9Hz, 1H), 7.35 (dd, J=2.3, 8.5Hz, 1H), 7.17-7.08 (m, 2H), 7.00 (br t,J=8.5Hz,2H),6.75(d,J=8.5Hz,1H),5.17-4.99(m,1H),4.94(br t,J=5.1Hz,1H),4.71(d,J=8.6Hz,2H),4.56-4.43(m,2H),4.30-4.17(m,2H), 3.81-3.57(m,2H),3.22-2.91(m,2H),2.80(s,3H),2.60-2.45(m,1H),1.79(br d,J=11.8Hz,1H). MS(ESI)m / z:473.2[M+1].

[0083] Example 2 Preparation of Fumarate Salt of Formula I Compound

[0084] Acetonitrile (513 mL), the compound of Formula I (49.3 g, 1.00 eq), and fumaric acid (13.46 g, 1.00 eq) were sequentially added to a 1 L single-necked flask. Stirred at 55±5°C for 2-3 hours. Cool to 20±5°C, incubate for 2-3 hours, filter, and dry in a vacuum drying oven at 30°C for 1 hour. Then, heat to 60°C and dry for 6 hours to obtain the fumarate salt of the compound of Formula I (white solid, 55.1 g, yield: 89.7%). 1 H NMR (600MHz, MeOD) δ7.88 (1H, t, J = 1.8, 2.4Hz), 7.44 (1H, dd, J = 2.4, 8.4Hz), 7.10 ( 2H,dd,J=5.4,8.4Hz),6.92(2H,dd,J=6.6,8.4Hz),6.70(1H,dd,J=0.6,8.4Hz),6.5 9(2H,s),4.92(1H,m),4.72(2H,m),4.50(1H,m),4.48(2H,m),4.17(2H,m),3.52(1H ,m),3.27(1H,m),3.05(1H,m),2.85(1H,m),2.62(3H,s),2.15(1H,m),1.65(1H,m).

[0085] Example 3 Preparation of Fumarate Form A of Compound of Formula I

[0086] 1.5 g of the fumarate salt of the compound of Formula I was weighed, 37 mL of acetonitrile was added, and the mixture was stirred at 50°C until the sample completely dissolved. The clear solution was suspended at room temperature overnight, resulting in the precipitation of a large amount of solid. The suspension was centrifuged, and the resulting solid was vacuum-dried at room temperature overnight. The resulting solid was vacuum-dried at 40°C overnight. 700 mg of the crystalline form A of the fumarate salt of the compound of Formula I was obtained.

[0087] Using XRPD, 1 The material was characterized by H NMR, TGA, and DSC. The XRPD pattern is shown in Figure 1-1, and the locations of the characteristic peaks are shown in Table 1. TGA / DSC results (Figure 1-2) show a 0.2% weight loss during heating to 120°C, possible decomposition above 180°C, and an endothermic signal at 110.4°C (peak temperature). 1 H NMR results (Figures 1-3) show no obvious solvent signal peak, a fumaric acid peak is visible at 6.71 ppm, and the salt ratio is 1:0.9. In summary, Form A is an anhydrate form.

[0088] Table 1 XRPD pattern analysis data of the fumarate salt of the compound of formula I, Form A

[0089] Example 4 Preparation of Fumarate Form B of Formula I Compound

[0090] Weigh 20 mg of the fumarate salt of the compound of Formula I and add 0.1 ml of tetrahydrofuran dropwise at room temperature to completely dissolve the sample. Then, add 0.2 ml of n-heptane dropwise until solid precipitates. After stirring at room temperature for ~30 minutes, the precipitated solid is centrifuged and dried under vacuum at room temperature to obtain Form B of the fumarate salt of the compound of Formula I.

[0091] Using XRPD, 1 Form B was characterized by H NMR, TGA, and DSC. The XRPD is shown in Figure 2-1, and the locations of characteristic peaks are shown in Table 2. TGA / DSC results (Figure 2-2) show that Form B experienced a 0.1% weight loss upon heating to 80°C and a 2.2% weight loss from 80°C to 130°C. Decomposition may occur above 180°C, and an endothermic signal is observed at approximately 105.5°C (peak temperature). 1 The H NMR spectrum is shown in Figures 2-3. No significant residual solvent is present in the sample, and a fumaric acid peak is visible at 6.71 ppm, indicating a salt formation ratio of 1:0.9. In summary, Form B is an anhydrous crystalline form.

[0092] Table 2 XRPD pattern analysis data of the fumarate salt of the compound of formula I, Form B

[0093] Example 5 Preparation of Fumarate Crystal Form C of Compound of Formula I

[0094] Weigh 20.1 mg of the fumarate salt of the compound of formula I, add 0.1 mL of tetrahydrofuran dropwise at room temperature to completely dissolve the sample, and add the clear solution dropwise to 1.0 mL of dichloromethane. Stir at room temperature for about 30 minutes, centrifuge, and the resulting solid is vacuum-dried at room temperature overnight to obtain the fumarate salt of the compound of formula I, Form C. XRPD, 1 H NMR was used to characterize Form C. XRPD is shown in Figure 3-1, and the positions of characteristic peaks are shown in Table 3. 1 The H NMR spectrum is shown in Figure 3-2. Tetrahydrofuran signal peaks are visible at 3.74-3.71 ppm and 1.88-1.85 ppm. Based on the integration results, the ratio of compound to tetrahydrofuran is 1:0.3, with a rough estimate of approximately 3.5% by mass. A fumaric acid peak is visible at 6.71 ppm, indicating a salt ratio of 1:0.95.

[0095] Table 3 XRPD pattern analysis data of the fumarate salt of the compound of formula I, Form C

[0096] Example 6 Preparation of Fumarate Form D of Compound of Formula I

[0097] 20.8 mg of the fumarate salt of the compound of Formula I was weighed and suspended in 2.0 mL of ethyl acetate / n-heptane (v / v, 1:4) at room temperature for 7 days to obtain Form D of the fumarate salt of the compound of Formula I. Form D was characterized by XRPD. The XRPD is shown in Figure 4, and the positions of the characteristic peaks are shown in Table 4.

[0098] Table 4 XRPD pattern analysis data of the fumarate salt of the compound of formula I, Form D

[0099] Example 7 Preparation of Fumarate Form E of Compound I

[0100] 20.1 mg of the fumarate salt form A of the compound of formula I was weighed and placed in a vacuum drying environment at 60° C. overnight to obtain the fumarate salt form E of the compound of formula I with a yield of 100.0% and a purity of 99.96%.

[0101] Using XRPD, DSC, TGA, 1 The product was characterized by H NMR. The XRPD pattern is shown in Figure 5-1, and the locations of the characteristic peaks are shown in Table 5. TGA / DSC results (Figure 5-2) show no weight loss during heating to 120°C, possible decomposition above 190°C, and an endothermic signal at around 111.7°C (peak temperature). 1 The H NMR results (Figure 5-3) show no obvious solvent signal peak, a fumaric acid peak is visible at 6.70 ppm, and the salt formation ratio is 1:0.96. In summary, Form E is an anhydrate form.

[0102] Table 5 XRPD pattern analysis data of the fumarate salt of the compound of formula I, Form E

[0103] Test Example 1. 5-HT2A receptor inverse agonist activity test

[0104] 1.1 Experimental Materials:

[0105] Cell line: adherent cells NIH3T3-5-HT 2A R

[0106] Cell culture medium: DMEM + 10% FBS (purchased from GBICO)

[0107] Cell culture plate: 96-well plate with white wall and transparent bottom (purchased from Perkin Elmer)

[0108] Detection kit: Bright-Glo TM Luciferase (purchased from Promega)

[0109] Detection instrument: BioTek multifunctional microplate reader

[0110] 1.2 Trial Drugs

[0111] Pimavanserin: purchased from MCE

[0112] Formula I compound: prepared according to the above example

[0113] 1.3 Experimental methods:

[0114] NIH3T3-5HT cells in the logarithmic growth phase 2A R cells were seeded in a 96-well plate with a white wall and transparent bottom at a density of 1000 cells per well and cultured in a 37°C, 5% CO2 incubator overnight. On the second day, the test compound was added to the cells. The highest concentration of the test compound was 10uM. The compound was diluted with PBS at a concentration gradient of 3.16 times to 9 concentrations, with duplicate wells for each concentration. PBS was used as the negative control group, and the same concentration of pimavanserin was used as the positive control group. After adding the drug, the cells were cultured in a 37°C, 5% CO2 incubator for 120 hours. On the sixth day, Bright-Glo was added to the cells at an equal volume to the cell fluid. TM Luciferase reagent was added to the cells and incubated at room temperature in the dark for 20 min. The plate was shaken every 5 min. The luminescence intensity was measured by a microplate reader and the cell inhibition rate was calculated. The data were processed using GraphPad Prism 7.0 to obtain the cell inhibition rate curve and calculate the IC 50 , the test results are shown in Table 6.

[0115] Cell inhibition rate (%) = [100-(Lum test drug-Lum culture medium) / (Lum cell control-Lum culture medium) × 100]%

[0116] Test Example 2. hERG Inhibitory Activity

[0117] 1. Test materials and instruments

[0118] 1.1 Positive control compound

[0119] Name: Cisapride

[0120] 1.2 Solvent

[0121] Name: DMSO (dimethyl sulfoxide)

[0122] 1.3 Cells

[0123] Species & Strain: CHO-hERG cell line (Chinese hamster ovary cells stably expressing the hERG channel)

[0124] Culture medium: 90% F12, 10% fetal bovine serum, 100 μg / mL G418, 100 μg / mL Hygromycin B

[0125] Culture conditions: 5% CO2, 37°C incubator

[0126] Freezing conditions: liquid nitrogen

[0127] 1.4 Experimental Instruments

[0128] Patch clamp amplifier (Axoclamp 200B, Multiclamp 700B, Axon, USA)

[0129] Digital-to-analog converter (DigiData 1440A, DigiData 1550B, Axon, USA)

[0130] Inverted microscope (IX51, IX71, Olympus, Japan)

[0131] Rapid drug delivery system (RSC-200, Bio-Logic, France)

[0132] Micromanipulator (MX7600R, Syskiyou, USA)

[0133] Electrode pulling apparatus (P-97, Sutter, USA)

[0134] Glass electrode (BF150-86-10, Sutter, USA)

[0135] Anti-vibration table and shielding net (63-534, TMC, USA)

[0136] Data acquisition and analysis software (pClamp 10, Axon, USA)

[0137] CO2 incubator (HERAcell 150i, Thermo, USA)

[0138] Biological safety cabinet (MODEL 1384, Thermo, USA)

[0139] Water purifier (Milli Q, Millipore, USA)

[0140] 2. Experimental Methods

[0141] 2.1 Cell culture and treatment

[0142] CHO cells stably expressing hERG were cultured in 35 mm diameter cell culture dishes in a 37°C, 5% CO2 incubator, and passaged every 48 hours at a 1:5 ratio. On the day of the experiment, the cell culture medium was aspirated, the cells were rinsed with extracellular fluid, and then digested with 0.25% Trypsin-EDTA (Invitrogen) solution at room temperature for 3-5 minutes. The digestion solution was aspirated, the cells were resuspended in the extracellular fluid, and transferred to a dish for electrophysiological recording.

[0143] 2.2 Compound preparation

[0144] On the day of testing, dilute the compound to an intermediate concentration with DMSO. Transfer 10 μL of the intermediate concentration compound to 4990 μL of extracellular fluid and dilute 500-fold to the final concentration to be tested.

[0145] Preparation of the positive control compound Cisapride: 10 μL of 150 μM Cisapride DMSO stock solution was transferred to 4990 μL of extracellular fluid and diluted 500-fold to obtain the final concentration of 300 nM to be tested.

[0146] 2.3 Electrophysiological recording process

[0147] CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents using the whole-cell patch clamp technique at room temperature. Glass microelectrodes were pulled from glass electrode blanks (BF150-86-10, Sutter) using a puller. The tip resistance after perfusion of the electrode solution was approximately 2-5 MΩ. The glass microelectrode was inserted into the amplifier probe to connect to the patch clamp amplifier. The clamping voltage and data recording were controlled and recorded by a computer using pClamp 10 software, with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After obtaining the whole-cell recording, the cell was clamped at -80 mV to induce the hERG potassium current (I hERG ) was administered with a 2-second depolarization step from -80 mV to +20 mV, followed by repolarization to -50 mV for 1 second before returning to -80 mV. This voltage stimulus was administered every 10 seconds, and administration began after confirming that the hERG potassium current was stable (1 minute). Compounds were administered for at least 1 minute at each test concentration, and at least two cells (n ≥ 2) were tested for each concentration.

[0148] 2.4 Data Processing and Analysis

[0149] Data were analyzed using pClamp 10 and GraphPad Prism 5.0 software.

[0150] The calculation formula for the degree of inhibition of hERG potassium current (peak value of hERG tail current induced at -50 mV) by different compound concentrations is:

[0151] Inhibition%=[1–(I / Io)]×100%

[0152] Wherein, Inhibition% represents the inhibition percentage of the compound on hERG potassium current, and I and Io represent the amplitude of hERG potassium current before and after drug addition, respectively.

[0153] Compound IC 50 The results were calculated using the following equation using GraphPad Prism 5 software. See Table 6 for the experimental results:

[0154] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0155] Where X is the Log value of the test sample concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0156] Table 6 In vitro test results of compounds of formula I

[0157] The results showed that the 5-HT 2A It has better inverse agonist activity than pimavanserin and lower cardiotoxicity.

[0158] Test Example 3. In vitro liver microsome stability evaluation

[0159] 1. Solution Preparation

[0160] 1) Preparation of test sample working solution: dilute the test sample to 100 μM with methanol;

[0161] 2) Preparation of liver microsome working solution: Dilute liver microsomes to 0.56 mg / ml with 100 mM phosphate buffer;

[0162] 3) Prepare the reduced nicotinamide adenine dinucleotide phosphate (NADPH) working solution: Weigh an appropriate amount of NADPH and dilute it to 20 mM with phosphate buffer. Then add an equal volume of 60 mM MgCl2 solution.

[0163] 4) Preparation of stop solution: dilute tolbutamide to 20 ng / mL with acetonitrile as the stop solution containing internal standard.

[0164] 2. Incubation process

[0165] 1) Prepare incubation anti-adsorption EP tubes and label the species, test substance, reference substance (testosterone, dextromethorphan), time point (0, 5, 10, 20, 30, 60 min, Blank60, NCF60), etc.

[0166] 2) Add 2 μL of test sample or control working solution and 178 μL of liver microsome working solution to each tube. Add 2 μL of acetonitrile to the blank tube instead of the test sample. Pre-incubate in a 37°C water bath for approximately 10 minutes. Each sample should be repeated in triplicate.

[0167] 3) After the preincubation, 20 μL of NADPH working solution was added to each tube except for 0 min and NCF60 to start the reaction. 20 μL of phosphate buffer (containing 30 mM MgCl2) was added to the NCF60 tube. The final concentration of the test or control in the incubation system was 1 μM, the final concentration of liver microsomes was 0.5 mg / mL, the final concentration of NADPH was 1 mM, and the final concentration of MgCl2 was 3 mM.

[0168] 4) For the 0 min sample, add 600 μL of stop solution first, then add NADPH working solution. After incubating each sample for the corresponding time, add 600 μL of stop solution to terminate the reaction;

[0169] 5) After terminating the reaction, each sample was vortexed for 30 seconds and then centrifuged at 13,500 rpm for 10 minutes. 100 μL of the supernatant was placed in an EP tube, 100 μL of Milli-Q water was added, and vortexed to mix thoroughly before LC-MS / MS analysis.

[0170] 6) Testosterone and dextromethorphan were used as positive controls under the same conditions to test the stability and reliability of the system.

[0171] 3. Data Analysis

[0172] The remaining percentage of the test sample after 60 minutes of testing is shown in Table 7.

[0173] Table 7 Experimental data of compound of formula I in human and rat liver microsomes

[0174] The results showed that the compound of formula I had better stability in canine liver microsomes in vitro than pimavanserin and had better drug-forming properties.

[0175] Test Example 4. In vivo pharmacodynamic evaluation

[0176] 1. Experimental Plan

[0177] According to the in vivo pharmacokinetic data of a series of compounds, the drug reaches C 1.0 to 1.5 h after a single oral administration in SD rats. max At this time point, SD rats were intraperitoneally injected with 4-iodo-2,5-dimethoxy-α-methyl-phenylethylamine hydrochloride (DOI, 5-HT 2A Receptor agonist) at a dose of 2.5 mg / kg was used to induce head shaking behavior in SD rats to establish the model.

[0178] The low, medium, and high dose groups of the compound of Formula I were set at 0.22, 0.66, and 2.0 mg / kg, respectively. The dose of pimavanserin tartrate (Pim-T) was set at 0.7 mg / kg. Both the compound of Formula I and Pim-T were administered via oral gavage.

[0179] 2. Experimental Grouping and Drug Administration

[0180] The compound was dissolved in DMSO:20% solutol (5%:95%). SD rats (200-250 g) were randomly divided into six groups based on body weight: solvent control, model, Pim-T 0.7 mg / kg, and Formula I 0.22, 0.66, and 2.0 mg / kg groups, with seven animals per group. Animal grouping and dosing information are detailed in Table 8.

[0181] Table 8 Animal grouping and drug administration Note: The dosages of Pim-T (Pimavanserin tartrate) and the compound of formula I are all calculated based on the free base.

[0182] 3. Experimental Operation

[0183] Rats were fasted at 5:00 PM on the day before the experiment. On the day of the experiment, animals were acclimated to the testing laboratory for at least 1 hour. Each group of rats received a single oral gavage of the drug according to the dosage in Table 3. One hour after administration, all groups except the control group received an intraperitoneal injection of 2.5 mg / kg DOI. The control group received an equal volume of saline. The rats' behavior was immediately observed after injection. The observations were randomized, double-blind, and no human factors were involved. The number of head shakes observed within 1.0 to 1.5 hours after administration was recorded.

[0184] The experimental data were expressed as mean ± standard error (Mean ± SEM). SPSS statistics 20.0 software was used to perform one-way analysis of variance (ANOVA) to compare the differences between the groups at each time point. All tests were two-sided, and P < 0.05 indicated statistical significance.

[0185] 4. Data Analysis

[0186] Compared with the control group, the number of head shakes in the model group rats was significantly increased (P < 0.05). Compared with the model group, the number of head shakes in the Pim-T 0.7 mg / kg group was significantly reduced (P < 0.05), and the number of head shakes in the Formula I 0.22, 0.66, and 2.0 mg / kg groups was extremely significantly reduced (P < 0.01). At equimolar doses, the number of head shakes in the Formula I 0.66 mg / kg group was lower than that in the Pim-T 0.7 mg / kg group. Specific results are shown in Table 9 and Figure 6.

[0187] Table 9 Number of head shakes in SD rats 1.0-1.5 hours after single oral administration Note: # P<0.05, compared with the Control group; *P<0.05, **P<0.01, compared with the Model group.

[0188] Results showed that 1.0 to 1.5 hours after a single oral administration to SD rats, the compound of Formula I significantly inhibited head shaking in a dose range of 0.22 to 2.0 mg / kg, with an onset dose of 0.22 mg / kg. At equimolar doses, the compound of Formula I exhibited superior pharmacodynamics to Pim-T.

[0189] Test Example 5. Evaluation of in vivo tissue distribution

[0190] 1. Experimental Plan

[0191] SD rats (200g-250g) were given a single oral administration of the compound of formula I at a dose of 11 mg / kg. Plasma and brain, heart, liver, and lung tissues were collected 0.25h, 1h, and 6h after administration, with 3 animals at each time point.

[0192] 2. Experimental Operation

[0193] The rats were fasted at around 18:00 the day before the experiment, with free access to water. On the day of the experiment, the rats were weighed and randomly divided into 3 groups according to body weight, with one group of animals at one time point. The compound was dissolved in DMSO:20% solutol (5%:95%), and the rats were given a single oral administration of the compound of formula I at a dose of 11 mg / kg, a dosing volume of 5 mL / kg, and a drug solution concentration of 2.2 mg / mL. At each collection time point, the animals were anesthetized with ether, and about 1 mL of blood was collected from the heart and placed in a heparinized EP tube. The tube was centrifuged at 10,000 rpm for 10 minutes to separate the plasma, and then the brain, heart, liver, and lung tissues were collected after the blood was removed by cardiac perfusion. The blood stains were absorbed with filter paper and then weighed separately. The weighing paper was wrapped and stored at -80°C for testing.

[0194] 3. Sample Measurement and Data Analysis

[0195] Plasma samples and tissue homogenates (each tissue was homogenized in water at a weight-to-volume ratio of 1:4) were pretreated and then analyzed by LC-MS / MS to determine the concentrations of the analytes in plasma and tissues. The experimental data are expressed as mean ± standard deviation (Mean ± SD). The specific results are shown in Table 10.

[0196] Table 10 Plasma and tissue concentrations of the compound of formula I in SD rats after single oral administration

[0197] The results showed that 0.25 h, 1 h, and 6 h after a single oral administration to SD rats, the concentration of the compound of formula I in tissues was higher than that in plasma, indicating that the compound of formula I has good permeability; in particular, the distribution in brain tissue was high, with a brain-to-blood ratio of 9.51 to 10.5, and the concentration in the brain was stable between 0.25 and 6 h.

[0198] Test Example 6. Stability Study of Form E

[0199] The stability of Form E, a fumarate salt of the compound of Formula I, was studied under conditions of high temperature (60°C) and illumination (25°C / 4500 Lux). Samples were collected for XRPD characterization and HPLC analysis after 7 and 15 days, respectively. The results are shown in Table 11. XRPD and HPLC results showed that Form E did not undergo any crystal transformation under the conditions of high temperature and illumination for 15 days, and the purity did not change significantly.

[0200] Table 11 Stability study results of the fumarate crystal form E of the compound of formula I

[0201] Test Example 7. Biological media and water solubility test

[0202] The dynamic solubility of the fumarate crystalline form E of the compound of formula I was determined in three biological media (FaSSIF, FeSSIF and FaSSGF) and water. The preparation process of the biological medium is shown in Table 12. Crystal E was added to the biological medium and water and shaken at a constant temperature of 37°C for 24 hours. Samples were taken at 0.5h, 2h and 24h, respectively. The sampled solution was filtered with a 0.22μm water filter membrane. Some samples with higher concentrations were appropriately diluted with diluents. The signal peak area of ​​the solution was measured by HPLC. Finally, the concentration of the compound in the solution was calculated based on the peak area, the HPLC standard curve of the raw material and the dilution factor. In addition, the 24h supernatant was taken to test its pH value, and the remaining solid was subjected to XRPD testing. The test results are shown in Table 13.

[0203] Table 12 Preparation process of biological medium

[0204] Table 13 Dynamic solubility test in biological media and water

[0205] The results showed that the 24h solubility of Form E in biological media and water was greater than 9 mg / mL, and no residual solids were found in FaSSIF, FeSSIF, FaSSGF, and water.

Claims

1. A pharmaceutically acceptable salt of a compound of formula I, wherein the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, p-toluenesulfonate, maleate, phosphate, dihydroxybenzoate, mandelate, malate, succinate, acetate, hexanoate, palmitate, pamoate, citrate, L-tartrate or fumarate, preferably fumarate, 2. The crystalline form A of the fumarate salt of the compound of formula I according to claim 1 has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 7.564±0.2°, 18.942±0.2°, 22.787±0.2°, and 26.629±0.2°; preferably, it has characteristic diffraction peaks at the following 2θ angles: 7.564±0.2°, 11.335±0.2°, 15.212±0.2°, 18.942±0.2°, 22.787±0.2°, 24.571±0.2°, and 26.629±0.2°; more preferably, the X-ray powder diffraction pattern using Cu-Kα radiation is shown in Figure 1-1. The crystalline form A according to claim 2 , which is an anhydrous crystalline form.

4. The crystalline form B of the fumarate salt of the compound of formula I according to claim 1 has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 3.665±0.2°, 7.299±0.2°, 18.225±0.2°, 21.887±0.2°, 25.564±0.2°, 29.164±0.2°; preferably has characteristic diffraction peaks at the following 2θ angles: 3.665±0.2°, 7.299±0.2°, 10.921±0.2°, 18.225±0.2°, 19.628±0.2°, 21.887±0.2° °, 25.564±0.2°, 25.949±0.2°, 29.164±0.2°; more preferably, there are characteristic diffraction peaks at the following 2θ angles: 3.665±0.2°, 7.299±0.2°, 10.921±0.2°, 11.923±0.2°, 18.225±0.2°, 19.628±0.2°, 21.061±0.2°, 21.887±0.2°, 25.564±0.2°, 25.949±0.2°, 29.164±0.2°; most preferably, the X-ray powder diffraction pattern using Cu-Kα radiation is shown in Figure 2-1. The crystalline form B according to claim 4 , which is an anhydrous crystalline form.

6. Form C of the fumarate salt of the compound of formula I according to claim 1 has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 24.435±0.2°, 28.829±0.2°, 38.312±0.2°; preferably, it has characteristic diffraction peaks at the following 2θ angles: 21.245±0.2°, 24.435±0.2°, 28.829±0.2°, 38.312±0.2°, 39.979±0.2°; more preferably, the X-ray powder diffraction pattern using Cu-Kα radiation is shown in Figure 3-1.

7. The crystalline form D of the fumarate salt of the compound of formula I according to claim 1 has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern using Cu-Kα radiation: 7.160±0.2°, 18.004±0.2°, 21.436±0.2°, 25.082±0.2°; preferably has characteristic diffraction peaks at the following 2θ angles: 3.537±0.2°, 7.160±0.2°, 15.745±0.2°, 18.004±0.2°, 18.893±0.2°, 19.269±0.2°, 21. .436±0.2°, 25.082±0.2°; more preferably, there are characteristic diffraction peaks at the following 2θ angles: 3.537±0.2°, 7.160±0.2°, 10.700±0.2°, 15.745±0.2°, 18.004±0.2°, 18.893±0.2°, 19.269±0.2°, 20.965±0.2°, 21.436±0.2°, 25.082±0.2°, 28.762±0.2°; most preferably, the X-ray powder diffraction pattern using Cu-Kα radiation is shown in Figure 4.

8. The crystalline form E of the fumarate of the compound of formula I according to claim 1 has characteristic diffraction peaks at the following 2θ angles in the X-ray powder diffraction pattern using Cu-Kα radiation: 7.570±0.2°, 15.357±0.2°, 18.889±0.2°, 21.436±0.2°, 23.168±0.2°, 27.084±0.2°; preferably has characteristic diffraction peaks at the following 2θ angles: 3.769±0.2°, 7.570±0.2°, 15.357±0.2°, 16.889±0.2°, 21.436±0.2°, 23.168±0.2°, 27.084±0.2°; .847±0.2°, 18.410±0.2°, 18.889±0.2°, 19.210±0.2°, 20.780±0.2°, 21.436±0.2°, 23.168±0.2°, 25.411±0.2°, 26.639±0.2°, 27.084±0.2°, 28.770±0.2°, 31.065±0.2°, 32.507±0.2°; more preferably, the X-ray powder diffraction pattern using Cu-Kα radiation is shown in Figure 5-1. The crystalline form E according to claim 8 , which is an anhydrous crystalline form.

10. A pharmaceutical composition comprising the pharmaceutically acceptable salt according to claim 1 or the crystalline form according to any one of claims 2 to 9, and a pharmaceutically acceptable carrier.

11. The pharmaceutically acceptable salt according to claim 1, the crystalline form according to any one of claims 2 to 9, or the pharmaceutical composition according to claim 10 for use in the preparation of a pharmaceutical composition for treating 5-HT 2A Application of drugs in the treatment of receptor-related diseases.

12. The use according to claim 11, wherein the 5-HT 2A Receptor-related diseases include: Schizophrenia, psychosis, schizoaffective disorder, mania, psychotic depression, affective disorder, dementia, anxiety disorder, sleep disorder, appetite disorder, bipolar disorder, psychosis secondary to hypertension, migraine, hypertension, thrombosis, vasospasm, ischemia, motor tics, depression, major depressive disorder, anxiety, sleep disturbance and appetite disturbance, non-motor symptoms due to Parkinson's disease (including delusions, hallucinations, depression, anxiety, cognitive impairment or sleep disturbance), psychotic disorder due to Alzheimer's disease (including delusions, hallucinations), negative symptoms of schizophrenia, Parkinson's disease, Huntington's disease, Alzheimer's disease, spinocerebellar atrophy, Tourette syndrome, Friedreich's ataxia, Machado-Joseph disease, dementia with Lewy bodies, movement disorders, dystonia, myoclonus, tremor or progressive supranuclear palsy and frontotemporal dementia.

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