WO2023061372A1 - Malate salt of xanomeline derivative, crystalline form a, and preparation method therefor and use thereof - Google Patents

Abstract

The present invention relates to the field of medicinal chemistry, and in particular, to a malate salt of a xanomeline derivative, the malate salt having a structure as shown in formula (I). The malate salt of the compound of formula (I) has excellent effects on at least one aspect of physical stability, solubility, hygroscopicity, biological activity, safety, bioavailability, toxic and side effects, etc.

Description

Malate salt of zanameline derivative, crystal form A, preparation method and use thereof

This application claims the priority of the following earlier application: the patent application number 202111198168.4 filed with the State Intellectual Property Office of China on October 14, 2021, and the title of the invention is "malate, crystal form A of zanomeline derivatives and its Preparation method and use of "prior application. The entirety of said prior application is incorporated by reference into this application.

technical field

The present invention relates to the field of medicinal chemistry, in particular to a malate salt of a jenomeline derivative, a crystal form A and a preparation method thereof, which also includes the preparation of the malate salt and a crystal form A of a jenomeline derivative The application of drugs for the prevention or treatment of disorders of the central nervous system.

Background technique

Neurotransmitters are chemical messengers secreted by neurons to facilitate the flow of information and communicate with other cells in the central and peripheral nervous systems, such as muscle or similar nerve cells. Acetylcholine, one of the key neurotransmitters in the brain, has two distinct receptor classes: muscarinic receptors (M receptors, G protein-coupled receptors) and nicotinic receptors (N receptors , ion channel receptors).

The M receptor family includes five subtypes from M1 to M5, all of which are expressed in the brain and peripheral tissues and play many key physiological roles in cognition, behavior, sensory, motor and autonomic processes. Disruption of M-type receptor signaling leads to memory impairment and cognitive impairment, triggers a variety of diseases including schizophrenia and Alzheimer's disease (AD), and exacerbates psychosis. On the contrary, third-party preclinical and clinical data show that the enhancement of M-type receptor signaling can improve these symptoms. In addition, M-type receptors, especially M1, M2, and M4 receptors, are also considered to be related to analgesia.

Xanomeline is a partial agonist of muscarinic receptors, which can produce agonistic effects on all five subtypes of muscarinic receptors without selectivity. Jointly developed and marketed by Eli Lilly and Novo Nordisk, it is mainly used clinically for the treatment of Alzheimer's disease. The chemical name of Normeline is 3-[(4-hexyloxy)-1,2,5 -Thiadiazol-3-yl]-1,2,5,6-tetrahydro-1-picoline, the chemical structure is as follows:

Patent document CN94192681.8 discloses that oxalate can be converted into oxalate, but oxalate has potential side effects on the patient's kidney function, so it is not suitable for medicine, especially when treating the elderly. And it is further disclosed that in the series of twelve kinds of pharmaceutically acceptable acids (the name of the specific pharmaceutically acceptable acid is not disclosed), only zomeline tartrate has good bioavailability, good handling properties and reproducible crystal form .

Currently, common general knowledge generally teaches that selecting a salt with a desired combination of properties remains a difficult semi-empirical choice, requiring a compromise in the properties of the salt form, but there remains the question of which salt form is most suitable for screening a particular candidate Medication difficulties.

The screening of drug salt form is a difficult semi-empirical choice, and the hygroscopicity of the drug will seriously affect the fluidity of the drug, and even affect the stability of the drug. The solubility of drugs has a crucial impact on the preparation of pharmaceuticals, drug dissolution, absorption and so on. But how to improve the solubility of the drug, without the expense of the hygroscopicity of the drug, it is difficult to obtain a candidate drug salt with suitable stability, solubility and hygroscopicity.

Alternatively, Xanomeline as an M-receptor activator has shown encouraging therapeutic efficacy in the clinic for the treatment of psychosis and related behavioral symptoms in patients with schizophrenia and AD, but its potential has been limited by cholinergic side effects, including salivation , nausea, dizziness, etc., which are thought to be due to stimulation of M receptors in peripheral nervous tissue. The metabolism of Zanameline in the human body is complex and unpredictable, and Zanameline lacks selectivity for muscarinic receptor subtypes, thus causing difficulties in the drug development of Zanameline.

Therefore, it is necessary to further search for novel compounds suitable for drug-making with good curative effect, small side effects, and better pharmacokinetic properties; it is also necessary to develop crystalline salts and polymorphs thereof with suitable and reliable formulation and preparation characteristics. Models.

Contents of the invention

The object of the present invention is to provide a malate salt of a zanmeline derivative shown in formula I, which can be used for the preparation of medicines for preventing or treating central nervous system disorders and the dissolution of this derivative Improved ability, stable storage, convenient administration, improved drug metabolism, drug toxicity and side effects, and high patient compliance during administration.

Another object of the present invention is to provide a crystal form A of the malate salt of phenomeline derivatives shown in formula I, the crystal form A can have excellent thermodynamic stability and mechanical stability, good repeatability, Suitable for commercial mass production.

In a first aspect, the present invention provides a malate salt of a compound of formula I.

In some solutions of the present invention, the malate salt of the compound of formula I above is shown in formula II, wherein x is selected from 0.5-2.

In some solutions of the present invention, the above-mentioned x is 0.5, 1.0, 1.5, 2.0.

In some aspects of the present invention, x in the compound of formula II above is 1.0.

In some solutions of the present invention, the compound of formula II above, wherein the malic acid is L-malic acid.

In a second aspect, the present invention provides the A crystal form of the malate salt of the compound of formula I, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 12.007±0.2°, 14.827±0.2°, 16.796±0.2° , 20.012±0.2° and 21.942±0.2°. The crystal form A of the malate salt of the compound of formula I is the compound of formula II with x being 1.0, and the malic acid therein is L-malic acid.

In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2θ angles: 12.007±0.2°, 14.827±0.2°, 16.796±0.2°, 20.012±0.2°, 21.942±0.2 °, 22.473±0.2° and 25.333±0.2°.

In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2θ angles: 12.007±0.2°, 13.288±0.2°, 14.827±0.2°, 16.796±0.2°, 20.012±0.2 °, 21.942±0.2°, 22.473±0.2°, and 25.333±0.2°.

In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2θ angles: 12.007±0.2°, 13.288±0.2°, 14.827±0.2°, 15.399±0.2°, 16.796±0.2 °, 20.012±0.2°, 20.327±0.2°, 21.942±0.2°, 22.473±0.2°, and 25.333±0.2°.

In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2θ angles: 12.007±0.2°, 13.288±0.2°, 14.827±0.2°, 15.399±0.2°, 16.796±0.2 °, 20.012±0.2°, 20.327±0.2°, 21.942±0.2°, 22.473±0.2°, 24.996±0.2°, 25.333±0.2°, and 27.718±0.2°.

In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2θ angles: 12.007±0.2°, 12.755±0.2°, 13.288±0.2°, 13.903±0.2°, 14.827±0.2 °, 15.399±0.2°, 16.796±0.2°, 17.686±0.2°, 18.906±0.2°, 20.012±0.2°, 20.327±0.2°, 21.942±0.2°, 22.473±0.2°, 24.996±0.2°, 25.333±0.2 ° and 27.718±0.2°.

In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2θ angles: 12.007±0.2°, 12.755±0.2°, 13.288±0.2°, 13.903±0.2°, 14.827±0.2 °, 15.399±0.2°, 16.796±0.2°, 17.686±0.2°, 18.906±0.2°, 20.012±0.2°, 20.327±0.2°, 20.660±0.2°, 21.942±0.2°, 22.473±0.2°, 24.996±0.2 °, 25.333±0.2°, 27.382±0.2°, and 27.718±0.2°.

In some solutions of the present invention, the above crystal form A has an XRPD pattern as shown in FIG. 1 .

In some solutions of the present invention, the above crystal form A has a DSC spectrum substantially as shown in FIG. 2 .

In some solutions of the present invention, the differential scanning calorimetry curve of the above crystal form A has an endothermic peak at 111.03±3°C.

In some solutions of the present invention, the above crystal form A has a TGA curve substantially as shown in FIG. 3 .

In a third aspect, the present invention also provides a method for preparing malate of the compound of formula I, comprising reacting the compound of formula I with malic acid.

In some schemes of the present invention, the preparation method of the A crystal form of the compound malate of the above formula I comprises the following steps:

Mix the compound of formula I, malic acid and a solvent, heat until completely dissolved, then cool to precipitate crystals; wherein, the solvent is selected from ethanol, isopropanol, n-propanol, butanol, acetone, ethyl acetate, n-heptyl One or more mixtures of alkanes, acetonitrile, tetrahydrofuran; preferably one or more mixtures of ethanol, isopropanol, ethyl acetate, n-heptane; or

Mix the compound of formula I, malic acid and the first solvent, heat until completely dissolved, then add the second solvent, cool and crystallize. The first solvent is selected from one or more mixtures of methanol, ethanol, isopropanol, n-butanol; the second solvent is selected from methyl tert-butyl ether, esters, acetonitrile, alkanes The mixture of one or more than one of them means that the esters are selected from ethyl acetate and/or, the lipids are, for example, isopropyl acetate; the alkanes are selected from n-heptane and/or n-hexane.

In some solutions of the present invention, the heating temperature is 50-80°C, such as 60-70°C.

In some solutions of the present invention, the compound of formula I, malic acid and the solvent used to dissolve the compound or the first solvent are mixed and then stirred. The stirring time may be 1-5 hours, preferably 2-3 hours.

The weight/volume ratio (g/mL) of the compound of formula I to the solvent used to dissolve the compound or the first solvent is 1:4-10, preferably 1:6-8, such as 1:6, 1:7 , 1:8.

In some solutions of the present invention, the cooling may be to 0-30°C, preferably to 2-8°C, for example to 5°C. It can be filtered once before cooling.

In some solutions of the present invention, stirring is carried out during the cooling process, and the stirring time may be 6 to 24 hours, preferably 18 hours.

According to the present invention, after the crystals are precipitated, filter and dry; in some solutions of the present invention, the step of washing with a solvent is also included before drying, and the washing solvent is selected from ethanol, isopropanol, n-propanol, One or a mixture of acetone, ethyl acetate, acetonitrile, tetrahydrofuran.

In some schemes of the present invention, the molar ratio of the compound of formula I to malic acid is 1:0.9-1.3, preferably, the molar ratio of the compound of formula I to malic acid is 1:1-1.1, for example 1: 1. 1:1.05, 1:1.1.

In a fourth aspect, the present invention provides a pharmaceutical composition, the pharmaceutical composition comprising the malate of the compound of formula I or the malate A crystal form of the compound of formula I, and optional pharmaceutically acceptable excipients agent.

In a fifth aspect, the present invention provides the malate of the compound of formula I, the malate A crystal form of the compound of formula I above, or the pharmaceutical composition comprising the malate of the compound of formula I, or the malate of the compound of formula I Use of the pharmaceutical composition of crystal form A in the preparation of medicines for treating disorders of the central nervous system.

In some aspects of the present invention, the disorders of the central nervous system include but are not limited to schizophrenia, Alzheimer's disease, Parkinson's disease, depression, movement disorders, drug addiction, pain and neurodegeneration (eg Dow disease or synucleinopathies).

In some aspects of the present invention, the central nervous system disorder is schizophrenia.

In a sixth aspect, the present invention provides a method for treating or preventing central nervous system disorders in mammals (such as humans), the method comprising administering a therapeutically effective amount of malic acid of a compound of formula I to mammals (such as humans) salt, malate A crystal form of the compound of formula I, a pharmaceutical composition comprising the malate salt of the compound of formula I and a pharmaceutical composition comprising the malate A crystal form of the compound of formula I.

In some aspects of the present invention, the disorders of the central nervous system include but are not limited to schizophrenia, Alzheimer's disease, Parkinson's disease, depression, movement disorders, drug addiction, pain and neurodegeneration (eg Dow disease or synucleinopathies).

In some aspects of the present invention, the central nervous system disorder is schizophrenia.

Beneficial effect

1. The present invention provides the malate of the compound of formula I for the first time; the malate of the compound of formula I has at least one aspect such as physical stability, solubility, hygroscopicity, biological activity, safety, bioavailability, toxic side effect Excellent effect.

2. The crystal form A of the malate salt of the compound of formula I has good stability, low hygroscopicity, good water solubility, small batch-to-batch variation, and good prospects for making a drug.

3. The preparation process of the salt form and crystal form of the present invention is simple and suitable for industrial production.

Description of drawings

Fig. 1 is the XRPD pattern of A crystal form of compound L-malate of formula I;

Fig. 2 is the DSC spectrum of the A crystal form of formula I compound L-malate;

Fig. 3 is the TGA spectrum of the A crystal form of formula I compound L-malate;

Fig. 4 is the XRPD patterns of crystal form A of compound L-malate of formula I at high temperature (60° C.) for 0 days, 6 days, 14 days, and 30 days;

Fig. 5 is the XRPD patterns of crystal form A of compound L-malate of formula I under high humidity (RH92.5%) conditions at 0 days, 6 days, 14 days, and 30 days;

Fig. 6 is the XRPD pattern of crystal form A of L-malate of the compound of formula I under light conditions (4500±500Lux) at 0 days, 6 days, 14 days and 30 days.

Fig. 7 is the pharmacokinetic curve of the compound of formula I in rat plasma after oral administration of crystal form A of compound L-malate of formula I (sample of Example 2) and compound of formula I (sample of Example 1).

Detailed ways

The compound of the general formula of the present invention and its preparation method and application will be further described in detail below in conjunction with specific examples. It should be understood that the following examples are only for illustrating and explaining the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies realized based on the above contents of the present invention are covered within the scope of protection intended by the present invention.

Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

The present invention adopts the following abbreviations: rt stands for room temperature; aq stands for aqueous solution; DCM stands for dichloromethane; THF stands for tetrahydrofuran; MeOH stands for methanol; EtOH stands for ethanol; IPA stands for isopropanol; DSC stands for differential scanning calorimeter; TGA stands for thermogravimetric analysis; ¹ H-NMR stands for hydrogen nuclear magnetic resonance spectrum; XRPD stands for X-ray powder diffraction; eq stands for molar equivalent.

The compounds were named manually or by ChemDraw software, and the commercially available compounds used the supplier catalog names.

For the experimental methods without specific conditions indicated in the following examples, the conventional conditions or the conditions suggested by the manufacturer are usually followed. Percentages and parts are by weight unless otherwise indicated.

The test methods and instruments used to characterize salts and crystals in the embodiments of the present invention are as follows:

Powder X-ray diffraction (also known as "X-ray powder diffraction", X-ray powder diffractometer, XRPD) method

Instrument model: Bruker D8advance X-ray diffractometer

Test method: About 10-20 mg of sample is used for XRPD detection.

The detailed XRPD parameters are as follows:

Light pipe: Cu, kα,

Phototube voltage: 40kV, phototube current: 40mA

Divergence slit: 0.60mm

Detector slit: 10.50mm

Anti-scatter slit: 7.10mm

Scanning range: 4-40deg

Step: 0.02deg

Step size: 0.12 seconds

It should be noted that in X-ray powder diffraction (XRPD), the diffraction pattern obtained from a crystalline compound is often characteristic for a particular crystal, where the relative intensities of the bands (especially at low angles) may vary. Varies due to the effect of preferred orientation due to differences in crystallization conditions, particle size, and other measurement conditions. Therefore, the relative intensity of the diffraction peaks is not characteristic of the targeted crystal, and when judging whether it is the same as a known crystal, more attention should be paid to the relative positions of the peaks rather than their relative intensities. Furthermore, for any given crystal there may be slight errors in the position of the peaks, as is well known in the art of crystallography. For example, due to temperature changes, sample movement, or instrument calibration when analyzing samples, the position of the peak can move, and the measurement error of the 2θ value is sometimes about ±0.2°. Therefore, this error should be taken into account when determining each crystal structure. In the XRPD spectrum, the 2θ angle or the crystal plane distance d is usually used to represent the peak position, and there is a simple conversion relationship between the two: d=λ/2sinθ, where d represents the crystal plane distance (also known as "planar distance"), and λ represents The wavelength of the incident X-ray, θ is the diffraction angle. For the same crystal of the same compound, the peak positions of their XRPD spectra are similar on the whole, and the relative intensity error may be large. It should also be pointed out that in the identification of mixtures, due to factors such as content decline, some diffraction lines will be missing. At this time, it is not necessary to rely on all the bands observed in the high-purity sample, and even one band may affect the given Certain crystallization is characteristic.

Measurement variance associated with such X-ray powder diffraction analysis results arises from a variety of factors including: (a) errors in sample preparation (e.g., sample height), (b) instrument errors, (c) calibration differences, ( d) operator errors (including errors in determining peak positions), and (e) properties of the species (eg, preferred orientation errors). Calibration errors and sample height errors often cause all peaks to shift in the same direction. Small differences in sample height will result in large shifts in XRPD peak positions when using flat supports. Systematic studies have shown that a sample height difference of 1 mm can result in a peak shift in 2θ of up to 1°. These shifts can be identified from the X-ray diffraction pattern and can be eliminated by compensating for them (using a system calibration factor for all peak position values) or recalibrating the instrument. Measurement errors from different instruments can be corrected for by applying system calibration factors to make peak positions consistent, as described above.

Differential thermal analysis (also known as "differential scanning calorimetry", Differential Scanning Calorimeter, DSC) method

Instrument Model: METTLER TOLEDO DSC3+ Differential Scanning Calorimeter

Test method: Take a sample (~1mg) and place it in a DSC aluminum pot for testing. Under the condition of 50mL/ _minN2 , heat the sample from 25°C to 300°C at a heating rate of 10°C/min. In the present invention, differential scanning calorimetry (DSC) is used to determine the melting point. DSC measures the transition temperature when a crystal absorbs or releases heat due to a change in its crystal structure or melting of the crystal. For the same crystal of the same compound, in consecutive analysis, the error of thermal transition temperature and melting point is typically within about 5°C, usually within about 3°C, when we say that a compound has a given DSC peak or melting point, this means ±5°C of the DSC peak or melting point. DSC provides an auxiliary method for distinguishing between different crystals. Different crystalline forms can be identified based on their different transition temperature characteristics. It should be pointed out that for mixtures, the DSC peak or melting point may vary in a larger range. In addition, since the melting process of the substance is accompanied by decomposition, the melting temperature is related to the heating rate.

Thermal Gravimetric Analyzer (TGA) method

Instrument Model: TAQ5000IR Thermogravimetric Analyzer

Test method: Take a sample (2~5mg) and place it in a TGA platinum pot for testing. Under the condition of 25mL/ _minN2 , heat the sample from room temperature to 350°C at a heating rate of 10°C/min.

High performance liquid chromatography (HPLC) analysis method:

The instrument used is Waters ARC 2998HPLC; Chromatographic column: Agilent Poroshell bonus-RP 4.6×100mm, 2.7μm;

The measurement conditions are as follows:

Injection volume: 10ul;

Flow rate: 1.0mL/min;

Detection wavelength: 275nm;

Sample concentration: 1.0mg/mL;

Diluent: 20% acetonitrile aqueous solution;

Column temperature: 40°C;

Mobile phase A: 0.2% phosphoric acid aqueous solution;

Mobile phase B: acetonitrile-methanol (1:1) solution;

The elution gradient is shown in Table 1:

Table 1 Elution gradient conditions

time (min)	%A		%B
0	90	10

15	60	40
20	25	75
30	25	75
31	90	10
40	90	10

Currently, common general knowledge generally teaches that selecting a salt with a desired combination of properties remains a difficult semi-empirical choice, requiring a compromise in the properties of the salt form, but there remains the question of which salt form is most suitable for screening a particular candidate Medication difficulties.

During the experiment, the inventor found that the hygroscopicity of the drug will seriously affect the fluidity of the drug, and even affect the stability of the drug. The solubility of drugs has a crucial impact on the preparation of pharmaceuticals, drug dissolution, absorption and so on. But how to improve the solubility of the drug, without the expense of the hygroscopicity of the drug, it is difficult to obtain a drug candidate salt with suitable drug stability, solubility and hygroscopicity.

After extensive and in-depth research, the inventor unexpectedly found that the malate of the compound of formula I has a higher melting point as determined by DSC, and the stability experiment confirmed that the malate of the compound of formula I has higher stability. In addition, the malate salt of the compound of formula I has low hygroscopicity and moderate solubility. The combination of high stability, low hygroscopicity and appropriate solubility of compound malate of formula I is unexpected, which makes compound malate of formula I (especially compound L-malate of formula I) suitable for the preparation of oral solid dosage forms , especially the preparation of tablets.

The solubility of the active ingredient is of great importance for the choice of dosage form because the dosage form has a direct effect on bioavailability. For oral dosage forms, it is generally considered to be advantageous to have a higher solubility of the active ingredient because it leads to increased bioavailability.

On this basis, the inventors have discovered the A crystal form of malate of the compound of formula I, which has advantages in at least one of physical stability, thermodynamic stability and mechanical stability; the prepared formula I compound malate The crystal form A of the acid salt has a suitable crystal size and is suitable for industrial production and preparation.

A crystalline form of malate A of the compound of formula I can significantly improve the water solubility of the compound of formula I, and has good stability and extremely low hygroscopicity, which is beneficial for making oral solid preparations. The preparation made of malate of the compound of formula I can maintain the effective physiological concentration of the free base of formula I in the body for a long time and is convenient to administer, so it has the advantages of improving the compliance of patients and the like.

Embodiment 1. the synthesis of formula I compound

The preparation of step 1,2-hydroxyl-2-(3-pyridyl)acetonitrile (intermediate 1)

3-Pyridinecarbaldehyde (6.00g, 56.02mmol, 1.0eq), glacial acetic acid (3.36g, 56.02mmol, 1.0eq) and 6mL of pure water were successively added into a 100mL single-port reaction flask, and stirred and mixed at room temperature. Add dropwise trimethylsilyl cyanide (7.42g, 74.42mmol, 1.3eq) into an aqueous solution of trimethylsilyl cyanide (7.42g, 74.42mmol, 1.3eq) at 2-8°C, stir to react, confirm the completion of the reaction on a TLC (thin-layer chromatography) plate, cool down to -5°C in an ice-salt bath, stir and analyze crystals. After filtering, the filter cake was washed with ice water (5 mL*3) to obtain a white solid (6.72 g, yield 89%).

¹ H NMR (400MHz, CDCl ₃ )δ8.66–8.52(m,2H),7.96(m,1H),7.45(dd,J＝8.0,4.9Hz,1H),5.64(s,1H).MS m /z:134.9[M+H] ⁺ .

The preparation of step 2,2-amino-2-(3-pyridyl)acetonitrile (intermediate 2)

Add NH ₄ Cl (1.81g, 33.80mmol, 1.5eq), water (15.00mL) and ammonia water (4.80mL, 25%, 1.1eq) to a 50mL two-necked reaction flask in turn, stir at room temperature to dissolve, then add intermediate 1 ( 3.00 g, 22.37 mmol, 1.0 eq), stirring was continued for 20 hours. Extract with dichloromethane (15mL*7), combine the organic phases, and dry with 2g of anhydrous sodium sulfate for 5 minutes. Filter and evaporate to dryness under reduced pressure to obtain a reddish-brown oil (1.30 g, yield 43%). Without purification, it was directly used in the next reaction.

Preparation of step 3, 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (intermediate 3)

Add S ₂ Cl ₂ (13.99g, 103.62mmol, 2.0eq) and DMF (56.00mL) to a 250mL three-necked reaction flask in turn, and stir in an ice-water bath, then drop in DMF (28.00mL) at 0-5°C to dissolve Intermediate 2 ( 6.90 g, 51.82 mmol, 1.0 eq). Stir the reaction for 40 minutes, add 9M NaOH (60 mL) dropwise at the same temperature, and filter. The aqueous phase was extracted with dichloromethane (120 mL*3), and the combined organic phases were washed with pure water (80 mL*3), dried over anhydrous sodium sulfate, and filtered. Evaporated to dryness under reduced pressure to obtain a tan solid (7.99 g, yield 78%).

¹ H NMR (400MHz, CDCl ₃ ) δ9.24(s, 1H), 8.75(d, J=4.8Hz, 1H), 8.29(m, 1H), 7.46(dd, J=8.1, 4.9Hz, 1H) .MS m/z: 197.8, 199.8[M+H] ⁺ .

Preparation of Step 4, 3-(4-hexyloxy-1,2,5-thiadiazol-3-yl)pyridine (intermediate 4)

Add 60% NaH (6.21g, 155.28mmol, 9.0eq) and tetrahydrofuran (9.00mL) to a 100mL three-necked reaction flask in sequence, and add n-hexanol (6.27g, 61.47mmol, 3.0 eq), stirred at room temperature for 2 hours. Intermediate 3 (3.41 g, 17.25 mmol, 1.0 eq) dissolved in tetrahydrofuran (15.00 mL) was dropped into the system at room temperature, and magnetically stirred for 3 hours. The reaction solution was washed with saturated aqueous sodium bicarbonate (30 mL), the aqueous phase was extracted with dichloromethane (30 mL*3), and concentrated under reduced pressure. Column chromatography of the crude product (petroleum ether (60-90)/ethyl acetate 5:1-3:1) gave an off-white solid (3.61 g, yield 79%).

¹ H NMR (400MHz, CDCl ₃ ) δ9.40(d, J=2.2Hz, 1H), 8.65(dd, J=4.8, 1.7Hz, 1H), 8.43(dt, J=8.0, 2.0Hz, 1H) ,7.40(dd,J=8.1,4.8Hz,1H),4.53(t,J=6.6Hz,2H),1.89(m,2H),1.71(s,2H),1.44–1.29(m,4H), 0.97–0.87(m,3H).MS m/z:264.0[M+H] ⁺ .

Step 5, Preparation of iodide-1-deuteromethyl-3-(4-hexyloxy-1,2,5-thiadiazol-3-yl)pyridine (intermediate 5)

Intermediate 4 (3.47g, 13.2mmol, 1.0eq), acetone (50.00mL) and deuteroiodomethane (5.72g, 39.5mmol, 3.0eq) were sequentially added to a 100mL three-neck reaction flask and stirred at room temperature for 24 hours. Intermediate 5 was precipitated from the system and filtered to obtain a bright yellow solid (5.18 g, yield 96%).

¹ H NMR (400MHz, CDCl ₃ ) δ9.68(m, 1H), 9.44(m, 1H), 9.14(dt, J=8.4, 1.5Hz, 1H), 8.29(dd, J=8.3, 6.0Hz, 1H), 4.61(t, J＝6.9Hz, 2H), 1.95(m, 2H), 1.55–1.45(m, 2H), 1.45–1.28(m, 4H), 0.92(t, J＝7.0Hz, 3H ).MS m/z:281.0.

Step 6, the preparation of deuterated phenomeline (compound of formula I)

Add intermediate 5 (2.00g, 4.9mmol, 1.0eq) and ethanol (24.00mL) to a 250mL three-necked reaction flask in sequence, stir to dissolve, and add NaBH ₄ (371mg, 9.8mmol, 2.0eq) in ethanol dropwise at -5～0°C (16.00 mL) suspension, stirred at the same temperature for 1 hour. Purified water (100.00 mL) was added to quench, and the aqueous phase was extracted with dichloromethane (100 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography (dichloromethane/methanol 20:1) of the crude product gave a tan solid (1.11 g, yield 79%). Melting point: 38.26°C.

¹ H NMR (400MHz, CDCl ₃ ) δ7.07(m, 1H), 4.44(t, J=6.6Hz, 2H), 3.46(m, 2H), 2.58(t, J=5.7Hz, 2H), 2.46 (m,2H),1.88–1.79(m,2H),1.46(m,2H),1.34(m,4H),0.91–1.79(m,3H).MS m/z:285.1[M+H] ⁺ .

Embodiment 2. The preparation of formula I compound L-malate A crystal form

Weigh the compound of formula I (10.0g, 35.2mmol) and L-malic acid (4.81g, 35.8mmol) into a flask, add 70mL of isopropanol, heat up to 60-70°C, stir and mix, so that the mixture is completely dissolved. Filtrate hot to obtain a clear liquid, cool, lower the temperature to 2-8°C, stir and crystallize, filter to obtain the product, wash with ice isopropanol to obtain a wet product, place the wet product at 40°C for vacuum drying, and obtain White solid (13.83g, yield 93.9%), melting point 11.03°C. ¹ H NMR (400MHz, CDCl ₃ ) δ7.22(m, 1H), 4.47(t, J=6.7Hz, 2H), 4.25(dd, J=9.6, 4.5Hz, 1H), 4.12(s, 2H) ,3.29(s,2H),2.85–2.69(m,4H),1.85(m,2H),1.50–1.41(m,2H),1.35(m,4H),0.95–0.86(t,J＝6.5Hz 3H).MS m/z:285.1[M+H] ⁺ .

The obtained white solid was submitted for inspection by XRPD, DSC and TGA. After testing, it was found that the obtained white solid existed in the form of crystals, and the obtained crystal form was named as the compound of formula I L-malate A crystal form, referred to as A crystal form. The XRPD pattern, DSC pattern and TGA pattern of the obtained crystal form A are basically shown in Fig. 1 , Fig. 2 and Fig. 3 respectively. In the X-ray powder diffraction pattern of the obtained crystal, the peak positions and intensities of the characteristic peaks are shown in Table 2; the diffraction angle data of the XRPD pattern of the obtained crystal form are basically shown in Table 3, and the error range of the 2θ value is ±0.2°.

The peak position and intensity of the characteristic peaks of the X-ray powder diffraction pattern of Table 2.A crystal form

serial number	2θ angle (°)	Relative Strength(%)	serial number	2θ angle (°)	Relative Strength(%)
1	12.007	26.3	10	20.012	39.9
2	12.755	3.9	11	20.327	26.3
3	13.288	4.7	12	20.660	8.6
4	13.903	7.4	13	21.942	100.0
5	14.827	25.7	14	22.473	24.0
6	15.399	20.3	15	24.996	21.1
7	16.796	21.6	16	25.333	30.4
8	17.686	6.1	17	27.382	7.8
9	18.906	11.3	18	27.718	17.5

Table 3. XRPD analysis data of crystal form A

Embodiment 3, preparation of formula I compound L-malate A crystal form

Add the compound of formula I (10.0 g, 35.2 mmol), L-malic acid (4.72 g, 35.2 mmol) and 40 mL of isopropanol into a 100 mL flask, heat the mixture until completely dissolved, and filter while hot to obtain a clear liquid. The solution was cooled slowly under stirring to 2-8°C for crystallization, and the product was collected by filtration, washed with cold isopropanol, and dried in vacuum at 40°C to obtain a white solid (13.3 g, yield 90.3%). The product obtained through testing is the crystal form A of compound L-malate of formula I.

Example 4. Preparation of Form A of Compound L-Malate of Formula I

Add the compound of formula I (4.9 g, 17.2 mmol), L-malic acid (2.54 g, 18.9 mmol) and 5 mL of methanol into a 100 mL flask, heat the mixture until it is completely dissolved, and filter while hot to obtain a clear liquid. Then 34 mL of ethyl acetate was added thereto. The solution was cooled slowly under stirring to 2-8°C for crystallization, and the product was collected by filtration, washed with cold ethyl acetate, and dried in vacuum at 40°C to obtain a white solid (6.6 g, yield 91.7%). The product obtained through testing is the crystal form A of compound L-malate of formula I.

Example 5. Preparation of Form A of Compound L-Malate of Formula I

Add the compound of formula I (5.0 g, 17.6 mmol), L-malic acid (2.83 g, 21.1 mmol) and 12 mL of isopropanol into a 100 mL flask, heat the mixture until completely dissolved, and filter while hot to obtain a clear liquid. Then 38 mL of ethyl acetate was added thereto. The solution was cooled slowly under stirring to 2-8°C for crystallization, and the product was collected by filtration, washed with cold isopropanol, and dried in vacuum at 40°C to obtain a white solid (6.8 g, yield 92.4%). The product obtained through testing is the crystal form A of malate salt of the compound of formula I.

Example 6. Preparation of Form A of Compound L-Malate of Formula I

Add formula I compound (1.0g, 3.52mmol), L-malic acid (0.6g, 4.47mmol) and 0.5mL of methanol, 0.5mL of methyl tert-butyl ether into a 50mL flask, heat the mixture until completely dissolved, and filter while hot , Obtain clarification liquid. An additional 5 mL of methyl tert-butyl ether was then added to the solution. The solution was cooled slowly under stirring to 2-8°C for crystallization, and the product was collected by filtration, washed with cold methyl tert-butyl ether, and dried in vacuum at 40°C to obtain a white solid (1.3 g, yield 88.4%). The product obtained through testing is the crystal form A of malate salt of the compound of formula I.

Embodiment 7. the preparation of formula I compound nitrate

Add 1085 mg of the compound of formula I and 3 mL of ethyl acetate into a 25 mL flask, stir the mixture until it is completely dissolved, and filter while hot to obtain a clear liquid. Add nitric acid to it under stirring until the pH value is between 3 and 4, then add 12 mL of methyl tert-butyl ether to it, stir and crystallize, collect the product by filtration, wash with cold methyl tert-butyl ether, °C and dried in vacuo to obtain 1000 mg of white solid with a yield of 75.5%. The product obtained through testing is the compound nitrate of formula I. Melting point: 64.5°C (DSC). ¹ H NMR (400MHz, CDCl ₃ ): δ12.31 (brs, 1H), 7.26–7.23 (m, 1H), 4.75–4.38 (m, 1H), 4.47 (t, J=6.7Hz, 2H), 4.00 –3.56(m,2H),3.26–2.86(m,2H),2.73–2.49(m,1H),1.85(quint,J＝6.8Hz,2H),1.57–1.25(m,6H),0.91(t ,J＝6.9Hz,3H).MS m/z:285.2[M+H] ⁺ .

Embodiment 8. Preparation of formula I compound succinate

Add 505 mg of the compound of formula I, 210 mg of succinic acid and 2 mL of isopropanol to a 50 mL flask, heat the mixture until it is completely dissolved, filter while hot to obtain a clear liquid, and then add 18 mL of ethyl acetate to it. The solution was slowly cooled under stirring to 2-8°C for crystallization, and the product was collected by filtration, washed with cold ethyl acetate, and dried in vacuum at 40°C to obtain 630 mg of white solid with a yield of 88.2%. The product obtained through testing is the compound succinate of formula I. Melting point: 93.4°C (DSC). ¹ H NMR (400MHz, CDCl ₃ ): δ7.23–7.12 (m, 1H), 4.46 (t, J=6.7Hz, 2H), 4.05–3.85 (m, 2H), 3.22–2.98 (m, 2H) ,2.77–2.52(m,2H),2.57(s,4H),1.85(quint,J＝6.8Hz,2H),1.55–1.27(m,6H),0.91(t,J＝6.6Hz,3H). MS m/z:285.1[M+H] ⁺ .

Embodiment 9. Preparation of formula I compound tosylate

Add 501 mg of the compound of formula I, 337 mg of p-toluenesulfonic acid and 2 mL of isopropanol into a 50 mL flask, heat the mixture until it is completely dissolved, filter while hot to obtain a clear liquid, and then add 18 mL of ethyl acetate to it. The solution was cooled slowly under stirring to 2-8°C for crystallization, and the product was collected by filtration, washed with cold ethyl acetate, and dried in vacuum at 40°C to obtain 720 mg of a white solid with a yield of 90%. The product obtained through testing is the p-toluenesulfonate of the compound of formula I. ¹ H NMR (400MHz, CDCl ₃ ): δ11.41(brs, 1H), 7.72(d, J=7.9Hz, 2H), 7.23–7.16(m, 1H), 7.12(d, J=7.9Hz, 2H ),4.60–4.40(m,1H),4.45(t,J＝6.7Hz,2H),3.90–3.66(m,2H),3.20–2.94(m,2H),2.70–2.45(m,1H), 2.33(s,3H),1.84(quint,J=6.8Hz,1H),1.56–1.18(m,6H),0.91(t,J=6.8Hz,3H).MS m/z:285.1[M+H ] ⁺ .

Embodiment 10. Preparation of formula I compound tartrate

Add 3.0 g of the compound of formula I, 1.6 g of L-tartaric acid and 15 mL of isopropanol to a 100 mL flask, heat the mixture until it is completely dissolved, filter while hot to obtain a clear liquid, and then add 45 mL of ethyl acetate to it. The solution was cooled slowly under stirring to 2-8°C for crystallization, and the product was collected by filtration, washed with cold ethyl acetate, and dried in vacuum at 40°C to obtain 4.2 g of white solid, with a yield of 91.5%. The product obtained through testing is the compound tartrate of formula I. ¹ H NMR (400MHz, CDCl ₃ ) δ7.16 (1H, brs), 4.43 (4H, m), 4.09 (2H, brs), 3.29 (2H, brs), 2.69 (2H, brs), 1.83 (2H, m),1.43(2H,m),1.40(4H,m),0.9(t,J=6.5Hz,3H).MS m/z:285.1[M+H] ⁺ .

Embodiment 11. Preparation of other salts of compounds of formula I

Select methanesulfonic acid, benzenesulfonic acid, benzoic acid, malonic acid, adipic acid, and refer to the preparation method of Example 2-10 to form a salt with the compound of formula I, but none of the salts of the compound of formula I in solid form were obtained.

The physical and chemical property determination experiment of each compound and salt synthesized in Test Example 1 Example 1-10

1. Melting point determination experiment

Measure the compound of formula I synthesized in Examples 1-10 (the sample obtained in Example 1), the compound of formula I L-malate A crystal form (the sample obtained in Example 2) and the compound of formula I by differential scanning calorimetry (DSC). Compound nitrate (samples gained in Example 7), compound succinate of formula I (samples gained in Example 8), compound p-toluenesulfonate of formula I (samples gained in Example 9), compound tartrate of formula I (samples gained in Example 8) 10 obtained sample), the melting points of different salt forms are shown in Table 4.

2. Solubility determination experiment

Get seven parts of 2mL purified water and add the compound of formula I (the sample obtained in Example 1), the compound of formula I L-malate A crystal form (the sample obtained in Example 2), the compound nitrate of formula I (the sample obtained in Example 7) to it successively. Gained sample), formula I compound succinate (embodiment 8 gained sample), formula I compound p-toluenesulfonate (embodiment 9 gained sample), formula I compound tartrate (embodiment 10 gained sample) until insoluble, And record the corresponding dosage m, visual solubility S=m/2mL. After stirring for another 24 hours, take the supernatant and send it to HPLC for analysis, and the measured solution concentration is the HPLC analysis method to determine the solubility. The solubility results of different salt types in water are shown in Table 4. The solubility in this experiment was measured at ambient temperature (the measured ambient temperature was 10°C).

3. Investigation of hygroscopicity

Take an appropriate amount of each sample synthesized in the above-mentioned Examples 1, 2, 7-10, accurately weigh it, and weigh it as m1. Place the sample flat in a flat weighing bottle, and weigh the total weight as m2. After placing it at 25±1°C and 80±1% RH for 24 hours, weigh it as m3. The moisture absorption weight gain ΔW is calculated by the following formula, ΔW=(m3-m2)/m1*100%, and the results of moisture absorption weight gain of different salt types are shown in Table 4.

See Table 5 for hygroscopicity evaluation index:

Table 4. Physicochemical properties of each sample

sample	Melting point/℃	Solubility S(mg/mL)	Moisture absorption weight gain ΔW/%
Formula I compound (embodiment 1)	38.26	S< 1.07a	NA
Formula I compound L-malate A crystal form (Example 2)	111.03	40.48 a	1.97
Formula I compound nitrate (embodiment 7)	64.59	S> 244.2b	liquid after moisture absorption
Formula I compound succinate (embodiment 8)	93.43	7.99a	17.00
Formula I compound tosylate (embodiment 9)	112.50	5.39a	1.00
Formula I compound tartrate (embodiment 10)	95.9	86.05<S< 98.9b	3.03

In Table 4, a: Solubility was measured by HPLC; b: Solubility was measured by visual inspection. NA means not determined.

Table 5. Hygroscopicity evaluation index

Hygroscopicity Classification	Moisture weight gain (ΔW%)
deliquescence	Absorb enough water to form a liquid
Very hygroscopic	ΔW%≥15%
Hygroscopic	2%≤ΔW%<15%
slightly hygroscopic	0.2%≤ΔW%<2%
No or almost no hygroscopicity	ΔW%<0.2%

Experimental results of melting point determination: the melting point of compound L-malate of formula I is 111.03°C, and the compound L-malate of formula I has good stability.

Solubility measurement experiment results: the solubility of the compound L-malate of the formula I is 40.48 mg/mL, and the solubility of the compound L-malate of the formula I is better.

Hygroscopicity test results: the moisture absorption weight gain of compound L-malate of formula I was 1.97% under the conditions of 25±1° C. and 80±1% RH, indicating that compound L-malate of formula I was slightly hygroscopic.

Experimental result analysis: formula I compound L-malate has higher fusing point (promptly having higher stability), lower hygroscopicity, and suitable solubility is arranged, and this makes formula I compound malate be suitable for preparing oral Preparation of solid dosage forms, especially tablets.

Test example 2. The physical stability research of the prepared salt of embodiment 2,7-10

The formula I compound L-malate A crystal form (the sample obtained in Example 2), the formula I compound nitrate (the sample obtained in Example 7), the formula I compound succinate (the sample obtained in Example 8), the formula I Compound p-toluenesulfonate (samples obtained in Example 9), compound tartrate of formula I (samples obtained in Example 10) are respectively exposed and laid flat, and placed under high temperature (60° C.), high humidity (RH92.5%), light Carry out the stability test of sample under (4500 ± 500Lux) condition, measure in different sampling time (0 day, 6 days, 14 days, 30 days) in the sample active substance (formula I compound or phenomeline) and related substances content, as shown in Table 6.

Table 6. Stability experiments of salt forms

In Table 6, a: the nitrate of the compound of formula 1 is liquid under high temperature conditions, and its physical properties are unstable. NA means not determined.

From the results in Table 6 above, it can be seen that the crystal form A of compound L-malate of formula I of the present invention has very low impurity content, and has very good stability under high temperature, high humidity and light conditions, and has a good prospect for pharmaceutical preparation; Unexpectedly, the malate A crystal form of the compound of formula I is more stable under light conditions than other salt forms, which is convenient for the storage of raw materials and pharmaceutical preparations.

Test example 3. Toxic and side effects research of different salt types

Experimental materials: SD rats (purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., production license number: SCXK (Beijing) 2016-0006), formula I compound (Example 1), formula I compound malate ( Embodiment 2), formula I compound tartrate (embodiment 10), purified water (self-made).

Experimental method: 24 SD rats are randomly divided into 4 groups (6 in every group), administered by oral gavage, and given formula I compound malate ( Example 2 obtained sample) aqueous solution, formula I compound tartrate (embodiment 10 obtained sample) aqueous solution, phenomeline (embodiment 1 obtained sample) aqueous solution and an appropriate amount of purified water. The mental state of the SD rats was observed before and after the administration, and the salivation of the SD rats in each group was observed after the administration, and the number of the salivating rats was recorded. If any abnormality occurs before and during the administration, it should be recorded in time, and the specific results are shown in Table 7.

Table 7. Side effects induced by different salt types

group	number of salivating rats
Formula I compound L-malate A crystal form (Example 2)	0
Formula I compound tartrate (embodiment 10)	1
Formula I compound (embodiment 1)	1
purified water	0

Analysis of experimental results: Zanomeline is an M receptor activator, which can not only act on the central nervous system, but also stimulate M receptors in peripheral nervous tissue, resulting in cholinergic side effects, such as salivation, nausea , dizziness, etc. In this experiment, the toxic and side effects of each compound were evaluated by observing the salivation of SD rats in each group. According to the experimental results, it can be seen that the cholinergic side effect of the crystal form A of the compound L-malate of formula I is small and has good safety.

Polymorphic Research of Test Example 4 Formula I Compound L-Malate

The crystal form A of compound L-malate prepared by the method in Example 2 was suspended and beaten in the solvent shown in Table 8, stirred at 40°C in the dark for 2 days, the solution was centrifuged to remove the precipitate and dried, and then detected by XRPD , the results are shown in Table 8:

Table 8. Test Solvents

According to the analysis of the results in the above table, it can be concluded that the crystal form A has good stability and can be kept stable under different solvent systems.

Test Example 5. Accelerated Experimental Study on the Stability of Formula I Compound L-Malate A Crystal Form

Place the sample of formula I compound L-malate A crystal form prepared by the method of Example 2 open and flat, and investigate the conditions of high temperature (60°C), high humidity (RH92.5%) and light conditions (4500 ± 500Lux) Under the chemical stability of the sample, a certain amount of samples were taken at 0 days, 7 days, 14 days and 30 days to detect the purity of the samples (detected by HPLC) and the crystal form of the samples to evaluate the deuterium phenomeline malate A crystal Type stability, the experimental results are shown in Table 9.

Table 9. Physicochemical stability test results of crystal form A

Through experiments and the XRPD patterns shown in Fig. 4, Fig. 5 and Fig. 6, it can be seen that the crystal form of malate A of the compound of formula I is stable under high temperature (60°C), high humidity (RH92.5%) and light conditions (4500±500Lux) Under these conditions, the XRPD patterns at the time points of 0 day, 6 days, 14 days, and 30 days are basically the same as the XRPD patterns of crystal form A in Figure 1, and the stability of crystal form A is good. Under high temperature (60°C), high humidity (RH92.5%) and light conditions (4500±500Lux), after 30 days of accelerated stability experiments, the purity of Form A remained basically unchanged, and no impurities were produced. The type has not changed.

Test example 6. Pharmacokinetic study of different salt forms

Experimental materials: male SD rats (weight 180-220g, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., production license number: SCXK (Beijing) 2016-0006), formula I compound L-malate A crystal Type (Example 2), formula I compound (Example 1), purified water (self-made).

Experimental method: 6 male SD rats were randomly divided into 2 groups (3 rats in each group), free to drink water during the test period, fasted for more than 12 hours before administration, and fed 4 hours after administration. Oral gavage administration, two groups of SD rats were given formula I compound malate A crystal form A aqueous solution and formula I compound aqueous solution at a dose of 30 mg/kg (calculated as free base). 0min before administration, 15min, 30min, 45min, 1.0h, 1.5h, 2h, 3h, 4h, 6h, 8h, and 10h after administration, blood samples were collected into K ₂ EDTA anticoagulant tubes, and temporarily stored on ice until centrifugal. Plasma needs to be centrifuged within 60 minutes after blood collection (at 2-8°C, centrifuge at 8000rpm for 5min), after centrifugation, transfer the plasma to a 96-well plate or centrifuge tube, transport it in an ice box, and store it at ≤ -15°C for LC-MS/MS detection. The LC-MS/MS bioanalysis method was used to detect the drug concentration in SD rat plasma, and the non-compartmental model was used to analyze the blood drug concentration-time data using WinNonlin ^TM (Version8.3, Certara, USA) to evaluate its SD rat pharmacokinetic (PK) characteristics in vivo, the data are shown in Table 10.

Table 10. Pharmacokinetic parameters of different compounds

As can be seen from the data in Table 10: after giving rats the compound L-malate A crystal form of formula I, the _Tmax (peak time) time is short and can quickly reach the therapeutically effective concentration; _Cmax (peak concentration ) is moderate, it can effectively reduce cholinergic side effects while playing a good therapeutic effect, and has good bioavailability.

The embodiments of the present invention have been described above. However, the present invention is not limited to the above-mentioned embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims (10)

1. The malate salt of a compound of formula I,

   
2. The malate of the compound of formula I according to claim 1, wherein the malate of the compound of formula I is represented by formula II, wherein x is selected from 0.5-2.

   
3. The malate of the compound of formula I as claimed in claim 1, wherein x is 0.5, 1.0, 1.5, 2.0;

   Preferably, x is 1.0;

   Preferably, the malate is L-malate.
4. The malate of the compound of formula I as claimed in claim 2, wherein the malate of the compound of formula I is crystal form A, which is the compound of formula II with x being 1.0, and wherein the malic acid is L-malate Acid, the X-ray powder diffraction pattern of the A crystal form has characteristic diffraction peaks at the following 2θ angles: 12.007±0.2°, 14.827±0.2°, 16.796±0.2°, 20.012±0.2° and 21.942±0.2°.
5. The malate salt of the compound of formula I as claimed in claim 4, wherein the X-ray powder diffraction pattern of the A crystal form has characteristic diffraction peaks at the following 2θ angles: 12.007±0.2°, 14.827±0.2°, 16.796± 0.2°, 20.012±0.2°, 21.942±0.2°, 22.473±0.2°, and 25.333±0.2°.
6. The malate salt of the compound of formula I according to claim 4, wherein the X-ray powder diffraction pattern of the crystal form A has characteristic diffraction peaks at the following 2θ angles: 12.007±0.2°, 13.288±0.2°, 14.827± 0.2°, 16.796±0.2°, 20.012±0.2°, 21.942±0.2°, 22.473±0.2° and 25.333±0.2°;

   Preferably, the X-ray powder diffraction pattern of the A crystal form has characteristic diffraction peaks at the following 2θ angles: 12.007±0.2°, 13.288±0.2°, 14.827±0.2°, 15.399±0.2°, 16.796±0.2°, 20.012 ±0.2°, 20.327±0.2°, 21.942±0.2°, 22.473±0.2°, and 25.333±0.2°.

   Preferably, the X-ray powder diffraction pattern of the A crystal form has characteristic diffraction peaks at the following 2θ angles: 12.007±0.2°, 13.288±0.2°, 14.827±0.2°, 15.399±0.2°, 16.796±0.2°, 20.012 ±0.2°, 20.327±0.2°, 21.942±0.2°, 22.473±0.2°, 24.996±0.2°, 25.333±0.2°, and 27.718±0.2°.

   Preferably, the X-ray powder diffraction pattern of the A crystal form has characteristic diffraction peaks at the following 2θ angles: 12.007±0.2°, 12.755±0.2°, 13.288±0.2°, 13.903±0.2°, 14.827±0.2°, 15.399 ±0.2°, 16.796±0.2°, 17.686±0.2°, 18.906±0.2°, 20.012±0.2°, 20.327±0.2°, 21.942±0.2°, 22.473±0.2°, 24.996±0.2°, 25.333±0.2° and 27.718 ±0.2°.

   Preferably, the X-ray powder diffraction pattern of the A crystal form has characteristic diffraction peaks at the following 2θ angles: 12.007±0.2°, 12.755±0.2°, 13.288±0.2°, 13.903±0.2°, 14.827±0.2°, 15.399 ±0.2°, 16.796±0.2°, 17.686±0.2°, 18.906±0.2°, 20.012±0.2°, 20.327±0.2°, 20.660±0.2°, 21.942±0.2°, 22.473±0.2°, 24.996±0.2°, 25.333 ±0.2°, 27.382±0.2°, and 27.718±0.2°.

   Preferably, the crystal form A has an XRPD pattern substantially as shown in FIG. 1 .

   Preferably, the crystal form A has a DSC spectrum substantially as shown in FIG. 2 .

   Preferably, the differential scanning calorimetry curve of the crystal form A has an endothermic peak at 111.03±3°C.

   Preferably, the crystal form A has a TGA curve substantially as shown in FIG. 3 .
7. The preparation method of the malate of the compound of formula I according to any one of claims 1-6, comprising reacting the compound of formula I with malic acid.
8. The preparation method according to claim 7, wherein, the preparation method of the A crystal form of malate of the compound of formula I comprises the following steps: mixing the compound of formula I, malic acid and a solvent, heating, cooling, and precipitation of crystals; wherein, The solvent is selected from one or more mixtures of ethanol, isopropanol, n-propanol, butanol, acetone, ethyl acetate, n-heptane, acetonitrile, tetrahydrofuran; or;

   Mix the compound of formula I, malic acid and the first solvent, heat until completely dissolved, then add the second solvent, cool, and crystallize; wherein, the first solvent is selected from methanol, ethanol, isopropanol, n-butanol One or more mixtures; the second solvent is selected from methyl tert-butyl ether; esters, such as ethyl acetate, isopropyl acetate; acetonitrile; alkanes, such as n-heptane, n-hexane, etc. One or more than one mixture.
9. A pharmaceutical composition, wherein the pharmaceutical composition comprises the malate salt of the compound of formula I according to any one of claims 1-6 and optional pharmaceutically acceptable excipients.
10. Use of the malate salt of the compound of formula I described in any one of claims 1-6, or the pharmaceutical composition described in claim 9 in the preparation of medicines for the treatment of central nervous system disorders;

    Preferably, the disorders of the central nervous system include but are not limited to schizophrenia, Alzheimer's disease, Parkinson's disease, depression, movement disorders, drug addiction, pain and neurodegeneration (such as Dow's disease or synucleinopathies).

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