Crystal form of gaba a receptor modulator, preparation method therefor and use thereof

Abstract

The present invention relates to a crystal form of a GABAA receptor modulator, a preparation method, and the use. Specifically, provided are a crystal form of a compound of formula (I), a preparation method, and the use in the preparation of a GABAA receptor modulator drug.

Description

A type of GABA A Crystal form of receptor modulator, preparation method and application thereof Technical Field

[0001] The present disclosure belongs to the field of pharmaceutical chemistry, and specifically relates to a crystal form of a GABAA receptor modulator, a preparation method, and an application thereof. Background Art

[0002] GABA (γ-aminobutyric acid) is an important inhibitory neurotransmitter in the central nervous system of vertebrates. It can regulate the excitability of neurons and the secretion of other neurotransmitters through GABA receptors. There are three subtypes of GABA receptors, namely GABA A receptors, GABA B Receptors and GABA C Receptors. Among GABA receptors, the most abundant and important one is GABA A GABA receptors A The receptor is distributed throughout the nervous system and is a pentameric chloride channel receptor, mainly composed of two α subunits (α1-α6), two β subunits (β1-β3) and one additional subunit (γ1-γ3, δ, ε, π or θ). These subunits can randomly form different types of GABA A Isoform. GABA expressed on neuronal cell membranes A The subtype is mainly composed of five subunits (including α, β, γ subunits and two other subunits). A After the receptor binds to GABA, the chloride ion channel on the receptor opens, selectively allowing chloride ions to flow into the neurons, causing hyperpolarization of the cell membrane, thereby reducing the action potential generated by the neurons and ultimately reducing the excitability of the neurons.

[0003] GABA A GABA receptors are related to mood changes such as anxiety, tension, and depression, and alcohol, barbiturates, steroid drugs, and benzodiazepines can adjust the activity of GABA receptors after binding to them, thus producing a series of effects. A large amount of data confirms that GABA A The receptor has a specific binding site for steroids, which are powerful GABA A A broad-spectrum positive modulator of GABA receptors A It binds to multiple sites of the receptor, producing anxiolytic, anesthetic, anti-epileptic, sedative, and antidepressant effects.

[0004] PCT / CN2023 / 099369 provides a compound with the structure shown below. The test results show that the compound has good GABA A Receptor modulator activity.

[0005] 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

[0006] In one aspect, the present disclosure provides 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: 6.752±0.2°, 13.684±0.2°, 15.748±0.2°, and 17.744±0.2°.

[0007] In some embodiments, the crystalline form A 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: 6.752±0.2°, 13.684±0.2°, 15.483±0.2°, 15.748±0.2°, and 17.744±0.2°.

[0008] In some embodiments, the crystalline form A 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: 6.752±0.2°, 9.943±0.2°, 12.794±0.2°, 13.684±0.2°, 14.750±0.2°, 15.483±0.2°, 15.748±0.2°, and 17.744±0.2°.

[0009] In some embodiments, the crystalline form A 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: 6.752±0.2°, 9.943±0.2°, 12.794±0.2°, 13.684±0.2°, 14.750±0.2°, 15.483±0.2°, 15.748±0.2°, 17.744±0.2°, 20.669±0.2°, and 22.253±0.2°.

[0010] In some embodiments, the crystalline form A of the compound of Formula I has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Figure 1-1.

[0011] In one aspect, the present disclosure provides 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: 15.962±0.2°, 16.497±0.2°, 17.275±0.2°, and 17.757±0.2°.

[0012] In some embodiments, the present disclosure provides 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: 11.753±0.2°, 15.312±0.2°, 15.962±0.2°, 16.497±0.2°, 17.275±0.2°, 17.757±0.2°, 18.395±0.2°, 19.191±0.2°, 23.754±0.2°, 24.571±0.2°.

[0013] In some embodiments, the present disclosure provides 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: 11.428±0.2°, 11.753±0.2°, 15.312±0.2°, 15.962±0.2°, 16.497±0.2°, 17.275±0.2°, 17.757±0.2°, 19.191±0.2°, 23.754±0.2°, 24.571±0.2°, 25.672±0.2°.

[0014] In some embodiments, the 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.

[0015] In some embodiments, the Form B of the compound of Formula I is a hydrated form.

[0016] In one aspect, the present disclosure provides a method for preparing Form B of the compound of Formula I, characterized in that Form A is subjected to gas-liquid diffusion, stirring at room temperature, stirring at 50°C, cyclic heating and cooling, etc. to obtain Form B.

[0017] In some embodiments, the present disclosure provides a method for preparing Form B of the compound of Formula I, characterized in that Form A is subjected to cyclic heating and cooling and stirring in an NPA / H2O (1:3, v / v) solvent system to obtain Form B.

[0018] In some embodiments, the present disclosure provides a method for preparing Form B of the compound of Formula I, characterized in that Form A is stirred in an EtOH / H2O (855:145, v / v) system at room temperature to obtain Form B.

[0019] In some embodiments, the present disclosure provides a method for preparing Form B of the compound of Formula I, characterized in that Form A is dissolved in ethyl acetate, and then an anti-solvent n-heptane is added to obtain Form B.

[0020] In some embodiments, the present disclosure provides a method for preparing Form B of the compound of Formula I, characterized in that Form A is stirred in an ACN / H2O (1:3, v / v) system at 50°C to obtain Form B.

[0021] In one aspect, the present disclosure provides a methanol solvate crystalline 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: 15.574±0.2°, 16.065±0.2°, 17.384±0.2°, and 17.834±0.2°.

[0022] In some embodiments, the methanol solvate crystalline 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: 11.112±0.2°, 11.631±0.2°, 15.574±0.2°, 16.065±0.2°, 17.384±0.2°, 17.834±0.2°, 19.166±0.2°, 23.507±0.2°, 23.791±0.2°, and 24.810±0.2°.

[0023] In some embodiments, the methanol solvate crystalline 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: 11.112±0.2°, 11.631±0.2°, 14.307±0.2°, 15.574±0.2°, 16.065±0.2°, 17.384±0.2°, 17.834±0.2°, 19.166±0.2°, 23.507±0.2°, 23.791±0.2°, 24.810±0.2°, and 31.474±0.2°.

[0024] In some embodiments, the methanol solvate 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.

[0025] In some embodiments, the molar ratio of MeOH to the compound of Formula I in the methanol solvate Form C is about 0.8 to 1.2:1.

[0026] In one aspect, the present disclosure provides a method for preparing Form C of a methanol solvate of a compound of Formula I, characterized by stirring Form A of a compound of Formula I in a solvent at room temperature and drying at room temperature to obtain the methanol solvate. The solvent is a MeOH / H2O system.

[0027] In one aspect, the present disclosure provides a methanol solvate crystalline 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: 15.782±0.2°, 16.288±0.2°, 17.575±0.2°, and 17.819±0.2°.

[0028] In some embodiments, the methanol solvate crystalline 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: 11.731±0.2°, 15.398±0.2°, 15.782±0.2°, 16.288±0.2°, 17.314±0.2°, 17.575±0.2°, 17.819±0.2°, and 19.192±0.2°.

[0029] In some embodiments, the methanol solvate crystalline 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: 11.731±0.2°, 15.398±0.2°, 15.782±0.2°, 16.288±0.2°, 17.314±0.2°, 17.575±0.2°, 17.819±0.2°, 19.192±0.2°, 23.653±0.2°, and 24.595±0.2°.

[0030] In some embodiments, the methanol solvate crystalline 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: 11.256±0.2°, 11.731±0.2°, 15.398±0.2°, 15.782±0.2°, 16.288±0.2°, 17.314±0.2°, 17.575±0.2°, 17.819±0.2°, 19.192±0.2°, 19.414±0.2°, 23.653±0.2°, 24.595±0.2°, and 25.43±0.2°.

[0031] In some embodiments, the methanol solvate crystalline form D of the compound of Formula I has an X-ray powder diffraction pattern using Cu-Kα radiation as shown in Figure 4-1.

[0032] In some embodiments, the molar ratio of MeOH to the compound of Formula I in the methanol solvate Form D is about 0.5.

[0033] In one aspect, the present disclosure provides a method for preparing Form D of a methanol solvate of a compound of Formula I, characterized by stirring Form A of a compound of Formula I in a solvent at room temperature and drying at room temperature to obtain the methanol solvate. The solvent is a MeOH / H2O system.

[0034] The present disclosure also provides a pharmaceutical composition comprising any one of the aforementioned 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.

[0035] In one aspect, the present disclosure further provides use of any one of the aforementioned crystalline forms or pharmaceutical compositions of the compound of Formula I in the preparation of GABAA receptor modulator drugs.

[0036] The present disclosure further provides the use of any one of the aforementioned pharmaceutically acceptable crystalline forms or pharmaceutical compositions of the compound of formula I in the preparation of a medicament for treating a CNS-related disease. Wherein the CNS-related disease is, but is not limited to, sleep disorders (e.g., insomnia), mood disorders (e.g., depression (e.g., major depressive disorder (MDD)), mania, dysthymia (e.g., mild depression), bipolar disorder (e.g., type I and / or type II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (e.g., obsessive-compulsive disorder (OCD)), schizophrenia spectrum disorders (e.g., schizophrenia, schizoaffective disorder), convulsive disorders (e.g., epilepsy (e.g., status epilepticus (SE)), epileptic seizures), memory and / or cognitive disorders (e.g., attention disorders (e.g., attention deficit hyperactivity disorder (ADHD)), dementia, Dementia (e.g., Alzheimer's disease, Lewy body dementia, vascular dementia), movement disorders (e.g., Huntington's disease, Parkinson's disease, essential tremor), personality disorders (e.g., antisocial personality disorder, obsessive-compulsive personality disorder), autism spectrum disorders (ASD) (e.g., autism, monoetiological autism, such as synaptophathy, such as Rett syndrome, fragile X syndrome, Angelman syndrome), pain (e.g., neuropathic pain, injury-related pain syndrome, acute pain, chronic pain), traumatic brain injury (TBI), vascular disease (e.g., stroke, ischemia, vascular malformation), substance abuse disorders and / or withdrawal syndromes (e.g., addiction to opiates, cocaine, and / or alcohol), and tinnitus.

[0037] The present disclosure further provides the use of any of the aforementioned pharmaceutically acceptable crystalline forms or pharmaceutical compositions of the compound of Formula I in the preparation of a medicament for treating depression. The depression is selected from mild depression, major depressive disorder (MDD), persistent depressive disorder (PDD), psychotic depression, postpartum depression (PPD), or seasonal affective disorder.

[0038] Definition and Description

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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 14C. 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

[0045] Figures 1-1, 1-2, and 1-3 are XRPD patterns, TGA / DSC patterns, and 1 H NMR spectrum.

[0046] Figures 2-1, 2-2, 2-3, and 2-4 are respectively XRPD patterns, TGA / DSC patterns, 1 H NMR spectra and XRPD comparison before and after heating.

[0047] Figures 3-1, 3-2, 3-3, and 3-4 are respectively XRPD patterns, TGA / DSC patterns, and 1 H NMR spectra and XRPD comparison before and after heating.

[0048] Figures 4-1, 4-2, 4-3, and 4-4 are XRPD patterns, TGA / DSC patterns, and 1 H NMR spectra and XRPD comparison before and after heating. DETAILED DESCRIPTION

[0049] 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.

[0050] Test conditions of the instruments used in the experiment:

[0051] X-ray powder diffraction (XRPD)

[0052] X-ray powder diffraction data of the sample were collected under ambient conditions using a Malvern Panalytical Aeris model X-ray powder diffractometer. Several milligrams of sample were spread flat on a zero-background silicon sample plate, flattened with a glass slide through a weighing paper, and then tested. The X-ray tube used a Cu target (Kα), and the Kα2 / Kα1 intensity ratio was The X-ray emitter power was 300 W, the voltage was 40 kV, and the current was 7.5 mA. The test range was 3-40° (2θ), the scanning speed was 0.14° / s, and the step size was 0.02° (2θ).

[0053] Thermogravimetric Analyzer (TGA)

[0054] Thermogravimetric data were collected using a TA Discovery TGA5500 thermogravimetric analyzer. A few milligrams of sample were placed in a Tzero aluminum pan (automatically weighed during testing) and heated from room temperature to the target temperature under nitrogen at a flow rate of 25 mL / min and a heating rate of 10°C / min.

[0055] Differential Scanning Calorimetry (DSC)

[0056] Thermal data for the samples were collected using a TA Discovery DSC2500 differential scanning calorimeter. Several milligrams of sample were weighed into a Tzero aluminum pan and sealed with a Tzero seal lid. The pan was heated to the target temperature (before decomposition) under nitrogen at a flow rate of 50 mL / min and a heating rate of 10°C / min.

[0057] H NMR spectroscopy ( 1 H NMR)

[0058] The sample was dissolved in DMSO-d6 to prepare a solution with a concentration of about 2 to 10 mg / mL, and the H NMR spectrum data of the sample was collected using a Bruker AVANCE NEO 400 MHZ.

[0059] Example 1 Synthesis and Characterization of Compounds of Formula I

[0060] 1.1 Synthesis of intermediate M2

[0061] M1 (200 g, 734 mmol, 1.00 eq) and HBr (5.96 g, 35.4 mmol, 4.00 mL, 0.048 eq) were added to THF (1400 mL) and then Pd / C (10.0 g, 9.43 mmol, 0.013 eq) was added. The system was placed at 25°C and stirred under H2 (1.00 MPa) for 24 hours. After the system was filtered and concentrated, the solid was crushed and dissolved in 600 mL of acetone. After filtration, a white crude product was obtained. The crude product was purified by column chromatography (dichloromethane / methanol (10:1-5:1) to obtain M2 (180 g, white solid).

[0062] 1.2 Synthesis of intermediate M3

[0063] M2 (100 g, 364 mmol, 1.00 eq) was added to 1 L of toluene, and then methylaluminum bis(2,6-di-tert-butyl-4-anisole) (525 g, 1.09 mol, 571 mL, 3.00 eq) was added. The system was stirred at -60 ° C for 1 hour, and then bromomethylmagnesium (3 M, 364 mL, 3.00 eq) was added at -60 ° C. The system was stirred at -60 ° C for 3 hours, and then saturated NH4Cl (500 mL) was added and filtered. The filter cake was washed with ethyl acetate (200 mL × 2), and the organic phases were combined and then washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. It was separated by column chromatography (dichloromethane / methanol (100:1-10:1) and purified to obtain M3 (46 g, white solid, recovered M2 98 g).

[0064] 1.3 Synthesis of intermediate M4

[0065] Ethyltriphenylphosphonium bromide (102 g, 275 mmol, 4.00 eq) was added to THF (120 mL) at 0°C, followed by the addition of t-BuOK (30.9 g, 275 mmol, 4.00 eq) in THF (200 mL). The system was then stirred at 60°C for 1 hour. M3 (20.0 g, 68.9 mmol, 1.00 eq) was then dissolved in THF (120 mL) and added to the system. The mixture was stirred at 60°C for 13 hours. NH4Cl solution (150 mL) was added to the system under ice bath conditions to quench the mixture. The mixture was then extracted with ethyl acetate (150 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The organic phase was separated by column chromatography (dichloromethane / methanol (100:1-3:1) to give M4 (18.3 g, 60.6 mmol, yield: 88.0%).

[0066] 1.4 Synthesis of Intermediate M5

[0067] M4 (18.3 g, 60.6 mmol, 1.00 eq) was dissolved in THF (180 mL), and then BH3·Me2S (10.0 M, 30.3 mL, 5.00 eq) was added at 0°C. The system was stirred at 25°C for 3 hours, and then 3.00 M NaOH (100 mL) and H2O2 (86.5 g, 763 mmol, 73.3 mL, 12.6 eq) were placed in the system at 25 ° C for 4 hours, the system was filtered and the filtrate was quenched with Na2SO3 solution (60.0 mL × 2), extracted with ethyl acetate (150 mL × 2), and the organic phases were combined and then washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. It was separated by column chromatography (dichloromethane / methanol (100:1-3:1)) and purified to obtain M5 (13.0 g, 40.6 mmol, yield: 66.9%).

[0068] 1.5 Synthesis of Intermediate M6

[0069] M5 (13.0 g, 40.6 mmol, 1.00 eq) was dissolved in dichloromethane (130 mL) and PCC (17.5 g, 81.1 mmol, 2.00 eq) was added at 0°C. The system was stirred at 25°C for 3 hours. The system was filtered and the filtrate was quenched with Na2SO3 solution (100 mL), extracted with dichloromethane (100 mL×2), and the organic phases were combined and washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The organic phase was separated and purified by column chromatography (dichloromethane / methanol (100:1-3:1)) to obtain M6 (9.03 g, 28.3 mmol, yield: 69.9%).

[0070] 1.6 Synthesis of Intermediate M7

[0071] M6 (9.03 g, 28.3 mmol, 1.00 eq) was dissolved in MeOH (90.0 mL), and then Br2 (4.53 g, 28.3 mmol, 1.46 mL, 1.00 eq) and HBr (927 mg, 5.50 mmol, 622 μL, 0.190 eq) were added at 0°C. The system was then stirred at 25°C for 12 hours. The system was quenched with NaHCO3 solution (50 mL) and extracted with ethyl acetate (50.0 mL x 2). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The organic phase was separated and purified by column chromatography (dichloromethane / methanol (100:1-1:1) to give M7 (7.1 g, 17.8 mmol, yield: 63.0%) as a white solid. 1H NMR (400MHz, CDCl3) δ3.99-3.85(m,2H),2.92-2.69(m,1H),2.25-2.12(m,1H),1.98- 1.58(m,9H),1.53-1.28(m,11H),1.27-1.18(m,3H),1.15-1.03(m,3H),0.64(s,3H).

[0072] 1.7 Synthesis of Intermediate 1-2

[0073] Compound 1-1 (20.0 g, 7.51 mmol, 1.00 eq) was added to a 1 L three-necked flask protected by a nitrogen balloon, and then tetrahydrofuran (400 mL) was added at 20-30 ° C and stirred evenly. N2H4·H2O (23.03 g, 450.89 mmol, 22.32 mL, 98% purity, 3.0 eq) was added at 20-30 ° C, and then the system was stirred at 60 ° C for 16 hours. The reaction solution was directly concentrated to obtain a light yellow solid compound 1-2 (23.3 g, crude product). 1 H NMR(400MHz,DMSO-d6)δ8.42(br s,1H),6.28-5.98(m,2H),4.47(br s,2H).

[0074] 1.8 Synthesis of Intermediates 1-3

[0075] Compound 1-2 (20 g, 137.83 mmol, 1 eq) was placed in a 500 mL flask, followed by the addition of water (200 mL). The reaction mixture was then cooled to 0°C, and hydrochloric acid (12 M, 22.97 mL, 2.0 eq) and glyoxylic acid (20.41 g, 137.83 mmol, 15.34 mL, 1.00 eq) were added. The mixture was stirred at 0°C for 1 hour. The reaction mixture was filtered, and the filter cake was concentrated to afford compound 1-3 (26.0 g, crude) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 7.39 (s, 1H), 6.65 (br s, 2H).

[0076] 1.9. Synthesis of Intermediates 1-4

[0077] Compound 1-3 (8.00 g, 39.78 mmol, 1 eq) was added to a 250 ml three-necked flask. Toluene (100 mL), triethylamine (8.05 g, 79.55 mmol, 11.07 mL, 2.0 eq), and DPPA (10.95 g, 39.78 mmol, 8.59 mL, 1 eq) were added to the reaction system at 20-30°C. The reaction was stirred at 100°C for 16 hours. The reaction solution was then concentrated to yield a crude brown oil. The crude product was purified by HPLC (column: Welch Xtimate C18 250*50 mm*10 μm; mobile phase: [water(HCl)-ACN]; gradient: 0%-35% B over 25 min) to afford compound 1-4 (1.50 g, 7.27 mmol, 36.55% yield) as a yellow powdery solid. MS (ESI) m / z = 199.2 [M+H] +, 1 H NMR (400MHz, DMSO-d6) δ12.43(br s,1H),8.32(s,1H),7.54(s,2H).

[0078] 1.10. Synthesis of Compounds of Formula I

[0079] K2CO3 (634 mg, 4.59 mmol, 10.0 eq), compound M7 (182 mg, 459 μmol, 1.00 eq) and compound 1-4 (100 mg, 505 μmol, 1.10 eq) were added to THF (4.0 mL), and the system was stirred at 50°C for 12 hours. The system was quenched with water (5 mL) and extracted with ethyl acetate (10.0 mL×2). The organic phases were combined and then washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was separated and purified by HPLC to obtain a light yellow solid, namely, the compound of formula I (153 mg, 185.2 μmol, yield: 62.3%, identified as the compound of formula I, crystalline form A), MS (ESI) m / z=497.2[M+H]+, 1 H NMR (400MHz, DMSO-d6) δ = 8.35 (s, 1H), 7.55 (s, 2H), 4.84-4.49 (m, 2H), 4.25 (s, 1H), 4.03 (q, J = 7.2Hz, 1H), 2.77 (br t, J = 8.8Hz, 1H), 2.06 (br d,J=9.6Hz,2H),1.78-0.98(m,23H),0.59(s,3H).

[0080] Example 2 Preparation of Form A of Compound of Formula I

[0081] Weigh 1.00g of Form A of the compound of Formula I, heat it to 75-78°C in 12mL of anhydrous ethanol solvent system to dissolve it, slowly cool it to 20-30°C, and stir it for 2h. The obtained compound was identified as Form A of the compound of Formula I, with a yield of 74% and a purity of 99.7%. XRPD, 1 The product was characterized by H NMR, TGA, and DSC. The XRPD pattern is shown in Figure 1-1, and the positions of the characteristic peaks are shown in Table 1. TGA / DSC results (Figure 1-2) show almost no weight loss before decomposition, and an endothermic signal at 188.73°C (peak temperature). 1 H NMR results (Figures 1-3) showed that the product was in an anhydrous crystalline form.

[0082] Table 1 XRPD pattern analysis data of Form A of Formula I compound

[0083] Example 3 Preparation of Form B of Compound I

[0084] 20.38 mg of Form A was weighed and stirred in a solvent system of n-propanol / H2O (1:3, v / v) under cyclic heating and cooling to obtain Form B with a purity of 99.3%. XRPD, 1 Form B was characterized by H NMR, TGA, and DSC. The XRPD is shown in Figure 2-1, and the positions of the characteristic peaks are shown in Table 2. TGA / DSC results (Figure 2-2) show that the sample experienced a weight loss of approximately 3.6 wt% before 150°C (the corresponding weight loss for monohydrate was 3.4 wt%); there were also two endothermic signals at 112.71°C and 189.29°C (peak temperatures), and two continuous exothermic signals at 134.5°C and 139.8°C. 1 The HNMR spectrum (DMSO-d6) is shown in Figure 2-3, indicating no significant residual solvent in the sample. A heating experiment was conducted on Form B, and a comparison of its XRPD patterns before and after heating is shown in Figure 2-4. Upon heating to 120°C, the first endothermic signal is observed, indicating amorphous formation; heating to 150°C results in Form A. Combining the characterization data and the heating experiment, it is clear that Form B is a hydrated crystalline form.

[0085] Another preparation method: Approximately 200 mg of Form A of the compound of Formula I was stirred in an EtOH / H₂O (855:145, v / v) system at room temperature for 3 days, then air-dried at room temperature (26°C, 57% RH) for approximately 6 hours. The yield was 93.4%, and the sample purity was 99.5% by HPLC. The crystalline form obtained by this method was also identified as the hydrated Form B.

[0086] Table 2 XRPD pattern analysis data of Form B of Formula I compound

[0087] Example 4 Preparation of Methanol Solvate Form C of Formula I

[0088] 7.88 mg of Form A and 8.90 mg of Form B were weighed and stirred in a methanol system at room temperature for about 5 days. After drying at room temperature (26° C., 57% RH) for about 3 hours, Form C was obtained.

[0089] XRPD, 1H NMR, TGA, and DSC were used for characterization. The XRPD is shown in Figure 3-1, and the locations of the characteristic peaks are shown in Table 3. TGA / DSC results (Figure 3-2) show that the sample experienced a weight loss of approximately 5.9 wt% before 150°C; there were two endothermic signals at 109.3°C and 189.05°C (peak temperatures), and an exothermic signal at 139.1°C. 1 The H NMR spectrum (DMSO-d6) is shown in Figure 3-3. The molar ratio of MeOH to the compound of Formula I in the sample is 1.1 (corresponding to a mass fraction of 6.4%). A heating experiment was conducted on this crystalline form, and the XRPD comparison before and after heating is shown in Figure 3-4. Heating to 110°C past the first endothermic signal indicates conversion to low-crystalline Form A; heating to 150°C converts to Form A. Combining the characterization data and heating experiments, it is clear that this crystalline form is a methanol solvate.

[0090] Table 3 XRPD pattern analysis data of methanol solvate of compound of formula I Form C

[0091] Example 5 Preparation of Methanol Solvate Form D of Formula I

[0092] 7.46 mg of Form A and 8.12 mg of Form B were weighed and stirred in a methanol / H2O (840:160, v / v) system at room temperature for about 5 days. After drying at room temperature (26°C, 57% RH) for about 3 h, Form D was obtained.

[0093] Using XRPD, 1 The sample was characterized by H NMR, TGA, and DSC. The XRPD is shown in Figure 4-1, and the locations of the characteristic peaks are shown in Table 4. TGA / DSC results (Figure 4-2) show that the sample experienced a 4.2 wt% weight loss before 150°C; there were two endothermic signals at 112.7°C and 188.9°C (peak temperatures), and an exothermic signal at 139.1°C. 1 The H NMR spectrum (DMSO-d6) is shown in Figure 4-3. The sample contains a MeOH to API molar ratio of 0.5 (corresponding to a mass fraction of 3.2%). A heating experiment was conducted on this crystalline form, and the XRPD comparison before and after heating is shown in Figure 4-4. Heating to 110°C reveals the first endothermic signal, indicating amorphous transformation; heating to 150°C results in Form A. Combining the characterization data and the heating experiment, it is clear that this crystalline form is a methanol solvate.

[0094] Table 4 XRPD pattern analysis data of methanol solvate of compound of formula I, Form D

[0095] Experimental Example 1. Evaluation of the functional activity of synapses in vitro

[0096] 1.1 Experimental Materials

[0097] 1.2 Experimental methods

[0098] The α4β3δ-HEK-FlpIn-TRex stable cell line was cultured in DMEM / F12 medium supplemented with 10% FBS, supplemented with 10 μg / ml blasticidin, 100 μg / ml zeocin, 100 μg / ml hygromycin, and 0.2 μg / ml puromycin. The α1β2γ2-CHO-TRex stable cell line was cultured in DMEM / F12 medium supplemented with 10% FBS, supplemented with 10 μg / ml blasticidin, 100 μg / ml zeocin, 300 μg / ml hygromycin, and 1 μg / ml puromycin.

[0099] The day before the patch-clamp experiment, cells were seeded on poly-lysine-coated 12 mm coverslips and cultured in 35 mm culture dishes. Tetracycline (1 μg / ml) was supplemented to induce GABA receptor expression. The extracellular solution (mM) consisted of: 140% NaCl, 3% KCl, 1.5% MgCl₂, 2% CaCl₂, 10% HEPES, and 10% glucose. After thorough mixing, the pH was adjusted to 7.4 with NaOH, and the osmolarity was adjusted to 300–320 mOsm with sucrose. The solution was stored at 4°C. The electrode solution (mM) consisted of: 145% KCl, 1% MgCl₂, 5% EGTA, 10% HEPES, and 5% MgATP. After thorough mixing, the pH was adjusted to 7.3 with KOH, and the osmolarity was adjusted to 290–300 mOsm with sucrose. The solution was filtered through a 0.22 μM filter and ready for use.

[0100] This experiment mainly uses the whole-cell patch clamp recording method. The membrane potential is clamped at -60mV. GABA (~1μM) with an activation amplitude in the EC10-20 range is used to activate the receptor. The test compound is prepared in 0.1% DMSO. When GABA stimulation is given, it is first perfused for 30s. Finally, the positive allosteric regulatory effect of the test compound on α1β2γ2 or α4β3δ is detected.

[0101] The experimental results of each concentration are expressed as the multiple of the compound's increase in GABA-induced current. First, find the minimum concentration of the compound that can just enhance the GABA-induced current, and then gradually increase the test concentration by 3 times until the compound's activation effect reaches EC 80 The test concentrations should be at least 5, until the complete EC 50 Curve and EC 50 All experiments were repeated for 3 cells or more. Data processing was completed by GraphPad Prism software. The dose-dependent curve was fitted with the Hill equation, and the half-maximal activation concentration EC was finally obtained. 50 and E max The results are shown in Table 5.

[0102] Table 5 Functional activity results of compounds of formula I on intrasynaptic and extrasynaptic receptors

[0103] The results showed that the compound of formula I had good intra- and extra-synaptic functional activities.

[0104] Test Example 2: In vitro liver microsome stability evaluation

[0105] 2.1 Solution preparation

[0106] 1) Preparation of test sample working solution: dilute the test sample to 100 μM with acetonitrile;

[0107] 2) Preparation of liver microsome working solution: Dilute liver microsomes to 0.56 mg / mL with 100 mM phosphate buffer;

[0108] 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.

[0109] 4) Preparation of stop solution: dilute tolbutamide to 20 ng / mL with acetonitrile to serve as the stop solution containing the internal standard.

[0110] 2.2 Incubation process

[0111] 1) Prepare incubation anti-adsorption EP tubes and label them with species, test / control, time points (0, 5, 10, 20, 30, 60 min, Blank60, NCF60), etc.

[0112] 2) Add 2 μL of the test article or control working solution diluted to 100 μM with acetonitrile and 178 μL of liver microsome working solution to each tube. Add 2 μL of acetonitrile to the Blank60 tube instead of the test article and pre-incubate in a 37°C water bath for approximately 10 minutes. Repeat three times for each sample.

[0113] 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.

[0114] 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;

[0115] 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 analysis by LC-MS / MS.

[0116] 6) Testosterone and dextromethorphan were used as positive controls under the same conditions to test the stability and reliability of the system.

[0117] 2.3 Data Analysis

[0118] The parameters of the half-life, liver microsomal intrinsic clearance and liver intrinsic clearance of the test sample were calculated based on the remaining percentage of the test sample. The results are shown in Table 6.

[0119] Table 6 Half-life, liver microsomal intrinsic clearance, liver intrinsic clearance of the compounds

[0120] As shown in the table above, most of the compounds of formula I provided by the present disclosure have good stability in rat and human liver microsomes, indicating that they have good metabolic stability.

[0121] Test Example 3: Loss of righting reflex test in SD rats injected with the compound of formula I

[0122] 3.1 Purpose of the test

[0123] The loss of righting reflex threshold of SD rats injected with the compound of formula I was tested to evaluate the sedative effect and therapeutic safety window of the compound.

[0124] 3.2 Experimental process

[0125] Male SD rats weighing 180-200 g were acclimated to the animal room facility for 7 days and randomly divided into groups according to body weight one day before the experiment. The rats were fasted for half a day before the experiment, but were not allowed to drink water. The compound of formula I was designed with a 0.8-fold dose gradient, and the dosage was set at 23.5 mg / kg, 18.8 mg / kg, 15 mg / kg, 12 mg / kg, and 9.6 mg / kg. The rats were observed for the loss of righting reflex within 4 hours after intraperitoneal injection of the compound of formula I. The judgment standard for the loss of righting reflex in rats: after the injection of the compound of formula I, if the rat in the supine position fails to turn over within 30 seconds, it is considered to be positive for the loss of righting reflex; otherwise, it is considered to be negative for the loss of righting reflex.

[0126] 3.3 Test results

[0127] The test results showed that at doses of 23.5 mg / kg, 18.8 mg / kg, 15 mg / kg, 12 mg / kg, and 9.6 mg / kg, the incidence of righting reflex in rats was 80%, 50%, 30%, 0%, and 0%, respectively. Under the experimental conditions, the threshold dose of the compound of Formula I for the disappearance of the righting reflex in SD rats after intraperitoneal injection was 12 mg / kg, indicating that the compound of Formula I has a wide therapeutic safety window.

[0128] Test Example 4: Loss of righting reflex test in SD rats after oral administration of the compound of formula I

[0129] 4.1 Test Purpose

[0130] The loss of righting reflex threshold of SD rats after oral administration of the compound of formula I was detected to evaluate the sedative effect and therapeutic safety window of the compound of formula I.

[0131] 4.2 Test methods

[0132] Male SD rats weighing 180-200 g were acclimated to the animal room facility for 7 days and randomly divided into groups according to body weight one day before the experiment. The rats were fasted overnight before the experiment, but water was not allowed. The compound of formula I was designed with a 0.8-fold dose gradient, and the dosage was set at 39 mg / kg, 31.25 mg / kg, 25 mg / kg, 20 mg / kg, and 16 mg / kg, with 10 rats in each group. The rats were observed for the disappearance of righting reflex within 4 hours after oral administration. The judgment standard for the disappearance of righting reflex in rats: after the administration of the test compound, if the rat in the supine position fails to turn over within 30 seconds, it is considered to be positive for the disappearance of righting reflex, otherwise it is considered to be negative for the disappearance of righting reflex.

[0133] 4.3 Test results

[0134] The results showed that the incidence of righting reflex in rats was 100%, 90%, 50%, 0%, and 0% at doses of 39 mg / kg, 31.25 mg / kg, 25 mg / kg, 20 mg / kg, and 16 mg / kg, respectively. Under the experimental conditions, the threshold dose for loss of righting reflex in SD rats administered with the compound of Formula I by oral gavage was 20 mg / kg. The threshold for loss of righting reflex in rats administered with the compound of Formula I by oral gavage (20 mg / kg) was 5.7 times the effective dose for anticonvulsant effects (3.5 mg / kg), indicating a wide therapeutic safety window.

[0135] Experimental Example 5: Pharmacokinetic Study of Compound I in CD-1 Mice

[0136] 4.1 Test Animals and Solvents

[0137] CD-1 mice, male, weighing approximately 25 g, were randomly divided into groups, 3 mice per group.

[0138] DMSO: 30% SBECD (10%: 90%)

[0139] 4.2 Test methods

[0140] The intravenous (IV) dose was 1 mg / kg, and the oral (IG) dose was 5 mg / kg. Animals were fasted for 12 hours prior to administration, with free access to water. They were fed uniformly 3 hours after administration. Approximately 0.15 mL of blood was collected from heparinized EP tubes at 5 minutes (intravenous), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours after administration. The blood was centrifuged at 13,500 rpm for 10 minutes to separate the plasma. Mouse brain tissue was then collected 30 minutes, 2 hours, and 8 hours after cardiac perfusion. After pretreatment, the samples were analyzed by LC-MS / MS to determine the concentrations of the analyte in plasma and brain, and pharmacokinetic parameters were calculated.

[0141] 4.3 Test results

[0142] Table 7 Pharmacokinetic parameters of the compound of formula I after intravenous (1 mg / kg) and oral gavage (5 mg / kg) administration to CD-1 mice

[0143] Table 8 Brain concentrations of the compound of formula I in CD-1 mice after oral administration (5 mg / kg)

[0144] The data in Table 7 show that after intravenous and oral administration of the compound of Formula I to CD-1 mice, there was a high plasma exposure (AUC), a long half-life, and an absolute bioavailability of up to 109% by oral administration, indicating that the compound of Formula I has good in vivo metabolic stability and a high degree of in vivo absorption. The data in Table 8 show that the compound of Formula I has a strong ability to enter the brain, a high brain exposure, and a high brain concentration.

[0145] Test Example 6: Pharmacokinetic study of the compound of formula I in SD rats

[0146] 5.1 Test Animals and Solvents

[0147] SD rats, male, weighing about 250 g, were randomly divided into groups, 3 in each group.

[0148] DMSO: 30% SBECD (10%: 90%)

[0149] 5.2 Test methods

[0150] The intravenous dose was 6.1 μmol / kg, and the oral dose was 24.4 μmol / kg. Animals were fasted for 12 hours before administration, with free access to water. They were fed uniformly 3 hours after administration. Approximately 0.3 mL of blood was collected from heparinized EP tubes at 5 minutes (intravenous), 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration. The blood was centrifuged at 13,500 rpm for 10 minutes to separate the plasma. Brain tissue was collected from rats at 30 minutes, 2 hours, and 6 hours after cardiac perfusion. After pretreatment, LC-MS / MS analysis was performed to determine the concentrations of the analyte in plasma and brain, and pharmacokinetic parameters were calculated.

[0151] 5.3 Test results

[0152] Table 9 Pharmacokinetic parameters of the compound of formula I after intravenous (6.1 μmol / kg) and oral gavage (24.4 μmol / kg) administration to SD rats

[0153] Table 10 Brain concentrations of the compound of formula I in SD rats after oral administration (24.4 μmol / kg)

[0154] The data in Table 9 show that after intravenous and oral administration of the compound of Formula I to SD rats, there was a high plasma exposure (AUC), a long half-life, and an absolute bioavailability of 84% by oral administration, indicating that the compound of Formula I has good in vivo metabolic stability and a high degree of in vivo absorption. The data in Table 10 show that the compound of Formula I has a strong ability to enter the brain, a high brain exposure, and a high brain concentration.

[0155] Test Example 7: Evaluation of the anticonvulsant effect of the compound of formula I in SD rats

[0156] 6.1 Test Purpose

[0157] 50 mg / kg pentylenetetrazol (PTZ) was intraperitoneally injected into SD rats to establish an epileptic convulsion animal model in SD rats, and the anticonvulsant effect of the compound of formula I was detected.

[0158] 6.2 Test method

[0159] Male Sprague-Dawley rats weighing 300 ± 10 g were acclimated to the animal facility for 7 days and randomly divided into groups based on body weight one day before dosing. They were fasted for half a day prior to the experiment, but water was not withheld. During the experiment, the rats were orally administered 3.5 mg / kg of the compound of Formula I. Two hours after the oral administration, 50 mg / kg of PTZ solution was intraperitoneally injected. Epileptic seizures were observed within one hour of PTZ-induced seizures. The latency of clonic and tonic seizures was measured.

[0160] 6.3 Test results

[0161] The behavioral raw data were finally expressed as mean ± standard error (Mean ± SEM) and statistically analyzed using One-way ANOVA Dunnett post hoc. P < 0.05 indicated a significant difference, P < 0.01 indicated a very significant difference, and P < 0.001 indicated an extremely significant difference.

[0162] The results of behavioral observations on epileptic seizures showed that within 1 hour after intraperitoneal injection of 50 mg / kg PTZ to induce epileptic seizures, the latency of clonic seizures in the drug-treated group (2764.6±1330.9s) was significantly higher than that in the solvent control group (114.5±36.9s) (P<0.001); the latency of tonic-clonic seizures in the drug-treated group (3600±0s) was significantly higher than that in the solvent control group (115.8±37.1s) (P<0.001).

Claims

1. Form A 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: 6.752±0.2°, 13.684±0.2°, 15.748±0.2°, 17.744±0.2°; preferably has characteristic diffraction peaks at the following 2θ angles: 6.752±0.2°, 13.684±0.2°, 15.483±0.2°, 15.748±0.2°. 2°, 17.744±0.2°; more preferably, there are characteristic diffraction peaks at the following 2θ angles: 6.752±0.2°, 9.943±0.2°, 12.794±0.2°, 13.684±0.2°, 14.750±0.2°, 15.483±0.2°, 15.748±0.2°, 17.744±0.2°; most preferably, the X-ray powder diffraction pattern using Cu-Kα radiation is shown in Figure 1-1, 2. Form B of the compound of formula I, in an X-ray powder diffraction pattern using Cu-Kα radiation, has characteristic diffraction peaks at the following 2θ angles: 15.962±0.2°, 16.497±0.2°, 17.275±0.2°, 17.757±0.2°; preferably has characteristic diffraction peaks at the following 2θ angles: 11.753±0.2°, 15.312±0.2°, 15.962±0.2°, 16.497±0.2°, 17.275±0.2°, 17.757±0.2°, 18.395±0.2°, 19.191±0.2 °, 23.754±0.2°, 24.571±0.2°; more preferably, there are characteristic diffraction peaks at the following 2θ angles: 11.428±0.2°, 11.753±0.2°, 15.312±0.2°, 15.962±0.2°, 16.497±0.2°, 17.275±0.2°, 17.757±0.2°, 19.191±0.2°, 23.754±0.2°, 24.571±0.2°, 25.672±0.2°; most preferably, the X-ray powder diffraction pattern using Cu-Kα radiation is shown in Figure 2-1.

3. The crystalline form B according to claim 2, which is a hydrate crystalline form.

4. The methanol solvate crystalline 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: 15.574±0.2°, 16.065±0.2°, 17.384±0.2°, 17.834±0.2°; preferably has characteristic diffraction peaks at the following 2θ angles: 11.112 ±0.2°, 11.631±0.2°, 15.574±0.2°, 16.065±0.2°, 17.384±0.2°, 17.834±0.2°, 19.166±0.2°, 23.507±0.2°, 23.791±0.2°, 24.810±0.2°; more preferably, the X-ray powder diffraction pattern using Cu-Kα radiation is shown in Figure 3-1.

5. The methanol solvate crystalline form C of the compound of formula I according to claim 4, wherein the molar ratio of MeOH to the compound of formula I in the methanol solvate crystalline form C is about 0.8 to 1.2:

1.

6. The methanol solvate crystalline 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: 15.782±0.2°, 16.288±0.2°, 17.575±0.2°, 17.819±0.2°; preferably, it has characteristic diffraction peaks at the following 2θ angles: 11.731±0.2°, 15.398±0.2°, 15.782±0.2°, 16.288±0.2°, 17.314±0.2°, 17.575±0.2°, 17.819±0.2°, 19.192±0.2°; more preferably, the X-ray powder diffraction pattern using Cu-Kα radiation is shown in Figure 4-1.

7. The crystalline form D of the compound of formula I according to claim 6, wherein the molar ratio of MeOH to the compound of formula I in the methanol solvate crystalline form D is about 0.

5.

8. A pharmaceutical composition comprising the crystal form according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier.

9. Use of the crystal form according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8 in the preparation of a GABAA receptor modulator drug.

10. Use of the crystal form according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8 in the preparation of a medicament for preventing and / or controlling diseases or symptoms related to the central nervous system.

11. The use according to claim 10, wherein the central nervous system disease or disorder comprises: sleep disorders, depression, mood disorders, mania, dysthymic disorder, bipolar disorder, anxiety disorders, stress, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder, schizophrenia spectrum disorder, convulsive disorders, memory and / or cognitive impairment, dementia, movement disorders, personality disorders, autism, autism spectrum disorder (ASD), pain, traumatic brain injury (TBI), vascular disease, substance abuse disorders and / or withdrawal syndrome, and tinnitus.

12. The use according to claim 11, wherein the depression comprises mild depression, major depressive disorder, persistent depressive disorder, psychotic depression, postpartum depression or seasonal affective disorder.

13. The use according to claim 10, wherein the central nervous system-related diseases include insomnia, bipolar I disorder, bipolar II disorder, generalized anxiety disorder (GAD), social anxiety disorder, social anxiety disorder, schizophrenia, schizoaffective disorder, attention disorders, Alzheimer's dementia, Lewy body dementia, vascular dementia, Huntington's disease, Parkinson's disease, essential tremor, antisocial personality disorder, obsessive-compulsive personality disorder, autism, monogenic autism, synaptophathy, Rett syndrome, fragile X syndrome, Angelman syndrome, neuropathic pain, injury-related pain syndrome, acute pain, chronic pain, stroke, ischemia, vascular malformations, addiction to opiates, cocaine and / or alcohol.

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