Use of PSPH inhibitor in preparation of drug for preventing, treating, or ameliorating nervous system diseases

Abstract

Disclosed is use of a PSPH inhibitor in the preparation of a drug for preventing, treating, or ameliorating nervous system diseases, which relates to the technical field of small molecule drugs. Provided is use of a PSPH (phosphoserine phosphatase) inhibitor in the preparation of a drug for treating nervous system diseases. A small molecule chemical inhibitor is used to inhibit the activity of PSPH, so as to achieve the treatment of nervous system diseases, particularly demonstrating excellent anti-epileptic effects. Furthermore, a small molecule compound having PSPH inhibitory activity is provided, addressing the current gap in the lack of potent PSPH inhibitors.

Description

Use of PSPH inhibitor in preparation of medicine for preventing, treating or improving nervous system diseases TECHNICAL FIELD

[0001] The present application relates to the technical field of small molecule drugs, in particular to the use of PSPH inhibitor in preparation of medicine for preventing, treating or improving nervous system diseases. BACKGROUND

[0002] The nervous system is the most complex structure and function in the human body, and plays a leading role in the regulation system. When the nervous system is diseased, symptoms such as consciousness, cognition, motor dysfunction and intracranial pressure abnormalities often occur, which seriously reduces the quality of life of patients. Common nervous system diseases include cerebrovascular disease, neurodegenerative disease, epilepsy, central nervous system infectious disease, etc.

[0003] Chinese patent CN 112585154A discloses a novel serine derivative compound with improved blood-brain barrier permeability and its use, more specifically, a novel serine derivative compound with improved blood-brain barrier permeability compared to L-serine and a pharmaceutical composition for preventing or treating / improving central nervous system diseases containing the above-mentioned compound as an active ingredient, etc. The compound disclosed in the invention or its pharmaceutically acceptable salt has significantly improved blood-brain barrier permeability compared to L-serine, activates the proliferation of nerve cells, has a nerve cell protection effect by inhibiting oxidative stress-induced mitochondrial membrane potential damage and / or endoplasmic reticulum stress-induced nerve cell apoptosis, and has excellent prevention, treatment and improvement effects on central nervous system diseases such as cognitive impairment, intellectual impairment, cerebellar syndrome, epilepsy, neurodevelopmental disorders, dementia, autism spectrum disorders, Down syndrome, Rett syndrome, fragile X syndrome, Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis.

[0004] Excitotoxicity is an important cause of neuronal injury and death in various acute and chronic neurological diseases, which is caused by excessive activation of NMDA receptors due to excessive release or impaired uptake of glutamate. Studies have shown that D-serine is related to excitotoxicity, for example, application of D-serine deaminase can significantly reduce neuronal injury and death. The above research results show that D-serine is an endogenous ligand of most NMDA receptors.

[0005] D-serine is unevenly distributed in the brain of animals, with the highest levels in the cerebral cortex, hippocampus and striatum, followed by the diencephalon and midbrain, and the lowest levels in the pons, medulla, cerebellum and spinal cord. It has also been reported that D-serine is present in the retina. Studies on the mouse brain have shown that the concentration of D-serine is about 1 / 3 of that of L-serine, and is higher than that of many common amino acids. In the human brain, the concentration of D-serine is high from the 14th week of pregnancy until birth, and decreases to half of the level in the adolescent and mature brain. Compared with glycine, D-serine released by astrocytes is more effective and selective as a co-agonist in binding to the glycine site of the NMDA (N-methyl-D-aspartate) receptor. The binding of D-serine to the glycine site can enhance the agonistic effect of glutamate on the NMDA receptor, resulting in the depolarization of the postsynaptic membrane and the influx of calcium ions, etc.

[0006] Under pathological conditions, the over-activation of the NMDA receptor caused by the excessive concentration of D-serine can be related to many nervous system diseases, such as stroke, epilepsy, chronic pain, Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), ischemia-reperfusion injury, etc. It has been reported that ischemia-reperfusion injury is alleviated after administration of a glycine site antagonist; the level of D-serine in the body of a stroke patient is significantly increased. Although no abnormality in the concentration of D-serine has been detected in the bodies of patients with PD and AD, the application of a glycine site antagonist can improve the abnormal behavior of patients with PD. On the contrary, the under-functioning of the NMDA receptor can lead to schizophrenia. Compared with normal people, the level of D-serine in the serum and prefrontal cortex of such patients is decreased. In epilepsy, the binding of D-serine to the glycine site of the NMDA receptor can produce opposite results. It has been reported that the activation of the NMDA receptor caused by such binding can lead to grand mal seizures; however, another study has shown that such binding can increase the threshold of grand mal seizures. For convulsions, D-serine has a similar effect: on the one hand, NMDA receptor antagonists can inhibit convulsions, and on the other hand, D-serine as a co-agonist of the NMDA receptor can enhance the activity of anticonvulsant drugs. The dual effect of D-serine can be related to different subtypes of NMDA receptors to which D-serine binds, etc. The mechanism is not completely clear.

[0007] Among the nervous system diseases, epilepsy is induced by abnormal function of central nervous system, and is one of the most common chronic neurological diseases. However, nearly one-third of patients do not respond to anti-epileptic drugs targeting ion channels, and are drug-resistant epilepsy. Temporal lobe epilepsy (TLE) is the most common type of adult drug-resistant epilepsy. Patients cannot effectively control seizures even after taking the correct amount of antiepileptic drugs, and can only be treated by surgical resection of the hippocampus. Drug-resistant epilepsy brings much higher medical and economic burden to society and family than general epilepsy syndrome. Therefore, elucidating the pathogenesis of drug-resistant epilepsy such as temporal lobe epilepsy and developing new effective drugs will provide non-surgical treatment options for patients and fill the gap in the treatment of drug-resistant epilepsy.

[0008] NMDA is a widely expressed ionotropic glutamate receptor, and its expression or function plays a crucial role in epileptic discharge. Although small molecule antagonists targeting NMDA, most of which are channel blockers, show anti-epileptic effects in the clinic, they cannot be used as daily drugs for TLE patients due to their strong toxic side effects. For example, high-dose ketamine can treat patients in status epilepticus, but it may affect the respiratory, cardiovascular and nervous systems. In addition to the glutamate binding site, NMDA also requires D-serine or glycine binding at the glycine modulatory site to function. Studies have shown that D-serine is a co-activator of hippocampal synapses, which affects neuronal electrophysiological activity in a gate-regulated manner, and an increase in D-serine levels significantly increases hippocampal neuron firing.

[0009] In the brain, astrocytes synthesize L-serine from scratch through a three-step enzymatic reaction from glucose, which is released to surrounding neurons and converted to D-serine by serine racemase (SR) in a mode called "serine shuttle". Then, D-serine is released to the postsynaptic membrane to act on NMDAR receptors to further regulate synaptic activity. Studies have shown that inhibitors targeting serine racemase have certain anti-excitatory effects in cell and animal epilepsy models, but existing serine racemase inhibitors have no potential for clinical development due to off-target effects and low inhibition potency. On the other hand, blocking the upstream de novo synthesis pathway may be another potential method to reduce D-serine levels and treat temporal lobe epilepsy. However, the molecular cascade involved and drug targets still need to be studied.

[0010] In summary, there is still a need to study small molecule drugs with effective therapeutic effects for nervous system diseases including epilepsy. SUMMARY

[0011] The present application aims to provide the use of a PSPH (phosphoserine phosphatase) inhibitor in the preparation of a medicament for treating a nervous system disease, to inhibit the activity of PSPH using a small molecule chemical inhibitor, to achieve the treatment of a nervous system disease, and to provide a small molecule compound having a PSPH inhibitory activity, and to fill the gap of a potent PSPH inhibitor.

[0012] In the present application, the compound Z218484536 is the compound 1 as described.

[0013] To achieve the above-mentioned application purposes, the technical solutions of the present application are as follows:

[0014] In a first aspect, the present application provides the use of a PSPH inhibitor in the preparation of a medicament for preventing, treating or improving a nervous system disease.

[0015] The term "PSPH inhibitor" refers to an agent capable of crossing the blood-brain barrier and capable of inhibiting the activity of a phosphoserine phosphatase target substance.

[0016] Preferably, the PSPH inhibitor achieves the prevention, treatment or improvement of a nervous system disease by inhibiting the activity of phosphoserine phosphatase, thereby inhibiting the production and release of L-serine in astrocytes, and thereby inhibiting the upregulation of D-serine.

[0017] Preferably, the nervous system disease is at least one of cognitive impairment, intellectual impairment, cerebellar syndrome, epilepsy, neurodevelopmental disorder, dementia, autism spectrum disorder, Down syndrome, Rett syndrome, fragile X syndrome, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and ischemia-reperfusion injury.

[0018] Further preferably, the nervous system disease is at least one of stroke, epilepsy, chronic pain, Parkinson's disease, Alzheimer's disease, Huntington's disease, and ischemia-reperfusion injury.

[0019] Still further preferably, the nervous system disease is epilepsy.

[0020] Still further preferably, the nervous system disease is temporal lobe epilepsy.

[0021] Preferably, the PSPH inhibitor is a compound of formula I or a stereoisomer, geometric isomer, tautomer, nitroso, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof:

[0022] In the formula, R1 is selected from H, substituted or unsubstituted C 1-8 alkyl, C 3-8 cycloalkyl, aryl, heterocyclyl, halogen, C 1-8 alkoxy, and the substituted substituent is C 1-4 alkyl, C1-4 Alkoxy, C 1-4 At least one of the following: haloalkyl, halogen, cyano, phenyl, oxygen- and / or nitrogen-containing 5-6-membered aromatic heterocyclic group, and oxygen- and / or nitrogen-containing 5-6-membered heterocyclic group;

[0023] R2 is either -CH=N- or -CH2CH2-.

[0024] Preferably, R1 is selected from substituted or unsubstituted C. 1-5 Alkyl, C 3-5 cycloalkyl, aryl, 3-6 membered heterocyclic groups, halogen, C 1-5 alkoxy group, wherein the substituent is C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 At least one of the following: haloalkyl, halogen, cyano, phenyl, oxygen- and / or nitrogen-containing 5-6-membered aromatic heterocyclic group, and oxygen- and / or nitrogen-containing 5-6-membered heterocyclic group;

[0025] More preferably, R1 is selected from C 1-5 Alkyl, C 3-5 cycloalkyl, phenyl, halogen, C 1-5 Alkoxy;

[0026] More preferably, R1 is selected from C 1-3 Alkyl, phenyl, halogen, C 1-3 Alkoxy;

[0027] More preferably, R1 is selected from C 1-3 Alkyl, halogen, C 1-3 Alkoxy;

[0028] More preferably, R1 is selected from halogens, C 1-3 Alkoxy;

[0029] More preferably, R1 is selected from F, Cl, Br, C. 1-3 Alkoxy;

[0030] More preferably, R1 is selected from F and methoxy; most preferably, it is F.

[0031] More preferably, the compound of formula I is selected from the following compounds:

[0032] Preferably, the compound of formula I is selected from the following compounds:

[0033] Preferably, the drug can be prepared into dosage forms such as pills, capsules, granules, oral liquids, powders, tablets, lozenges, sugar lozenges, and injections, and a suitable drug carrier in the art can be selected for different dosage forms.

[0034] The pharmaceutical carrier employed can be a solid, liquid, or gas. Examples of solid carriers include lactose, talc, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0035] In preparing the pharmaceuticals for oral administration, any convenient pharmaceutical media can be employed. For example, water, ethanol, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs, solutions, and the like. Alternatively, solid carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, emulsifying agents, lubricants, binders, and disintegrating agents can be used to form oral solid preparations such as powders, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. Either tablets or capsules can optionally be coated by standard aqueous or nonaqueous techniques.

[0036] Tablets can be prepared by compression or molding, optionally, with one or more accessory ingredients or adjuvants. Tablets can be prepared by compressing an active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding an inactive mixture of the powdered compound moistened with a suitable liquid diluent. Each tablet preferably contains from about 0.05 mg to about 5 g of the active ingredient. Each saucer or capsule preferably contains from about 0.05 mg to about 5 g of the active ingredient. For instance, a preparation intended to supply 25 mg of active agent per day to an adult person can be in the form of a tablet containing 25 mg of the active agent, and a suitable quantity of a diluent, or in the form of a capsule containing 25 mg of the active agent mixed with a suitable diluent. A unit dosage form can contain from about 1 mg to about 2 g of the active ingredient, usually 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

[0037] The pharmaceuticals suitable for parenteral administration can be formulated as solutions or suspensions of the active compounds in either aqueous or nonaqueous liquids, or as emulsions. Suitable excipients for such formulations include, for example, water, saline, dextrose, glycerol, and the like. Also included are suspensions, solutions, or emulsions containing the active compound in either a hydrophilic or a hydrophobic carrier. Examples of such carriers include, but are not limited to, honey, sorbitol, and the like. Also included are sterile aqueous or nonaqueous solutions, suspensions, and emulsions, which can contain antioxidants, buffers, bactericides, and solutes that render the formulation isotonic with the blood. Aqueous and nonaqueous sterile suspensions and emulsions can be formulated as appropriate using diluents such as water, saline, ethanol, polyol glycols, and the like.

[0038] The pharmaceuticals of the present application can be in a form suitable for local use, such as a cream, ointment, lotion, powder, or the like. Also, the composition can be in a form suitable for use in a transdermal delivery device. For example, a cream or ointment having a desired consistency can be prepared by mixing a hydrophilic material and water, along with from about 5 wt% to about 10 wt% of the compound.

[0039] The pharmaceuticals of the present application can be in a form suitable for rectal administration wherein the carrier is a solid. The composition can be prepared as a unit dosage suppository form by mixing the ingredients with a softening or melting carrier and then chilling and shaping in moulds.

[0040] In addition to the carrier ingredients, the pharmaceuticals described above can contain, as is required, one or more additional carrier ingredients such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives (including antioxidants), and the like. Additionally, other adjuvants can be included, e.g., lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, colouring agents, and flavouring agents, and the like. The formulations are prepared so that they are isotonic with the blood of the intended recipient. The components of the pharmaceutical compositions of the application can also be prepared in powder or liquid concentrate form.

[0041] The pharmaceuticals also include other active ingredients.

[0042] The other active ingredients are selected from at least one of the following ingredients.

[0043] In a second aspect, the present application provides use of a D-serine inhibitor in the manufacture of a medicament for treating a nervous system disease.

[0044] Preferably, the nervous system disease has the same definition as aforementioned.

[0045] Preferably, the medicament has the same definition as aforementioned.

[0046] Preferably, the D-serine inhibitor is a compound of Formula I or a stereoisomer, geometric isomer, tautomer, nitroso, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, the compound of Formula I has the same definition as aforementioned.

[0047] In a third aspect, the present application provides use of an L-serine inhibitor in the manufacture of a medicament for treating a nervous system disease.

[0048] Preferably, the L-serine inhibitor can inhibit the production and release of L-serine in astrocytes.

[0049] Preferably, the nervous system disease has the same definition as aforementioned.

[0050] Preferably, the medicament has the same definition as aforementioned.

[0051] Preferably, the L-serine inhibitor is a compound of Formula I or a stereoisomer, geometric isomer, tautomer, nitroso, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, the compound of Formula I has the same definition as aforementioned.

[0052] In a fourth aspect, the present application provides a compound or a stereoisomer, a geometric isomer, a tautomer, a nitroso, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, having the following structural formula:

[0053] wherein R1 has the same definition as aforementioned.

[0054] Specifically, R1 is selected from H, substituted or unsubstituted C 1-8 alkyl, C 3-8 cycloalkyl, aryl, 3-6 membered heterocyclyl, halogen, C 1-8 alkoxy, wherein the substituted substituent is C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, halogen, cyano, phenyl, 5-6 membered oxygen- and / or nitrogen- containing aromatic heterocyclyl, 5-6 membered oxygen- and / or nitrogen-containing heterocyclyl;

[0055] Preferably, R1 is selected from substituted or unsubstituted C 1-5 alkyl, C 3-5 cycloalkyl, aryl, 3-6 membered heterocyclyl, halogen, C 1-5 alkoxy, wherein the substituted substituent is C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, halogen, cyano, phenyl, 5-6 membered oxygen- and / or nitrogen- containing aromatic heterocyclyl, 5-6 membered oxygen- and / or nitrogen-containing heterocyclyl;

[0056] Further preferably, R1 is selected from C 1-5 alkyl, C 3-5 cycloalkyl, phenyl, halogen, C 1-5 alkoxy;

[0057] Still further preferably, R1 is selected from C 1-3 alkyl, phenyl, halogen, C 1-3 alkoxy;

[0058] Still further preferably, R1 is selected from C 1-3 alkyl, halogen, C 1-3 alkoxy;

[0059] Still further preferably, R1 is selected from halogen, C 1-3 alkoxy;

[0060] Still further preferably, R1 is selected from F, Cl, Br, C 1-3 alkoxy;

[0061] Still further preferably, R1 is selected from F, methoxy;

[0062] Most preferably, F, preferably, the structure is as follows:

[0063] In a fifth aspect, the present application provides a preparation method of the compound of the fourth aspect, comprising the following steps:

[0064] Preferably, the method comprises the following steps:

[0065] (1) adding compound 1 in a solvent, adding a base, a catalyst and (Boc)2O, and reacting at 20-40℃ for 1-5 hours to obtain compound 2;

[0066] (2) adding NaBH4 to a solution of compound 2 at a temperature of -10-10℃, and reacting for 0.2-1 hours to obtain compound 3;

[0067] (3) dissolving compound 3 in a solvent, cooling to -5-5℃, and sequentially adding a base and MsCl (methylsulfonyl chloride), and reacting at -10-10℃ for 2-4 hours to obtain compound 4;

[0068] (4) adding compound 4 in a solvent and a reducing agent at -5-5℃ under an inert atmosphere, and heating the mixture to 20-40℃ and reacting for 1-3 hours to obtain compound 5;

[0069] (5) mixing compound 5 and potassium cyanate in a solvent, and reacting at 55-75℃ under an inert atmosphere for 2-4 hours to obtain the product.

[0070] In a sixth aspect, the present application provides a medicine comprising the compound of the fourth aspect or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof.

[0071] Preferably, the medicine can be prepared into a dosage form for administration, such as a pill, a capsule, a granule, an oral solution, a powder, a tablet, a lozenge, a sugar lozenge, an injection, etc., and a suitable pharmaceutical carrier in the art can be selected for different dosage forms.

[0072] The pharmaceutical carrier used can be solid, liquid or gas. Examples of solid carriers include lactose, kaolin, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers include sugar syrup, peanut oil, olive oil and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0073] In preparing the pharmaceuticals for oral administration, any convenient pharmaceutical media can be employed. Thus, for example, water, ethanol, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, emulsifying agents, lubricants, binders, disintegrating agents and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. If desired, tablets can be sugar coated or enteric coated by standard techniques.

[0074] Tablets can be prepared by compression or molding, optionally, with one or more accessory ingredients or adjuvants. Tablets can be prepared by compressing an active ingredient in a free-flowing form such as a powder or granules, optionally, with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made directly from a mixture of powdered compound moistened with a minimal amount of liquid binder or otherwise moistened, if needed to clump or agglomerate powders into molded shapes. Each tablet preferably contains from about 0.05 mg to about 5 g of active ingredient. Each cachet or capsule preferably contains from about 0.05 mg to about 5 g of active ingredient. For instance, a formulation intended to supply 25 mg of active ingredient per day to an adult human can be compounded as a tablet or capsule to provide a dosage of 25 mg daily. The compounds can also be formulated to provide slow or delayed release of the active ingredient.

[0075] Pharmaceuticals suitable for parenteral administration can be formulated as solutions or suspensions of the active compounds in either aqueous or non-aqueous liquids, such as water, ethanol, oils, glycols or other solvents. Pharmaceutically acceptable dispersing agents, wetting agents or suspending agents can be used.

[0076] Pharmaceuticals of the present application can be in a form suitable for local administration, e.g., as an aerosol, cream, ointment, lotion, powder or the like. Additionally, the composition can be in a form suitable for transdermal administration. For example, a cream or ointment can be formulated by mixing the active ingredient with a suitable cream or ointment base.

[0077] Pharmaceuticals of the present application can be in a form suitable for local administration, e.g., as an aerosol, cream, ointment, lotion, powder or the like. Additionally, the composition can be in a form suitable for transdermal administration. For example, a cream or ointment can be formulated by mixing the active ingredient with a suitable cream or ointment base.

[0078] In addition to the carrier ingredients, the pharmaceuticals described above can include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants), and the like. Additionally, other ingredients can be included, for example, lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, colorings, flavorings, and the like. The formulations are rendered isotonic with the blood of the intended recipient by means known in the art. The components of the pharmaceutical compositions of the present application can also be prepared in powder or concentrated liquid form.

[0079] The pharmaceuticals also include other active ingredients.

[0080] The other active ingredients are selected from at least one of the following ingredients.

[0081] In a seventh aspect, the present application provides a method of treating a nervous system disease, comprising administering a specific dosage of a PSPH inhibitor, a D-serine inhibitor, or an L-serine inhibitor.

[0082] Preferably, the pharmaceuticals for administration can be adapted for administration by any appropriate route, for example, by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) routes. Such compositions can be prepared by any method known in the art of pharmacy, for example, by mixing the active ingredient with the carrier under aseptic conditions.

[0083] Further preferably, the pharmaceuticals adapted for oral administration can be provided in the form of capsules or tablets; as a powder or granules; as a solution, syrup or suspension (in an aqueous or non-aqueous liquid); or as an emulsion.

[0084] Tablets or hard capsules can include lactose, corn starch or derivatives thereof, stearic acid or salts thereof.

[0085] Soft gelatin capsules can include vegetable oils, waxes, fats, semi-solid or liquid polyols, etc.

[0086] Solutions and syrups can include water, polyols and sugars. To prepare suspensions, oils (e.g., vegetable oils) can be used to provide oil-in-water or water-in-oil suspensions.

[0087] Further preferably, the pharmaceuticals adapted for transdermal administration can be provided as discrete patches for maintaining close contact with the epidermis of the recipient over an extended period of time. For example, the active ingredient can be delivered from the patch by iontophoresis.

[0088] Further preferably, the pharmaceuticals adapted for topical administration can be provided in the form of ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

[0089] For infections of the eye or other external tissues, e.g. the mouth and skin, it is preferable to use a topical ointment or cream. When formulated in an ointment, the active ingredient can be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient can be formulated in a cream with an oil-in-water cream base or a water-in-oil base.

[0090] Pharmaceuticals adapted for topical administration in the eye include eye drops. Here, the active ingredient can be dissolved or suspended in a suitable carrier, e.g. an aqueous solvent.

[0091] Pharmaceuticals adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.

[0092] Further preferably, pharmaceuticals suitable for rectal administration can be provided as suppositories or enemas.

[0093] Further preferably, pharmaceuticals suitable for nasal administration using solid carriers include coarse powders (e.g. having a particle size in the range 20-500 microns). These can be administered in the manner in which snuff is taken, i.e. by rapid inhalation from a powder container placed close to the nose.

[0094] Compositions for nasal administration using liquid carriers include nasal sprays or nasal drops. These can include aqueous or oily solutions of the active ingredient.

[0095] Pharmaceuticals adapted for administration by inhalation include fine dusts or mists which can be generated by a variety of types of device, e.g. pressurised aerosols, atomisers or nebulisers. Such devices can be constructed so as to provide a pre-metered dose of the active ingredient.

[0096] Further preferably, pharmaceuticals suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

[0097] Further preferably, pharmaceuticals suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions or suspensions. These compositions can contain anti-oxidants, buffers, bactericides and solutes, which render the composition substantially isotonic with the blood of the intended recipient. Additional components that can be present in these compositions include, for example, water, alcohols, polyols, glycerine and vegetable oils. Compositions suitable for parenteral administration can be presented in unit-dose or multi-dose containers, e.g. sealed ampoules and vials, and can be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, e.g. water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets.

[0098] Preferably, the dose is readily determined by routine testing and is controlled by a physician or clinician. A guiding principle for determining a suitable dose is to deliver an amount of material that is appropriate to be effective but not toxic or acceptably toxic. For NB-DNJ or similar compounds, a daily dose for an adult can be expected to be in the range of 1 mg to 2 g of active agent, and can be in the range of 100 to 800 mg or 300 to 600 mg. The dose can be administered in a single dose during the day, or in two, three or more doses during the day.

[0099] Preferably, the PSPH inhibitor, D-serine inhibitor or L-serine inhibitor is administered in combination with other active ingredients.

[0100] The other active ingredients are selected from at least one of the following ingredients.

[0101] Preferably, the PSPH inhibitor, D-serine inhibitor or L-serine inhibitor has the same definition as previously described.

[0102] Explanation and specification of terms:

[0103] In the present application, the term "prevention" refers to a method of avoiding or averting a disease or condition or delaying the recurrence or appearance of one or more symptoms of the condition in a subject. The term "improvement" refers to a method of lessening or slowing the trend of development of symptoms already present in a subject. The term "treatment" refers to obtaining a desired pharmacological and / or physiologic effect, which can be prophylactic in terms of completely or partially preventing a disease or symptom thereof, and / or therapeutic in terms of a partial or complete cure for a disease and / or adverse effect attributable to the disease. The term "treatment" as used herein includes any treatment of a disease in a mammal, particularly a human, and includes (a) preventing the disease from occurring in an individual that is predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing the disease to regress and / or relieving one or more symptoms of the disease. "Treatment" shall also include the delivery of an agent to provide a pharmacological effect, even if the disease or condition is not present.

[0104] In the present application, the terms "comprising", "containing" and "including" mean including, but not limited to, for example, other additives, components.

[0105] The term "alkyl" as used herein, unless otherwise indicated, includes both straight chain and branched chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms, including all isomers. Common abbreviations for alkyl groups are represented, for example, by "Me" or CH3for methyl, "Et" or CH2CH3for ethyl, "Pr" or CH2CH2CH3for propyl, "Bu" or CH2CH2CH2CH3for butyl, and the like. For example, "C1-C4alkyl" means an alkyl group having from 1 to 4 carbon atoms. 1-4 The term "alkyl" as used herein, unless otherwise indicated, includes both straight chain and branched chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms, including all isomers. Common abbreviations for alkyl groups are represented, for example, by "Me" or CH3for methyl, "Et" or CH2CH3for ethyl, "Pr" or CH2CH2CH3for propyl, "Bu" or CH2CH2CH2CH3for butyl, and the like. For example, "C1-C4alkyl" means an alkyl group having from 1 to 4 carbon atoms. 1-4 The term "alkyl" as used herein, unless otherwise indicated, includes both straight chain and branched chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms, including all isomers. Common abbreviations for alkyl groups are represented, for example, by "Me" or CH3for methyl, "Et" or CH2CH3for ethyl, "Pr" or CH2CH2CH3for propyl, "Bu" or CH2CH2CH2CH3for butyl, and the like. For example, "C1-C4alkyl" means an alkyl group having from 1 to 4 carbon atoms. 1-10 The term "alkyl" as used herein, unless otherwise indicated, includes both straight chain and branched chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms, including all isomers. Common abbreviations for alkyl groups are represented, for example, by "Me" or CH3for methyl, "Et" or CH2CH3for ethyl, "Pr" or CH2CH2CH3for propyl, "Bu" or CH2CH2CH2CH3for butyl, and the like. For example, "C1-C4alkyl" means an alkyl group having from 1 to 4 carbon atoms.

[0106] The term "alkyl" as used herein, unless otherwise indicated, includes both straight chain and branched chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms, including all isomers. Common abbreviations for alkyl groups are represented, for example, by "Me" or CH3for methyl, "Et" or CH2CH3for ethyl, "Pr" or CH2CH2CH3for propyl, "Bu" or CH2CH2CH2CH3for butyl, and the like. For example, "C1-C4alkyl" means an alkyl group having from 1 to 4 carbon atoms.

[0107] The term "halogen" (or halo) means fluorine, chlorine, bromine and iodine (or fluorinated (F), chlorinated (Cl), brominated (Br) and iodinated (I)).

[0108] The term "aryl" means an aromatic mono- and polycarbocyclic ring system wherein the individual carbocyclic rings are fused or linked by single bonds. Typical aryl groups include phenyl, naphthyl and biphenylene.

[0109] The term "heterocycle" means a ring structure composed of carbon atoms and non-carbon atoms, such as nitrogen, oxygen and sulfur. Typical heterocyclic groups include pyridine, quinoline, tropane, phenothiazine, benzodiazepine, furan, pyrazolone and pyrimidine.

[0110] The term "heteroaryl" means a 5- or 6-membered monocyclic aromatic ring or a 7- to 12-membered bicyclic ring composed of carbon atoms and one or more heteroatoms selected from N, O and S. Examples of heteroaryl groups include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl (or thiophenyl), thiazolyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, dioxazolyl, thiazolyl, isothiazolyl and thiadiazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, isochromanyl, tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo-l,4-dioxinyl, imidazo(2,l-b)(l,3)thiazole and benzo-l,3-dioxolyl.

[0111] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable, non-toxic alkali or acid. When the compounds of the present invention are acidic, their corresponding salts can be readily prepared from inorganic or organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (copper and cuprous), iron, ferrous, lithium, magnesium, manganese (manganese and manganese), potassium, sodium, zinc, etc. Preferred are ammonium, calcium, magnesium, potassium, and sodium salts. Salts prepared from organic bases include primary, secondary, and tertiary amines derived from natural and synthetic sources. Pharmaceutically acceptable, non-toxic organic bases that can form salts include arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, halogen, isopropylamine, dicyclohexylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When the compounds of the present invention are basic, their corresponding salts can be readily prepared from inorganic or organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethylsulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, viscous acid, nitric acid, pyric acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, etc.

[0112] The term "solvate" refers to a variable stoichiometric complex formed by a solute (i.e., a compound of formula I) or a pharmaceutically acceptable salt thereof and a solvent that does not interfere with the biological activity of the solute. Examples of solvents include, but are not limited to, water, ethanol, and acetic acid. When the solvent is water, the solvate is called a hydrate. Hydrates include, but are not limited to, hemihydrates, monohydrates, sesquihydrates, dihydrates, and trihydrates.

[0113] The term "prodrug" refers to a functional derivative of the compound of this invention that is readily converted into the desired compound in vivo.

[0114] The beneficial effects of this invention are as follows:

[0115] This invention discovers that PSPH (phosphoserine phosphatase) can serve as a novel therapeutic target for neurological diseases, particularly epilepsy, thus providing a new direction for the treatment of these conditions. Furthermore, based on this PSPH target, this invention provides small molecule compounds that can act as PSPH inhibitors. By utilizing these small molecule chemical inhibitors to suppress PSPH activity, the invention aims to treat neurological diseases, particularly exhibiting excellent anti-epileptic effects. The newly discovered PSPH inhibitor compounds demonstrate favorable pharmacological properties, showing good anti-epileptic activity in a mouse TLE model, and exhibiting fewer toxic side effects compared to other channel blockers targeting NMDARs. Attached Figure Description

[0116] Figure 1. D-Serine promotes KA-induced acute seizures. (a-c) The levels of glutamate, serine and glycine in hippocampal samples of patients with hippocampal sclerosis (HS, n=6), patients without hippocampal sclerosis (nonHS, n=3) and autopsy controls without neurological disease (n=7) were analyzed by metabolomics. (d, e) The levels of L / D-serine in the hippocampus of control mice and chronic TLE mice were determined by microdialysis and zero-flow retrograde method and statistically analyzed (n=6). (f) Representative 2-minute electroencephalogram. The kainic acid-induced acute seizure model was established and low-dose D-serine (10 μΜ), high-dose D-serine (100 μΜ), D-amino acid oxidase (1 U / mL), heat-inactivated D-amino acid oxidase (1 U / mL), 7-CKA (100 μΜ) or glycine (200 μΜ) was injected into the ipsilateral hippocampus before the seizure-inducing site. (g-k) The differences in the time to seizure onset (g), the total number of seizures (h), the duration of each seizure (i), the total number of electroclinical seizures (j) and the seizure induction rate (k) were analyzed among control, low-dose D-serine, high-dose D-serine, D-amino acid oxidase, hiDAAO, 7-CKA and glycine groups (n=9).

[0117] Figure 2. D-Serine modulates spontaneous seizures. (a) Schematic diagram of experimental protocol (n=4 for glycine group and n=8 for other groups). (b-p) Representative 1-minute electroencephalogram (left), seizure distribution diagram during the experiment (middle) and statistical analysis of hippocampal interictal spikes at baseline, 0-12 hours after injection and 12-28 hours after injection (right) for each group after injection of solvent (d), D-amino acid oxidase (g), 7-CKA (j), D-serine (m) or glycine (p) into the ipsilateral hippocampus. After 20 hours of baseline electroencephalogram detection, 0.5 μL of solvent, D-amino acid oxidase (1 U / ml), 7-CKA (100 μΜ), D-serine (10 μΜ) or glycine (200 μΜ) was injected into the ipsilateral hippocampus of the kainic acid injection site through the pre-implanted catheter at 8:00 on the second day to observe the changes in hippocampal interictal spikes.

[0118] Figure 3. Astrocytic L-serine regulates D-serine levels and seizures. (a) Schematic of the serine shuttle between astrocytes and neurons. (b) Schematic of the reverse microdialysis (1 μL / min) and simultaneous electroencephalogram recording protocol. (c) Schematic of the experimental procedure and grouping information. (d) Hippocampal epileptiform discharges induced by KA injection into the hippocampus by reverse microdialysis. (e-j) Grid plots showing the effect of specific treatments on the hippocampal epileptiform discharges, with each occurrence of a hippocampal epileptiform discharge indicated by a red line. (k-m) Statistical analysis of the number of seizures (k) and the levels of L-serine (1) and D-serine (m) in the dialysate (n = 6).

[0119] Figure 4. PSPH is upregulated in TLE and regulates interstitial L-serine and D-serine levels. (a) Schematic of the three-step enzymatic reaction for de novo L-serine synthesis in astrocytes. (b, c) Cultures were treated with a set of siRNAs to knock down PSPH, PSAT1, or PHGDH in astrocytes, and the L-serine levels in cell lysates (b) and media supernatants (c) were statistically analyzed. (d) PSPH, PSAT1, and PHGDH levels were measured in seven different brain regions of mice (left) and statistically analyzed (right). (e) Western blotting (left) and statistical analysis (right) of hippocampal lysates from mice injected intraperitoneally with pentyltetrazole (PTZ) or PTZ + chloral hydrate (CH) at 0, 1, 2, and 4 h. (f, g) Immunofluorescence staining of GFAP and PSPH in the hippocampus of surgically resected patients with hippocampal sclerosis (TLE-HS) and autopsy controls without neurological disease (control) (f) or in the hippocampus of normal mouse controls and mice with temporal lobe epilepsy (4 weeks after kainic acid-induced status epilepticus) (g); scale bar = 50 μm. (h) Immunofluorescence staining of PSPH, GFP, and GFAP in the hippocampus of mice injected bilaterally with AAV5-gfa104-eGFP (control) or AAV5-gfa104-PSPH-IRES-eGFP (PSPH overexpression) for one month; scale bar = 50 μm. (i, j) Levels of L-serine (i) and D-serine (j) in the extracellular fluid of the hippocampus of control and PSPH overexpression mice were measured using microdialysis (n = 6). (k-n) Kainic acid (7 ng) was injected into the hippocampus of control and PSPH overexpression mice via a pre-implanted cannula to induce acute seizures, and the differences in the responses of control and PSPH overexpression mice to kainic acid were statistically analyzed, including the onset time of seizures (k), the number of seizures (1), the duration of each seizure (m), and the number of electroclinical seizures (n) (n = 8).

[0120] Figure 5. Mass spectrometry analysis of Compound 1.

[0121] Figure 6 is a mass spectrometry analysis of compound 2.

[0122] Figure 7 is a mass spectrometry analysis of compound 3.

[0123] Figure 8 is the result of PSPH inhibition activity test of compound 1. (a, b) The level of L-serine in supernatant and cell lysate. Primary astrocytes treated with compound 1 were cultured in serine-free medium, and then treated with compound 1 for 24 hours. The medium was replaced with fresh serine-free medium, and the cells were cultured for another 24 hours. The level of L-serine in supernatant and cell lysate was detected (n = 4). (c, d) The level of L-serine (t) and D-serine (u) in hippocampus of chronic epilepsy mice was measured by microdialysis after intraperitoneal injection of solvent or 4 mg / kg Z218484536 for five times (n = 6).

[0124] Figure 9 is the result of PSPH inhibition activity test of compound 2. (a) The ability of compound 2 to inhibit the degradation of substrate O-phospho-L-serine to produce L-serine by recombinant PSPH was observed in vitro. (b, c) The level of L-serine in supernatant and cell lysate. Primary astrocytes treated with compound 2 were cultured in serine-free medium, and then treated with 40-2000 μΜ compound 2 for 24 hours. The medium was replaced with fresh serine-free medium, and the cells were cultured for another 24 hours. The level of L-serine in supernatant and cell lysate was detected (n = 4).

[0125] Figure 10 is the result of PSPH inhibition activity test of compound 3. (a) The ability of derivative-2 to inhibit the degradation of substrate O-phospho-L-serine to produce L-serine by recombinant PSPH was observed in vitro. (b, c) The level of L-serine in supernatant and cell lysate. Primary astrocytes treated with compound 3 were cultured in serine-free medium, and then treated with compound 3 for 24 hours. The medium was replaced with fresh serine-free medium, and the cells were cultured for another 24 hours. The level of L-serine in supernatant and cell lysate was detected (n = 4).

[0126] Figure 11 is the result of animal experiment of four compounds.

[0127] Figure 12 is the result of molecular docking experiment and pharmacokinetics of compound 1.

[0128] Figure 13 is a schematic diagram of the target engagement of Compound 1. (a) Sequence alignment of PSPH protein across 11 species, finding four binding sites of PSPH with high evolutionary conservation. (b) Enzymatic activity assay of wild type (WT) and PSPH mutants with Asp22Ala, Ala51Val, Ala51Gly, Gly110Val, Gly110Ala, Lys158Ala, or Ala51Val / Gly110Ala site mutations. (c) MST analysis of Compound 1 binding to PSPH Ala51Val / Gly110Ala mutant. (d, e) L-serine content in cell lysate (d) and culture supernatant (e). PSPH knockdown and PSPH-MT overexpression (Ala51Val / Gly110Ala) were achieved by lentivirus-mediated gene transfer.

[0129] Figures 14-15 are activity assays of Compound 1 on a panel of 25 protein phosphatases. (a-z) Statistical analysis of Z218484536 and positive controls on inhibition of PSPH, 20 protein tyrosine phosphatase superfamily enzymes (including SHP1, SHP2, PTPN2, PTPN4, PTPN7, PTPN9, PTPN12, PTPN13, PTPN22, PTPRB, PTPRC, PTPRE, PTPRM, DUSP3, DUSP10, DUSP13, DUSP22, YopH, LMPTP-a, LMPTP-B), and five protein serine / threonine phosphatase superfamily enzymes (including PP1A, PP1B, PP2A, lambda PP, and PP5). On the left of each panel is a known positive inhibitor of the enzyme, and on the right is the result of Compound 1 testing.

[0130] Figure 16 is Compound 1 exhibits antiepileptic effects in a kainic acid chronic temporal lobe epilepsy mouse model. (a) Experimental design. (b-e) Daily recording of spontaneous seizure frequency in vehicle, lamotrigine, and Z218484536 groups. Lamotrigine was administered at a dose of 20 mg / kg per day intraperitoneally (n = 8). Z218484536 was administered at a dose of 2 or 4 mg / kg per day intraperitoneally (n = 9). DMSO was used as a vehicle control (n = 8). (f) Line graph showing the daily seizure frequency of mice during the 3-week baseline recording and the subsequent 7-week drug treatment period. (g-j) Statistical analysis of seizure frequency before and after treatment in the vehicle group, lamotrigine group, Compound 1 at 2 mg / kg group, and 4 mg / kg group. DETAILED DESCRIPTION

[0131] The following non-limiting examples can provide a more complete understanding of the application to those of ordinary skill in the art, but are not intended in any way to limit the scope of the application. The following merely illustrates the scope of the application claimed, and those skilled in the art can make many changes and modifications to the application as disclosed without departing from the scope of the application claimed.

[0132] The application is further described in the following specific examples. The various chemical reagents used in the examples of the application are obtained from conventional commercial sources unless otherwise specified. The amounts described below are amounts by mass unless otherwise specified. It is understood that the procedures are carried out at room temperature unless otherwise specified.

[0133] In the following examples, the abbreviations are defined as follows: PSPH: Phosphoserine Phosphatase; PSAT1: Phosphoserine Aminotransferase 1; PHGDH: Phosphoglycerate dehydrogenase; ASM: Anti-seizure Medication; NMDAR: N-methyl-D-aspartate receptor; SR: Serine Racemase; TLE: Temporal lobe epilepsy; HS: Hippocampal sclerosis; NonHS: Non-hippocampal sclerosis; KA: Kainicacid; DAAO: D-α-amino acid oxidase; hiDAAO: Heat inactivated D-α-amino acid Oxidase, heat-inactivated DAAO; 7-CKA: 7-Chlorokynurenic acid; Gly: Glycine; HPDs: hippocampal paroxysmal discharges; CH: chloral hydrate; SE: status epilepticus; GFP: Green fluorescent protein; GFAP: glial fibrillary acidic protein; HTVS: High-throughput virtual screening; PTZ: pentylenetetrazol; PK: Pharmacokinetics; CCK8: Cell Counting Kit-8; LD50: Lethal Dose (50%); HepG2: Human hepatocellular carcinomas; LTG: lamotrigine; AST: Aspartate aminotransferase (AST); ALT (alanine aminotransferase)BUN: blood urea nitrogen; Cr: creatinine; ASCT1 / 2: Alanine / Serine / Cysteine / Threonine Transporter 1 / 2; ASC1: Alanine / Serine / Cysteine Transporter 1; L-4FPG: L-4-Fluorophenylglycine; ATA1 / 2: amino acid transporter 1 / 2; Gln: Glutamine; KO: Knockout; OE: Overexpression; SESs: Spontaneous electroclinical seizures; IC50: half maximal inhibitory concentration; Kd: The equilibrium dissociation constant; IP: Intraperitoneal Injections; LC-MS: Liquid Chromatograph Mass Spectrometer; EEG: Electroencephalogram; NAD: Nicotinamide Adenine Dinucleotide; KEGG: Kyoto Encyclopedia of Genes and Genomes; RT (rt): room temperature, usually 25℃.

[0134] Example 1 Verification experiment of PSPH as a therapeutic target

[0135] (1) Effect of D-serine on acute seizures induced by kainic acid (KA)

[0136] The levels of neurotransmitters in the hippocampal samples of patients with hippocampal sclerosis, non-hippocampal sclerosis patients, and autopsy control group without nervous system diseases were analyzed, as shown in a, b of FIG. 1. Compared with normal samples and non-hippocampal sclerosis samples, the concentrations of glutamate and serine in hippocampal sclerosis samples were significantly increased, while there was no significant difference in the levels of glycine among the three groups (c of FIG. 1). To further detect the levels of L-serine and D-serine in the extracellular fluid of the hippocampus, a mouse model of chronic epilepsy induced by kainic acid was established. After unilateral hippocampal injection of kainic acid for 4 weeks, the mice developed spontaneous recurrent seizures. Through microdialysis and zero-flow back extrapolation, we calculated that the levels of L-serine and D-serine in the control group of mice injected with normal saline were 7.1 μM and 1.5 μM, respectively (d, e of FIG. 1). However, after injection of kainic acid, the contents of L-serine and D-serine in the extracellular fluid of the hippocampus of mice increased by 2.7 times (19.0 μM) and 3.7 times (5.5 μM), respectively, compared with the control group. The excessive release of D-serine to the postsynaptic membrane to act on NMDAR receptors further regulates synaptic activity, thereby affecting seizures, indicating that changes in the level of D-serine may affect kainic acid-induced acute seizures. Through a pre-implanted catheter, unilateral hippocampal injection of 7 ng kainic acid in conscious mice can induce several hippocampal paroxysmal discharges (HPDs) within about an hour, and a few mice will show convulsive symptoms, which is manifested as electroclinical seizures in electroencephalogram recordings (f of FIG. 1). It was found that pre-injection of a low dose of D-serine (10 μM) can significantly shorten the onset time of KA-induced seizures (g of FIG. 1), and lead to more severe epilepsy phenotypes, including an increase in the number of seizures (h of FIG. 1), an increase in the duration of each seizure (i of FIG. 1), and an increase in the number of electroclinical seizures (j of FIG. 1). In contrast, after pre-injection of D-amino acid oxidase (DAAO) to degrade extracellular D-serine, kainic acid-induced acute seizures were almost completely inhibited (h, j, k of FIG. 1). We heat inactivated D-amino acid oxidase by heating it at 95°C for 3 min, and then injected the heat-inactivated D-amino acid oxidase into the brain of mice, and found that it did not inhibit seizures in mice (g-k of FIG. 1). In addition, 7-CKA (7-chlorokynurenic acid), as a selective antagonist of the glycine site of NMDARs, can also significantly inhibit KA-induced acute seizures, but we speculate that this effect is not caused by glycine, because pre-injection of glycine does not have a proconvulsant effect (g-k of FIG. 1). At the same time, it was found that high-dose hippocampal injection of D-serine had the opposite effect of low-dose D-serine, and seizures were inhibited under the action of high-dose serine (g-k of FIG. 1).This inhibitory effect might be due to the non-specific competition of high dose D-serine with glutamate binding sites of NMDARs. Taken together, D-serine plays a pro-epileptic role in KA-induced acute seizures.

[0137] (2) D-serine modulates spontaneous recurrent seizures

[0138] To further demonstrate the effect of D-serine on spontaneous chronic seizures, we established a chronic temporal lobe epilepsy mouse model. After 4 weeks of intrahippocampal injection of kainic acid in one hemisphere of mice, we implanted subdural electrodes for electroencephalogram (EEG) monitoring and cannula for intrahippocampal drug injection (a in Fig. 2). We first continuously recorded the EEG of temporal lobe epilepsy mice for 20 hours to obtain the baseline of hippocampal paroxysmal discharges. Compared with the baseline (b-d in Fig. 2), D-amino acid oxidase significantly inhibited hippocampal paroxysmal discharges within 12 hours after intrahippocampal injection (e-g in Fig. 2). Similarly, the same results were observed when mice were injected with 7-CKA (h-j in Fig. 2). However, injection of additional D-serine did not increase the frequency of hippocampal paroxysmal discharges (k-m in Fig. 2), and we speculate that D-serine on NMDARs might be saturated in temporal lobe epilepsy mice, and injection of glycine also had no effect on hippocampal paroxysmal discharges (n-p in Fig. 2). These data collectively indicate that the upregulation of D-serine is a prerequisite for the generation of seizures in chronic temporal lobe epilepsy mice, and the elimination of D-serine or the prevention of its effect on NMDARs can exert an antiepileptic effect.

[0139] (3) L-serine produced by astrocytes modulates D-serine levels and seizures

[0140] Astrocytes are the main cell type in the brain that synthesizes L-serine, which is synthesized de novo from glucose via a three-step enzymatic reaction, released and taken up by surrounding neurons to generate D-serine by the action of serine racemase, a pattern called "serine shuttle". Therefore, we tried to prove whether L-serine produced by astrocytes would affect D-serine levels and seizures. As shown in Fig. 3a, L-serine is first released by astrocytes via the alanine-serine-cysteine-threonine transporters 1 and 2 (ASCT1 / 2), then taken up into neurons by the amino acid transporters 1 and 2 (ATA1 / 2) and converted to D-serine by the action of serine racemase, and finally released by neurons via the alanine-serine-cysteine transporter-1 (Asc-1) to facilitate synaptic NMDARs activation. To verify the role of the above pathway in epilepsy, we injected kainic acid and inhibitors of the above transporters into the hippocampus of awake mice by reverse microdialysis, collected dialysate synchronously to analyze serine levels, and detected seizures in real time by electroencephalogram (Fig. 3b). There were 6 groups in the experiment, and the group settings are shown in Fig. 3c. We first perfused 7 ng / μL kainic acid at a speed of 1 μL / min and found that it could successfully induce seizures, which was manifested as hippocampal paroxysmal discharges in EEG (Fig. 3d). Compared with the solvent control group, perfusion of kainic acid for 1 hour induced 4 to 5 hippocampal paroxysmal discharges (Fig. 3e, f). When L-4FPG was perfused to inhibit ASCT1 and ASCT2, KA-induced seizures were almost completely blocked (Fig. 3g). When exogenous L-serine was supplemented again, it could offset the inhibitory effect of L-4FPG on hippocampal paroxysmal discharges (Fig. 3h). When we further inhibited the uptake of L-serine by neurons (inhibition of ATA1 and ATA2) with glutamine or blocked the release of D-serine by neurons (inhibition of Asc-1) with BMS-466442, hippocampal paroxysmal discharges were almost eliminated again (Fig. 3i, l). The statistical results of seizures in each group are shown in Fig. 3k. We also detected the levels of L-serine and D-serine in the dialysate of each group, and found that L-4FPG effectively prevented the increase in L-serine and D-serine levels induced by kainic acid (Fig. 3l, m). In the presence of L-4FPG, exogenous L-serine would again cause an increase in D-serine; glutamine or BMS-466442 would further block the increase in D-serine (Fig. 3l, m). In summary, L-serine produced by astrocytes plays an important role in regulating interstitial D-serine levels and seizures.

[0141] (4) PSPH is a key target for regulating L-serine production and release in astrocytes

[0142] Given the potential role of L-serine in seizure regulation, we examined whether modulation of L-serine synthesis is an effective antiepileptic approach. As shown in Fig. 4a, astrocytes synthesize L-serine from the glycolytic intermediate 3-phosphoglycerate through a three-step enzymatic reaction, which is catalyzed by phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH) in turn. PSPH was validated as a therapeutic target based on the following evidence. First, knockdown of PSPH resulted in the most significant decrease in intracellular and extracellular L-serine levels compared with PSAT1 and PHGDH (Figs. 4b, c). Second, we measured the expression of these three enzymes in seven different brain regions of mice and found that PSPH was most abundant in the hippocampus (Fig. 4d), which is the epileptogenic brain region in temporal lobe epilepsy. In addition, we found that the expression of PSPH protein in the hippocampus was associated with neuronal activity (Fig. 4e). Finally, the level of PSPH was abnormally elevated in the hippocampal astrocytes of the resected epileptogenic hippocampus from temporal lobe epilepsy patients and in the hippocampus of chronic temporal lobe epilepsy mice (Figs. 4f, g). Through the above experiments, we speculated that modulation of the level of PSPH would affect the level of serine in vivo and seizure activity. To confirm this hypothesis, we first overexpressed PSPH in the hippocampal astrocytes of normal mice by AAV5-gfa104-PSPH-IRES-eGFP (Fig. 4h) and found that both L-serine and D-serine levels were significantly increased in the hippocampus (Figs. 4i, j) using microdialysis. Similarly, compared with control mice, PSPH-overexpressing mice were more susceptible to kainic acid-induced acute seizures, as indicated by shorter seizure onset time, more seizure frequency, longer duration of each seizure, and more electroclinical seizure frequency after kainic acid injection (Figs. 4k-n).

[0143] Example 2. Compound synthesis examples

[0144] (1) Synthesis of Compound 1

[0145] To 3-(4-fluorophenyl)-1H-pyrazole-4-carbaldehyde (1 g, 5.26 mmol) was added hydrazinecarboxamide hydrochloride (0.59 g, 5.26 mmol) in a 20 mL 50% alcohol solution, and then refluxed for 1 hour. After cooling, the precipitate was filtered and recrystallized in ethanol to obtain a white solid product (600 mg, 46.15%).

[0146] LCMS(5_95_3min,Rt=1.540min),MS(ESI):m / z=248.0[M+H]+1H NMR (400MHz, DMSO-d6): δ13.26,13.19(s,1H),9.91(s,1H),8.27,8.02(s,1H) ,7.91,7.87(s,1H),7.60–7.58(m,2H),7.40–7.26(m,2H),6.30-6.26(m,2H).

[0147] (2) Synthesis of Compound 2

[0148] To a solution of 3-(4-methoxyphenyl)-1H-pyrazole-4-carbaldehyde (200 mg, 0.99 mmol) in 4.0 mL of 50% ethanol, hydrazinecarboxamide hydrochloride (111 mg, 0.99 mmol) was added, and the reaction mixture was refluxed for 1 hour. After cooling, the precipitate was filtered and recrystallized from 50% ethanol to give the product (150 mg, 58.43% yield) as a pale yellow solid.

[0149] LCMS:IDSUF06-DE-2-4R-GU Method:5_95_3min,t=1.509min,MS(ESI):m / z=260.0[M+H]

[0150] 1H NMR (400.30MHz, DMSO) δ13.13 (s, 1H), 9.88 (s, 1H), 8.11 (d, J = 92.9Hz, 1H), 7.89(s,1H),7.47(d,J=7.8Hz,2H),7.06(s,2H),6.29(s,2H),3.81(s,3H).

[0151] (3) Synthesis of compound 3

[0152] Step 1, To a solution of 3-(4-fluorophenyl)-lH-pyrazole-4-carbaldehyde (5.0 g, 26 mmol) in THF (50 mL) was added TEA (7.87 g, 78 mmol), DMAP (0.3 g, 2.6 mmol) and (Boc)20 (17.0 g, 78 mmol). The mixture was stirred at room temperature for 3 h. The resulting mixture was diluted with water (300 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine (200 mL x 3) and dried over anhydrous Na2S04. The filtrate was concentrated under vacuum. The crude product was purified by silica gel column chromatography eluting with EA / PE (0-10%) to give 3-(4-fluorophenyl)-4-formyl-lH-pyrazole-l- carboxylic acid tert-butyl ester (7.0 g, 24.11 mmol, 92%) as a white solid.

[0153] LCMS: m / z calcd. ([M+H-56]+): 235.0

[0154] Step 2, NaBH4(1.9 g, 52 mmol) was added to a solution of 3-(4-fluorophenyl)-4- formyl-lH-pyrazole-l-carboxylic acid tert-butyl ester (5.0 g, 26 mmol) in MeOH (50 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. The resulting mixture was diluted with water (300 mL). The resulting mixture was extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with brine (300 mL x 3) and dried over anhydrous Na2S04. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with [PE / EtOAc] (10: 1) to give the desired product (3.5 g, 11.97 mmol, 70%) as a white solid.

[0155] LCMS: m / z calcd. ([M+H]+): 237.0

[0156] Step 3, 3-(4-Fluorophenyl)-4-(hydroxymethyl)-lH-pyrazole-l-carboxylic acid tert- butyl ester (0.50 g, 1.71 mmol) was dissolved in DCM (5 mL) and cooled to 0 °C. TEA (865.46 mg, 8.55 mmol) and MsCl (293.89 mg, 2.57 mmol) were added successively and stirred at 0 °C for 3 h. The mixture was concentrated over an evaporator, water was added, extracted with chloroform, dried over magnesium sulfate and concentrated to give a light orange oil.

[0157] To a stirred solution of the resulting compound in DMF (10 mL) was added NaCN (125.74 mg, 2.59 mmol) at RT and the reaction mixture was stirred at RT for 3 h, monitoring the progress of the reaction by TLC. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to obtain the title compound (250 mg, 1.24 mmol, 72%) as a light yellow oil.

[0158] LCMS: m / z calcd. ([M+H+ACN]+): 243.0

[0159] Step 4, To a stirred solution of 2-(3-(4-fluorophenyl)-1H-pyrazol-4-yl)acetonitrile (250 mg, 1.24 mmol) in THF (5 mL) was added LiAlH4(2 mL, 2 mmol, 1 M in THF) at 0 °C under nitrogen atmosphere and the mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was quenched with 5 mL of water and the residue was extracted with ethyl acetate (20 mL). The organic layer was washed with saturated brine solution (5 mL*2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum and purified by pre-TLC (5% methanol / dichloromethane) to obtain 2-(3-(4-fluorophenyl)-1H-pyrazol-4-yl)ethylamine (120 mg, 584.69 umol, 47%) as a yellow solid.

[0160] LCMS: m / z calcd. ([M+H]+): 206.2

[0161] Step 5, 2-(3-(4-Fluorophenyl)-1H-pyrazol-4-yl)ethylenediamine (110 mg, 0.54 mmol) and potassium cyanate (48.19 mg, 0.59 mmol) were mixed with methanol (5 mL) AcOH (0.2 mL) and stirred at 65 °C under nitrogen for 3 h. The mixture was filtered and the filtrate was concentrated in vacuum and purified by pre-high performance liquid chromatography (10 mmol / L NH4HCO3 in H2O, B: ACN) to obtain 1-(2-(3-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)urea (21 mg, 84.59 umol, 15.78%) as a white solid.

[0162] LCMS: m / z calcd. ([M+H]+): 249.2

[0163] Example 4 PSPH Inhibitory Activity Test

[0164] Test method: Recombinant PSPH-FLAG protein (recombinant PSPH) was expressed in HEK293 cells and purified. The substrate O-phospho-L-serine was hydrolyzed to L-serine in an in vitro reaction system. The level of L-serine in the test tube was detected by LC-MS method. Each inhibitor was pre-mixed with PSPH before the reaction to test the effect of the inhibitor.

[0165] Test results are shown in Figures 8-10.

[0166] Figure 8 results show that compound 1 inhibits L-serine release into the culture medium by astrocytes with a half-maximal inhibitory concentration (IC50) of 0.4 μM, and inhibits intracellular L-serine levels with an IC50of 0.38 μM. Using the kainic acid mouse model of chronic temporal lobe epilepsy combined with microdialysis technology to analyze the level of serine in the extracellular fluid of the hippocampus, the results show that after three consecutive intraperitoneal injections of compound 1, the levels of L-serine and D-serine in the hippocampus are significantly reduced. These data show that compound 1, which can penetrate into the brain, has relatively strong binding affinity to PSPH, is less toxic, and has anti-epileptic potential.

[0167] Figure 9 results show that some key atoms in the structure of Z218484536 form interactions with PSPH. We considered whether the fluorine atom at position 16 on the benzene ring could be replaced. Therefore we synthesized a derivative, 16-Methoxy-Z218484536, in which the original fluorine atom was replaced with a methoxy group. We found that this change in chemical structure did not change the ability to inhibit the activity of recombinant PSPH protein in vitro (Figure 10a), nor did it change the ability to inhibit the production and release of L-serine by primary astrocytes (Figures 10b, c). This indicates that some replacement of the group at position 16 does not change the ability of the compound to inhibit PSPH.

[0168] Figure 10 results show that the C=N bond at positions 5-6 was changed to a C-C bond. It was found that it also had the ability to inhibit the activity of PSPH enzyme and to inhibit the production and release of L-serine by primary astrocytes.

[0169] Example 5 Anti-epileptic effect verification

[0170] Test method: The acute mouse epilepsy model induced by pentylenetetrazole (PTZ) was used. Each compound was administered to mice by intraperitoneal injection for 3 consecutive days at a dose of 0.5, 1, 2, 4, 20 mg / kg. The onset time of PTZ-induced epilepsy and the Racine seizure level of the seizure were evaluated.

[0171] The results show that compound 1 has a significant anti-epileptic effect, including prolonging the PTZ-induced seizure onset time and reducing the seizure level, and its anti-epileptic effect has reached the highest at a dose of 4 mg / kg (a-c in FIG. 11), wherein Z218484536 is compound 1. At the same time, we tested some compounds close to the effect of compound 1, and the results are shown in d-l in FIG. 11, and the other three compounds have no anti-epileptic effect.

[0172] Example 6 Molecular docking experiment and pharmacokinetics

[0173] The pyrazole NH group of compound 1 forms a hydrogen bond with Ala51 of PSPH, and the urea group forms four hydrogen bonds with Asp22, Gly110 and Lys158 of PSPH. In addition, the benzene ring of compound 1 forms a cation-π interaction with Lys158. The microcalorimetric fluctuation experiment results show that the dissociation constant (Kd) of PSPH binding compound 1 is about 0.27 μM, indicating that the intermolecular attraction is relatively strong. The competition study of compound 1 and O-phospho-L-serine shows the competitive inhibition mode of compound 1 to PSPH.

[0174] The in vivo evaluation of the pharmacokinetics (PK) of compound 1 in mice in vivo shows that after intraperitoneal injection at a dose of 4 mg / kg, the compound has good exposure (AUClast=1088 h x ng / mL), half-life (t1 / 2=2.7 h) and (Cmax=5.75 μM) in plasma. Analysis of the content of compound 1 in the hippocampus of mice brain shows that the brain-plasma ratio is 0.33. CCK8 detection shows that compound 1 and the control anti-epileptic drug lamotrigine (LTG) have no toxic effect on the proliferation of HepG2 cells at the tested concentration (0.078-40 μM). The median lethal dose (LD50) of acute toxicity of compound 1 is 596 mg / kg.

[0175] Example 7 Verification of the targeting specificity of compound 1

[0176] To test the targeting specificity of Compound 1 in cells, we performed single-point mutations in the amino acids of PSPH that interact with Compound 1, which showed high evolutionary conservation (a in Fig. 13). The results showed that mutations of Asp22 and Lys158 completely abolished the activity of PSPH (b in Fig. 13). The effect of Ala51Val mutation on the activity of PSPH was negligible. Both Gly110Ala and Ala51Val / Gly110Ala double mutations reduced the activity of PSPH by about 40% (b in Fig. 13). The microscale thermophoresis results showed that the Kd of Ala51Val / Gly110Ala PSPH mutant (PSPH-MT) was 6.1 μΜ (c in Fig. 13), indicating that the binding affinity of Ala51Val / Gly110Ala PSPH mutant to Compound 1 was reduced by 26-fold compared with wild-type PSPH. When we knocked out endogenous wild-type PSPH in primary astrocytes and overexpressed PSPH-MT using a viral vector, we found that the inhibitory effect of 1 μΜ Compound 1 on the levels of cellular and extracellular L-serine disappeared (d, e in Fig. 13). This result suggests that Compound 1 affects serine production through PSPH.

[0177] In addition, we evaluated the effect of Compound 1 on the activity of 20 protein tyrosine phosphatases and 5 protein serine / threonine phosphatases. Compared with PSPH, Compound 1 had weak or no effect on all the tested targets (Fig. 14-15). In summary, Compound 1 downregulated the levels of L-serine and D-serine by inhibiting PSPH.

[0178] Example 8 Role of Compound 1 in reducing spontaneous convulsive seizures in temporal lobe epilepsy mice

[0179] A stereotactic method was used to construct a chronic temporal lobe epilepsy mouse model by unilateral hippocampal injection of kainic acid (KA). Detailed parameters: the coordinates of hippocampal injection with Bregma as the origin: -1.8, -1.8, -2.0 mm, unilateral injection of kainic acid 12 mg / kg. The anti-epileptic effect of Compound 1 on spontaneous seizures in mice was detected: four weeks after kainic acid-induced status epilepticus, mice were implanted with wired EEG electrodes to monitor the spontaneous electroclinical seizures (SESs) and convulsive behavior of mice every day. The first three weeks of electroencephalogram recording were used to evaluate the baseline frequency of SESs in each mouse. In the next six weeks, mice were treated with solvent (control group), lamotrigine (LTG) or Compound 1 (b-e in FIG. 16). As previously described, in the solvent control group, spontaneous electroclinical seizures gradually increased over time (b, f, g in FIG. 16). Lamotrigine treatment led to a sudden decrease in SESs in the first week, but the therapeutic effect gradually decreased as the treatment continued (c, f, h in FIG. 16). This result is consistent with previous reports that kainic acid chronic TLE mouse models exhibit resistance to traditional antiepileptic drugs. Although Compound 1 treatment at 2 mg / kg prevented the increase in SESs, the frequency of SESs was still higher than the baseline (d, f, i in FIG. 16). Higher doses of Compound 1 (4 mg / kg) were able to significantly suppress SESs to 0.44 ± 0.15 per day, with an average reduction of 75% compared to the baseline (1.79 ± 1.1) (d, f, j in FIG. 16). Overall, these data suggest that Compound 1 can be used as a therapeutic drug for temporal lobe epilepsy.

Claims

1. Use of a PSPH inhibitor for the preparation of a medicament for preventing, treating or ameliorating a neurological disease.

2. Use according to claim 1, characterized in that, The PSPH inhibitor prevents, treats or ameliorates a neurological disease by inhibiting the activity of phospho-serine phosphatase, thereby inhibiting the production and release of L-serine in astrocytes, and thereby inhibiting the upregulation of D-serine.

3. Use according to claim 1, characterized in that, The neurological disease is selected from at least one of cognitive impairment, intellectual impairment, cerebellar syndrome, epilepsy, neurodevelopmental disorder, dementia, autism spectrum disorder, Down syndrome, Rett syndrome, fragile X syndrome, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, ischemia-reperfusion injury.

4. Use according to claim 3, characterized in that, The neurological disease is selected from at least one of stroke, epilepsy, chronic pain, Parkinson's disease, Alzheimer's disease, Huntington's disease, ischemia-reperfusion injury.

5. Use according to claim 4, characterized in that, The neurological disease is epilepsy.

6. Use according to claim 5, characterized in that, The neurological disease is temporal lobe epilepsy.

7. Use according to claim 1, characterized in that, The PSPH inhibitor is a compound of Formula I or a stereoisomer, geometric isomer, tautomer, nitroso, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof: wherein R1is selected from substituted or unsubstituted C 1-8 alkyl, C 3-8 cycloalkyl, aryl, heterocyclyl, halo, C 1-8 alkoxy, the substituted substituent being C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, halo, cyano, phenyl, oxygen- and / or nitrogen-containing 5-6 membered heteroaryl, oxygen- and / or nitrogen-containing 5-6 membered heterocyclyl; R2 is -CH=N- or -CH2CH2-.

8. Use according to claim 7, characterized in that, R1is selected from substituted or unsubstituted C 1-5 alkyl, C 3-5 cycloalkyl, aryl, 3-6 membered heterocyclyl, halo, C 1-5 alkoxy, the substituted substituent is C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, halo, cyano, phenyl, 5-6 membered oxygen and / or nitrogen containing heteroaryl, 5-6 membered oxygen and / or nitrogen containing heterocyclyl.

9. Use according to claim 8, characterized in that, R1is selected from C 1-5 alkyl, C 3-5 cycloalkyl, phenyl, halo, C 1-5 alkoxy.

10. Use according to claim 9, characterized in that, R1is selected from C 1-3 alkyl, phenyl, halo, C 1-3 alkoxy.

11. Use according to claim 10, characterized in that, R1is selected from C 1-3 alkyl, halo, C 1-3 alkoxy.

12. Use according to claim 11, characterized in that, R1is selected from halogen, C 1-3 alkoxy.

13. Use according to claim 12, characterized in that, R1is selected from F, Cl, Br, C 1-3 alkoxy.

14. Use according to claim 13, characterized in that, R1 is selected from F, methoxy, preferably F.

15. Use according to claim 14, characterized in that, The compound of formula I is selected from the following compounds:

16. Use according to claim 15, characterized in that, The compound of formula I is selected from the following compounds:

17. Use of a D-serine inhibitor for the preparation of a medicament for treating a neurological disease, The neurological disease has the same definition as the disease defined in the use of any one of claims 3-6.

18. Use according to claim 17, characterized in that, The D-serine inhibitor comprises a compound of Formula I or a stereoisomer, geometric isomer, tautomer, nitroso, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, the compound of Formula I having the same definition as the compound of Formula I defined in the use of any one of claims 7-16.

19. Use of an L-serine inhibitor for the preparation of a medicament for treating a neurological disease, The neurological disease has the same definition as the disease defined in the use of any one of claims 3-6.

20. Use according to claim 19, characterized in that, The L-serine inhibitor can inhibit the production and release of L-serine in astrocytes.

21. The use according to claim 19, characterized in that, The L-serine inhibitor comprises a compound of Formula I or a stereoisomer, geometric isomer, tautomer, nitroso, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, the compound of Formula I having the same definition as the compound of Formula I defined in the use of any one of claims 7-16.

22. A compound, or a stereoisomer, geometric isomer, tautomer, nitroso, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof, characterized in that, The compound has the following structural formula: wherein R1 has the same definition as any one of claims 7-14.

23. The compound of claim 22, or a stereoisomer, geometric isomer, tautomer, nitroso, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof, wherein, The compound has the following structural formula:

24. A process for the preparation of a compound according to claim 22 or 23, characterized in that, comprising the following steps:

25. The method of claim 24, wherein, comprising the following steps: (1) adding compound 1 in a solvent, adding a base, a catalyst and (Boc)2O, reacting at 20-40°C for 1-5 hours to obtain compound 2; (2) adding NaBH4 to a solution of compound 2, at a temperature of -10-10°C, reacting for 0.2-1 hour to obtain compound 3; (3) dissolving compound 3 in a solvent, cooling to -5-5°C, sequentially adding a base and MsCl (methylsulfonyl chloride), reacting at -10-10°C for 2-4 hours to obtain compound 4; (4) adding compound 4 in a solvent, a reducing agent at -5-5°C under an inert atmosphere, heating the mixture to 20-40°C for 1-3 hours to obtain compound 5; (5) mixing compound 5 and potassium cyanate, solvent, reacting at 55-75 °C under inert atmosphere for 2-4 hours to obtain the product.

26. A medicament, characterized by comprising: including a compound of claim 22 or 23 or a stereoisomer, geometric isomer, tautomer, nitroso, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof.

27. A method of treating a neurological disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-26. including administering a PSPH inhibitor, a D-serine inhibitor, or an L-serine inhibitor comprising a compound of formula I or a stereoisomer, geometric isomer, tautomer, nitroso, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof, said compound of formula I having the same definition as the compound of formula I defined in the use of any one of claims 7-16.

28. The method of treatment according to claim 27, wherein, The daily dose for an adult can be in the range of 1 mg to 2 g of active agent.

29. The method of treatment according to claim 27, wherein, The PSPH inhibitor, the D-serine inhibitor, or the L-serine inhibitor is administered in combination with other active ingredients.

30. The method of treatment according to claim 29, wherein, The other active ingredients are selected from at least one of the following ingredients: phenytoin sodium, phenobarbital, carbamazepine, oxcarbazepine, gabapentin, lacosamide, valproic acid, lamotrigine, topiramate, levetiracetam, clonazepam, Rufinamide.

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