Xav939-based n-carbonyl-substituted sulfur-containing fused pyrimidinone derivatives, and synthetic methods and applications thereof

Abstract

The application belongs to the technical field of biological medicine, and particularly relates to an N-carbonyl-substituted sulfur-containing fused pyrimidinone derivative based on XAV939 as well as a synthesis method and application thereof. The application provides a compound structure with a sulfur-containing fused pyrimidinone skeleton. The application introduces a carbonyl substituent at a specific nitrogen site of a parent nucleus, effectively improves pharmacokinetic properties of the compound XAV939, improves blood-brain barrier permeability, and realizes systemic administration. In addition, the application has a high bioavailability, and can be used for treating autism spectrum disorders. Shank3b In mutant autism model mice, the N-carbonyl-substituted sulfur-containing fused pyrimidinone derivative based on XAV939 first proposed by the application can significantly inhibit Wnt-glycolysis signals, improve social barriers, and has no obvious cytotoxicity, thereby providing a new drug selection for treating autism spectrum disorders.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology and relates to a sulfur-containing fused pyrimidinone derivative, its synthesis method, and its pharmaceutical use in autism spectrum disorders. Specifically, it relates to an N-carbonyl-substituted sulfur-containing fused pyrimidinone derivative based on XAV939, its synthesis method, and its application. Background Technology

[0002] Autism spectrum disorder (ASD) is a neurodevelopmental mental disorder characterized by social impairment and repetitive, stereotyped behaviors, often accompanied by language and communication difficulties and cognitive deficits. The number of people with ASD is increasing annually, placing a significant burden on families and society. However, ASD has an insidious onset, its pathogenesis is not fully understood, and current treatments, primarily focused on rehabilitation training, have extremely limited effectiveness. Therefore, researching effective new methods for treating ASD has significant scientific and clinical value.

[0003] Previous data reports indicate that XAV939 is intended to treat social impairments in autistic individuals by targeting and inhibiting Wnt-glycolysis signaling. However, this compound lacks druggability; its limited blood-brain barrier permeability and high level of first-pass hepatic metabolism prevent systemic administration via oral or intravenous routes. Therefore, there is an urgent need to develop a therapeutic agent for ASD that improves pharmacokinetic properties, enables systemic administration, and delivers significant efficacy. Summary of the Invention

[0004] In order to overcome the shortcomings of the prior art, the present invention aims to provide an N-carbonyl-substituted sulfur-containing fused pyrimidinone derivative based on XAV939, its synthesis method and application, which achieves the technical effects of improving drug metabolism properties, increasing blood-brain barrier permeability and effectively treating autism spectrum disorders.

[0005] To achieve the above objectives, the present invention employs the following technical solution: In a first aspect, the present invention discloses an N-carbonyl-substituted sulfur-containing fused pyrimidinone derivative based on XAV939, the structure of which is shown in the following formula: ; R is selected from acyl or carbamoyl.

[0006] Preferably, the acyl group is a C1-C6 alkyl acyl group; the carbamoyl group is an N-C1-C6 alkyl carbamoyl group or an N,N-di-C1-C6 alkyl carbamoyl group.

[0007] More preferably, the N-carbonyl-substituted sulfur-containing fused pyrimidinone derivatives based on XAV939 of the present invention comprise two compounds, named XAV939-L1 and XAV939-L2, respectively, with the following structural formulas: .

[0008] A second aspect of the present invention discloses a method for synthesizing N-carbonyl-substituted sulfur-containing fused pyrimidinone derivatives based on XAV939, comprising: In the presence of an acid-binding agent, XAV939 was reacted with an acylation reagent in anhydrous tetrahydrofuran, and the target product was obtained after post-treatment.

[0009] Preferably, the acylation reagent is acetyl chloride or dimethylcarbamoyl chloride.

[0010] More preferably, the amount of the acylation reagent is 1.1-1.3 times the molar amount of XAV939.

[0011] More preferably, the acid-binding agent is triethylamine.

[0012] More preferably, the molar amount of triethylamine is 1.5-2.5 times the molar amount of XAV939.

[0013] In a third aspect, the present invention also discloses the use of the above-mentioned XAV939-based N-carbonyl-substituted sulfur-containing fused pyrimidinone derivatives and their pharmaceutically acceptable salts in the preparation of medicaments for treating autism spectrum disorder.

[0014] In a fourth aspect, the present invention discloses a medicament for treating autism spectrum disorder, comprising the above-described XAV939-based N-carbonyl-substituted sulfur-containing fused pyrimidinone derivatives and their pharmaceutically acceptable salts, with or without the addition of a pharmaceutically acceptable dressing.

[0015] Compared with the prior art, the present invention has the following beneficial effects: This invention discloses an N-carbonyl-substituted sulfur-containing fused pyrimidinone derivative based on XAV939, which... Shank3b In mutant autism mouse models, a comprehensive evaluation based on Western blotting, extracellular acidification rate (ECAR), and behavioral experiments showed superior potential compared to XAV939. Specifically, systemic administration of this XAV939 derivative resulted in a stronger inhibitory effect on the Wnt-glycolysis signaling pathway and a more significant improvement in social impairment. Specifically, in… Shank3bIn mutant mice, Western blot (WB) results showed that treatment with the XAV939 derivative significantly reduced Wnt signaling levels; ECAR (electro-assay) results showed that treatment with the XAV939 derivative effectively inhibited high glycolysis levels; three-box behavior experiments showed that the XAV939 derivative-treated group had increased contact time with social mice and corresponding preference scores; and the inhabit-invasion behavior experiment showed that the XAV939 derivative-treated group had increased contact time and frequency with young mice. Furthermore, the XAV939 derivative did not exhibit significant cytotoxicity at different drug concentrations. Therefore, the animal experimental results disclosed in this invention demonstrate that the XAV939 derivative can significantly improve the social abilities of autistic mice by effectively inhibiting Wnt-glycolysis signaling, fully supporting the application of the XAV939 derivative in the preparation of drugs for treating autistic social disorders. Attached Figure Description

[0016] Figure 1 for 1 H and 13 Compound verification data from XAV939 nuclear magnetic resonance (NMR) and HRMS spectra; where A is XAV939. 1 1H-NMR spectrum; B is XAV939-L1 1 1H-NMR spectrum; C is XAV939-L1 13 C10-NMR carbon spectrum; D is XAV939-L2. 1 1H-NMR spectrum; E is XAV939-L2. 13 C1-NMR carbon spectrum; Figure 2 The effects of different drug treatments on Wnt signaling levels in mouse brain tissue were shown; where A represents changes in Axin2 protein expression; B represents changes in p-β-catenin (phosphorylated β-catenin) expression; and C represents changes in active-β-catenin (active β-catenin) expression. Figure 3 The effects of different drug treatment groups on the glycolytic level of cortical neurons in mice are shown; where A is the dynamic glycolytic curve; B is the statistical data of glycolytic level; and C is the statistical graph of maximum glycolytic capacity. Figure 4 The effects of different drug treatment groups on the social behavior of mice are shown in the following figures: A represents the dwell time and index during the social preference stage; B represents the dwell time and index during the social novelty stage; C represents the statistical results of social interaction behavior-contact frequency; and D represents the statistical results of social interaction behavior-interaction time. Figure 5 The effects of XAV939-L1 and XAV939-L2 at different drug concentrations on the toxicity of primary neurons in mice; Figure 6 This is a schematic diagram of the synthetic routes for two N-carbonyl-substituted sulfur-containing fused pyrimidinone derivatives (XAV939-L1 and XAV939-L2) based on XAV939 according to the present invention. Detailed Implementation

[0017] To enable those skilled in the art to better understand the present invention, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of the present invention.

[0018] It should be noted that the terms "first," "second," etc., in the specification, claims, and accompanying drawings of this invention are used to distinguish similar objects and are not necessarily used to describe a specific order or sequence. It should be understood that such data can be interchanged where appropriate so that the embodiments of the invention described herein can be implemented in orders other than those illustrated or described herein. Furthermore, the terms "comprising" and "having," and any variations thereof, are intended to cover a non-exclusive inclusion; for example, a process, method, system, product, or apparatus that comprises a series of steps or units is not necessarily limited to those steps or units explicitly listed, but may include other steps or units not explicitly listed or inherent to such processes, methods, products, or apparatus.

[0019] The present invention will now be described in further detail with reference to the accompanying drawings: Unless otherwise stated, all reagents and solvents were purchased commercially and were not further purified before use. Solvents used in the reaction included methanol and tetrahydrofuran. The reaction progress was monitored by thin-layer chromatography, and the developing solvent system could be adjusted according to the polarity of the substrate and product. Product purification was performed using 200–300 mesh silica gel column chromatography and detected under 254 nm UV light.

[0020] 1 H NMR and 13 C10 NMR spectra were determined on a Bruker-400 NMR spectrometer using CDCl3 or DMSO-d6 as the test solvent. Chemical shifts are expressed in ppm, with tetramethylsilane TMS as the internal standard. The coupling constant J is expressed in Hz. High-resolution mass spectrometry (HRMS) was performed using an Agilent 6550 iFunnel LC / Q-TOF mass spectrometer equipped with an ESI ion source.

[0021] Example 1: Synthesis of N-carbonyl-substituted sulfur-containing fused pyrimidinone derivatives based on XAV939 See Figure 6 The synthetic routes for XAV939-L1 and XAV939-L2 are both based on XAV939. XAV939 has the molecular formula C2. 14 H 11 F3N2OS, with a molecular weight of 312.31, is a white or off-white powder that is readily soluble in DMSO.

[0022] 1. Synthesis of XAV939: 0.39 g (approximately 2 mmol) of 4-(trifluoromethyl)phenylphenylurea was added to a dry reaction flask, followed by 0.36 g (approximately 2 mmol) of methyl 4-oxotetrahydro-2H-thieno[4,3-d]pyrimidine-3-carboxylic acid ester. 10 mL of methanol was added to the reaction flask to ensure thorough dispersion or dissolution of the reactants, and then 0.55 g (approximately 4 mmol) of anhydrous potassium carbonate was added as a basic promoter. After the addition was complete, the reaction system was stirred under reflux for 12 hours. During the reaction, potassium carbonate promoted condensation or cyclization reactions between the substrates, leading to the gradual formation of the target XAV939 core structure. After the reaction, the reaction solution was allowed to cool naturally to room temperature, and inorganic salts and other insoluble solid impurities were removed by filtration. The resulting filtrate was concentrated under reduced pressure until the residual volume was approximately 1-2 mL. Then, 10 mL of water was added to the concentrate to increase the polarity of the system and promote the precipitation of the target product. The pH of the system was slowly adjusted to 3-4 using 2 M hydrochloric acid. Under acidic conditions, the target product gradually precipitated as a solid. Stirring was continued for a period of time to promote complete crystallization, and then the precipitate was collected by vacuum filtration. The obtained solid was washed with an appropriate amount of water to remove residual inorganic salts and acidic impurities, and then dried in a vacuum drying oven at 60°C for 10 hours to obtain 0.45 g of a white solid product, XAV939, with a yield of 71%. The obtained product was processed... 1 H NMR, 13 Its structure was confirmed by C10 NMR spectroscopy and HRMS. See NMR results for details. Figure 1 A.

[0023] 2. Synthesis of XAV939-L1: Add 0.30 g (approximately 1 mmol) of the XAV939 prepared above to a dry reaction flask, followed by 10 mL of tetrahydrofuran (THF) to ensure complete dissolution or uniform dispersion. Add 0.21 g (approximately 2 mmol) of triethylamine to the reaction system. Triethylamine acts as an acid-binding agent in this reaction, neutralizing the hydrogen chloride produced during acylation and promoting the acetylation reaction of reactive nitrogen atoms in the XAV939 core. Separately, prepare an acetyl chloride solution by diluting 0.10 g (approximately 1.3 mmol) of acetyl chloride with 2 mL of THF. Under stirring at room temperature, slowly add the acetyl chloride solution dropwise to the XAV939 and triethylamine THF reaction solution. Control the dropping rate during the addition process to avoid excessively high local acetyl chloride concentrations or excessively rapid exothermic reactions in the system. After the addition is complete, continue stirring the reaction at room temperature for 6 hours to allow the reactive nitrogen sites on the XAV939 core to fully react with acetyl chloride, generating the corresponding N-acetylated XAV939 derivative, namely XAV939-L1.

[0024] After the reaction was complete, the consumption of XAV939 starting material was monitored by thin-layer chromatography. The reaction solution was then concentrated under reduced pressure to remove volatile solvents such as THF. The resulting residue was purified by silica gel column chromatography. The elution system was dichloromethane / methanol at a volume ratio of 20:1. The eluent containing the target product was collected and concentrated under reduced pressure to remove the solvent, yielding 0.28 g of a white solid, XAV939-L1, with a yield of 80%.

[0025] Compared to the parent XAV939, XAV939-L1 introduces an acetyl group onto the reactive nitrogen atom of the parent nucleus, classifying it as an N-acylated XAV939 derivative. The resulting product can be further processed... 1 H NMR, 13 Its structure was confirmed by C10 NMR spectroscopy and HRMS. See NMR results for details. Figure 1 B and C.

[0026] 3. Synthesis of XAV939-L2: Using a similar reaction strategy to XAV939-L1, XAV939 was used as the parent compound to prepare the corresponding N-dimethylcarbamoyl XAV939 derivative, namely XAV939-L2, by reacting with dimethylcarbamoyl chloride.

[0027] Specifically, XAV939 is added to a dry reaction flask, using THF as the reaction solvent, to ensure complete dissolution or uniform dispersion. Triethylamine is then added as an acid-binding agent, preferably in an amount approximately 2.0 times the molar amount of XAV939. Triethylamine absorbs the hydrogen chloride generated during the reaction and maintains the system in an alkaline environment conducive to the carbamylation reaction. Dimethylcarbamoyl chloride is then diluted with an appropriate amount of THF, preferably in an amount approximately 1.1-1.5 times the molar amount of XAV939, more preferably approximately 1.3 times. Under stirring at room temperature, the dimethylcarbamoyl chloride solution is slowly added dropwise to the THF reaction system containing XAV939 and triethylamine. After the addition is complete, the reaction is continued with stirring at room temperature, allowing the reactive nitrogen sites in the XAV939 core to undergo carbamylation with the dimethylcarbamoyl chloride, forming the N-dimethylcarbamoylated product.

[0028] After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography. A dichloromethane / methanol system can be selected as the eluent depending on the actual separation conditions, and the target product component can be tracked by thin-layer chromatography. After collecting the target component, the solvent was removed under reduced pressure to obtain 0.12 g of XAV939-L2 white solid, with a yield of 63%. The obtained product was then purified by... 1 H NMR, 13 The structure was confirmed by C10 NMR and HRMS. See the NMR results for details. Figure 1 D and E in the middle.

[0029] Example 2 Novel Uses of N-Carbonyl-Substituted Sulfur-Fused Pyrimidinone Derivatives Based on XAV939 1. For autism animal models, select commonly used ones. Shank3b A mouse model of autism induced by mutation was established, with normal mice (C57BL6J strain) serving as the control group; all mice were selected from 6-week-old young adult male mice.

[0030] 2. Preparation methods for different drugs: XAV939, XAV939-L1 and XAV939-L2 were dissolved in DMSO (2%), CremophorEL-40 (2%) and physiological saline (96%) at a concentration of 1 mg / mL, respectively.

[0031] 3. Methods of administration for different drugs: 1) Animal preparation: Before the experiment, the mouse was properly fixed in a restraint and its tail was gently wiped with warm water at 45-50℃ for 1-2 minutes to allow the tail vein to fully dilate and become congested.

[0032] 2) Injection procedure: Select either tail vein on both sides and disinfect the skin with an alcohol swab. Hold the insulin syringe (with a No. 4 needle) at an angle of approximately 15-30° to the tail vein and insert the needle smoothly. After observing blood return, fix the needle and inject the medication at a uniform and slow pace (within 4-5 seconds).

[0033] 3) Key controls: The injection volume is calculated based on the mouse's body weight, and the daily dosage is 0.1 mL / 10g. Ensure smooth and unobstructed injection with no bulging at the injection site; otherwise, stop immediately and change the injection site.

[0034] 4) Postoperative observation: After the injection, gently press the needle hole with a dry cotton ball for a moment to stop the bleeding, put the mouse back into the cage, feed it as usual and closely observe its immediate response.

[0035] 5) Administer the drug for 5 consecutive days following the above administration steps, and then conduct subsequent experiments.

[0036] 4. Observe the effects of different drugs on Shank3b Effects of Wnt signaling in cortical neurons of mutant mice: 1) Take Shank3b Primary neurons were cultured from the fetal cortex of mutant mice and wild-type mice (C57BL / 6J) for 7 days. 2) Take 2×10 6 Primary cortical neurons were used to purify protein components, and Western blotting was used to observe the effects of different drugs on key Wnt signaling molecules such as Axin2 (a target gene product of the Wnt pathway), active-β-catenin (a core protein for Wnt pathway activation), and p-β-catenin (a negative regulatory protein of the Wnt pathway).

[0037] XAV939-L1 can significantly reduce Shank3b The results of Wnt signaling expression levels in mutant mouse neurons are as follows: Figure 2 As shown, in the XAV939-L1 processing group, Shank3b The expression levels of Axin2 and p-β-catenin are increased in primary cortical neurons of mutant mice. Figure 2 In A and C), while the level of active-β-catenin decreased ( Figure 2 (B) Compared with the model group, the expression levels of Axin2 protein and phosphorylated β-catenin (p-β-catenin) in neurons of the XAV939-L1 treatment group were significantly reduced, while the level of active β-catenin was increased. This indicates that XAV939-L1 can effectively inhibit the overactivation of the Wnt signaling pathway.

[0038] 5. Observe the effects of different drugs on Shank3b Effects of mutant mice on glycolysis levels in cortical neurons: 1) Take the same Shank3b Primary cortical neurons from mutant mice and wild-type mice (C57BL / 6J) were used to divide the primary cortical neurons into 8 × 10⁻⁶ cells. 5 / well density was inoculated in 24-well plates and sent for testing on the third day after inoculation.

[0039] 2) Analysis was performed using a Seahorse XF-24 extracellular throughput analyzer (Seahorse Bioscience). The sensor cartridge was calibrated overnight the day before measurement. On the day of measurement, extracellular acidification rate (ECAR) was measured sequentially before or after adding the following reagents: glucose (10 mM), oligomycin (1 μM), and 2-DG (50 mM). Alternatively, OCR values ​​were measured sequentially by adding oligomycin (1 μM), uncoupling agent FCCP (1 μM), antimycin A (1 μM), and rotenone (1 μM). Each measurement cycle consisted of the following steps: 2 min mixing, 1 min waiting, and 3 min measurement.

[0040] 3) After the last assay cycle, remove the plates and perform cell counting. Normalize the measured ECAR values ​​using total cell data.

[0041] XAV939-L1 can significantly inhibit Shank3b Results of glycolysis levels in mutant mouse neurons as follows Figure 3 As shown, in the XAV939-L1 processing group, Shank3b The baseline and maximum ECAR values ​​in primary cortical neurons of mutant mice are reduced. Shank3b Both the baseline and maximum ECAR values ​​of neurons in mutant mice were significantly higher than those in wild-type mice. Figure 3 (A) indicates that the model mouse neurons are in a state of high glycolytic activity. Treatment with XAV939-L1 significantly reduced the ECAR value ( Figure 3 The results (B and C) indicate that XAV939-L1 can effectively inhibit abnormally elevated glycolysis levels, further supporting the neuroprotective effect of XAV939-L1 by regulating energy metabolism pathways.

[0042] 6. Observe the effects of different drugs on Shank3b Effects of mutant mice on social behavior: 1) Utilize Shank3bMutant mice were injected via tail vein with XAV939, XAV939-L1 and XAV939-L2 reagents (1 mg / mL) or a placebo, including DMSO (2%), Cremophor EL-40 (2%) and saline (96%). 2) The three-box experiment and the dwell-invasion experiment, both of which are animal behavioral techniques, were used to observe changes in the social behavior of mice.

[0043] The behavioral characterization results of XAV939-L1 mice with autism were as follows: Figure 4 As shown. In the three-box experiment, the system provides XAV939-L1 with... Shank3b The mutant mice spent significantly more time exploring socially-biased mice (S1). Figure 4 The exploration time of the social novelty mouse (S2) was also significantly increased (in the middle A). Figure 4 (B) indicates that its social interest has been restored. In the inhabit-intrusion experiment, the results also showed that the system provided XAV939-L1 with... Shank3b The mutant mice had significantly increased exposure time and frequency to same-sex stranger mice. Figure 4 (C and D). The above behavioral experimental data fully demonstrate that the novel compounds synthesized in this invention can significantly improve social impairments in patients with autism spectrum disorder.

[0044] 7. Observe the effects of different drugs on the toxicity of primary neurons in mice. 1) Primary neurons were isolated and cultured from the cortex of fetal rats. After 7 days of culture, different concentrations of XAV939-L1, XAV939-L2, and a negative control were added and incubated for 24-48 hours. Cell viability was detected using the CCK-8 assay.

[0045] 2) Compared with the negative control group, there was no significant decrease in neuronal cell viability in any of the XAV939-L1 and XAV939-L2 concentration treatment groups. Figure 5 The cell morphology remained normal, indicating that neither compound had significant cytotoxicity on primary mouse neurons. This result demonstrates that the novel compounds synthesized in this invention exhibit good safety while exerting therapeutic effects, providing a safety guarantee for their application as drugs.

[0046] This invention improves the pharmacokinetics and blood-brain barrier permeability of the compound by introducing a carbonyl substituent at a specific nitrogen site in the parent nucleus, thereby achieving systemic drug delivery. Specifically, XAV939-L1 exhibits dual inhibitory effects on both Wnt and glycolytic signals; more importantly, XAV939-L1 overcomes the poor drug-likeness of the lead compound XAV939, and can effectively alleviate symptoms through systemic administration routes such as intravenous injection. Shank3bThe mutant autistic mice exhibited social behavioral impairments and showed no significant cytotoxicity within the effective dose range, demonstrating a relatively ideal safety profile. Notably, XAV939-L1, while ensuring effective behavioral improvement, also demonstrated superior in vitro and in vivo safety compared to the positive control drug, making it the most promising candidate compound currently screened. These results provide strong experimental support for the development of novel, highly effective, and safe ASD treatments.

[0047] The above content is only for illustrating the technical concept of the present invention and should not be construed as limiting the scope of protection of the present invention. Any modifications made to the technical solution based on the technical concept proposed in this invention shall fall within the scope of protection of the claims of this invention.

Claims

1. An N-carbonyl-substituted sulfur-containing fused pyrimidinone derivative based on XAV939, characterized in that, The structure is shown in the following formula: ； R is selected from acyl or carbamoyl.

2. The N-carbonyl-substituted sulfur-containing fused pyrimidinone derivative based on XAV939 according to claim 1, characterized in that, The acyl group is a C1-C6 alkyl acyl group; the carbamoyl group is an N-C1-C6 alkyl carbamoyl group or an N,N-di-C1-C6 alkyl carbamoyl group.

3. The N-carbonyl-substituted sulfur-containing fused pyrimidinone derivative based on XAV939 according to claim 1, characterized in that, This includes two compounds, named XAV939-L1 and XAV939-L2, with the following structural formulas: 。 4. The method for synthesizing N-carbonyl-substituted sulfur-containing fused pyrimidinone derivatives based on XAV939 according to claim 3, characterized in that, include: In the presence of an acid-binding agent, XAV939 was reacted with an acylation reagent in anhydrous tetrahydrofuran, and the target product was obtained after post-treatment.

5. The method for synthesizing N-carbonyl-substituted sulfur-containing fused pyrimidinone derivatives based on XAV939 according to claim 4, characterized in that, The acylation reagent is acetyl chloride or dimethylcarbamoyl chloride.

6. The method for synthesizing N-carbonyl-substituted sulfur-containing fused pyrimidinone derivatives based on XAV939 according to claim 5, characterized in that, The amount of the acylation reagent used is 1.1-1.3 times the molar amount of XAV939.

7. The method for synthesizing N-carbonyl-substituted sulfur-containing fused pyrimidinone derivatives based on XAV939 according to claim 4, characterized in that, The acid-binding agent is triethylamine.

8. The method for synthesizing N-carbonyl-substituted sulfur-containing fused pyrimidinone derivatives based on XAV939 according to claim 7, characterized in that, The molar amount of triethylamine is 1.5-2.5 times that of XAV939.

9. The use of the XAV939-based N-carbonyl-substituted sulfur-containing fused pyrimidinone derivatives and their pharmaceutically acceptable salts as described in any one of claims 1-3 in the preparation of medicaments for treating autism spectrum disorder.

10. A drug for treating autism spectrum disorder, characterized in that, It is made from an N-carbonyl-substituted sulfur-containing fused pyrimidinone derivative based on any one of claims 1-3 and its pharmaceutically acceptable salt, with or without the addition of a pharmaceutically acceptable dressing.

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