Quinazolinone 5-HT2A receptor antagonist as well as preparation method and medical application thereof

Abstract

The invention discloses a quinazolinone 5-HT2A receptor antagonist or agonist compound as shown in a formula I, pharmaceutically acceptable salts of the quinazolinone 5-HT2A receptor antagonist or agonist compound as well as a preparation method and medical application of the quinazolinone 5-HT2A receptor antagonist or agonist compound and the pharmaceutically acceptable salts. The quinazolinone 5-HT2A receptor antagonist or agonist compound is a powerful 5-HT2A receptor antagonist and has potential anti-mental disease activity.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and relates to a quinazolinone 5-HT 2A receptor antagonist or inverse agonist and its use. The compounds can be used for treating certain mental diseases (such as depression, anxiety, psychosis, schizophrenia, insomnia, autism) and mental disorder symptoms associated with or concurrent with central nervous system degenerative diseases (such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Lewy body dementia). BACKGROUND

[0002] Serotonin or 5-hydroxytryptamine (5-HT) plays an extremely important role in human physiological functions. It exists in both peripheral and nervous systems. Since 5-HT receptors were discovered in 1953, more and more different subtypes have been found in the central nervous system. 5-HT is an important neurotransmitter and neuromodulator, and plays an extremely important role in regulating various behaviors such as sleep, diet, activity, learning and memory, body temperature, blood pressure, and pathological states (such as anxiety, mania, schizophrenia, obesity, drug addiction, migraine and hypertension). Abnormal 5-hydroxytryptamine (5-HT) neurotransmission in the brain is considered to be a potential cause of mood disorders (depression and anxiety) (Alenina N, et al., (2009) Proc Natl Acad Sci USA, 106, 10332-10337; Filip M, et al., (2005) Pharmacol Rep, 57, 685-700; Greek AR, (2006) Br J Pharmacol, 147, Suppl 1: S145-S152). 5-HT exerts its effects through its receptors, and 5-HT receptors are divided into 7 families (5-HT1-5-HT7) and at least 15 different subtypes according to structural (amino acid sequence), biochemical (post-receptor mechanisms of signal transduction) and pharmacological differences (Barnes NM, et al., (1999) Neuropharmacology, 38, 1083-1152; Hannon J, et al., (2008) Behav Brain Res, 195, 198-213; Hoyer D, et al., (2002) Pharmacol Biochem Behav, 71, 533-554; Pauwels PJ. (2003) Tocris Reviews, No. 25). The distribution, ligand preference and related functions of different subtypes of receptors are different.

[0003] 5-HT 2AThe subtypes are widely and discretely expressed in the central nervous system, with the highest expression in the cerebral cortex, limbic, hippocampus, hypothalamus and basal ganglia, which are involved in the regulation of higher cognitive and emotional functions. 5-HT 2A The receptors are expressed on dopamine, GABA, glutamate and Ach neurons and play a role as dendritic heteroreceptors (Buhot MC, (1997) Curr Opin Neurobiol, 7, 243-254; Leysen JE, (2004) Curr Drug Targets CNS Neuro Disord, 3, 11-26). Like most 5-HT receptors, 5-HT 2A The receptors are G-protein coupled receptors that complete signal transduction by activating guanine nucleotide binding proteins (G proteins), leading to the increase or decrease of second messenger molecules such as cyclic adenosine monophosphate (cAMP), inositol phosphates and diacylglycerol. These second messenger molecules regulate the function of various intracellular enzymes (such as kinases and ion channels), ultimately affecting cell excitability and cell function.

[0004] Abnormalities in 5-HT transmission are associated with the pathogenesis of a variety of mental diseases, such as mental diseases (depression, panic attack, schizophrenia, suicidal tendency, etc.) and neurodegenerative diseases (Alzheimer's disease, Huntington's disease, Parkinson's disease, etc.) (Fioravanti et al., (1992) Brain Cogn. 18, 116-124; Sinopoli VM, et al., (2017) Neurosci Biobehav Rev, 80:372-381). In recent years, it has been found that 5-HT 2A The receptors are closely related to the pathological state of neuropsychiatric diseases, and 5-HT 2A The receptors are involved in the molecular mechanism of action of atypical antipsychotic drugs such as clozapine, olanzapine and risperidone (Gonzalez-Maeso J, et al., (2009) Trends Neurosci, 32:225-232; Fribourg M, et al., (2011) Cell, 147:1011-1023; Kurita M, et al., (2012) Nat Neurosci, 15:1245-1254); 5-HT 2AReceptor antagonists are important for the treatment of negative symptoms of schizophrenia (e.g. affective disturbances, reduced speech, etc.) (Blier P, et al., (2005) J Clin Psychiatry 66, Suppl 8, 30-40; Richtand N M, et al., (2008) Prog Brain Res, 172, 141-153; Meltzer, H.Y. (2013) Annu Rev Med 64, 3932 / 47 pages 406); other studies have demonstrated that 5-HT 2A Receptor modulation pathways are critical for mediating the signaling and behavioral responses elicited by hallucinogens (Gonzalez-Maeso J, et al., (2009) Trends Neurosci, 32:225-232), suggesting that 5-HT 2A Receptors play a role in the treatment of hallucinatory symptoms in various neurodegenerative diseases.

[0005] Drugs for the treatment of psychotic disorders, i.e. antipsychotic drugs, are divided into two major categories. “Typical” antipsychotic drugs or drugs of the previous generation are rarely used in the clinic due to the motor side effects (extrapyramidal side effects, Parkinson-like symptoms, etc.) caused in the human body, and the current drugs focus more on “atypical” antipsychotic drugs (Prim Cre Companion J Clin Psychiatry. (2007) 9(6):444-54). However, this second generation of antipsychotic drugs has broad spectrum receptor activity, and these compounds modulate various monoaminergic receptors such as 5-HT, dopaminergic, adrenergic, muscarinic or histaminergic receptors as agonists, competitive antagonists or inverse agonists, and this broad spectrum modulation is likely to be the cause of side effects such as sedation abnormalities, motor abnormalities, type 2 diabetes, etc. Most antipsychotic drugs have dopamine D2 receptor antagonistic effects, which have been shown to be associated with extrapyramidal side effects (Strange P G. (2001) Pharmacol Rev, 53(1):119-33; Tuppurainen H, et al., (2010) Nord J Psychiatry, 64(4):233-8; Sykes DA, et al., (2017) Nat Commun, 8(1):763). Therefore, the development of more 5-HT2A receptor antagonists or inverse agonists, especially those with high selectivity and / or no dopamine D2 receptor binding activity, etc., is of great importance for the development of antipsychotic drugs, and such compounds can avoid many side effects caused by non-selective receptor interactions while treating the disease. SUMMARY

[0006] The technical purpose of the present invention is to provide a class of quinazolinone 5-HT 2A Receptor antagonist or agonist compound and its pharmaceutically acceptable salt, as well as its preparation method and medical use, which is a potent 5-HT 2A Receptor antagonist with potential antipsychotic activity.

[0007] According to one aspect of the present invention, an object of the present invention is to provide quinazolinone derivatives represented by the following formula I and pharmaceutically acceptable salts thereof:

[0008]

[0009] wherein, in Formula I, n is selected from an integer from 1 to 4;

[0010] R1 is located at position 5, 6, 7 or 8 of the quinazolinone ring and is selected from H, halogen, hydroxyl, cyano, -NR 11 R 12 , nitro, trifluoromethyl, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 alkoxy; wherein, the substitution in substituted or unsubstituted C1-6 alkyl and substituted or unsubstituted C1-6 alkoxy means that the group is further substituted by C1-6 alkyl, halogen, hydroxyl or amino; wherein, -NR 11 R 12 R in 11 and R 12 Each independently selected from H, C1-6 alkyl, C1-6 alkyl substituted by C3-6 cycloalkyl;

[0011] R2 is selected from H, substituted or unsubstituted C1-10 straight or branched alkyl, substituted or unsubstituted C2-10 straight or branched alkenyl, substituted or unsubstituted C2-10 straight or branched alkynyl, or substituted or unsubstituted C6-18 aryl, wherein the substituents on the C6-18 aryl are each independently selected from unsubstituted or halogen-substituted C1-8 straight or branched alkyl, or the adjacent substituents of the C6-18 aryl together with the carbon atom to which they are attached form a C6-18 aryl or a 5- to 9-membered heterocyclic or heteroaromatic ring containing 1 to 3 heteroatoms selected from O, N and S;

[0012] Y is a nitrogen atom or a CH (methine) group;

[0013] X is a chemical bond, a C1-6 alkylene group, or C=O (carbonyl);

[0014] R3 and R4 are located at any chemically acceptable substitution position of the ring where they are located, and are independently selected from H, halogen, hydroxyl, cyano, amino, nitro, trifluoromethyl, C1-6 alkylcarbonyl, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C1-6 alkylamino; the substitution means that the group is further substituted by C1-6 alkyl, halogen, hydroxyl or amino.

[0015] Preferably, in formula I, n is selected from an integer of 0 to 3;

[0016] R1 is located at the 5-position of the quinazolinone ring, and R1 is selected from H, halogen, hydroxyl, cyano, -NR 11 R 12 , nitro, trifluoromethyl, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted C1-4 alkoxy; wherein, the substitution in substituted or unsubstituted C1-4 alkyl and substituted or unsubstituted C1-4 alkoxy means that the group is further substituted by C1-4 alkyl, halogen, hydroxyl or amino; wherein, -NR 11 R 12 R in 11 and R 12 Each independently selected from H, C1-4 alkyl, C1-4 alkyl substituted by C3-5 cycloalkyl;

[0017] R2 is selected from H, substituted or unsubstituted C1-4 straight or branched alkyl, substituted or unsubstituted C2-4 straight or branched alkenyl, substituted or unsubstituted C2-4 straight or branched alkynyl, or substituted or unsubstituted C6-10 aryl, wherein the substituents on the C6-10 aryl are each independently selected from unsubstituted or halogen-substituted C1-3 straight or branched alkyl, or the adjacent substituents of the C6-10 aryl, together with the carbon atom to which they are attached, form a 5- to 9-membered heterocyclic or heteroaromatic ring;

[0018] X is a chemical bond, a C1-4 alkylene group, or C=O (carbonyl);

[0019] R3 and R4 are located at chemically acceptable substitution positions on the ring where they are located, and are independently selected from H, halogen, hydroxyl, cyano, amino, nitro, trifluoromethyl, C1-4 alkylcarbonyl, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted C1-4 alkoxy, substituted or unsubstituted C1-4 alkylamino; the substitution means that the group is further substituted by C1-4 alkyl, halogen, hydroxyl or amino.

[0020] More preferably, in formula I, n is an integer selected from 2 or 3;

[0021] R1 is selected from H, halogen, -NR 11 R 12, substituted or unsubstituted C1-3alkyl, substituted or unsubstituted C1-3alkoxy, substituted or unsubstituted C1-3alkylamino; wherein the substitution in the substituted or unsubstituted C1-3alkyl and the substituted or unsubstituted C1-3alkoxy means that the group is further substituted with C1-3alkyl, halogen, hydroxyl or amino; wherein -NR 11 R 12 R 11 and R 12 are each independently selected from H, C1-3alkyl, C3-4cycloalkyl substituted C1-3alkyl;

[0022] R2is selected from H, substituted or unsubstituted C1-3alkyl, substituted or unsubstituted C6-8aryl, wherein the substituents on the C6-8aryl are each independently selected from C1-3alkyl, or adjacent substituents of the C6-8aryl together with the carbon atoms to which they are attached form a 5- to 7-membered ring;

[0023] X is a bond, C1-3alkylene or C=O (carbonyl);

[0024] R3and R4are at chemically acceptable substitution positions on the ring on which they are located and are each independently selected from H, halogen, hydroxyl, cyano, amino, nitro, trifluoromethyl, C1-3alkylcarbonyl, substituted or unsubstituted C1-3alkyl, substituted or unsubstituted C1-3alkoxy, substituted or unsubstituted C1-3alkylamino; the substitution means that the group is further substituted with C1-3alkyl, halogen, hydroxyl or amino.

[0025] Further preferably, n is the integer 2 in formula I;

[0026] R1is selected from H, halogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH2cyclopropyl, -NCH2cyclobutyl, -NCH2cyclopentyl, -NH(CH3)2, -NH(CH2CH3)2, -NH(CH2CH2CH3)2;

[0027] R2is selected from H, methyl, ethyl, propyl;

[0028] X is a bond, methylene, ethylene, propylene or C=O (carbonyl);

[0029] R3and R4are at chemically acceptable substitution positions on the ring on which they are located and are each independently selected from H, halogen, cyano, trifluoromethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, methyl, ethyl, propyl, methoxy, ethoxy, propoxy.

[0030] More preferably, the 5-HT2A receptor antagonist or agonist compound represented by Formula I and pharmaceutically acceptable salts thereof are selected from the following compounds:

[0031]

[0032]

[0033]

[0034]

[0035] According to another aspect of the present application, another object of the present application is to provide a method for preparing a 5-HT2A receptor antagonist or agonist compound represented by Formula I and pharmaceutically acceptable salts thereof, the preparation route of which is shown in the following Reaction Formula 1:

[0036] As shown in the above Reaction Formula 1, the method comprises the following steps:

[0037] i) condensation of R1-substituted o-nitrobenzoic acid (1) with amino alcohol (2) under the action of a condensing agent (such as EDCI, DCC, DIC, etc.) to obtain intermediate 1a;

[0038] ii) reduction of the nitro group of intermediate 1a under reaction conditions such as iron acid reduction, catalytic hydrogenation, etc. to obtain intermediate 1b;

[0039] iii) ring closure reaction of intermediate 1b with R2-substituted trimethyl orthoformate or R2-substituted triethyl orthoformate (3) under anhydrous conditions to obtain intermediate 1c;

[0040] iv) reaction of intermediate 1c with a chlorinating agent (such as thionyl chloride, phosphorus trichloride, phosphorus pentachloride, etc.) to obtain intermediate 1d;

[0041] v) N-hydrocarbylation reaction of intermediate 1d with compound 4 under the catalysis of an inorganic base (sodium carbonate, potassium carbonate, cesium carbonate) or an organic base (triethylamine, diisopropylethylamine, DMAP, DBU, etc.) to obtain a compound of Formula I;

[0042] In the above reaction formula, the substituents R1, R2, R3, R4, X, Y, n are as described above.

[0043] According to another aspect of the present application, another object of the present application is to provide the use of a 5-HT2A receptor antagonist or agonist compound represented by Formula I and pharmaceutically acceptable salts thereof in the preparation of a medicament for treating mental diseases, symptoms of mental disorders associated with or concurrent with central nervous system degenerative diseases. 2A receptor antagonist or agonist.

[0044] Preferably, the mental disease comprises depression, anxiety, psychosis, schizophrenia, insomnia, autism, the central nervous system degenerative disease comprises Alzheimer's disease, Parkinson's disease, Huntington's disease, Lewy body dementia.

[0045] According to another aspect of the present application, another object of the present application is to provide a pharmaceutical composition comprising a therapeutically effective amount of the 5-HT 2A receptor antagonist or agonist compound and pharmaceutically acceptable salts and pharmaceutically acceptable excipients thereof.

[0046] According to another aspect of the present application, another object of the present application is to provide a method for treating mental diseases, symptoms of mental disorders associated with or concurrent with central nervous system degenerative diseases, the method comprising administering to a subject in need thereof a therapeutically effective amount of the 5-HT 2A receptor antagonist or agonist compound and pharmaceutically acceptable salts or the pharmaceutical composition according to the present application.

[0047] Advantages

[0048] The present application provides the 5-HT 2A receptor antagonist or agonist compound, which has stronger in vivo activity than the marketed drug pimavanserin, and has potential therapeutic effects on depression, anxiety, psychosis, schizophrenia, insomnia, autism. BRIEF DESCRIPTION OF DRAWINGS

[0049] In order to more clearly illustrate the specific embodiments of the present application or the technical solutions in the prior art, the drawings required to be used in the specific embodiments or prior art description will be briefly introduced as follows. Obviously, the drawings in the following description are some embodiments of the present application, and those skilled in the art can also obtain other drawings according to these drawings without creative labor.

[0050] Figure 1 The 5-HT 2A receptor in vivo activity test diagram. DETAILED DESCRIPTION

[0051] Hereinafter, the present application will be described in detail. Before undertaking the description, it should be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, unless explicitly so defined herein. Furthermore, it should be understood that the use of terminology, such as "including", "having", "with", or "comprising" or "comprise", "comprising", or "having" is intended to be broad and encompass the term "consisting of" or "consisting." Thus, the description is not intended to be limited to the particular form set forth herein, but includes all functionalities falling within the spirit and scope of the present application.

[0052] As used herein, the terms "comprise", "comprising", "including", "have", "has", "including", "contains", "containing", or any other similar phrase are all the open terms and are intended to mean "including but not limited to", "comprising but not limited to", or "containing but not limited to" and are not intended to exclude other unspecified elements or method steps. As used herein, the term "or" is intended to mean an inclusive "or" and not an exclusive "or", unless explicitly indicated to the contrary. For example, the phrase "A or B" means "A or B or both A and B". In addition, the terms "a", "an" and "the" are intended to be interpreted to include the plural forms as well as the singular forms, unless explicitly indicated to the contrary. In addition, the terms "comprising", "having", "including", and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to") unless explicitly indicated to the contrary.

[0053] As used herein, all features or conditions of a range or a percentage range are intended to be merely for convenience and brevity in providing the disclosure. Accordingly, the description of a range or a percentage range is intended to be construed as having specifically disclosed and encompassing all possible sub-ranges and individual numerical values within the range, particularly the integer values. For example, a range of "1 to 8" is intended to be construed as having specifically disclosed all sub-ranges, particularly the sub-ranges defined by the integer values, such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, and the like, and as having specifically disclosed the individual numerical values within the range, such as 1, 2, 3, 4, 5, 6, 7, 8, and the like. The foregoing interpretation is applicable to all aspects of the present application, whether the range is broad or narrow, unless otherwise indicated.

[0054] If a range or other numerical value or parameter is expressed herein as comprising an upper value or a lower value, or both, an intended application also contemplates the full range including the upper and lower values, unless otherwise indicated. In addition, all numerical ranges herein should be understood to include whole integer values and whole decimal values within the indicated ranges, unless otherwise indicated.

[0055] In this document, the use of the terms "about" and "substantially" with reference to a given reference numeric value X is intended to mean the range of values extending + / - 10% of the value X. For example, the term "about X" or "substantially X" is intended to encompass a range of values extending from (X - 0.1X) to (X + 0.1X). In this document, numerical values should be construed in a manner consistent with their declaration of significant figures, assuming that the numerical value has been reported with the number of significant figures necessary to express the precision of the measurement that is typical in the field of the application. For example, the number 40.0 should be interpreted as encompassing the range from 39.50 to 40.49.

[0056] In this document, for situations in which Markush group or list of alternatives is used to describe features or examples of the application, those of ordinary skill in the art will understand that the subgroups of all elements supporting the Markush group or list of alternatives or any permutation of individual elements are also described herein. For example, if X is described as "selected from the group consisting of X1, X2, and X3," it is intended to also fully describe the claim where X is X1, the claim where X is X1 and / or X2, the claim where X is X1 and / or X3, the claim where X is X2 and / or X3, the claim where X is X1, X2, and / or X3, and the like. In this document, for situations in which Markush group or list of alternatives is used to describe features or examples of the application, those of ordinary skill in the art will further appreciate that any combination of subgroups of all elements supporting the Markush group or list of alternatives, or individual elements, is also described herein. For example, if X is described as "selected from the group consisting of X1, X2, and X3," and Y is described as "selected from the group consisting of Y1, Y2, and Y3," it is intended to also fully describe the claim where X is X1 or X2 or X3 and Y is Y1 or Y2 or Y3.

[0057] Definitions

[0058] The compounds of the application or pharmaceutically acceptable salts thereof can exist in hydrate, solvate, or prodrug form. Accordingly, the hydrates, solvates, or prodrugs of the compounds of the application or pharmaceutically acceptable salts thereof are also included within the scope of this application.

[0059] The term "pharmaceutically acceptable," as used herein, pertains to compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0060] The term "pharmaceutically acceptable salt" means a salt of a compound of this application which is found to possess the specific substituents discovered by the inventors, prepared from the compounds of this application with relatively non-toxic, inorganic or organic acids or bases. Alkali addition salts are obtained by contacting the neutral form of such compounds, either in pure form or in an appropriate inert solvent, with a sufficient amount of the base to produce the neutral form of the compound. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. Acid addition salts are obtained by contacting the neutral form of such compounds, either in pure form or in an appropriate inert solvent, with a sufficient amount of the acid to produce the neutral form of the compound (i.e., a pharmaceutically acceptable salt). Examples include inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, boric, sulfuric, sulfamic, phosphoric, nitrous, and the like; and organic acids such as, for example, acetic, 2-hydroxyethanesulfonic, benzenesulfonic, benzoic, 3-(4- hydroxybenzoyl)benzoic, cinnamic, citric, cyclohexanesulfonic, fauric, fumaric, gentisic, isethionic, lactic, mandelic, oxalic, propionic, pyroglutamic, salicylic, succinic, tartaric, p-toluenesulfonic, trifluoromethylsulfonic, ascorbic, phthalic, maleic, citraconic, glutamic, muconic, glycolic, glycerophosphoric, hydroxymaleic, hydroxyethanesulfonic, lactic, lactobionic, dodecylsulfonic, pamoic, salicylic, aspartic, glutamic, methanesulfonic, ethanesulfonic, and the like; similar acids such as aspartic, glutamic, and glycolic acids; and salts of amino acids such as arginate and gluconate; and salts of organic acids not otherwise specified (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of this application contain both basic and acidic functionalities as a result of which, they are capable of being converted into either base or acid addition salts. The parent form of the compound differs from its various salt forms in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound in all other properties.

[0061] The term "pharmaceutically acceptable excipient (or carrier)" means any formulation or carrier medium which does not interfere with the effectiveness of the active ingredient of the present application, and which is not toxic to the host or patient in which it is placed. Representative carriers include water, oil, vegetable and mineral, ointment bases, lotion bases, ointment bases and the like. These bases include suspending agents, viscosity increasing agents, transdermal enhancers and the like. Their formulation is well known to those skilled in the art of cosmetics or topical pharmaceuticals.

[0062] The term "effective amount" or "therapeutically effective amount" in reference to a drug or a pharmacologically active agent means a nontoxic but sufficient amount of the drug or agent to provide the desired effect. For oral dosage forms of the present application, an "effective amount" of one active agent in a composition means the amount needed to achieve the desired effect in conjunction with the other active agent in the composition. The determination of an effective amount is dependent on the age and general condition of the recipient, on the particular active agent, and an appropriate effective amount in a given case will be determined by one of ordinary skill in the art using routine testing.

[0063] The term "treat" as used herein refers to eliminating, reducing, or ameliorating a disease or condition and / or symptoms associated therewith. While not precluded, treating a disease or condition does not require complete eradication of the disease, condition, or symptoms associated therewith. The term "treat" and the like, as used herein, can include "prophylactic treatment," which refers to reducing the likelihood of redeveloping a disease or condition or the likelihood of a recurrence of a previously controlled disease or condition in a subject who does not have or who is not at risk of developing or having a recurrence of the disease or condition. The term "treat" and synonyms contemplate administration of a therapeutically effective amount of a compound described herein to a subject in need of such treatment.

[0064] An "optionally substituted" group, such as optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, means an unsubstituted or substituted corresponding group. In general, the term "substituted," whether preceded by the term "optionally" or not, refers to the replacement of hydrogen present on a group, such as a carbon or nitrogen atom, with an allowed substituent (e.g., a substituent that results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction). Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions on the group, and when more than one position is substituted in any given structure, the substituents can be the same or different at each position. Generally, when substituted, an optionally substituted group herein can be substituted with 1-5 substituents. If applicable, a substituent can be a carbon atom substituent, a nitrogen atom substituent, an oxygen atom substituent, or a sulfur atom substituent.

[0065] Combinations of substituents and / or variables are permissible only if such combinations result in chemically sensible, stable compounds. "Stable compound" is a compound that can be prepared and isolated and that retains its structure and properties for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic administration to a subject).

[0066] The compounds described herein can contain one or more asymmetric centers and thus can exist in various isomeric forms, such as enantiomeric and / or diastereomeric forms. For example, the compounds described herein can be in the form of a single enantiomer, diastereomer or geometric isomer, or can be a mixture of stereoisomers, including a racemic mixture and a mixture enriched in one or more stereoisomers. Isomers can be separated by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and formation and crystallization of chiral salts; or the preferred isomer can be prepared by asymmetric synthesis. See, e.g., Jacques et al., “Enantiomers, Racemates and Resolutions” (Wiley Interscience, New York, 1981); Wilen et al., “Tetrahedron” 33:2725 (1977); Eliel, “Stereochemistry of Carbon Compounds” (McGraw-Hill, New York, 1962); and Wilen, “Tables of Resolving Agents and Optical Resolutions”, 268 pages (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers, including racemic mixtures.

[0067] When a range of values is listed, it is intended to include each value and sub-range within the range. For example, “C 1–6 ” is intended to encompass C1, C2, C3, C4, C5, C6, C 1–6 , C 1–5 , C 1–4 , C 1–3 , C 1–2 , C 2–6 , C 2–5 , C 2–4 , C 2–3 , C 3–6 , C 3–5 , C 3–4 , C 4–6 , C 4–5 and C 5–6 .

[0068] The term “alkyl” refers to a straight-chain or branched-chain saturated hydrocarbon radical (“C 1-6In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C 2-6 C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl) and hexyl (C6) (e.g., n-hexyl). Unless otherwise specified, each instance of alkyl is independently unsubstituted or substituted with one or more substituents (e.g., halogen, such as F). In certain embodiments, alkyl is unsubstituted C 1-6 In certain embodiments, the alkyl group is a substituted C 1-6 Alkyl groups, such as -CF3.

[0069] "Alkoxy" or "oxyalkyl" refers to a monovalent -O-alkyl group, wherein the alkyl portion has the specified number of carbon atoms. In the present disclosure, alkoxy groups typically contain 1-6 carbon atoms ("C1-6 alkoxy"), for example, including methoxy, ethoxy, isopropoxy, tert-butyloxy, etc. Unless otherwise specified, each instance of alkoxy is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkoxy") or substituted ("substituted alkoxy") with one or more substituents, such as halogen atoms, nitro, amino, hydroxy, cyano, amide, etc. In certain embodiments, alkoxy is an unsubstituted C 1-6 In certain embodiments, alkoxy is substituted C 1-6 Alkoxy.

[0070] "Cycloalkyl" refers to a non-aromatic ring system having 3 to 6 ring carbon atoms ("C 3-6 cycloalkyl”) and a non-aromatic cyclic hydrocarbon group having zero heteroatoms. Exemplary C 3-6Cycloalkyl includes but is not limited to cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6) etc. As shown in the above examples, in certain embodiments, cycloalkyl is monocyclic ("monocyclic cycloalkyl") or contains fused ring, bridged ring or spirocyclic ring system, such as bicyclic system ("bicyclic cycloalkyl") and can be saturated or can be partially unsaturated. "Cycloalkyl" also includes a ring system in which the point of attachment of the cycloalkyl as defined above to one or more aryl or heteroaryl groups is fused to the carbocyclic ring, and in this case, the carbon number continues to refer to the carbon number in the carbocyclic ring system. Unless otherwise indicated, each example of a cycloalkyl group is independently optionally substituted, i.e., unsubstituted or substituted by one or more substituents.

[0071] "Aryl" refers to a group having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system, either monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the cyclic array) ("C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 "Aryl"; for example, anthracenyl). "Aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more carbocyclic or heterocyclic groups, and in which case the number of carbon atoms continues to refer to the number of carbon atoms in the aromatic ring system. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted ("substituted aryl") with one or more substituents, such as halogen atoms, nitro groups, amino groups, hydroxyl groups, cyano groups, amide groups, and the like. In certain embodiments, an aryl group is an unsubstituted C 6-14 In certain embodiments, aryl is a substituted C 6-14 Aryl.

[0072] "Alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, one or more carbon-carbon double bonds and no triple bonds ("C 2-6 The carbon-carbon double bond can be located at the end of the carbon chain or at any position allowed by the chemical structure. In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2-5("C2-C6alkenyl"). In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C2-C4alkenyl"). In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C2-C3alkenyl"). In some embodiments, the alkenyl group has 2 carbon atoms ("C2alkenyl"). The one or more carbon-carbon double bonds can be internal (as in 2-butenyl) or terminal (as in 1-butenyl).C 2-4 ("C2-C6alkenyl"). In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C2-C4alkenyl"). In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C2-C3alkenyl"). In some embodiments, the alkenyl group has 2 carbon atoms ("C2alkenyl"). The one or more carbon-carbon double bonds can be internal (as in 2-butenyl) or terminal (as in 1-butenyl).C 2-3 ("C2-C6alkenyl"). In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C2-C4alkenyl"). In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C2-C3alkenyl"). In some embodiments, the alkenyl group has 2 carbon atoms ("C2alkenyl"). The one or more carbon-carbon double bonds can be internal (as in 2-butenyl) or terminal (as in 1-butenyl).C 2-4 Examples of alkenyl groups include ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1 -butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like.C 2-6 Examples of alkenyl groups include the foregoing C 2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkenyl") or substituted (a "substituted alkenyl") with one or more substituents. In certain embodiments, an alkenyl group is an unsubstituted C 2-6 alkenyl group. In certain embodiments, an alkenyl group is a substituted C 2-6 alkenyl group. In alkenyl groups, the C=C double bond for which stereochemistry is not specified (e.g., -CH=CHCH3or ) can be either an (E)- or (Z)-double bond.

[0073] "Alkynyl" refers to a straight or branched hydrocarbon group (the "C2-C6alkynyl") having from 2 to 6 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds. The carbon-carbon triple bond(s) can be located at any position in the carbon chain that the chemical structure permits, including terminal (as in 1-pentynyl) or internal (as in 2-pentynyl).C 2-6 ("C2-C6alkynyl"). In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C2-C6alkynyl"). In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C2-C5alkynyl"). In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C2-C4alkynyl"). In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C2-C3alkynyl"). In some embodiments, the alkynyl group has 2 carbon atoms ("C2alkynyl"). The one or more carbon-carbon triple bonds can be internal (as in 2-butynyl) or terminal (as in 1-butynyl).C 2-6 ("C2-C6alkynyl"). In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C2-C6alkynyl"). In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C2-C5alkynyl"). In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C2-C4alkynyl"). In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C2-C3alkynyl"). In some embodiments, the alkynyl group has 2 carbon atoms ("C2alkynyl"). The one or more carbon-carbon triple bonds can be internal (as in 2-butynyl) or terminal (as in 1-butynyl).C 2-5 ("C2-C6alkynyl"). In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C2-C6alkynyl"). In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C2-C5alkynyl"). In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C2-C4alkynyl"). In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C2-C3alkynyl"). In some embodiments, the alkynyl group has 2 carbon atoms ("C2alkynyl"). The one or more carbon-carbon triple bonds can be internal (as in 2-butynyl) or terminal (as in 1-butynyl).C 2-4 ("C2-C6alkynyl"). In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C2-C6alkynyl"). In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C2-C5alkynyl"). In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C2-C4alkynyl"). In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C2-C3alkynyl"). In some embodiments, the alkynyl group has 2 carbon atoms ("C2alkynyl"). The one or more carbon-carbon triple bonds can be internal (as in 2-butynyl) or terminal (as in 1-butynyl).C 2-3 ("C2-C6alkynyl"). In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C2-C6alkynyl"). In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C2-C5alkynyl"). In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C2-C4alkynyl"). In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C2-C3alkynyl"). In some embodiments, the alkynyl group has 2 carbon atoms ("C2alkynyl"). The one or more carbon-carbon triple bonds can be internal (as in 2-butynyl) or terminal (as in 1-butynyl).C 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1 -propynyl (C3), 2-propynyl (C3), 1 -butynyl (C4), 2-butynyl (C4), and the like.C 2-6 Examples of alkenyl groups include the foregoing C 2-4alkynyl and pentynyl (C5), hexynyl (C6), and the like. Unless otherwise indicated, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted ( "substituted alkynyl") with one or more substituents. In certain embodiments, an alkynyl group is an unsubstituted C 2-6 alkynyl. In certain embodiments, an alkynyl group is a substituted C 2-6 alkynyl.

[0074] Unless explicitly provided otherwise, an atom, moiety, or group described herein can be unsubstituted or substituted as valence permits.

[0075] "Halo" or "halogen" means fluoro (fluorinated, -F), chloro (chlorinated, -Cl), bromo (brominated, -Br), or iodo (iodinated, -I).

[0076] The following examples are set forth by way of illustration only and not as limitations of the application. Modifications of the examples, incorporating the spirit and substance of the application, are expressly intended to be within the scope of the present application. Unless otherwise indicated, the reagents and instruments used in the following examples are commercially available. The experimental methods used in the following examples are routine methods unless otherwise specified.

[0077] 1 H NMR spectra were determined using a Bruker instrument (400 MHz) and chemical shifts are expressed in ppm using tetramethylsilane as the internal standard (0.00 ppm). 1 H NMR notation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broad, dd = doublet of doublets, dt = doublet of triplets. If a coupling constant is provided, it is in Hz.

[0078] Mass spectra were determined using an LC / MS instrument and ionization can be ESI or APCI.

[0079] Example 1: 3-{2-[4-(4-bromophenyl)piperazin-1-yl]ethyl}-5-fluoro-3,4-dihydroquinazolin-4- one. Compound No. LXH0630

[0080]

[0081] First Step: Preparation of 6-fluoro-N-(2-hydroxyethyl)-2-nitrobenzamide (2a).

[0082]

[0083] Into a 50 mL vial, 407.2 mg (2.2 mmol) of 6-fluoro-2-nitrobenzoic acid, 422.6 mg (2.2 mmol) of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 325.8 mg (2.4 mmol) of 1-hydroxybenzotriazole (HOBT) and 20 mL of dichloromethane were added successively at room temperature, stirred for 30 min at room temperature, 294.5 mg (4.8 mmol) of ethanolamine was added to the reaction solution, and the reaction was allowed to proceed at room temperature for 1 h. The reaction was stopped after the starting material was completely consumed as monitored by TLC. The reaction solution was poured into 40 mL of water, extracted with dichloromethane (20 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography using petroleum ether / ethyl acetate (5: 1) as the mobile phase. The eluate was rotary evaporated to obtain 2a as a yellow solid (474.2 mg, 94.5%). 1 H NMR (600 MHz, Methanol-d4) δ 8.03 (dt, J = 8.3, 1.0 Hz, 1H), 7.69 (td, J = 8.3, 5.6 Hz, 1H), 7.62 (td, J = 8.5, 1.0 Hz, 1H), 3.72 (t, J = 6.1 Hz, 2H), 3.51 (t, J = 6.1 Hz, 2H). ESI-MS m / z: 229.06 [M+H] +

[0084] Second Step: Preparation of 2-amino-6-fluoro-N-(2-hydroxyethyl)benzamide (3a).

[0085]

[0086] Into a 50 mL vial, 407.2 mg (2.2 mmol) of 6-fluoro-2-nitrobenzoic acid, 422.6 mg (2.2 mmol) of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 325.8 mg (2.4 mmol) of 1-hydroxybenzotriazole (HOBT) and 20 mL of dichloromethane were added successively at room temperature, stirred for 30 min at room temperature, 294.5 mg (4.8 mmol) of ethanolamine was added to the reaction solution, and the reaction was allowed to proceed at room temperature for 1 h. The reaction was stopped after the starting material was completely consumed as monitored by TLC. The reaction solution was poured into 40 mL of water, extracted with dichloromethane (20 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography using petroleum ether / ethyl acetate (5: 1) as the mobile phase. The eluate was rotary evaporated to obtain 2a as a yellow solid (474.2 mg, 94.5%). 1 H NMR (600 MHz, Methanol-d4) δ 8.03 (dt, J = 8.3, 1.0 Hz, 1H), 7.69 (td, J = 8.3, 5.6 Hz, 1H), 7.62 (td, J = 8.5, 1.0 Hz, 1H), 3.72 (t, J = 6.1 Hz, 2H), 3.51 (t, J = 6.1 Hz, 2H). ESI-MS m / z: 229.06 [M+H] +

[0087] Step 3: Preparation of 5-fluoro-3-(2-hydroxyethyl)-3,4-dihydroquinazolin-4-one (4a).

[0088]

[0089] Into a 50 mL round bottom flask, was placed 1.3 g (6.4 mmol) of 2-amino-6-fluoro-N-(2-hydroxyethyl)benzamide, 1.5 g (12.8 mmol) of trimethyl orthoformate, 1.1 g (6.4 mmol) of p-toluenesulfonic acid and 15 mL of toluene, and the reaction was refluxed at 110 °C for 6 h. TLC monitoring showed that the starting material was completely consumed, and the reaction was stopped. The reaction solution was poured into 40 mL of water, extracted with dichloromethane (20 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow solid, which was washed with ethyl acetate to give a white solid (1.0 g, 75%). 1 H NMR (600 MHz, Methanol-d4) δ 8.26 (s, 1H), 7.79 (td, J = 8.2, 5.4 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.23 (ddd, J = 11.1, 8.2, 1.0 Hz, 1H), 4.20 - 4.04 (m, 2H), 3.87 - 3.81 (m, 2H). ESI-MS m / z: 209.07 [M+H] +

[0090] Step 4: Preparation of 3-(2-chloroethyl)-5-fluoro-3,4-dihydroquinazolin-4-one (5a).

[0091]

[0092] Into a 250 mL round bottom flask, was placed 2.5 g (12.0 mmol) of 5-fluoro-3-(2-hydroxyethyl)-3,4-dihydroquinazolin-4-one (4a) and 50 mL of dichloromethane, and the mixture was stirred uniformly. Then, 3.0 g (24.0 mmol) of dichloro sulfoxide was slowly added dropwise to the above solution under ice bath, and the reaction was stirred at 60 °C for 4 h after being transferred to an oil bath. TLC monitoring showed that the starting material was completely consumed, and the reaction was quenched by slowly pouring the reaction solution into 100 mL of ice water under ice bath. After stirring thoroughly, the organic phase was extracted with dichloromethane (70 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a red-brown solid (2.5 g, 89.2%). 1H NMR (600 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.84 (td, J = 8.2, 5.5 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.33 (ddd, J = 11.2, 8.2, 1.0 Hz, 1H), 4.30 (t, J = 6.0 Hz, 2H), 3.97 (t, J = 6.0 Hz, 2H). ESI-MS m / z: 227.04 [M+H] +

[0093] Fifth Step: Preparation of 3-{2-[4-(4-bromophenyl)piperazin-1-yl]ethyl}-5- fluoro-3,4-dihydroquinazolin-4-one, Compound No. LXH0630

[0094]

[0095] Weigh 3-(2-chloroethyl)-5-fluoro-3,4-dihydroquinazolin-4-one 200 mg (0.84 mmol) into a 25 mL round bottom flask, add 15 mL 4-methyl-2-pentanone, add 352 mg (3.32 mmol) sodium carbonate, 224 mg (0.84 mmol) 1-(4-bromophenyl)piperazine hydrochloride successively under stirring at room temperature. After addition, heat to 110 °C and reflux for 24 h. TLC monitoring shows that the reaction is complete. Cool the reaction liquid to room temperature, add water (15 mL) to the reaction liquid, extract with dichloromethane (20 mL x 3), dry the combined organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. Purify the crude product by silica gel column chromatography with petroleum ether / ethyl acetate (2:1) as the mobile phase. Dry the eluate under vacuum to obtain a yellow solid (137.3 mg, 38.0%) 1 H NMR (600 MHz, Chloroform-d) δ 7.56 (td, J = 7.5, 5.7 Hz, 1H), 7.46 (dd, J = 7.5, 2.1 Hz, 1H), 7.29 (ddd, J = 9.2, 7.4, 2.0 Hz, 1H), 7.24 - 7.18 (m, 2H), 6.67 - 6.61 (m, 2H), 6.40 (s, 1H), 3.30 (t, J = 7.3 Hz, 2H), 3.19 (t, J = 5.1 Hz, 4H), 2.63 - 2.54 (m, 6H). ESI-MS m / z: 431.08 [M+H] +

[0096] Example 2: 3-{2-[4-(4-bromophenyl)piperazin-1-yl]ethyl}-5-methoxy-3,4- dihydroquinazolin-4-one. Compound No. LXH0704

[0097]

[0098] The title compound was prepared according to the procedure of Example 1, replacing 3-(2-chloroethyl)-5-fluoro-3,4-dihydroquinazolin-4-one with 3-(2- chloroethyl)-5-methoxy-3,4-dihydroquinazolin-4-one, red-brown solid, 34.0% yield. 1 H NMR (600 MHz, Chloroform-d) δ 8.02 (s, 1H), 7.65 (t, J = 8.2 Hz, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.29 - 7.26 (m, 1H), 6.94 - 6.91 (m, 1H), 6.90 (d, J = 8.7 Hz, 2H), 4.08 (t, J = 6.2 Hz, 2H), 4.01 (s, 3H), 3.26 (t, J = 5.0 Hz, 4H), 2.79 (t, J = 6.0 Hz, 2H), 2.68 (t, J = 4.9 Hz, 4H). ESI-MS m / z: 433.19 [M+H] +

[0099] Example 3: 5-Methoxy-3-(2-{4-[4-(trifluoromethyl)phenyl]piperazin-1- yl}ethyl)-3,4-dihydroquinazolin-4-one.

[0100] Compound No: LXH0712

[0101]

[0102] The title compound was prepared according to the procedure of Example 2, replacing 1-(4-bromophenyl)piperazine with 4-(4-trifluoromethylphenyl)piperazine, red-brown solid, 28.4% yield. 1 H NMR (600 MHz, Chloroform-d) δ 8.02 (s, 1H), 7.65 (t, J = 8.2 Hz, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.29 - 7.26 (m, 1H), 6.94 - 6.91 (m, 1H), 6.90 (d, J = 8.7 Hz, 2H), 4.08 (t, J = 6.2 Hz, 2H), 4.01 (s, 3H), 3.26 (t, J = 5.0 Hz, 4H), 2.79 (t, J = 6.0 Hz, 2H), 2.68 (t, J = 4.9 Hz, 4H). ESI-MS m / z: 433.19 [M+H] +

[0103] Example 4: 5-Fluoro-3-(2-{4-[4-(trifluoromethyl)phenyl]piperazin-1- yl}ethyl)-3,4-dihydroquinazolin-4-one. Compound No: LXH0706

[0104]

[0105] The title compound was prepared according to the method of Example 1, replacing 1-(4-bromophenyl)piperazine with 4-(4-trifluoromethylphenyl)piperazine, red-brown solid, yield 58.3%. 1 H NMR (500 MHz, Chloroform-d) δ 7.56 (td, J = 7.4, 5.7 Hz, 1H), 7.46 (dd, J = 7.5, 2.0 Hz, 1H), 7.36 - 7.25 (m, 3H), 6.80 - 6.73 (m, 2H), 6.40 (s, 1H), 3.30 (t, J = 7.2 Hz, 2H), 3.19 (t, J = 5.2 Hz, 4H), 2.63 - 2.54 (m, 6H). ESI-MS m / z: 421.19 [M+H] +

[0106] Example 5: 3-{2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl}-5-fluoro-3,4-dihydroquinazolin-4-one. Compound No: LXH0703

[0107]

[0108] The title compound was prepared according to the method of Example 1, replacing 1-(4-bromophenyl)piperazine with 4-(4-chloromethylphenyl)piperazine, yellow solid, yield 43.4%. 1 H NMR (600 MHz, Chloroform-d) δ 7.56 (td, J = 7.5, 5.7 Hz, 1H), 7.46 (dd, J = 7.5, 2.0 Hz, 1H), 7.29 (ddd, J = 9.3, 7.4, 2.0 Hz, 1H), 7.09 - 7.02 (m, 2H), 6.72 - 6.66 (m, 2H), 6.40 (s, 1H), 3.30 (t, J = 7.3 Hz, 2H), 3.19 (t, J = 5.1 Hz, 4H), 2.63 - 2.54 (m, 6H). ESI-MS m / z: 387.14 [M+H] +

[0109] Example 6: 3-{2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl}-5-methoxy-3,4-dihydroquinazolin-4-one. Compound No: LXH0709

[0110]

[0111] The title compound was prepared according to the method of Example 2, replacing 1-(4-bromophenyl)piperazine with 4-(4-chloromethylphenyl)piperazine, yellow solid, yield 39.8%.1 H NMR (600 MHz, Chloroform-d) δ 8.02 (s, 1H), 7.65 (t, J = 8.2 Hz, 1H), 7.28 (d, 1H), 7.21 - 7.15 (m, 2H), 6.92 (d, J = 8.2 Hz, 1H), 6.83 - 6.79 (m, 2H), 4.08 (t, J = 5.9 Hz, 2H), 4.01 (s, 3H), 3.14 (t, J = 4.8 Hz, 4H), 2.79 (d, J = 6.4 Hz, 2H), 2.68 (s, 4H). ESI-MS m / z: 399.16 [M+H]+

[0112] Example 7: 5-Fluoro-3-(2-{4-[(4-fluorophenyl)carbonyl]piperidin-l-yl}ethyl)-3,4- dihydroquinazolin-4-one. Compound No. LXH0737

[0113]

[0114] The title compound was prepared according to the method of Example 1, except substituting (4-fluorophenyl)(piperidin-4-yl)methanone for l-(4-bromophenyl)piperazine, in 24.5% yield as a white solid. 1 H NMR (600 MHz, Chloroform-d) δ 7.93 - 7.86 (m, 2H), 7.56 (td, J = 7.5, 5.7 Hz, 1H), 7.47 (dd, J = 7.5, 2.0 Hz, 1H), 7.29 (ddd, J = 9.2, 7.4, 2.0 Hz, 1H), 7.15 - 7.07 (m, 2H), 6.40 (s, 1H), 3.30 (t, J = 7.2 Hz, 2H), 3.11 (dt, J = 12.2, 7.0 Hz, 2H), 2.97 (p, J = 6.9 Hz, 1H), 2.57 (t, J = 7.3 Hz, 2H), 2.14 (ddt, J = 36.1, 13.1, 7.0 Hz, 4H), 1.88 - 1.78 (m, 2H). ESI-MS m / z: 398.15 [M+H] +

[0115] Example 8: 3-(2-{4-[(4-Chlorophenyl)carbonyl]piperazin-l-yl}ethyl)-5-fluoro-3,4- dihydroquinazolin-4-one. Compound No. LXH0739

[0116]

[0117] The title compound was prepared according to the method of Example 1, replacing 1-(4-bromophenyl)piperazine with (4-chlorophenyl)(piperidin-4-yl)methanone, yellow solid, yield 23.1%. 1 H NMR (600 MHz, Chloroform-d) δ 8.07 (d, J = 24.1 Hz, 1H), 7.86 (d, J = 8.5 Hz, 2H), 7.69 (td, J = 8.1, 5.3 Hz, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.15 (dd, J = 10.6, 8.1 Hz, 1H), 4.15 - 4.05 (m, 2H), 3.20 (s, 1H), 2.89 (d, J = 146.6 Hz, 3H), 2.30 (s, 2H), 1.84 (s, 4H), 1.59 (s, 1H). ESI-MS m / z: 414.15 [M+H] +

[0118] Example 9: 3-{2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl}-5-fluoro-3,4- dihydroquinazolin-4-one. Compound No.: LXH0742

[0119]

[0120] The title compound was prepared according to the method of Example 1, replacing 1-(4-bromophenyl)piperazine with (2,3-dichlorophenyl)piperazine, yellow-white solid, yield 32.7%. 1 H NMR (600 MHz, Chloroform-d) δ 8.08 (s, 1H), 7.69 (td, J = 8.2, 5.3 Hz, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.20 - 7.06 (m, 3H), 6.93 (dd, J = 7.6, 2.0 Hz, 1H), 4.12 (s, 2H), 3.05 (s, 4H), 2.77 (d, J = 51.6 Hz, 6H). ESI-MS m / z: 421.10 [M+H] + .

[0121] Example 10: 3-{2-[4-(4-acetylphenyl)piperazin-1-yl]ethyl}-5-fluoro-3,4- dihydroquinazolin-4-one. Compound No.: LXH0745

[0122]

[0123] The title compound was prepared according to the method of Example 1, replacing 1-(4-bromophenyl)piperazine with (4-acetylphenyl)piperazine, yellow solid, yield 45.8%.1 H NMR (600 MHz, Chloroform-d) δ 8.05 (s, 1H), 7.87 (d, J = 8.5 Hz, 2H), 7.69 (td, J = 8.1, 5.1 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.16 (dd, J = 10.6, 8.2 Hz, 1H), 6.85 (d, J = 8.6 Hz, 2H), 4.12 (d, J = 6.3 Hz, 2H), 3.34 (s, 4H), 2.80 (d, J = 6.0 Hz, 2H), 2.68 (s, 4H), 2.52 (s, 3H). ESI-MS m / z: 395.19 [M+H] +

[0124] Example 11: 4-{4-[2-(5-fluoro-4-oximinioquinazolin-3-yl)ethyl]piperazin-1-yl}benzene-1- carbonitrile. Compound No.: LXH0749

[0125]

[0126] The title compound was prepared according to the method of Example 1, replacing 1-(4-bromophenyl)piperazine with (4-cyanophenyl)piperazine, in 70.2% yield as a yellow-white solid. 1 H NMR (600 MHz, Chloroform-d) δ 8.04 (s, 1H), 7.69 (td, J = 8.2, 5.3 Hz, 1H), 7.49 (dd, J = 8.3, 5.6 Hz, 3H), 7.16 (dd, J = 10.6, 8.1 Hz, 1H), 6.84 (d, J = 8.7 Hz, 2H), 4.11 (t, J = 5.9 Hz, 2H), 3.30 (t, J = 4.8 Hz, 4H), 2.79 (t, J = 5.9 Hz, 2H), 2.67 (t, J = 4.8 Hz, 4H). ESI-MS m / z: 378.18 [M+H] +

[0127] Example 12: 3-(2-{4-[(4-fluorophenyl)carbonyl]piperazin-1-yl}ethyl)-5-methoxy-3,4- dihydroquinazolin-4-one.

[0128] Compound No.: LXH0715

[0129]

[0130] The title compound was prepared according to the method of Example 1, replacing 1-(4-bromophenyl)piperazine with (4-chlorophenyl)(piperidin-4-yl)methanone, in 53.9% yield as a white solid. 1H NMR (500 MHz, Chloroform-d) δ 7.69 - 7.63 (m, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.53 (dd, J = 7.5, 2.0 Hz, 1H), 7.25 - 7.08 (m, 3H), 6.40 (s, 1H), 3.94 - 3.83 (m, 7H), 3.30 (t, J = 5.2 Hz, 2H), 2.57 (t, J = 5.2 Hz, 2H), 2.25 (t, J = 5.2 Hz, 4H). ESI-MS m / z: 410.19 [M+H] +

[0131] Example 13: 3-(2-{4-[(4-chlorophenyl)carbonyl]piperazin-1-yl}ethyl)-5- methoxy-3,4-dihydroquinazolin-4-one.

[0132] Compound No.: LXH0738

[0133]

[0134] The title compound was prepared according to the procedure of Example 2, except substituting (4-chlorophenyl)(piperidin-4-yl)methanone for 1-(4-bromophenyl)piperazine, as a yellow solid in 45.2% yield. 1 H NMR (600 MHz, Chloroform-d) δ 8.02 (s, 1H), 7.93 - 7.78 (m, 2H), 7.65 (t, J = 8.2 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 4.06 (d, J = 20.5 Hz, 2H), 4.01 (s, 3H), 3.19 (s, 2H), 3.01 (s, 2H), 2.77 (s, 2H), 2.25 (s, 1H), 1.84 (s, 4H). ESI-MS m / z: 426.19 [M+H] +

[0135] Example 14: 3-{2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl}-5-methoxy-3,4- dihydroquinazolin-4-one. Compound No.: LXH0744

[0136]

[0137] The title compound was prepared according to the procedure of Example 2, except substituting (2,3-dichlorophenyl)piperazine for 1-(4-bromophenyl)piperazine, as a white solid in 47.5% yield. 1H NMR (600 MHz, Chloroform-d) δ 8.04 (s, 1H), 7.66 (t, J = 8.2 Hz, 1H), 7.28 (d, 1H), 7.19 - 7.09 (m, 2H), 6.98 - 6.87 (m, 2H), 4.08 (s, 2H), 4.01 (s, 3H), 3.13 - 2.98 (m, 4H), 2.81 (s, 2H), 2.72 (s, 4H). ESI-MS m / z: 433.12 [M+H] +

[0138] Example 15: 3-{2-[4-(4-acetylphenyl)piperazin-1-yl]ethyl}-5-methoxy-3,4- dihydroquinazolin-4-one. Compound No. LXH0743

[0139]

[0140] The title compound was prepared according to the method of Example 2, except that 1-(4-acetylphenyl)piperazine was used instead of 1-(4-bromophenyl)piperazine, in a yield of 50.6% as a yellow solid. 1 H NMR (600 MHz, Chloroform-d) δ 8.02 (s, 1H), 7.91 - 7.82 (m, 2H), 7.66 (t, J = 8.2 Hz, 1H), 7.28 (s, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.88 - 6.78 (m, 2H), 4.09 (s, 2H), 4.01 (s, 3H), 3.34 (s, 4H), 2.79 (s, 2H), 2.67 (s, 4H), 2.52 (s, 3H). ESI-MS m / z: 407.23 [M+H] +

[0141] Example 16: 4-{4-[2-(5-methoxy-4-oxoquinazolin-3-yl)ethyl]piperazin-1-yl}benzene-1- carbonitrile. Compound No. LXH0902

[0142]

[0143] The title compound was prepared according to the method of Example 1, except that 1-(4- cyanophenyl)piperazine was used instead of 1-(4-bromophenyl)piperazine, in a yield of 54.2% as a white solid. 1H NMR (600 MHz, Chloroform-d) δ 8.01 (s, 1H), 7.66 (t, J = 8.2 Hz, 1H), 7.49 (d, J = 8.5 Hz, 2H), 7.28 (d, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.84 (d, J = 8.6 Hz, 2H), 4.08 (s, 2H), 4.01 (s, 3H), 3.30 (s, 4H), 2.79 (s, 2H), 2.66 (s, 4H). ESI-MS m / z: 390.20 [M+H] +

[0144] Example 17: 3-{2-[4-(4-bromophenyl)piperazin-l-yl]ethyl}-5-(methylamino)- 3,4-dihydroquinazolin-4-one. Compound No. LXH0903

[0145]

[0146] The title compound was prepared according to the procedure of Example 1, except substituting 3-(2-chloroethyl)-5-methylamino-3,4-dihydroquinazolin-4-one for 3-(2-chloroethyl)-5-fluoro-3,4-dihydroquinazolin-4-one, in a yield of 41.7% as a yellow-white solid. 1 H NMR (600 MHz, Chloroform-d) δ 8.49 (s, 1H), 7.93 (s, 1H), 7.53 (t, J = 8.1 Hz, 1H), 7.34 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 7.8 Hz, 1H), 6.77 (d, J = 8.6 Hz, 2H), 6.50 (d, J = 8.3 Hz, 1H), 4.04 (s, 2H), 3.15 (s, 4H), 2.93 (d, J = 5.0 Hz, 3H), 2.71 (m, 6H). ESI-MS m / z: 444.12 [M+H] +

[0147] Example 18: 5-(methylamino)-3-(2-{4-[4-(trifluoromethyl)phenyl]piperazin-l- yl}ethyl)-3,4-dihydroquinazolin-4-one. Compound No. LXH0904

[0148]

[0149] The title compound was prepared according to the procedure of Example 17, except substituting 1-(4-trifluoromethylphenyl)piperazine for 1-(4-bromophenyl)piperazine, in a yield of 50.5% as a yellow-white solid. 1H NMR (600 MHz, Chloroform-d) δ 8.48 (s, 1H), 7.94 (s, 1H), 7.53 (t, J = 8.1 Hz, 1H), 7.48 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.5 Hz, 2H), 6.83 (d, J = 7.8 Hz, 1H), 6.50 (d, J = 8.3 Hz, 1H), 4.07 (s, 2H), 3.33 (m, 4H), 2.93 (d, J = 4.9 Hz, 3H), 2.71 (s, 4H), 1.04 (s, 2H). ESI-MS m / z: 432.21 [M+H] +

[0150] Example 19: 3-{2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl}-5-(methylamino)-3,4- dihydroquinazolin-4-one. Compound No. LXH0905

[0151]

[0152] The title compound was prepared according to the method of Example 17, except substituting 1-(4-chlorophenyl)piperazine for 1-(4-bromophenyl)piperazine, in a yield of 51.7% as a yellow solid. 1 H NMR (600 MHz, Chloroform-d) δ 8.50 (s, 1H), 7.93 (s, 1H), 7.53 (t, J = 8.1 Hz, 1H), 7.20 (d, J = 8.5 Hz, 2H), 6.82 (dd, J = 8.3, 6.0 Hz, 3H), 6.50 (d, J = 8.3 Hz, 1H), 4.04 (s, 2H), 3.15 (s, 4H), 2.93 (d, J = 5.0 Hz, 3H), 2.71 (d, J = 40.7 Hz, 6H). ESI-MS m / z: 398.17 [M+H] +

[0153] Example 20: 3-(2-{4-[(4-fluorophenyl)carbonyl]piperazin-1-yl}ethyl)-5-(methylamino)- 3,4-dihydroquinazolin-4-one. Compound No. LXH0907

[0154]

[0155] The title compound was prepared according to the method of Example 17, except substituting (4-fluorophenyl)(piperidin-4-yl)methanone for 1-(4-bromophenyl)piperazine, in a yield of 47.3% as a yellow solid. 1H NMR (600 MHz, Chloroform-d) δ 8.49 (s, 1H), 8.01 - 7.87 (m, 3H), 7.53 (t, J = 8.1 Hz, 1H), 7.14 (t, J = 8.3 Hz, 2H), 6.84 (t, J = 6.5 Hz, 1H), 6.49 (d, J = 8.3 Hz, 1H), 4.02 (s, 2H), 3.40 - 2.96 (m, 3H), 2.93 (d, J = 5.0 Hz, 3H), 2.76 (d, J = 55.3 Hz, 2H), 2.28 (s, 2H), 1.85 (s, 3H), 1.58 (s, 1H). ESI-MS m / z: 409.21 [M+H] +

[0156] Example 21: 3-(2-{4-[(4-chlorophenyl)carbonyl]piperazin-1-yl}ethyl)-5- (methylamino)-3,4-dihydroquinazolin-4-one. Compound No. LXH0908

[0157]

[0158] The title compound was prepared according to the procedure of Example 17, except substituting (4-chlorophenyl)(piperidin-4-yl)methanone for 1-(4- bromophenyl)piperazine, in 36.8% yield as a white solid. 1 H NMR (600 MHz, Chloroform-d) δ 8.49 (s, 1H), 7.92 (s, 1H), 7.90 - 7.79 (m, 2H), 7.52 (t, J = 8.1 Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 6.83 (dd, J = 7.9, 0.9 Hz, 1H), 6.49 (d, J = 8.3 Hz, 1H), 4.03 (s, 2H), 3.10 (d, J = 110.9 Hz, 3H), 2.93 (d, J = 5.1 Hz, 3H), 2.68 (s, 2H), 2.23 (s, 2H), 1.84 (s, 3H), 1.61 (s, 1H). ESI-MS m / z: 425.17 [M+H] +

[0159] Example 22: 4-(4-{2-[5-(methylamino)-4-oxoquinazolin-3-yl]ethyl}piperazin-1- yl)benzene-1-carbonitrile. Compound No. LXH0750

[0160]

[0161] The title compound was prepared according to the procedure of Example 17, except substituting 1-(4-cyanophenyl)piperazine for 1-(4-bromophenyl)piperazine, in 25.4% yield as a yellow solid.1 H NMR (600 MHz, Chloroform-d) δ 8.48 (s, 1H), 7.93 (s, 1H), 7.59 - 7.43 (m, 3H), 6.84 (t, J = 8.8 Hz, 3H), 6.51 (d, J = 8.2 Hz, 1H), 4.10 (d, J = 31.6 Hz, 2H), 3.35 (s, 4H), 2.93 (d, J = 4.8 Hz, 3H), 2.89 - 2.54 (m, 6H). ESI-MS m / z: 389.22 [M+H] +

[0162] Example 23: 5-Ethoxy-3-(2-{4-[(4-fluorophenyl)carbonyl]piperazin-1-yl}ethyl)-3,4- dihydroquinazolin-4-one.

[0163] Compound No.: LXH0947

[0164]

[0165] The title compound was prepared according to the procedure of Example 20, replacing 3-(2-chloroethyl)-5-ethoxy-3,4-dihydroquinazolin-4-one with 3-(2- chloroethyl)-5-methylamino-3,4-dihydroquinazolin-4-one, yellow white solid, yield 49.1%. 1 H NMR (600 MHz, Chloroform-d) δ 8.05 (s, 1H), 8.00 - 7.90 (m, 2H), 7.62 (t, J = 8.2 Hz, 1H), 7.25 (d, J = 0.9 Hz, 1H), 7.14 (t, J = 8.6 Hz, 2H), 6.90 (dd, J = 8.2, 0.9 Hz, 1H), 4.18 - 4.03 (m, 4H), 3.25 (s, 1H), 3.05 (s, 2H), 2.90 - 2.66 (m, 2H), 2.35 (dt, J = 23.2, 7.7 Hz, 5H), 1.89 (s, 4H). ESI-MS m / z: 424.20 [M+H] +

[0166] Example 24: 3-(2-{4-[(4-chlorophenyl)carbonyl]piperazin-1-yl}ethyl)-5-ethoxy-3,4- dihydroquinazolin-4-one.

[0167] Compound No.: LXH0949

[0168]

[0169] The title compound was prepared according to the method of Example 23, replacing (4-fluorophenyl)(piperidin-4-yl)methanone with (4-chlorophenyl)(piperidin-4-yl)methanone, yellow solid, yield 52.0%. 1 H NMR (600 MHz, Chloroform-d) δ 8.01 (s, 1H), 7.91 - 7.82 (m, 2H), 7.62 (t, J = 8.2 Hz, 1H), 7.47 - 7.40 (m, 2H), 7.26 - 7.23 (m, 1H), 6.90 (d, J = 8.1 Hz, 1H), 4.21 (q, J = 6.9 Hz, 2H), 4.07 (s, 2H), 3.19 (s, 1H), 2.99 (d, J = 11.2 Hz, 2H), 2.76 (s, 2H), 2.36 - 2.19 (m, 2H), 1.83 (s, 4H), 1.57 (t, J = 6.9 Hz, 3H). ESI-MS m / z: 440.16 [M+H] +

[0170] Example 25: 3-{2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl}-5-ethoxy-3,4- dihydroquinazolin-4-one. Compound No. LXH1203

[0171]

[0172] The title compound was prepared according to the method of Example 20, replacing (4-fluorophenyl)(piperidin-4-yl)methanone with 1-(2,3-dichlorophenyl)piperazine, yellow solid, yield 58.3%. 1 H NMR (600 MHz, Chloroform-d) δ 8.05 (s, 1H), 7.63 (t, J = 8.2 Hz, 1H), 7.25 (d, J = 0.9 Hz, 1H), 7.19 - 7.11 (m, 2H), 6.94 (dd, J = 7.5, 2.0 Hz, 1H), 6.93 - 6.88 (m, 1H), 4.21 (q, J = 6.9 Hz, 2H), 4.18 - 3.98 (m, 2H), 3.06 (s, 4H), 2.85 (d, J = 0.8 Hz, 1H), 2.77 (d, J = 56.4 Hz, 5H), 1.58 (t, J = 7.0 Hz, 3H). ESI-MS m / z: 447.13 [M+H] +

[0173] Example 26: 5-(ethylamino)-3-(2-{4-[(4-fluorophenyl)carbonyl]piperazin-1-yl}ethyl)- 3,4-dihydroquinazolin-4-one. Compound No. LXH0946

[0174]

[0175] The title compound was prepared according to the procedure of Example 20, replacing 3-(2-chloroethyl)-5-methylamino-3,4-dihydroquinazolin-4-one with 3-(2- chloroethyl)-5-ethylamino-3,4-dihydroquinazolin-4-one, except that the reaction was stirred for 2 h. The title compound was obtained as a yellow-white solid in 41.9% yield. 1 H NMR (600 MHz, Chloroform-d) δ 8.15 (s, 1H), 8.00 - 7.90 (m, 2H), 7.64 (t, J = 8.2 Hz, 1H), 7.25 (d, J = 0.9 Hz, 1H), 7.14 (t, J = 8.6 Hz, 2H), 6.90 (dd, J = 8.2, 0.9 Hz, 1H), 4.18 - 4.03 (m, 4H), 3.25 (s, 1H), 3.05 (s, 2H), 2.90 - 2.66 (m, 2H), 2.35 (m, 5H), 1.89 (s, 4H). ESI-MS m / z: 423.22 [M+H] +

[0176] Example 27: 5-(Ethylamino)-3-(2-{4-[(4-fluorophenyl)carbonyl]piperazin-1-yl}ethyl)- 2-methyl-3,4-dihydroquinazolin-4-one. Compound No. LXH0948

[0177]

[0178] The title compound was prepared according to the procedure of Example 20, replacing 3-(2-chloroethyl)-5-methylamino-3,4-dihydroquinazolin-4-one with 3-(2- chloroethyl)-5-ethylamino-3,4-dihydroquinazolin-4-one, except that the reaction was stirred for 2 h. The title compound was obtained as a yellow-white solid in 41.9% yield. 1 H NMR (600 MHz, Chloroform-d) δ 8.15 (s, 1H), 8.00 - 7.90 (m, 2H), 7.64 (t, J = 8.2 Hz, 1H), 7.25 (d, J = 0.9 Hz, 1H), 7.14 (t, J = 8.6 Hz, 2H), 6.90 (dd, J = 8.2, 0.9 Hz, 1H), 4.18 - 4.03 (m, 4H), 3.25 (s, 1H), 3.05 (s, 2H), 2.90 - 2.66 (m, 2H), 2.35 (m, 5H), 1.89 (s, 4H). ESI-MS m / z: 423.22 [M+H] H NMR (600 MHz, Chloroform-d) δ 8.45 (d, J = 19.6 Hz, 1H), 8.04 - 7.89 (m, 2H), 7.46 (t, J = 8.1 Hz, 1H), 7.20 - 7.08 (m, 2H), 6.72 (dd, J = 7.9, 1.0 Hz, 1H), 6.45 (d, J = 8.0 Hz, 1H), 4.15 (s, 2H), 3.24 (qd, J = 7.2, 4.9 Hz, 2H), 3.07 (d, J = 11.1 Hz, 2H), 2.80 - 2.65 (m, 2H), 2.63 (s, 3H), 2.40 - 2.22 (m, 2H), 2.17 (s, 1H), 1.86 (s, 4H), 1.64 (d, J = 63.5 Hz, 1H), 1.35 (t, J = 7.2 Hz, 3H). ESI-MS m / z: 437.23 [M+H]+

[0179] Example 28: 3-(2-{4-[(4-fluorophenyl)carbonyl]piperazin-1-yl}ethyl)-2-methyl-5- (methylamino)-3,4-dihydroquinazolin-4-one. Compound No. LXH1201

[0180]

[0181] The title compound was prepared according to the procedure of Example 20, replacing 3-(2-chloroethyl)-5-methylamino-3,4-dihydroquinazolin-4-one with 2-methyl-3-(2- chloroethyl)-5-methylamino-3,4-dihydroquinazolin-4-one, as a yellow-white solid in 59.1% yield. 1 H NMR (600 MHz, Chloroform-d) δ 8.48 (q, J = 5.2 Hz, 1H), 8.08 - 7.88 (m, 2H), 7.49 (t, J = 8.1 Hz, 1H), 7.22 - 7.04 (m, 2H), 6.74 (dd, J = 8.0, 0.9 Hz, 1H), 6.43 (dd, J = 8.3, 0.9 Hz, 1H), 4.18 (s, 2H), 3.24 (s, 1H), 3.08 (dd, J = 9.9, 5.4 Hz, 2H), 2.92 (d, J = 5.1 Hz, 3H), 2.72 (s, 2H), 2.64 (s, 3H), 2.33 (s, 2H), 2.13 - 1.60 (m, 4H). ESI-MS m / z: 423.21 [M+H] +

[0182] Example 29: 3-(2-{4-[(4-chlorophenyl)carbonyl]piperazin-1-yl}ethyl)-2-methyl-5- (methylamino)-3,4-dihydroquinazolin-4-one. Compound No. LXH1202

[0183]

[0184] The title compound was prepared according to the procedure of Example 28, replacing (4-fluorophenyl)(piperidin-4-yl)methanone with (4-chlorophenyl)(piperidin-4-yl)methanone, as a yellow-white solid in 71.9% yield. 1H NMR (600 MHz, Chloroform-d) δ 8.47 (s, 1H), 7.99 - 7.78 (m, 2H), 7.49 (t, J = 8.1 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 6.74 (dd, J = 7.9, 0.9 Hz, 1H), 6.49 - 6.36 (m, 1H), 4.19 (s, 2H), 3.25 (t, J = 20.6 Hz, 1H), 3.08 (d, J = 11.1 Hz, 2H), 2.92 (d, J = 5.1 Hz, 3H), 2.73 (s, 2H), 2.64 (s, 3H), 2.50 - 2.14 (m, 2H), 1.88 (s, 4H). ESI-MS m / z: 439.17 [M+H] +

[0185] Example 30: 3-(2-{4-[(4-fluorophenyl)carbonyl]piperazin-1-yl}ethyl)-5-methoxy-2- methyl-3,4-dihydroquinazolin-4-one. Compound No. LXH1214

[0186]

[0187] The title compound was prepared according to the method of Example 20, except substituting 3-(2-methyl-3,4-dihydroquinazolin-4-yl)-2-methyl-5-methoxy-3,4- dihydroquinazolin-4-one for 3-(2-chloroethyl)-5-methoxy-3,4-dihydroquinazolin-4-one, in 39.2% yield as a yellow-white solid. 1 H NMR (600 MHz, Chloroform-d) δ 8.00 - 7.91 (m, 2H), 7.61 (t, J = 8.2 Hz, 1H), 7.18 (dd, J = 8.2, 0.9 Hz, 1H), 7.16 - 7.09 (m, 2H), 6.85 (dd, J = 8.3, 1.0 Hz, 1H), 4.20 (s, 2H), 4.00 (s, 3H), 3.22 (s, 1H), 3.08 (dd, J = 9.6, 5.4 Hz, 2H), 2.76 (s, 2H), 2.67 (s, 3H), 2.31 (s, 2H), 1.86 (s, 5H). ESI-MS m / z: 424.20 [M+H] +

[0188] Example 31: 3-(2-{4-[(4-chlorophenyl)carbonyl]piperazin-1-yl}ethyl)-5-methoxy-2- methyl-3,4-dihydroquinazolin-4-one. Compound No. LXH1218

[0189]

[0190] The title compound was prepared according to the method of Example 30, replacing (4-fluorophenyl)(piperidin-4-yl)methanone with (4-chlorophenyl)(piperidin-4-yl)methanone, white solid, yield 54.8%. 1 H NMR (600 MHz, Chloroform-d) δ 7.90 - 7.84 (m, 2H), 7.61 (t, J = 8.2 Hz, 1H), 7.47 - 7.42 (m, 2H), 7.18 (dd, J = 8.2, 0.9 Hz, 1H), 6.85 (dd, J = 8.3, 1.0 Hz, 1H), 4.19 (s, 2H), 4.00 (s, 3H), 3.19 (s, 1H), 3.10 - 3.03 (m, 2H), 2.75 (s, 2H), 2.67 (s, 3H), 2.29 (s, 2H), 1.85 (s, 4H). ESI-MS m / z: 440.18 [M+H] +

[0191] Example 32: 2-Ethyl-3-(2-{4-[(4-fluorophenyl)carbonyl]piperazin-1-yl}ethyl)-5- methoxy-3,4-dihydroquinazolin-4-one. Compound No. LXH1217

[0192]

[0193] The title compound was prepared according to the method of Example 20, replacing 3-(2-chloroethyl)-5-methoxy-3,4-dihydroquinazolin-4-one with 2-ethyl-3-(2- chloroethyl)-5-methoxy-3,4-dihydroquinazolin-4-one, yellow-white solid, yield 55.8%. 1 H NMR (600 MHz, Chloroform-d) δ 7.99 - 7.91 (m, 2H), 7.61 (t, J = 8.1 Hz, 1H), 7.22 (dd, J = 8.1, 0.9 Hz, 1H), 7.14 (t, J = 8.6 Hz, 2H), 6.85 (dd, J = 8.2, 0.9 Hz, 1H), 4.20 (s, 2H), 4.00 (s, 3H), 3.20 (s, 1H), 3.08 (d, J = 11.1 Hz, 2H), 2.90 (q, J = 7.4 Hz, 2H), 2.72 (s, 2H), 2.29 (s, 2H), 1.85 (s, 4H), 1.40 (t, J = 7.4 Hz, 3H). ESI-MS m / z: 438.23 [M+H] +

[0194] Example 33: 3-(2-{4-[(4-chlorophenyl)carbonyl]piperazin-1-yl}ethyl)-5- ethoxy-2-methyl-3,4-dihydroquinazolin-4-one. Compound No. LXH1224

[0195]

[0196] The title compound was prepared according to the procedure of Example 20, replacing 1-(4-fluorophenyl)(piperidin-4-yl)methanone with (4- chlorophenyl)(piperidin-4-yl)methanone, 2-methyl-3-(2-chloroethyl)-5- ethoxy-3,4-dihydroquinazolin-4-one with 3-(2-chloroethyl)-5-methylamino- 3,4-dihydroquinazolin-4-one, as a yellow-white solid in 32.5% yield. 1 HNMR (600 MHz, Chloroform-d) δ 8.02 - 7.87 (m, 2H), 7.58 (t, J = 8.2 Hz, 1H), 7.20 - 7.11 (m, 3H), 6.83 (dd, J = 8.3, 0.9 Hz, 1H), 4.20 (q, J = 7.0 Hz, 4H), 3.21 (s, 1H), 3.07 (dd, J = 9.7, 5.3 Hz, 2H), 2.75 (t, J = 6.6 Hz, 2H), 2.67 (s, 3H), 2.29 (s, 2H), 2.02 - 1.74 (m, 4H), 1.57 (t, J = 7.0 Hz, 3H). ESI-MS m / z: 454.19 [M+H] +

[0197] Example 34: 3-(2-{4-[(4-chlorophenyl)carbonyl]piperazin-1-yl}ethyl)-2- ethyl-5-methoxy-3,4-dihydroquinazolin-4-one. Compound No. LXH1222

[0198]

[0199] The title compound was prepared according to the procedure of Example 20, replacing 1-(4-fluorophenyl)(piperidin-4-yl)methanone with (4- chlorophenyl)(piperidin-4-yl)methanone, 2-methyl-3-(2-chloroethyl)-5- ethoxy-3,4-dihydroquinazolin-4-one with 3-(2-chloroethyl)-5-methylamino- 3,4-dihydroquinazolin-4-one, as a yellow-white solid in 32.5% yield. 1H NMR (600 MHz, Chloroform-d) δ 7.90 - 7.82 (m, 2H), 7.61 (t, J = 8.2 Hz, 1H), 7.48 - 7.40 (m, 2H), 7.22 (dd, J = 8.1, 0.9 Hz, 1H), 6.84 (dd, J = 8.2, 0.9 Hz, 1H), 4.19 (t, J = 7.3 Hz, 2H), 4.00 (s, 3H), 3.18 (dq, J = 10.1, 5.5, 4.4 Hz, 1H), 3.07 (dt, J = 11.8, 3.4 Hz, 2H), 2.89 (q, J = 7.3 Hz, 2H), 2.72 (t, J = 7.2 Hz, 2H), 2.30 (d, J = 11.7 Hz, 2H), 1.92 - 1.75 (m, 4H), 1.40 (t, J = 7.4 Hz, 3H). ESI-MS m / z: 454.19 [M+H] +

[0200] Example 35: 5-Ethoxy-3-(2-{4-[(4-fluorophenyl)carbonyl]piperazin-1-yl}ethyl)-2- methyl-3,4-dihydroquinazolin-4-one. Compound No.: LXH1225

[0201]

[0202] The title compound was prepared according to the method of Example 20, except substituting 3-(2-chloroethyl)-5-ethoxy-2-methyl-3,4-dihydroquinazolin-4-one for 3-(2- chloroethyl)-5-methylamino-3,4-dihydroquinazolin-4-one, in 33.0% yield as a white solid. 1 H NMR (600 MHz, Chloroform-d) δ 8.02 - 7.90 (m, 2H), 7.58 (t, J = 8.2 Hz, 1H), 7.19 - 7.07 (m, 3H), 6.83 (dd, J = 8.3, 1.0 Hz, 1H), 4.21 (q, J = 6.9 Hz, 4H), 3.22 (s, 1H), 3.06 (dt, J = 11.7, 3.7 Hz, 2H), 2.76 (t, J = 6.9 Hz, 2H), 2.67 (s, 3H), 2.30 (s, 2H), 1.96 - 1.78 (m, 4H), 1.57 (t, J = 7.0 Hz, 3H). ESI-MS m / z: 438.21 [M+H] +

[0203] Example 36: 3-(2-{4-[(4-chlorophenyl)carbonyl]piperazin-1-yl}ethyl)-5-(ethylamino)- 3,4-dihydroquinazolin-4-one. Compound No.: LXH1231

[0204]

[0205] The title compound was prepared according to the procedure of Example 20, replacing 1 -(4-fluorophenyl)(piperidin-4-yl)methanone with (4-chlorophenyl)(piperidin-4- yl)methanone, 3-(2-chloroethyl)-5-ethylamino-3,4-dihydroquinazolin-4-one with 3-(2- chloroethyl)-5-methylamino-3,4-dihydroquinazolin-4-one, yellow-white solid, 30.6% yield. 1 H NMR (600 MHz, Chloroform-d) δ 8.11 (s, 1H), 7.91 - 7.82 (m, 2H), 7.52 (t, J = 8.2 Hz, 1H), 7.47 - 7.40 (m, 2H), 7.26 - 7.23 (m, 1H), 6.90 (d, J = 8.1 Hz, 1H), 4.21 (q, J = 6.9 Hz, 2H), 4.07 (s, 2H), 3.19 (s, 1H), 2.99 (d, J = 11.2 Hz, 2H), 2.76 (s, 2H), 2.36 - 2.19 (m, 2H), 1.83 (s, 4H), 1.57 (t, J = 6.9 Hz, 3H). ESI-MS m / z: 439.19 [M+H] +

[0206] Example 37: 3-{2-[4-(2,3-Dimethylphenyl)piperazin-1-yl]ethyl}-5- (methylamino)-3,4-dihydroquinazolin-4-one. Compound No. LXH1232

[0207]

[0208] The title compound was prepared according to the procedure of Example 20, replacing 1 -(4-fluorophenyl)(piperidin-4-yl)methanone with (4-chlorophenyl)(piperidin-4- yl)methanone, 3-(2-chloroethyl)-5-ethylamino-3,4-dihydroquinazolin-4-one with 3-(2- chloroethyl)-5-methylamino-3,4-dihydroquinazolin-4-one, yellow-white solid, 30.6% yield. 1H NMR (600 MHz, Chloroform-d) δ 8.50 (q, J = 5.2 Hz, 1H), 7.93 (s, 1H), 7.52 (t, J = 8.1 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.82 (dd, J = 7.9, 1.0 Hz, 1H), 6.73 (d, J = 2.7 Hz, 1H), 6.67 (dd, J = 8.4, 2.7 Hz, 1H), 6.49 (dd, J = 8.4, 1.0 Hz, 1H), 4.07 (t, J = 6.3 Hz, 2H), 3.16 (t, J = 4.9 Hz, 4H), 2.93 (d, J = 5.0 Hz, 3H), 2.75 (d, J = 31.4 Hz, 6H), 2.20 (d, J = 27.1 Hz, 6H). ESI-MS m / z: 392.25 [M+H] +

[0209] Example 38: 3-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)hexahydropyridin-l-yl]ethyl}-5- methoxy-2-methyl-3,4-dihydroquinazolin-4-one. Compound No. LXH1230

[0210]

[0211] The title compound was prepared according to the procedure of Example 20, except substituting 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole for l-(4-fluorophenyl)(piperidin-4- yl)methanone and 2-methyl-3-(2-chloroethyl)-5-methoxy-3,4-dihydroquinazolin-4-one for 3-(2- chloroethyl)-5-methoxy-3,4-dihydroquinazolin-4-one, white solid, 39.3% yield. 1 H NMR (600 MHz, Chloroform-d) δ 7.67 (dt, J = 8.5, 4.3 Hz, 1H), 7.62 (t, J = 8.2 Hz, 1H), 7.24 (dd, J = 8.5, 2.2 Hz, 1H), 7.19 (dd, J = 8.2, 1.0 Hz, 1H), 7.06 (td, J = 8.8, 2.1 Hz, 1H), 6.86 (dd, J = 8.3, 0.9 Hz, 1H), 4.22 (t, J = 7.1 Hz, 2H), 4.00 (s, 3H), 3.21 - 3.03 (m, 3H), 2.79 (t, J = 7.0 Hz, 2H), 2.69 (s, 3H), 2.36 (s, 2H), 2.08 (s, 4H). ESI-MS m / z: 437.20 [M+H] +

[0212] Example 39: 5-(ethylamino)-3-(2-{4-[(4-fluorophenyl)carbonyl]piperazin-1- yl}ethyl)-2-methyl-3,4-dihydroquinazolin-4-one. Compound No: LXH1227

[0213]

[0214] The title compound was prepared according to the procedure of Example 20, except that 3-(2-chloroethyl)-5-methylamino-3,4-dihydroquinazolin-4-one was replaced by 2-methyl-3-(2-methoxyethyl)-5-ethylamino-3,4-dihydroquinazolin-4-one, as a white solid in 41.6% yield. 1 H NMR (600 MHz, Chloroform-d) δ 8.45 (s, 1H), 7.90 - 7.79 (m, 2H), 7.50 - 7.38 (m, 3H), 6.72 (dd, J = 8.0, 0.9 Hz, 1H), 6.45 (dd, J = 8.4, 0.9 Hz, 1H), 4.18 (s, 2H), 3.23 (qd, J = 7.2, 4.9 Hz, 2H), 3.08 (d, J = 11.1 Hz, 2H), 2.73 (s, 2H), 2.64 (s, 3H), 2.26 (d, J = 73.4 Hz, 2H), 1.88 (s, 5H), 1.35 (t, J = 7.2 Hz, 3H). ESI-MS m / z: 453.20 [M+H] +

[0215] Example 40: 4-((cyclobutylmethyl)amino)-3-(2-(4-(4-fluorobenzoyl)piperidin-1- yl)ethyl)quinazolin-4(3H)-one (YKW0533)

[0216]

[0217] The title compound was synthesized according to the procedure of Example 20, except that 3-(2-chloroethyl)-5-methylamino-3,4-dihydroquinazolin-4-one was replaced by 3-(2-chloroethyl)-5-cyclobutylmethylamino-3,4-dihydroquinazolin-4-one, as a yellow oil 0.39 g in 69% yield. 1HNMR (600 MHz, CDC13) δ 8.50 (t, J = 4.8 Hz, 1H), 7.92 (qd, J = 5.5, 2.4 Hz, 2H), 7.89 - 7.84 (m, 1H), 7.50 - 7.37 (m, 1H), 7.10 (dtd, J = 8.5, 5.9, 2.7 Hz, 2H), 6.78 (dd, J = 8.8, 3.4 Hz, 1H), 6.46 (dd, J = 9.6, 4.7 Hz, 1H), 3.97 (q, J = 5.9 Hz, 2H), 3.22 - 3.10 (m, 3H), 2.95 (dq, J = 11.7, 4.3 Hz, 2H), 2.74 - 2.63 (m, 3H), 2.22 (td, J = 10.9, 4.3 Hz, 2H), 2.15 (dqt, J = 10.2, 4.7, 2.4 Hz, 2H), 1.99 - 1.86 (m, 2H), 1.84 - 1.73 (m, 7H); ESI-MS m / z: 463.25 [M+H] +

[0218] Example 41: 5-((Cyclopropylmethyl)amino)-3-(2-(4-(4-fluorobenzoyl)piperidin-l- yl)ethyl)quinazolin-4(3H)-one (WBY1233)

[0219]

[0220] A pale yellow oil 0.39 g was synthesized according to the procedure of Example 20, with the exception that 3-(2-chloroethyl)-5-cyclopropylmethylamino-3,4-dihydroquinazolin-4- one was substituted for 3-(2-chloroethyl)-5-methylamino-3,4-dihydroquinazolin-4-one in a 71% yield. 1H NMR (600 MHz, CDC13) δ 8.63 (t, J = 4.8 Hz, 1H), 7.90 (dd, J = 8.5, 5.4 Hz, 2H), 7.86 (s, 1H), 7.43 (t, J = 8.1 Hz, 1H), 7.08 (t, J = 8.1 Hz, 2H), 6.77 (d, J = 7.8 Hz, 1H), 6.42 (d, J = 8.3 Hz, 1H), 3.96 (t, J = 6.0 Hz, 2H), 3.15 (tt, J = 9.9, 4.9 Hz, 1H), 3.01 (dd, J = 6.9, 5.0 Hz, 2H), 2.93 (dt, J = 11.3, 3.8 Hz, 2H), 2.66 (t, J = 6.0 Hz, 2H), 2.21 (td, J = 11.0, 3.8 Hz, 2H), 1.78 (tt, J = 10.7, 6.1 Hz, 4H), 1.18 - 1.11 (m, 1H), 0.60 - 0.54 (m, 2H), 0.27 (t, J = 5.0 Hz, 2H); ESI-MS m / z: 448.23 [M+H] +

[0221] Example 42: 5-(Cyclobutylamino)-3-(2-(4-(4-fluorobenzoyl)piperidin-l- yl)ethyl)quinazolin-4(3H)-one (YKW0542)

[0222]

[0223] A pale yellow oil 0.13 g was synthesized according to the procedure of Example 20, with the exception that 3-(2-chloroethyl)-5-cyclobutylamino-3,4-dihydroquinazolin-4-one was substituted for 3-(2-chloroethyl)-5-methylamino-3,4-dihydroquinazolin-4-one, in a 53% yield. 1 H NMR (600 MHz, CDC13) δ 8.67 (d, J = 5.6 Hz, 1H), 7.97 - 7.90 (m, 2H), 7.87 (s, 1H), 7.44 (t, J = 8.1 Hz, 1H), 7.15 - 7.08 (m, 2H), 6.80 (dd, J = 7.9, 1.0 Hz, 1H), 6.37 (d, J = 8.2 Hz, 1H), 3.96 (dt, J = 19.2, 6.9 Hz, 3H), 3.17 (tt, J = 9.9, 5.0 Hz, 1H), 2.96 (dt, J = 11.9, 3.7 Hz, 2H), 2.68 (t, J = 6.0 Hz, 2H), 2.50 - 2.43 (m, 2H), 2.24 (td, J = 11.0, 3.9 Hz, 2H), 2.02 - 1.93 (m, 2H), 1.90 - 1.75 (m, 6H); ESI-MS m / z: 449.23 [M+H] +

[0224] Example 43: 5-(Cyclopropylamino)-3-(2-(4-(4-fluorobenzoyl)piperidin-l- yl)ethyl)quinazolin-4(3H)-one (WBY1245)

[0225]

[0226] Example 20, except 3-(2-chloroethyl)-5-dimethylamino-3,4-dihydroquinazolin-4-one was used in place of 3-(2-chloroethyl)-5-methylamino-3,4-dihydroquinazolin-4-one to give a yellow oil 0.245 g in 63.7% yield. 1 H NMR (600 MHz, CDC13) δ 8.57 (t, J = 4.9 Hz, 1H), 7.88 (dd, J = 8.8, 5.5 Hz, 2H), 7.41 (t, J = 8.1 Hz, 1H), 7.10 - 7.03 (m, 2H), 6.75 (d, J = 7.9 Hz, 1H), 6.40 (d, J = 8.4 Hz, 1H), 5.23 (s, 1H), 3.98 (d, J = 7.1 Hz, 3H), 2.98 (dd, J = 6.9, 4.8 Hz, 2H), 2.94 (d, J = 11.1 Hz, 3H), 2.68 (s, 2H), 1.79 (d, J = 11.4 Hz, 5H), 1.12 (dddd, J = 14.9, 6.9, 3.2, 2.1 Hz, 1H), 0.81 (t, J = 7.0 Hz, 1H), 0.56 - 0.50 (m, 2H), 0.23 (dt, J = 6.1, 4.7 Hz, 2H); ESI-MS m / z: 425.23 [M+H] +

[0227] Example 44: 6-(Dimethylamino)-3-(2-(4-(4-fluorobenzoyl)piperidin-l- yl)ethyl)quinazolin-4(3H)-one (WBY0839)

[0228]

[0229] Example 20, except 3-(2-chloroethyl)-5-dimethylamino-3,4-dihydroquinazolin-4-one was used in place of 3-(2-chloroethyl)-5-methylamino-3,4-dihydroquinazolin-4-one to give a yellow oil 0.245 g in 63.7% yield. 1H NMR (600 MHz, DMSO-d6) δ 8.17 (s, 1H), 8.08 - 8.02 (m, 2H), 7.54 (t, J = 8.0 Hz, 1H), 7.37 - 7.32 (m, 2H), 7.03 (dd, J = 7.9, 1.0 Hz, 1H), 6.90 (dd, J = 8.3, 1.1 Hz, 1H), 4.02 (t, J = 6.0 Hz, 2H), 3.37 (td, J = 11.3, 5.6 Hz, 1H), 2.93 (dt, J = 12.5, 3.6 Hz, 2H), 2.80 (s, 6H), 2.59 (t, J = 6.1 Hz, 2H), 2.17 (td, J = 11.8, 2.4 Hz, 2H), 1.75 - 1.70 (m, 2H), 1.51 (dd, J = 12.7, 3.7 Hz, 2H); ESI-MS m / z: 423.22 [M+H] +

[0230] Example 45: 3-(2-(4-(4-bromobenzoyl)piperidin-l-yl)ethyl)-5-(ethylamino)quinazolin-4(3H)- one (WBY1214)

[0231]

[0232] Following the procedure of Example 20, except substituting (4-bromophenyl)(piperidin-4- yl)methanone for l-(4-fluorophenyl)(piperidin-4-yl)methanone and 3-(2-chloroethyl)-5- ethylamino-3,4-dihydroquinazolin-4-one for 3-(2-chloroethyl)-5-methylamino-3,4- dihydroquinazolin-4-one, a white solid 0.21 g, 77.6% yield was obtained. 1 H NMR (600 MHz, CDCl3) δ 8.48 (t, J = 5.0 Hz, 1H), 7.89 (s, 1H), 7.80 - 7.73 (m, 2H), 7.64 - 7.57 (m, 2H), 7.49 (t, J = 8.1 Hz, 1H), 6.81 (dd, J = 7.9, 1.0 Hz, 1H), 6.50 (dd, J = 8.3, 0.9 Hz, 1H), 4.00 (t, J = 6.1 Hz, 2H), 3.24 (qd, J = 7.2, 4.9 Hz, 2H), 3.20 - 3.12 (m, 1H), 2.98 (dt, J = 12.0, 3.7 Hz, 2H), 2.71 (t, J = 6.2 Hz, 2H), 2.28 (s, 2H), 1.87 - 1.78 (m, 5H), 1.35 (t, J = 7.2 Hz, 3H); ESI-MS (m / z): 485.14 [M+H] +

[0233] Example 46: 5-(ethylamino)-3-(2-(4-propionylpiperidin-l-yl)ethyl)quinazolin- 4(3H)-one (WBY1248)

[0234]

[0235] Following the procedure of Example 20, except substituting 1-(4- fluorophenyl)(piperidin-4-yl)methanone for 4-propionylpiperidine and 3-(2- chloroethyl)-5-ethylamino-3,4-dihydroquinazolin-4-one for 3-(2-chloroethyl)-5- methylamino-3,4-dihydroquinazolin-4-one, a yellow oil, 0.39 g, 82% yield was obtained. 1 H NMR (600 MHz, CDC13) δ 8.48 (t, J = 5.0 Hz, 1H), 7.87 (s, 1H), 7.48 (t, J = 8.1 Hz, 1H), 6.80 (dd, J = 7.9, 0.9 Hz, 1H), 6.49 (d, J = 8.2 Hz, 1H), 3.97 (t, J = 6.1 Hz, 2H), 3.23 (qd, J = 7.2, 4.9 Hz, 2H), 2.91 (dt, J = 12.0, 3.5 Hz, 2H), 2.65 (t, J = 6.1 Hz, 2H), 2.45 (q, J = 7.3 Hz, 2H), 2.29 (tt, J = 11.4, 3.9 Hz, 1H), 2.19 - 2.06 (m, 2H), 1.85 - 1.76 (m, 2H), 1.64 (qd, J = 11.7, 3.7 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H), 1.03 (t, J = 7.2 Hz, 3H); ESI-MS m / z: 357.22 [M+H] +

[0236] Example 47: 3-(2-(4-benzoylpiperidin-l-yl)ethyl)-5-(ethylamino)quinazolin- 4(3H)-one (WBY1249)

[0237]

[0238] Following the procedure of Example 20, except substituting 1-(4- fluorophenyl)(piperidin-4-yl)methanone for 4-propionylpiperidine and 3-(2- chloroethyl)-5-ethylamino-3,4-dihydroquinazolin-4-one for 3-(2-chloroethyl)-5- methylamino-3,4-dihydroquinazolin-4-one, a yellow oil, 0.39 g, 82% yield was obtained. 1H NMR (600 MHz, CDC13) δ 8.47 (t, J = 4.9 Hz, 1H), 7.88 (s, 1H), 7.49 (t, J = 8.1 Hz, 1H), 7.39 (dd, J = 8.6, 5.4 Hz, 2H), 7.08 (t, J = 8.6 Hz, 2H), 6.80 (d, J = 7.7 Hz, 1H), 6.50 (d, J = 8.3 Hz, 1H), 4.13 (q, J = 7.3 Hz, 2H), 4.00 (t, J = 6.0 Hz, 2H), 3.76 (d, J = 11.1 Hz, 2H), 3.42 (s, 2H), 3.23 (qd, J = 7.2, 4.9 Hz, 2H), 2.47 (s, 2H), 1.35 (s, 3H); ESI-MS m / z: 424.20 [M+H] +

[0239] Example 48: 4-(2-(4-(3-chlorobenzoyl)piperidin-l-yl)ethyl)-5- (ethylamino)quinazolin-4(3H)-one (WBY1315)

[0240]

[0241] A yellow solid 0.25 g, 88% yield was synthesized according to the procedure of Example 20, except 1-(4-fluorophenyl)(piperidin-4-yl)methanone was replaced with 4-(3- chlorobenzoyl)piperidine and 3-(2-chloroethyl)-5-methylamino-3,4-dihydroquinazolin-4-one was replaced with 3-(2-chloroethyl)-5-ethylamino-3,4-dihydroquinazolin-4-one. 1 H NMR (600 MHz, DMSO) δ 8.55 (t, J = 5.1 Hz, 1H), 8.12 (s, 1H), 7.97 - 7.90 (m, 2H), 7.73 - 7.67 (m, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.49 (t, J = 8.1 Hz, 1H), 6.72 - 6.67 (m, 1H), 6.51 (d, J = 8.2 Hz, 1H), 4.00 (t, J = 6.1 Hz, 2H), 3.40 (tt, J = 11.4, 3.8 Hz, 1H), 3.33 (s, 1H), 3.19 (qd, J = 7.1, 4.9 Hz, 2H), 2.93 (dt, J = 11.8, 3.5 Hz, 2H), 2.59 (t, J = 6.1 Hz, 2H), 2.19 (td, J = 11.6, 2.4 Hz, 2H), 1.80 - 1.67 (m, 3H), 1.58 - 1.44 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H); ESI-MS m / z: 439.19 [M+H] +

[0242] Example 49: 5-(Cyclopropylamino)-3-(2-(4-(4-fluorobenzoyl)piperazin-1- yl)ethyl)quinazolin-4(3H)-one (WBY0826)

[0243]

[0244] A yellow solid 0.28 g was synthesized according to the procedure of Example 20, with the exception that 3-(2-chloroethyl)-5-cyclopropylamino-3,4-dihydroquinazolin-4-one was used in place of 3-(2-chloroethyl)-5-methylamino-3,4-dihydroquinazolin-4-one, in 70% yield. 1 H NMR (600 MHz, CDC13) δ 8.66 - 8.61 (m, 1H), 7.87 (s, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.43 - 7.35 (m, 2H), 7.11 - 7.05 (m, 2H), 6.97 (dd, J = 8.3, 1.0 Hz, 1H), 6.87 (dd, J = 8.0, 1.0 Hz, 1H), 3.98 (t, J = 6.0 Hz, 2H), 3.75 (s, 2H), 3.41 (s, 2H), 2.71 (t, J = 6.0 Hz, 2H), 2.59 (s, 5H), 2.47 (ttd, J = 6.7, 3.6, 1.7 Hz, 1H), 0.82 (td, J = 6.8, 4.8 Hz, 2H), 0.63 - 0.55 (m, 2H); ESI-MS m / z: 436.21 [M+H] +

[0245] Example 50: 5-(Cyclobutylamino)-3-(2-(4-(4-fluorobenzoyl)piperazin-1- yl)ethyl)quinazolin-4(3H)-one (WBY1232)

[0246]

[0247] A yellow oil 0.18 g was synthesized according to the procedure of Example 20, with the exception that 1-(4-fluorobenzoyl)piperazine was used in place of 1-(4-fluorophenyl)(piperidin-4-yl)methanone, and 3-(2-chloroethyl)-5-cyclobutylamino-3,4-dihydroquinazolin-4-one was used in place of 3-(2-chloroethyl)-5-methylamino-3,4-dihydroquinazolin-4-one, in 73% yield. 1H NMR (600 MHz, DMSO) δ 8.75 (d, J = 5.9 Hz, 1H), 8.16 (s, 1H), 7.51 - 7.42 (m, 3H), 7.27 (t, J = 8.9 Hz, 2H), 6.71 (dd, J = 7.9, 1.0 Hz, 1H), 6.45 - 6.38 (m, 1H), 4.01 (t, J = 6.1 Hz, 2H), 3.97 (td, J = 7.6, 5.9 Hz, 1H), 3.33 (s, 7H), 2.63 (t, J = 6.1 Hz, 2H), 2.45 (qt, J = 8.6, 4.6 Hz, 4H), 1.90 - 1.73 (m, 4H); ESI-MS m / z: 450.21 [M+H] +

[0248] Example 51 : 6-(Ethylamino)-3-(2-(4-(4-fluorobenzoyl)piperazin-1-yl)ethyl)quinazolin-4(3H)- one (WBY1226)

[0249]

[0250] Following the procedure of Example 20, except substituting 1-(4-fluorobenzoyl)piperazine for 1-(4-fluorophenyl)(piperidin-4-yl)methanone and 3-(2-chloroethyl)-5- ethylamino-3,4-dihydroquinazolin-4-one for 3-(2-chloroethyl)-5-methylamino-3,4- dihydroquinazolin-4-one, a yellow oil, 0.24 g, was synthesized in 86% yield. 1 H NMR (600 MHz, CDCl3) δ 8.47 (t, J = 4.9 Hz, 1H), 7.88 (s, 1H), 7.49 (t, J = 8.1 Hz, 1H), 7.39 (dd, J = 8.6, 5.4 Hz, 2H), 7.08 (t, J = 8.6 Hz, 2H), 6.80 (d, J = 7.7 Hz, 1H), 6.50 (d, J = 8.3 Hz, 1H), 4.13 (q, J = 7.3 Hz, 2H), 4.00 (t, J = 6.0 Hz, 2H), 3.76 (d, J = 11.1 Hz, 2H), 3.42 (s, 2H), 3.23 (qd, J = 7.2, 4.9 Hz, 2H), 2.47 (s, 2H), 1.35 (s, 3H); ESI-MS m / z: 424.20 [M+H] +

[0251] Test Example 1

[0252] Tango-5-HT 2AR plasmid was transiently transfected into HTLA cells for 24 hours, then digested and seeded into white opaque 96-well plates at 20,000 cells per well for 8-12 hours, and then treated with drugs. Sample 1 mM stock solution was diluted to 10 -5 M, 10 -5 M sample was added to the wells to make the final drug concentration 10 -6 M, and incubated at 37°C in 5% CO2 for 18 hours. After that, 50 uL of Bright-Glo TM detection reagent was added for detection. 5-HT 2A R agonist DOM (10 -4.5 M) produced 5-HT 2A R agonist activity signal, while antagonists inhibited the signal. The positive drug control was pimavanserin (10 -6 M), and the blank control and control group (to verify that the activation system was stable and could function normally). Three replicate wells were set up. The test results are shown in Table 1 below.

[0253] Table 1. Inhibition of the effect of DOM on 5-HT2AR agonism by compounds

[0254]

[0255]

[0256] Test Example 2

[0257] By constructing a 5-HT 2A CHOK cell strain, when the 5-HT 2A receptor is inhibited, the calcium flow signal in the cell changes. Therefore, the change in intracellular calcium ion concentration can be detected by a calcium ion-sensitive fluorescent probe, and ultimately the degree of inhibition of the receptor can be reflected by reading the fluorescence value of the change in intracellular calcium flow, thereby screening compounds with 5-HT 2A receptor inhibition activity. The experimental steps are as follows:

[0258] 1. One day before detection, CHOK1 / 5-HT 2A cells were seeded in a 96-well cell plate at 100 uL of cell suspension per well, 40,000 cells per well, and the cell plate was incubated in a 37°C, 5% CO2 incubator overnight.

[0259] 2. On the day of detection, the cell culture medium was removed, and fluo-4AM fluorescent probe dye was added for incubation at 37°C for 1 hour.

[0260] 3. After the incubation was completed, the dye was removed, and the excess dye was washed away. After 50 uL of buffer was added, the compound working solution plate and the cell plate were placed in the FLPR instrument, which automatically added the drug and read the fluorescence.

[0261] The control compound was Ketanserin.

[0262] The compound screening results are shown in Table 2 below.

[0263] Table 2.5-HT 2A Receptor inhibitory activity rescreening results

[0264]

[0265]

[0266] Test Example 3 Mouse head shaking experiment

[0267] 5-HT 2A Receptor agonists trigger a head-twitch response in mice, while antagonists inhibit the agonist-induced head-twitch response. The inhibitory activity of the compounds of the present invention on the head-twitch response induced by 2,5-dimethoxy-4-methylamphetamine (DOM) was tested in vivo. Male C57 mice (Beijing Sibeifu Biotechnology Co., Ltd.), weighing 18-22 g, were randomly divided into groups of 8 per group. DOM (synthesized by our institute, purity >99%) was dissolved in saline to prepare a 0.1 mg / ml solution. The positive control drug, pimavanserin, was dissolved in DMSO at 1% of the solution volume and then diluted to volume with saline to prepare a 0.1 mg / ml solution. The new compounds were prepared as 40 mg / ml stock solutions in DMSO. An appropriate amount of the stock solution was then aspirated, and Tween-80 was added to half the volume of the stock solution. Finally, the solution was diluted with saline to a 1 mg / ml solution. In dose-response studies, each compound was diluted 10-fold to form a concentration series. After the above preparations were completed, 5-HT was injected into the left abdominal cavity of the mice. 2A Receptor antagonist, 1 mg / kg DOM was injected into the right abdominal cavity 30 minutes later, and the number of head shakes of the mice was observed within 20 minutes. Inhibition ratio = (HTRs of the solvent group - HTRs of the antagonist group) / HTRs of the solvent group. Figure 1 .

[0268] Test Example 4 Cytotoxicity Test

[0269] Experimental methods:

[0270] 1. Seed cells into 96-well plates: When the density of HEK293 cells reaches about 90%, discard the original culture medium, add 1 mL of trypsin, neutralize the residual culture medium in the culture dish, discard the trypsin, and then add 2 mL of trypsin to digest the cells. Observe under a microscope, and when the cells become round, discard the trypsin, add 1 mL of complete culture medium to resuspend the cells, transfer to a 1.5 mL PE tube, and dilute to 100 μL / 5000 cells according to the cell count results (for example: the cell count is 10 per 1 mL of cell suspension). 4 ×625=625×10 4 , 96×5000×2 (2 boards) = 96×10 4 cells, then 96÷625=0.1536, that is, 153.6 μL of cell stock solution should be aspirated and added to 20 ml (96 wells × 100 μL × 2 plates, about 20 mL) of complete culture medium (sample tank), mixed well), inoculated into 96-well plates, and cultured in a 37°C, 5% CO2 cell culture incubator for 24 h;

[0271] 2. Dosing: Since the cytotoxicity of the present invention is low, the test drug concentration is relatively high, which is 10 -5 After removing the excess culture medium in the wells, the example compound (10 -5 M) 200 μL, blank group with culture medium, control group with cells + culture medium. Culture in a 37°C, 5% CO2 cell culture incubator for 24 h / 48 h;

[0272] 3. Detection: After 24 hours and 48 hours of drug exposure, cell viability was measured. 10 μL CellTiter was added to each well. Aqueous, incubate for 30 min, and measure the photometric value using a microplate reader (490 nm).

[0273] 4. Calculate according to the formula:

[0274]

[0275] The experimental results are shown in Table 3.

[0276] Table 3. Cytotoxicity test results

[0277]

[0278] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any modifications or substitutions that can be easily conceived by a person skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be based on the scope of protection of the claims.

Claims

1. Quinazolinone derivatives represented by formula I and pharmaceutically acceptable salts thereof: in, n is an integer selected from 1 to 4; R1 is located at position 5, 6, 7 or 8 of the quinazolinone ring and is selected from H, halogen, hydroxyl, cyano, -NR 11 R 12 , nitro, trifluoromethyl, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 alkoxy; wherein, the substitution in substituted or unsubstituted C1-6 alkyl and substituted or unsubstituted C1-6 alkoxy means that the group is further substituted by C1-6 alkyl, halogen, hydroxyl or amino; wherein, -NR 11 R 12 R in 11 and R 12 Each independently selected from H, C1-6 alkyl, C1-6 alkyl substituted by C3-6 cycloalkyl; R2 is selected from H, substituted or unsubstituted C1-10 straight or branched alkyl, substituted or unsubstituted C2-10 straight or branched alkenyl, substituted or unsubstituted C2-10 straight or branched alkynyl, or substituted or unsubstituted C6-18 aryl, wherein the substituents on the C6-18 aryl are each independently selected from unsubstituted or halogen-substituted C1-8 straight or branched alkyl, or the adjacent substituents of the C6-18 aryl together with the carbon atom to which they are attached form a C6-18 aryl or a 5- to 9-membered heterocyclic or heteroaromatic ring containing 1 to 3 heteroatoms selected from O, N and S; Y is a nitrogen atom or a CH (methine) group; X is a chemical bond, a C1-6 alkylene group, or C=O (carbonyl); R3 and R4 are located at any chemically acceptable substitution position of the ring where they are located, and are independently selected from H, halogen, hydroxyl, cyano, amino, nitro, trifluoromethyl, C1-6 alkylcarbonyl, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C1-6 alkylamino; the substitution means that the group is further substituted by C1-6 alkyl, halogen, hydroxyl or amino.

2. The quinazolinone derivative and pharmaceutically acceptable salt thereof according to claim 1, characterized in that: Preferably, in formula I, n is selected from an integer of 0-3; preferably, n is selected from an integer of 2 or 3, more preferably, n is an integer of 2; Preferably, R1 is located at the 5-position of the quinazolinone ring, and R1 is selected from H, halogen, hydroxyl, cyano, -NR 11 R 12 , nitro, trifluoromethyl, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted C1-4 alkoxy; wherein, the substitution in substituted or unsubstituted C1-4 alkyl and substituted or unsubstituted C1-4 alkoxy means that the group is further substituted by C1-4 alkyl, halogen, hydroxyl or amino; wherein, -NR 11 R 12 R in 11 and R 12 Each independently selected from H, C1-4 alkyl, C1-4 alkyl substituted by C3-5 cycloalkyl; More preferably, R1 is selected from H, halogen, -NR 11 R 12 , substituted or unsubstituted C1-3 alkyl, substituted or unsubstituted C1-3 alkoxy, substituted or unsubstituted C1-3 alkylamino; wherein, the substitution in substituted or unsubstituted C1-3 alkyl and substituted or unsubstituted C1-3 alkoxy means that the group is further substituted by C1-3 alkyl, halogen, hydroxyl or amino; wherein, -NR 11 R 12 R in 11 and R 12 Each independently selected from H, C1-3 alkyl, C1-3 alkyl substituted by C3-4 cycloalkyl; More preferably, R1 is selected from H, halogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH2cyclopropyl, -NCH2cyclobutyl, -NCH2cyclopentyl, -NH(CH3)2, -NH(CH2CH3)2, -NH(CH2CH2CH3)2; Preferably, R2 is selected from H, substituted or unsubstituted C1-4 straight or branched alkyl, substituted or unsubstituted C2-4 straight or branched alkenyl, substituted or unsubstituted C2-4 straight or branched alkynyl, or substituted or unsubstituted C6-10 aryl, wherein the substituents on the C6-10 aryl are each independently selected from unsubstituted or halogen-substituted C1-3 straight or branched alkyl, or the adjacent substituents of the C6-10 aryl together with the carbon atom to which they are attached form a 5- to 9-membered heterocyclic ring or heteroaromatic ring; More preferably, R2 is selected from H, substituted or unsubstituted C1-3 alkyl, substituted or unsubstituted C6-8 aryl, wherein the substituents on the C6-8 aryl are each independently selected from C1-3 alkyl, or the adjacent substituents of the C6-8 aryl together with the carbon atom to which they are attached form a 5- to 7-membered ring; More preferably, R2 is selected from H, methyl, ethyl, propyl; Preferably, X is a chemical bond, a C1-4 alkylene group or C=O (carbonyl); More preferably, X is a chemical bond, methylene, ethylene, propylene or C=O (carbonyl); Preferably, R3 and R4 are located at chemically acceptable substitution positions of the ring, and are independently selected from H, halogen, hydroxyl, cyano, amino, nitro, trifluoromethyl, C1-4 alkylcarbonyl, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted C1-4 alkoxy, substituted or unsubstituted C1-4 alkylamino; the substitution means that the group is further substituted by C1-4 alkyl, halogen, hydroxyl or amino; More preferably, R3 and R4 are located at chemically acceptable substitution positions of the ring, and are independently selected from H, halogen, hydroxyl, cyano, amino, nitro, trifluoromethyl, C1-3 alkylcarbonyl, substituted or unsubstituted C1-3 alkyl, substituted or unsubstituted C1-3 alkoxy, substituted or unsubstituted C1-3 alkylamino; the substitution means that the group is further substituted by C1-3 alkyl, halogen, hydroxyl or amino; More preferably, R3 and R4 are located at chemically acceptable substitution positions of the ring and are independently selected from H, halogen, cyano, trifluoromethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, methyl, ethyl, propyl, methoxy, ethoxy, propoxy.

3. The quinazolinone derivative and pharmaceutically acceptable salt thereof according to claim 1, characterized in that: It is selected from the following compounds:

4. The method for preparing the quinazolinone derivatives and pharmaceutically acceptable salts thereof according to any one of claims 1 to 3, wherein the preparation route is as shown in the following reaction formula 1: As shown in the above reaction formula 1, the method comprises the following steps: i) R1-substituted o-nitrobenzoic acid (1) and amino alcohol (2) are condensed in the presence of a condensing agent (such as EDCI, DCC, DIC, etc.) to obtain intermediate 1a; ii) The nitro group of intermediate 1a is reduced with ferric acid, catalytic hydrogenation, etc. to obtain intermediate 1b; iii) intermediate 1b undergoes a ring-closure reaction with R2-substituted trimethyl orthoformate or R2-substituted triethyl orthoformate (3) under anhydrous conditions to obtain intermediate 1c; iv) intermediate 1c reacts with a chlorinating agent (such as thionyl chloride, phosphorus trichloride, phosphorus pentachloride, etc.) to obtain intermediate 1d; v) Intermediate 1d and compound 4 undergo N-alkylation reaction under base catalysis of an inorganic base (sodium carbonate, potassium carbonate, cesium carbonate) or an organic base (triethylamine, diisopropylethylamine, DMAP, DBU, etc.) to obtain a compound of formula I; In the above reaction formula, the substituents R1, R2, R3, R4, X, Y, and n are as shown in claim 1.

5. Use of the quinazolinone derivatives and pharmaceutically acceptable salts thereof according to any one of claims 1 to 3 in the preparation of 5-HT2A receptor antagonists or agonists for treating mental illnesses, or mental disorders associated with or complicated by central nervous system degenerative diseases.

6. The use according to claim 5, characterized in that The mental illnesses include depression, anxiety, psychosis, schizophrenia, insomnia, and autism; the central nervous system degenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, and Lewy body dementia.

7. A pharmaceutical composition comprising a therapeutically effective amount of the quinazolinone derivative according to any one of claims 1 to 3 and a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

8. A method for treating mental illness, or mental disorder symptoms associated with or concurrent with a degenerative disease of the central nervous system, the method comprising administering to a subject in need thereof a therapeutically effective amount of the quinazolinone derivatives and pharmaceutically acceptable salts thereof according to any one of claims 1 to 3, or the pharmaceutical composition according to claim 7.

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